Patent Publication Number: US-2021171946-A1

Title: COMPLEMENT COMPONENT C5 iRNA COMPOSITIONS AND METHODS OF USE THEREOF FOR TREATING PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH)

Description:
RELATED APPLICATIONS 
     This application is a continuation of U.S. patent application Ser. No. 16/307,963, filed on Dec. 7, 2018, which is a 35 U.S.C. § 371 national stage filing of International Application No. PCT/US2017/036775, filed on Jun. 9, 2017, which in turn claims the benefit of priority to U.S. Provisional patent Application No. 62/348,564, filed on Jun. 10, 2016, and U.S. Provisional patent Application No. 62/429,448, filed on Dec. 2, 2016. The entire contents of each of the foregoing patent applications are hereby incorporated herein by reference. 
    
    
     SEQUENCE LISTING 
     The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Oct. 2, 2020, is named 121301_06404_SL.txt and is 956,570 bytes in size. 
     BACKGROUND OF THE INVENTION 
     Complement was first discovered in the 1890s when it was found to aid or “complement” the killing of bacteria by heat-stable antibodies present in normal serum (Walport, M. J. (2001)  N Engl J Med.  344:1058). The complement system consists of more than 30 proteins that are either present as soluble proteins in the blood or are present as membrane-associated proteins. Activation of complement leads to a sequential cascade of enzymatic reactions, known as complement activation pathways, resulting in the formation of the potent anaphylatoxins C3a and C5a that elicit a plethora of physiological responses that range from chemoattraction to apoptosis. Initially, complement was thought to play a major role in innate immunity where a robust and rapid response is mounted against invading pathogens. However, recently it is becoming increasingly evident that complement also plays an important role in adaptive immunity involving T and B cells that help in elimination of pathogens (Dunkelberger J R and Song W C. (2010)  Cell Res.  20:34; Molina H, et al. (1996)  Proc Natl Acad Sci USA.  93:3357), in maintaining immunologic memory preventing pathogenic re-invasion, and is involved in numerous human pathological states (Qu, H, et al. (2009) Mol Immunol.  47:185; Wagner, E. and Frank M M. (2010)  Nat Rev Drug Discov.  9:43). 
     Complement activation is known to occur through three different pathways: alternate, classical, and lectin ( FIG. 1 ), involving proteins that mostly exist as inactive zymogens that are then sequentially cleaved and activated. All pathways of complement activation lead to cleavage of the C5 molecule generating the anaphylatoxin C5a and, C5b that subsequently forms the terminal complement complex (C5b-9). C5a exerts a predominant pro-inflammatory activity through interactions with the classical G-protein coupled receptor C5aR (CD88) as well as with the non-G protein coupled receptor C5L2 (GPR77), expressed on various immune and non-immune cells. C5b-9 causes cytolysis through the formation of the membrane attack complex (MAC), and sub-lytic MAC and soluble C5b-9 also possess a multitude of non-cytolytic immune functions. These two complement effectors, C5a and C5b-9, generated from C5 cleavage, are key components of the complement system responsible for propagating and/or initiating pathology in different diseases, including paroxysmal nocturnal hemoglobinuria, rheumatoid arthritis, ischemia-reperfusion injuries and neurodegenerative diseases. 
     To date, only one therapeutic that targets the C5-C5a axis is available for the treatment of complement component C5-associated diseases, the anti-C5 antibody, eculizumab (Soliris®). Although eculizumab has been shown to be effective for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) and is currently being evaluated in clinical trials for additional complement component C5-associated diseases, eculizumab therapy requires weekly high dose infusions followed by biweekly maintenance infusions at a yearly cost of about $400,000. Furthermore, there is a wide-inter-individual variation on the pharmcodynamics and clearance of eculizumab, and a significant number of patients being treated with eculizumab still require transfusions while undergoing treatment because of breakthrough or occult hemolysis (de Latour R (2015)  Blood  125(5):775-83; Jodele S, et al. (2015)  BBMT  21(2): S225-S226; Gatault P, et al (2015)  mAbs;  7:1205-11). Accordingly, there is a need in the art for alternative therapies and combination therapies which provide substantially consistent levels of efficacy and minimal breakthrough or occult hemolysis for subjects having a complement component C5-associated disease. 
     SUMMARY OF THE INVENTION 
     The present invention provides methods and combination therapies for treating a subject having a disorder that would benefit from inhibiting or reducing the expression of a C5 gene, e.g., a complement component C5-associated disease, such as paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), neuromyelitis optica (NMO), and myasthenia gravis, using iRNA compositions which effect the RNA-induced silencing complex (RISC)-mediated cleavage of RNA transcripts of a C5 gene for inhibiting the expression of a C5 gene and anti-C5 antibodies, e.g., eculizumab. 
     The data presented herein demonstrate that iRNA agents and compositions of the invention are effective at treating PNH in eculizumab naïve subjects when administered as monotherapy at the dose of 200 mg or 400 mg. The data presented herein also demonstrate that the iRNA agents and compositions of the invention may be effectively used as a part of a combination therapy with eculizumab for treating subjects having PNH. Administering the iRNA agents and compositions of the invention in combination with eculizumab, e.g., in the setting of ongoing AD-62643 phramacology, allows reducing the dose of eculizumab while maintaining C5 knockdown, inhibition of complement activity and reduction of LDH levels in subjects with PNH. The data also demonstrate that iRNA agents and compositions of the invention are suitable for treating subjects having PNH who are inadequate responders to therapy with eculizumab alone (e.g., subjects having breakthrough hemolysis, i.e., subjects being treated with eculizumab that develop symptoms of intravascular hemolysis 1 to 2 days prior to their next eculizumab infusion). 
     Accordingly, in one aspect, the present prevention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to an eculizumab naïve subject having PNH (i.e., a subject having PNH that has not been administered eculizumab) a 200-400 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every week; and administering to the subject a dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. 
     In another aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to an eculizumab naïve subject having PNH a 200-400 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every month; and administering to the subject a dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. 
     In one aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to an eculizumab naïve subject having PNH a 200 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every week for 10-15 weeks, followed by a 400 mg fixed dose of the dsRNA agent once every week; and administering to the subject, a dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose once every week for thirteen weeks, followed by a 400 mg fixed dose of the dsRNA agent once every week. 
     In one aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to an eculizumab naïve subject having PNH a 200 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every week for 10-15 weeks, followed by a 400 mg fixed dose of the dsRNA agent once every month; and administering to the subject, a dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose once every week for thirteen weeks, followed by a 400 mg fixed dose of the dsRNA agent once every month. 
     In another aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to an eculizumab naïve subject having PNH a 200 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every month for 2 to 4 months; and administering to the subject, a dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. 
     In one aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to an eculizumab naïve subject having PNH a 200 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every week; and administering to the subject, a dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to the administration of eculizumab. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to the administration of eculizumab, and once every month thereafter. In another embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to the administration of eculizumab, and once every three months thereafter. In another embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to the administration of eculizumab, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week. 
     In one aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to an eculizumab naïve subject having PNH a 200 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every week; and administering to the subject, a dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to the administration of eculizumab. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to the administration of eculizumab, and once every month thereafter. In another embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to the administration of eculizumab, and once every three months thereafter. In another embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to the administration of eculizumab, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week. 
     In one aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to an eculizumab naïve subject having PNH a 200 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every week; and administering to the subject, a dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to the administration of eculizumab. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to the administration of eculizumab, and once every month thereafter. In another embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to the administration of eculizumab, and once every three months thereafter. In another embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to the administration of eculizumab, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week. 
     In one aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to an eculizumab naïve subject having PNH a 200 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every week; and administering to the subject, a dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to the administration of eculizumab. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to the administration of eculizumab, and once every month thereafter. In another embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to the administration of eculizumab, and once every three months thereafter. In another embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to the administration of eculizumab, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week. 
     In another aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to an eculizumab naïve subject having PNH a 200 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every month; and administering to the subject, a dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of eculizumab. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of eculizumab, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of eculizumab, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month. 
     In another aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to an eculizumab naïve subject having PNH a 200 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every month; and administering to the subject, a dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of eculizumab. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of eculizumab, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of eculizumab, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month. 
     In another aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to an eculizumab naïve subject having PNH a 200 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every month; and administering to the subject, a dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of eculizumab. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of eculizumab, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of eculizumab, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month. 
     In another aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to an eculizumab naïve subject having PNH a 200 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every month; and administering to the subject, a dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of eculizumab. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of eculizumab, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of eculizumab, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month. In one aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to an eculizumab naïve subject having PNH a 400 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every week; and administering to the subject, a dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to the administration of eculizumab. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to the administration of eculizumab, and once every month thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every weeks for eight weeks, e.g., prior to the administration of eculizumab, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every weeks for eight weeks, e.g., prior to the administration of eculizumab, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 400 mg fixed dose of the dsRNA agent once every week. 
     In one aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to an eculizumab naïve subject having PNH a 400 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every week; and administering to the subject, a dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to the administration of eculizumab. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to the administration of eculizumab, and once every month thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every weeks for eight weeks, e.g., prior to the administration of eculizumab, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every weeks for eight weeks, e.g., prior to the administration of eculizumab, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 400 mg fixed dose of the dsRNA agent once every week. 
     In one aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to an eculizumab naïve subject having PNH a 400 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every week; and administering to the subject, a dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to the administration of eculizumab. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to the administration of eculizumab, and once every month thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every weeks for eight weeks, e.g., prior to the administration of eculizumab, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every weeks for eight weeks, e.g., prior to the administration of eculizumab, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 400 mg fixed dose of the dsRNA agent once every week. 
     In one aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to an eculizumab naïve subject having PNH a 400 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every week; and administering to the subject, a dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to the administration of eculizumab. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to the administration of eculizumab, and once every month thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every weeks for eight weeks, e.g., prior to the administration of eculizumab, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every weeks for eight weeks, e.g., prior to the administration of eculizumab, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 400 mg fixed dose of the dsRNA agent once every week. 
     In another aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to an eculizumab naïve subject having PNH a 400 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every month; and administering to the subject, a dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of eculizumab. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of eculizumab, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of eculizumab, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month. 
     In another aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to an eculizumab naïve subject having PNH a 400 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every month; and administering to the subject, a dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of eculizumab. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of eculizumab, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of eculizumab, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month. In another aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to an eculizumab naïve subject having PNH a 400 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every month; and administering to the subject, a dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of eculizumab. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of eculizumab, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of eculizumab, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month. 
     In another aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to an eculizumab naïve subject having PNH a 400 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every month; and administering to the subject, a dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of eculizumab. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of eculizumab, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of eculizumab, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month. In one aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to a subject having PNH and previously treated with eculizumab, a 400 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every week; and administering to the subject, a dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, and once every month thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every weeks for eight weeks, e.g., prior to administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every weeks for eight weeks, e.g., prior to administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 400 mg fixed dose of the dsRNA agent once every week. 
     In one aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to a subject having PNH and previously treated with eculizumab a 400 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every week; and administering to the subject, a dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, and once every month thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every weeks for eight weeks, e.g., prior to administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every weeks for eight weeks, e.g., prior to administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 400 mg fixed dose of the dsRNA agent once every week. 
     In one aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to a subject having PNH and previously treated with eculizumab a 400 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every week; and administering to the subject, a dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, and once every month thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every weeks for eight weeks, e.g., prior to administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every weeks for eight weeks, e.g., prior to administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 400 mg fixed dose of the dsRNA agent once every week. 
     In one aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to a subject having PNH and previously treated with eculizumab a 400 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every week; and administering to the subject, a dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, and once every month thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every weeks for eight weeks, e.g., prior to administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every weeks for eight weeks, e.g., prior to administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 400 mg fixed dose of the dsRNA agent once every week. 
     In another aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH), comprising administering to a subject having PNH and previously treated with eculizumab, a 400 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every month; and administering to the subject, a dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month. 
     In another aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH), comprising administering to a subject having PNH and previously treated with eculizumab, a 400 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every month; and administering to the subject, a dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month. 
     In another aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH), comprising administering to a subject having PNH and previously treated with eculizumab, a 400 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every month; and administering to the subject, a dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month. 
     In another aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH), comprising administering to a subject having PNH and previously treated with eculizumab, a 400 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every month; and administering to the subject, a dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month. In one aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to a subject having PNH and previously treated with eculizumab a 400 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every week for 2-8 weeks; and administering to the subject, a dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject a 400 mg fixed dose once every week for 2-8 weeks prior to the administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In one embodiment, the dsRNA agent is administered to the subject a 400 mg fixed dose once every week for 2-8 weeks prior to the administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every month thereafter. In one embodiment, the dsRNA agent is administered to the subject a 400 mg fixed dose once every week for 2-8 weeks prior to the administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject a 400 mg fixed dose once every week for 2-8 weeks prior to the administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 400 mg fixed dose of the dsRNA agent once every week. 
     In one aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to a subject having PNH and previously treated with eculizumab a 400 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every week for 2-8 weeks; and administering to the subject, a dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject a 400 mg fixed dose once every week for 2-8 weeks prior to the administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In one embodiment, the dsRNA agent is administered to the subject a 400 mg fixed dose once every week for 2-8 weeks prior to the administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every month thereafter. In one embodiment, the dsRNA agent is administered to the subject a 400 mg fixed dose once every week for 2-8 weeks prior to the administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject a 400 mg fixed dose once every week for 2-8 weeks prior to the administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 400 mg fixed dose of the dsRNA agent once every week. 
     In one aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to a subject having PNH and previously treated with eculizumab a 400 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every week for 2-8 weeks; and administering to the subject, a dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, once very four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject a 400 mg fixed dose once every week for 2-8 weeks prior to the administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In one embodiment, the dsRNA agent is administered to the subject a 400 mg fixed dose once every week for 2-8 weeks prior to the administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every month thereafter. In one embodiment, the dsRNA agent is administered to the subject a 400 mg fixed dose once every week for 2-8 weeks prior to the administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject a 400 mg fixed dose once every week for 2-8 weeks prior to the administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 400 mg fixed dose of the dsRNA agent once every week. 
     In one aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to a subject having PNH and previously treated with eculizumab a 400 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every week for 2-8 weeks; and administering to the subject, a dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject a 400 mg fixed dose once every week for 2-8 weeks prior to the administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In one embodiment, the dsRNA agent is administered to the subject a 400 mg fixed dose once every week for 2-8 weeks prior to the administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every month thereafter. In one embodiment, the dsRNA agent is administered to the subject a 400 mg fixed dose once every week for 2-8 weeks prior to the administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject a 400 mg fixed dose once every week for 2-8 weeks prior to the administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 400 mg fixed dose of the dsRNA agent once every week. In another aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to a subject having PNH and previously treated with eculizumab, a 400 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every month for 1-2 months; and administering to the subject, a dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose once every month for 1-2 months prior to the administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose once every month for 1-2 months prior to the administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose once every month for 1-2 months prior to the administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month. 
     In another aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to a subject having PNH and previously treated with eculizumab, a 400 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every month for 1-2 months; and administering to the subject, a dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose once every month for 1-2 months prior to the administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose once every month for 1-2 months prior to the administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose once every month for 1-2 months prior to the administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month. 
     In another aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to a subject having PNH and previously treated with eculizumab, a 400 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every month for 1-2 months; and administering to the subject, a dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose once every month for 1-2 months prior to the administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose once every month for 1-2 months prior to the administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose once every month for 1-2 months prior to the administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month. 
     In another aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to a subject having PNH and previously treated with eculizumab, a 400 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every month for 1-2 months; and administering to the subject, a dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose once every month for 1-2 months prior to the administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose once every month for 1-2 months prior to the administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose once every month for 1-2 months prior to the administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month. 
     In one aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to a subject having PNH and previously treated with eculizumab a 200 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every week; and administering to the subject, a dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to the administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In another embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for twelve weeks, e.g., prior to the administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, and once every month thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every weeks for eight weeks, e.g., prior to administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every weeks for eight weeks, e.g., prior to administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, and once every six months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for twelve weeks, e.g., prior to administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, and once every month thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every weeks for twelve weeks, e.g., prior to administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every weeks for twelve weeks, e.g., prior to administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week. 
     In one aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to a subject having PNH and previously treated with eculizumab a 200 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every week; and administering to the subject, a dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to the administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In another embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for twelve weeks, e.g., prior to the administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, and once every month thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every weeks for eight weeks, e.g., prior to administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every weeks for eight weeks, e.g., prior to administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, and once every six months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for twelve weeks, e.g., prior to administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, and once every month thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every weeks for twelve weeks, e.g., prior to administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every weeks for twelve weeks, e.g., prior to administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week. 
     In one aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to a subject having PNH and previously treated with eculizumab a 200 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every week; and administering to the subject, a dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to the administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In another embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for twelve weeks, e.g., prior to the administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, and once every month thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every weeks for eight weeks, e.g., prior to administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every weeks for eight weeks, e.g., prior to administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, and once every six months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for twelve weeks, e.g., prior to administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, and once every month thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every weeks for twelve weeks, e.g., prior to administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every weeks for twelve weeks, e.g., prior to administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week. 
     In one aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to a subject having PNH and previously treated with eculizumab a 200 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every week; and administering to the subject, a dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to the administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In another embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for twelve weeks, e.g., prior to the administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, and once every month thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every weeks for eight weeks, e.g., prior to administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every weeks for eight weeks, e.g., prior to administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, and once every six months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for twelve weeks, e.g., prior to administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, and once every month thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every weeks for twelve weeks, e.g., prior to administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every weeks for twelve weeks, e.g., prior to administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week. 
     In another aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to a subject having PNH and previously treated with eculizumab, a 200 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every month; and administering to the subject, a dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, since every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every six months thereafter. In another embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for three months, e.g., prior to the administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for three months, e.g., prior to the administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for three months, e.g., prior to the administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month. 
     In another aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to a subject having PNH and previously treated with eculizumab, a 200 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every month; and administering to the subject, a dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every six months thereafter. In another embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for three months, e.g., prior to the administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for three months, e.g., prior to the administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for three months, e.g., prior to the administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month. 
     In another aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to a subject having PNH and previously treated with eculizumab, a 200 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every month; and administering to the subject, a dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every six months thereafter. In another embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for three months, e.g., prior to the administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for three months, e.g., prior to the administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for three months, e.g., prior to the administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month. 
     In another aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to a subject having PNH and previously treated with eculizumab, a 200 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every month; and administering to the subject, a dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every six months thereafter. In another embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for three months, e.g., prior to the administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for three months, e.g., prior to the administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for three months, e.g., prior to the administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month. 
     In one aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to a subject having PNH and that has not responded to treatment with eculizumab a 200 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every week; and administering to the subject, a dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to the administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In another embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for twelve weeks, e.g., prior to the administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, and once every month thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every weeks for eight weeks, e.g., prior to administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every weeks for eight weeks, e.g., prior to administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, and once every six months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for twelve weeks, e.g., prior to administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, and once every month thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every weeks for twelve weeks, e.g., prior to administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every weeks for twelve weeks, e.g., prior to administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week. 
     In one aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to a subject having PNH and that has not responded to treatment with eculizumab a 200 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every week; and administering to the subject, a dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to the administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In another embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for twelve weeks, e.g., prior to the administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, and once every month thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every weeks for eight weeks, e.g., prior to administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every weeks for eight weeks, e.g., prior to administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, and once every six months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for twelve weeks, e.g., prior to administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, and once every month thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for twelve weeks, e.g., prior to administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every weeks for twelve weeks, e.g., prior to administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week. 
     In one aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to a subject having PNH and that has not responded to treatment with eculizumab a 200 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every week; and administering to the subject, a dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to the administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In another embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for twelve weeks, e.g., prior to the administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, and once every month thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every weeks for eight weeks, e.g., prior to administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every weeks for eight weeks, e.g., prior to administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, and once every six months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for twelve weeks, e.g., prior to administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, and once every month thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every weeks for twelve weeks, e.g., prior to administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every weeks for twelve weeks, e.g., prior to administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week. 
     In one aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to a subject having PNH and that has not responded to treatment with eculizumab a 200 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every week; and administering to the subject, a dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to the administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In another embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for twelve weeks, e.g., prior to the administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, and once every month thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every weeks for eight weeks, e.g., prior to administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every weeks for eight weeks, e.g., prior to administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, and once every six months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week for twelve weeks, e.g., prior to administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, and once every month thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every weeks for twelve weeks, e.g., prior to administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every weeks for twelve weeks, e.g., prior to administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 200 mg fixed dose of the dsRNA agent once every week. 
     In another aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to a subject having PNH and that has not responded to treatment with eculizumab, a 200 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every month; and administering to the subject, a dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every six months thereafter. In another embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for three months, e.g., prior to the administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for three months, e.g., prior to the administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for three months, e.g., prior to the administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month. 
     In another aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to a subject having PNH and that has not responded to treatment with eculizumab, a 200 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every month; and administering to the subject, a dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every six months thereafter. In another embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for three months, e.g., prior to the administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for three months, e.g., prior to the administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for three months, e.g., prior to the administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month. 
     In another aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to a subject having PNH and that has not responded to treatment with eculizumab, a 200 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every month; and administering to the subject, a dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every six months thereafter. In another embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for three months, e.g., prior to the administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for three months, e.g., prior to the administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for three months, e.g., prior to the administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month. 
     In another aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to a subject having PNH and that has not responded to treatment with eculizumab, a 200 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every month; and administering to the subject, a dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every six months thereafter. In another embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for three months, e.g., prior to the administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for three months, e.g., prior to the administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month for three months, e.g., prior to the administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 200 mg fixed dose of the dsRNA agent once every month. In one aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to a subject having PNH and that has not responded to treatment with eculizumab a 400 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every week; and administering to the subject, a dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to the administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In another embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every week for twelve weeks, e.g., prior to the administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, and once every month thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every weeks for eight weeks, e.g., prior to administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every weeks for eight weeks, e.g., prior to administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, and once every six months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every week for twelve weeks, e.g., prior to administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, and once every month thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every weeks for twelve weeks, e.g., prior to administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every weeks for twelve weeks, e.g., prior to administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 400 mg fixed dose of the dsRNA agent once every week. 
     In one aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to a subject having PNH and that has not responded to treatment with eculizumab a 400 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every week; and administering to the subject, a dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to the administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In another embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every week for twelve weeks, e.g., prior to the administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to administration of the dose of about 300 mg eculizumab, or an antigen-binding fragment thereof, and once every month thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every weeks for eight weeks, e.g., prior to administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every weeks for eight weeks, e.g., prior to administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, and once every six months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every week for twelve weeks, e.g., prior to administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, and once every month thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every weeks for twelve weeks, e.g., prior to administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every weeks for twelve weeks, e.g., prior to administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 400 mg fixed dose of the dsRNA agent once every week. 
     In one aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to a subject having PNH and that has not responded to treatment with eculizumab a 400 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every week; and administering to the subject, a dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to the administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In another embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every week for twelve weeks, e.g., prior to the administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to administration of the dose of about 600 mg eculizumab, or an antigen-binding fragment thereof, and once every month thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every weeks for eight weeks, e.g., prior to administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every weeks for eight weeks, e.g., prior to administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, and once every six months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every week for twelve weeks, e.g., prior to administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, and once every month thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every weeks for twelve weeks, e.g., prior to administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every weeks for twelve weeks, e.g., prior to administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 400 mg fixed dose of the dsRNA agent once every week. 
     In one aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to a subject having PNH and that has not responded to treatment with eculizumab a 400 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every week; and administering to the subject, a dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to the administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In another embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every week for twelve weeks, e.g., prior to the administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every week for eight weeks, e.g., prior to administration of the dose of about 900 mg eculizumab, or an antigen-binding fragment thereof, and once every month thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every weeks for eight weeks, e.g., prior to administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every weeks for eight weeks, e.g., prior to administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, and once every six months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every week for twelve weeks, e.g., prior to administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, and once every month thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every weeks for twelve weeks, e.g., prior to administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every weeks for twelve weeks, e.g., prior to administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 400 mg fixed dose of the dsRNA agent once every week. 
     In another aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to a subject having PNH and that has not responded to treatment with eculizumab, a 400 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every month; and administering to the subject, a dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every six months thereafter. In another embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month for three months, e.g., prior to the administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month for three months, e.g., prior to the administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month for three months, e.g., prior to the administration of the dose of about 300 mg to about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month. In another aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to a subject having PNH and that has not responded to treatment with eculizumab, a 400 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every month; and administering to the subject, a dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every six months thereafter. In another embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month for three months, e.g., prior to the administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month for three months, e.g., prior to the administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month for three months, e.g., prior to the administration of the dose of about 300 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month. 
     In another aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to a subject having PNH and that has not responded to treatment with eculizumab, a 400 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every month; and administering to the subject, a dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, once every four weeks, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every six months thereafter. In another embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month for three months, e.g., prior to the administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month for three months, e.g., prior to the administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month for three months, e.g., prior to the administration of the dose of about 600 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month. 
     In another aspect, the present invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to a subject having PNH and that has not responded to treatment with eculizumab, a 400 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every month; and administering to the subject, a dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month for two months, e.g., prior to the administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every six months thereafter. In another embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month for three months, e.g., prior to the administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month for three months, e.g., prior to the administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every three months thereafter. In one embodiment, the dsRNA agent is administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month for three months, e.g., prior to the administration of the dose of about 900 mg of eculizumab, or an antigen-binding fragment thereof, to the subject, and once every six months thereafter. In one embodiment, the dsRNA agent is chronically administered to the subject at a 400 mg fixed dose of the dsRNA agent once every month. 
     In some embodiments, the dose of eculizumab, or an antigen-binding fragment thereof, is about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75% of the eculizumab maintenance label dose. In one embodiment, the dose of eculizumab, or an antigen-binding fragment thereof, is about 25%-75%, 25%-70%, 25%-65%, 25%-60%, 30%-75%, 30%-70%, 30%-65%, 30%-60%, 25%-50%, 25%-40% or 25%-30% of the eculizumab maintenance label dose. 
     In some embodiments, the frequency of administration of eculizumab is reduced as compared to the frequency of administration required by the label. In some aspects, eculizumab is administered once every four weeks, every 2 months, every 3 months, every 4 months, every 5 months or every 6 months. 
     In some embodiments, eculizumab, or an antigen-binding fragment thereof, is administered to the subject as a 300 mg fixed dose once a month. In some embodiments, eculizumab, or an antigen-binding fragment thereof, is administered to the subject as a 600 mg fixed dose once a month. In some embodiments, eculizumab, or an antigen-binding fragment thereof, is administered to the subject as a 900 mg fixed dose every other week. In other embodiments, the eculizumab, or an antigen-binding fragment thereof, is administered to the subject as a 1200 mg fixed dose for four weeks, followed by a 900 mg fixed dose every other week. 
     In some embodiments, the eculizumab, or an antigen-binding fragment thereof, is administered to the eculizumab naïve subject as a 300 mg fixed dose once every four weeks. In some embodiments, the eculizumab, or an antigen-binding fragment thereof, is administered to the eculizxumab naïve subject as a 600 mg fixed dose once every four weeks. In other embodiments, the eculizumab, or an antigen-binding fragment thereof, is administered to the subject previously treated with eculizumab as a 900 mg fixed dose once every four weeks. 
     In one embodiment, the previous treatment of eculizumab or an antigen-binding fragment thereof, comprised administration to the subject of a 900 mg fixed dose of eculizumab twice weekly. In one embodiment, the eculizumab treatment that the subject did not respond to comprised administered to the subject of a 1200 mg fixed dose for four weeks. 
     In some aspects, the dsRNA agent and the eculizumab, or an antigen-binding fragment thereof, are administered to the subject simultaneously. In other aspects, the dsRNA agent is administered to the subject before the eculizumab, or an antigen-binding fragment thereof. In still other aspects, the eculizumab, or an antigen-binding fragment thereof, is administered to the subject before the dsRNA agent. 
     In some embodiments, the treatment prevents breakthrough hemolysis in the subject. 
     In some embodiments, the treatment reduces the mean maximum C5 mRNA level by at least about 98% relative to baseline, e.g., at least about 99% relative to the baseline. 
     In some embodiments, the treatment lowers the minimum residual C5 level to about 1.0 micrograms/mL or below, e.g., about 0.9 micrograms/mL or below, 0.8 micrograms/mL or below, 0.7 micrograms/mL or below, 0.6 micrograms/mL or below, 0.5 micrograms/mL or below, 0.4 micrograms/mL or below, 0.3 micrograms/mL or below, 0.2 micrograms/mL or below or 0.1 micrograms/mL or below. 
     In some aspects, the treatment lowers the classical complement pathway (CCP) activity by at least about 94% relative to baseline, e.g., at least about 95%, at least about 96%, at least about 97%, at least about 98% or at least about 99% relative to baseline. 
     In some embodiments, the treatment lowers the alternative complement pathway (CAP) activity by at least about 94% relative to baseline, e.g., at least about 95%, at least about 96%, at least about 97%, at least about 98% or at least about 99% relative to baseline. 
     In certain aspects, the treatment inhibits the mean maximum hemolysis, as measured by inhibition of sheep red blood cell hemolysis, by at least about 75% relative to baseline, e.g., at least about 76%, at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98% or at least about 99% relative to baseline. 
     In some embodiments, the treatment lowers the level of lactate dehydrogenase (LDH) in the subject to levels lower than about 1.5 times the upper limit of normal (ULN). 
     In some aspects, the subject previously treated with eculizumab did not have breakthrough hemolysis. In other aspects, the subject previously treated with eculizumab had breakthrough hemolysis. 
     In some embodiments, the treatment reduces the mean maximum C5 mRNA level by at least about 86% relative to baseline, e.g., at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98% or at least about 99% relative to baseline. 
     In some aspects, the treatment lowers the minimum residual C5 level to about 8.0 micrograms/mL or below, e.g., about 7.5 micrograms/mL or below, about 7.0 micrograms/mL or below, about 6.5 micrograms/mL or below, about 6.0 micrograms/mL or below, about 5.5 micrograms/mL or below, about 5.0 micrograms/mL or below, about 4.5 micrograms/mL or below, about 4.0 micrograms/mL or below, about 3.5 micrograms/mL or below, about 3.0 micrograms/mL or below, about 2.5 micrograms/mL or below, about 2.0 micrograms/mL or below, about 1.5 micrograms/mL or below, about 1.0 micrograms/mL or below or about 0.5 micrograms/mL or below. 
     In some embodiments, the treatment lowers the classical complement pathway (CCP) activity by at least about 98% relative to baseline, e.g., at least about 99% relative to baseline. 
     In some aspects, the treatment lowers the alternative complement pathway (CAP) activity by at least about 98% relative to baseline, e.g., at least about 99% relative to baseline. 
     In certain embodiments, the treatment inhibits the mean maximum hemolysis, as measured by inhibition of sheep red blood cell hemolysis, by at least about 98% relative to baseline, e.g., at least about 99% relative to baseline. 
     In some embodiments, the level of lactate dehydrogenase (LDH) in the subject is reduced to about 215-225 IU/L. 
     In some aspects, the dsRNA agent is administered to the subject subcutaneously. In other aspects, the eculizumab is administered to the subject intravenously. 
     In some embodiments, the dsRNA agent further comprises a ligand. The ligand may be one or more GalNAc derivatives attached through a bivalent or trivalent branched linker. In a specific aspect, the ligand is 
     
       
         
         
             
             
         
       
     
     In further aspects, the ligand is attached to the 3′ end of the sense strand. In a specific embodiment, the RNAi agent is conjugated to the ligand as shown in the following schematic 
     
       
         
         
             
             
         
       
     
     In one aspect, the invention provides methods for treating, e.g., chronically treating, a subject having paroxysmal nocturnal hemoglobinuria (PNH). The methods include administering to an eculizumab naïve subject a 200 mg fixed dose of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 once every week for thirteen weeks, followed by a 400 mg fixed dose of the dsRNA agent once every week wherein the dsRNA agent comprises a sense strand and an antisense strand, and wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO:2876) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO:2889), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage, thereby treating the subject. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  is a schematic of the three complement pathways: alternative, classical and lectin. 
         FIG. 2  is a graph showing the percentage of complement component C5 remaining in C57BL/6 mice following a single 10 mg/kg dose of the indicated iRNAs. 
         FIG. 3  is a graph showing the percentage of complement component C5 remaining in C57BL/6 mice following a single 10 mg/kg dose of the indicated iRNAs. 
         FIG. 4  is a graph showing the percentage of complement component C5 remaining in C57BL/6 mice 48 hours after a single 10 mg/kg dose of the indicated iRNAs. 
         FIG. 5A  is a graph showing the percentage of hemolysis remaining at days 4 and 7 in rats after a single 2.5 mg/kg, 10 mg/kg, or 25 mg/kg subcutaneous dose of AD-58642. 
         FIG. 5B  is a Western blot showing the amount of complement component C5 remaining at day 7 in rats after a single 2.5 mg/kg, 10 mg/kg, or 25 mg/kg subcutaneous dose of AD-58642. 
         FIGS. 6A and 6B  are graphs showing the percentage of complement component C5 remaining in C57BL/6 mice 5 days after a single 1.25 mg/kg, 2.5 mg/kg, 5 mg/kg, 10 mg/kg or 25 mg/kg dose of AD-58642. 
         FIGS. 7A and 7B  are graphs showing the percentage of hemolysis remaining at day 5 in C57BL/6 mice after a single 1.25 mg/kg, 2.5 mg/kg, 5 mg/kg, 10 mg/kg or 25 mg/kg dose of AD-58642. 
         FIG. 8  is a Western blot showing the amount of complement component C5 remaining at day 5 in C57BL/6 mice after a single 1.25 mg/kg, 2.5 mg/kg, 5 mg/kg, 10 mg/kg or 25 mg/kg dose of AD-58642. 
         FIG. 9  is a graph showing the amount of complement component C5 protein remaining at days 5 and 9 in mouse serum after a single 0.625 mg/kg, 1.25 mg/kg, 2.5 mg/kg, 5.0 mg/kg, or 10 mg/kg dose of AD-58641. The lower limit of quantitation (LLOQ) of the assay is shown as a dashed line. 
         FIG. 10  is a is a graph showing the amount of complement component C5 protein remaining at day 8 in mouse serum after a 0.625 mg/kg, 1.25 mg/kg, or 2.5 mg/kg dose of AD-58641 at days 0, 1, 2, and 3. The lower limit of quantitation (LLOQ) of the assay is shown as a dashed line. 
         FIGS. 11A and 11B  depict the efficacy and cumulative effect of repeat administration of compound AD-58641 in rats.  FIG. 11A  is graph depicting the hemolytic activity remaining in the serum of rats on days 0, 4, 7, 11, 14, 18, 25, and 32 after repeat administration at 2.5 mg/kg/dose or 5.0 mg/kg/dose, q2w×3 (twice a week for 3 weeks).  FIG. 11B  is a Western blot showing the amount of complement component C5 protein remaining in the serum of the animals. 
         FIG. 12  is a graph showing the amount of complement component C5 protein in cynomolgus macaque serum at various time points before, during and after two rounds of subcutaneous dosing at 2.5 mg/kg or 5 mg/kg of AD-58641 every third day for eight doses. C5 protein levels were normalized to the average of the three pre-dose samples. 
         FIG. 13  is a graph showing the percentage of hemolysis remaining in cynomolgus macaque serum at various time points before, during and after two rounds of subcutaneous dosing at 2.5 mg/kg or 5 mg/kg of AD-58641 every third day for eight doses. Percent hemolysis was calculated relative to maximal hemolysis and to background hemolysis in control samples. 
         FIG. 14  is a graph showing the percentage of complement component C5 protein remaining at day 5 in the serum of C57BL/6 mice following a single 1 mg/kg dose of the indicated iRNAs. 
         FIG. 15  is a graph showing the percentage of complement component C5 protein remaining at day 5 in the serum of C57BL/6 mice following a single 0.25 mg/kg, 0.5 mg/kg, 1.0 mg/kg, or 2.0 mg/kg dose of the indicated iRNAs. 
         FIG. 16  is a graph showing the percentage of complement component C5 protein remaining in the serum of C57BL/6 mice at days 6, 13, 20, 27, and 34 following a single 1 mg/kg dose of the indicated iRNAs. 
         FIG. 17  is a graph showing the percentage of hemolysis remaining in rat serum at various time points following administration of a 5 mg/kg dose of the indicated compounds at days 0, 4, and 7. 
         FIG. 18A  shows the nucleotide sequence of  Homo sapiens  Complement Component 5 (C5) (SEQ ID NO:1);  FIG. 18B  shows the nucleotide sequence of  Macaca mulatta  Complement Component 5 (C5) (SEQ ID NO:2);  FIG. 18C  shows the nucleotide sequence of  Mus musculus  Complement Component 5 (C5) (SEQ ID NO:3);  FIG. 18D  shows the nucleotide sequence of  Rattus norvegicus  Complement Component 5 (C5) (SEQ ID NO:4);  FIG. 18E  shows the reverse complement of SEQ ID NO:1 (SEQ ID NO:5);  FIG. 18F  shows the reverse complement of SEQ ID NO:2 (SEQ ID NO:6);  FIG. 18G  shows the reverse complement of SEQ ID NO:3 (SEQ ID NO:7); and  FIG. 18H  shows the reverse complement of SEQ ID NO:4 (SEQ ID NO:8). 
         FIG. 19A  is a graph showing the percentage of serum C5 levels in cynomolgus macaques treated with AD-62643 relative to pre-bleed levels.  FIG. 19B  is a graph showing the percentage of serum C5 levels in each individual cynomolgus macaque treated with AD-62643. 
         FIG. 20A  is a graph showing the percentage of hemolysis in cynomolgus macaques treated with a QM regimen (5 mg/kg, qd×5, qw×8/10 mg/kg qm thereafter) of AD-62643 and  FIG. 20B  is a graph showing the percentage of hemolysis in cynomolgus macaques treated with a Q2W regimen (5 mg/kg, qw×8, q2w thereafter) of AD-62643.  FIG. 20C  is a graph showing the percentage of alternative complement pathway activity in cynomolgus macaques treated with AD-62643. 
         FIG. 21  is a graph showing serum levels of C5 protein in a mouse model of anti-collagen antibody-induced arthritis (CAIA) following treatment with AD-61679 and anti-C5 antibody. 
         FIG. 22A  is a bar graph showing join histology scores in in CAIA mice following treatment with AD-61679 and anti-C5 antibody.  FIG. 22B  is a bar graph showing levels of C3 deposition in CAIA mice following treatment with AD-61679 and anti-C5 antibody. 
         FIG. 23A  is a bar graph showing the percentage of hemolysis in a rat model of Passive Neymann Nephritis treated with anti-Fx1a or with anti-Fx1a and AD-61679.  FIG. 23B  is a bar graph showing the levels of urinary protein in a rat model of Passive Neymann Nephritis treated with anti-Fx1a or with anti-Fx1a and AD-61679. 
         FIG. 24  is a graph showing the mean C5 knockdown, relative to baseline, in healthy human subjects administered a single subcutaneous dose of 50 mg, 200 mg, 400 mg, 600 mg, or 900 mg of AD-62643. 
         FIG. 25  is a graph showing the mean knockdown of alternative complement pathway (CAP) activity, relative to baseline, in healthy human subjects administered a single subcutaneous dose of 50 mg, 200 mg, 400 mg, 600 mg, or 900 mg of AD-62643. 
         FIG. 26  is a graph showing the mean knockdown of classical complement pathway (CCP) activity, relative to baseline, in healthy human subjects administered a single subcutaneous dose of 50 mg, 200 mg, 400 mg, 600 mg, or 900 mg of AD-62643. 
         FIG. 27  is a graph showing the percentage of mean hemolysis reduction in healthy human subjects administered a single subcutaneous dose of 50 mg, 200 mg, 400 mg, 600 mg, or 900 mg of AD-62643. 
         FIG. 28A  is a graph showing the correlation of the mean C5 knockdown in humans administered a single dose of AD-62643 versus non-human primates (NHP) administered a single dose of AD-62643. 
         FIG. 28B  is a graph showing the percentage of mean C5 knockdown, relative to baseline, in healthy human subjects administered a single subcutaneous dose of AD-62643 and in non-human primates administered a single subcutaneous dose of AD-62643. 
         FIG. 29  is a graph showing the mean knockdown of classical complement pathway (CCP) activity, relative to baseline, in healthy human subjects administered a single subcutaneous dose of AD-62643. 
         FIG. 30A  is a graph showing the percentage of mean hemolysis reduction in healthy human subjects administered a single subcutaneous dose of AD-62643. 
         FIG. 30B  is a graph showing the mean hemolysis reduction in non-human primates administered a single subcutaneous dose of AD-62643. 
         FIG. 31  is a graph showing the mean C5 knockdown, relative to baseline, in healthy human subjects subcutaneously administered the indicated doses of AD-62643. 
         FIG. 32  is a graph showing the mean knockdown of alternative complement pathway (CAP) activity, relative to baseline, in healthy human subjects subcutaneously administered the indicated doses of AD-62643. 
         FIG. 33  is a graph showing the mean knockdown of classical complement pathway (CCP) activity, relative to baseline, in healthy human subjects subcutaneously administered the indicated doses of AD-62643. 
         FIG. 34  is a graph showing the percentage of mean hemolysis reduction in healthy human subjects subcutaneously administered the indicated doses of AD-62643. 
         FIGS. 35A and 35B  depict an indirect graphical comparison of residual C5 levels in the serum of healthy human volunteers administered multiple doses of AD-62643 and the levels of free C5 in aHUS subjects administered eculizumab.  FIG. 35A  is a graph depicting the levels of free C5 in aHUS subjects administered eculizumab (ASCPT Annual Meeting, Atlanta, Ga.; Mar. 18-22, 2014; Abstract #387).  FIG. 35B  is a graph depicting the residual C5 levels in the serum of healthy human volunteers administered the indicated doses of AD-62643. 
         FIG. 36A  is a graph showing the mean C5 knockdown, relative to baseline, in human eculizumab naïve subjects with PNH who were subcutaneously administered AD-62643. 
         FIG. 36B  is a graph showing the mean C5 knockdown, relative to baseline, in human subjects with PNH receiving eculizumab who were subcutaneously administered AD-62643. 
         FIG. 37A  is a graph showing the mean knockdown of classical complement pathway (CCP) activity, relative to baseline, in human eculizumab naïve subjects with PNH who were subcutaneously administered AD-62643. 
         FIG. 37B  is a graph showing the mean knockdown of classical complement pathway (CCP) activity, relative to baseline, in human subjects with PNH receiving eculizumab who were also subcutaneously administered AD-62643. 
         FIG. 38A  is a graph showing the percentage of mean hemolysis reduction in human eculizumab naïve subjects with PNH who were subcutaneously administered AD-62643. 
         FIG. 38B  is a graph showing the percentage of mean hemolysis reduction in human subjects with PNH receiving eculizumab who were subcutaneously administered AD-62643. 
         FIG. 39  is a graph showing LDH levels in human eculizumab naïve subjects with PNH who were subcutaneously administered AD-62643. 
         FIG. 40  is a graph showing LDH level in a human subject with PNH who is an eculizumab inadequate responder. 
         FIG. 41  is a graph showing eculizumab plasma concentration before and after subcutaneous administration of AD-62643 to a subject with PNH receiving eculizumab. 
         FIG. 42  depicts the dosing schedule for the subjects in the extension of the Phase VII Part C clinical trial of AD-62643 to investigate the effect of reduced eculizumab administration (dose and frequency) in the setting of ongoing AD-62643 pharmacology (i.e., in the absence of additional dosing of AD-62643) (referred to herein as the “Ecu sparing study”). 
         FIG. 43  is a graph showing the effect of eculizumab administration in the setting of ongoing AD-62643 phramacology on LDH levels in human eculizumab naïve subjects with PNH and human eculizumab background subjects with PNH. 
         FIG. 44A  is a graph showing the effect of eculizumab administration in the setting of ongoing AD-62643 phramacology on percent classical complement pathway (CCP) activity in human eculizumab naïve subjects with PNH and human eculizumab background subjects with PNH. 
         FIG. 44B  is a graph showing the effect of eculizumab administration in the setting of ongoing AD-62643 phramacology on percent sheep red blood cell (sRBC) hemolysis in human eculizumab naïve subjects with PNH and human eculizumab background subjects with PNH. 
         FIG. 45  is a graph showing the effect of eculizumab administration in the setting of ongoing AD-62643 phramacology on eculizumab plasma concentration before and after subcutaneous administration eculizumab in human eculizumab naïve subjects with PNH and human eculizumab background subjects with PNH. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The present invention provides iRNA agents which effect the RNA-induced silencing complex (RISC)-mediated cleavage of RNA transcripts of a complement component C5 gene. 
     The iRNAs of the invention may include an RNA strand (the antisense strand) having a region which is about 30 nucleotides or less in length, e.g., 15-30, 15-29, 15-28, 15-27, 15-26, 15-25, 15-24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 18-30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-30, 20-29, 20-28, 20-27, 20-26, 20-25, 20-24, 20-23, 20-22, 20-21, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23, or 21-22 nucleotides in length, which region is substantially complementary to at least part of an mRNA transcript of a C5 gene. 
     In certain embodiments, the iRNAs of the invention include an RNA strand (the antisense strand) which can include longer lengths, for example up to 66 nucleotides, e.g., 36-66, 26-36, 25-36, 31-60, 22-43, 27-53 nucleotides in length with a region of at least 19 contiguous nucleotides that is substantially complementary to at least a part of an mRNA transcript of a complement component C5 gene. These iRNAs with the longer length antisense strands preferably include a second RNA strand (the sense strand) of 20-60 nucleotides in length wherein the sense and antisense strands form a duplex of 18-30 contiguous nucleotides. 
     The use of these iRNAs enables the targeted degradation of mRNAs of a C5 gene in mammals. Very low dosages of C5 iRNAs, in particular, can specifically and efficiently mediate RNA interference (RNAi), resulting in significant inhibition of expression of a C5 gene. The present inventors have demonstrated that iRNAs targeting C5 can mediate RNAi in vitro and in vivo, resulting in significant inhibition of expression of a C5 gene. Thus, methods and compositions including these iRNAs are useful for treating a subject who would benefit by a reduction in the levels and/or activity of a C5 protein, such as a subject having a complement component C5-associated disease, such as paroxysmal nocturnal hemoglobinuria (PNH), 
     The present invention also provides methods and combination therapies for treating a subject having a disorder that would benefit from inhibiting or reducing the expression of a C5 gene, e.g., a complement component C5-associated disease, such as paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), neuromyelitis optica (NMO), and myasthenia gravis, using iRNA compositions which effect the RNA-induced silencing complex (RISC)-mediated cleavage of RNA transcripts of a complement component C5 gene. 
     The present invention also provides methods for preventing at least one symptom, e.g., hemolysis, in a subject having a disorder that would benefit from inhibiting or reducing the expression of a C5 gene, e.g., a complement component C5-associated disease, such as paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), neuromyelitis optica (NMO), and myasthenia gravis. The present invention further provides iRNA compositions which effect the RNA-induced silencing complex (RISC)-mediated cleavage of RNA transcripts of a complement component C5 gene. The C5 gene may be within a cell, e.g., a cell within a subject, such as a human. 
     The combination therapies of the present invention include administering to a subject having a complement component C5-associated disease, an RNAi agent of the invention and an additional therapeutic, such as anti-complement component C5 antibody, or antigen-binding fragment thereof, e.g., eculizumab. The combination therapies of the invention reduce C5 levels in the subject (e.g., by about 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or about 99%) by targeting C5 mRNA with an iRNA agent of the invention and, accordingly, allow the therapeutically (or prophylactically) effective amount of eculizumab required to treat the subject to be reduced, thereby decreasing the costs of treatment and permitting easier and more convenient ways of administering eculizumab, such as subcutaneous administration. 
     The following detailed description discloses how to make and use compositions containing iRNAs to inhibit the expression of a C5 gene, as well as compositions, uses, and methods for treating subjects having diseases and disorders that would benefit from inhibition and/or reduction of the expression of this gene. 
     I. Definitions 
     In order that the present invention may be more readily understood, certain terms are first defined. In addition, it should be noted that whenever a value or range of values of a parameter are recited, it is intended that values and ranges intermediate to the recited values are also intended to be part of this invention. 
     The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element, e.g., a plurality of elements. 
     The term “including” is used herein to mean, and is used interchangeably with, the phrase “including but not limited to”. 
     The term “or” is used herein to mean, and is used interchangeably with, the term “and/or,” unless context clearly indicates otherwise. 
     As used herein, “complement component C5,” used interchangeably with the term “C5” refers to the well-known gene and polypeptide, also known in the art as CPAMD4, C3 and PZP-like alpha-2-macroglobulin domain-containing protein, anaphtlatoxin C5a analog, hemolytic complement (Hc), and complement C5. The sequence of a human C5 mRNA transcript can be found at, for example, GenBank Accession No. GI:38016946 (NM 001735.2; SEQ ID NO:1). The sequence of rhesus C5 mRNA can be found at, for example, GenBank Accession No. GI:297270262 (XM 001095750.2; SEQ ID NO:2). The sequence of mouse C5 mRNA can be found at, for example, GenBank Accession No. GI:291575171 (NM 010406.2; SEQ ID NO:3). The sequence of rat C5 mRNA can be found at, for example, GenBank Accession No. GI:392346248 (XM 345342.4; SEQ ID NO:4). Additional examples of C5 mRNA sequences are readily available using publicly available databases, e.g., GenBank. 
     The term“C5,” as used herein, also refers to naturally occurring DNA sequence variations of the C5 gene, such as a single nucleotide polymorphism in the C5 gene. Numerous SNPs within the C5 gene have been identified and may be found at, for example, NCBI dbSNP (see, e.g., ncbi.nlm.nih.gov/snp). Non-limiting examples of SNPs within the C5 gene may be found at, NCBI dbSNP Accession Nos. rs121909588 and rs121909587. 
     As used herein, “target sequence” refers to a contiguous portion of the nucleotide sequence of an mRNA molecule formed during the transcription of a C5 gene, including mRNA that is a product of RNA processing of a primary transcription product. In one embodiment, the target portion of the sequence will be at least long enough to serve as a substrate for iRNA-directed cleavage at or near that portion of the nucleotide sequence of an mRNA molecule formed during the transcription of a C5 gene. 
     The target sequence may be from about 9-36 nucleotides in length, e.g., about 15-30 nucleotides in length. For example, the target sequence can be from about 15-30 nucleotides, 15-29, 15-28, 15-27, 15-26, 15-25, 15-24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 18-30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-30, 20-29, 20-28, 20-27, 20-26, 20-25, 20-24, 20-23, 20-22, 20-21, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23, or 21-22 nucleotides in length. Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the invention. 
     As used herein, the term “strand comprising a sequence” refers to an oligonucleotide comprising a chain of nucleotides that is described by the sequence referred to using the standard nucleotide nomenclature. 
     “G,” “C,” “A,” “T” and “U” each generally stand for a nucleotide that contains guanine, cytosine, adenine, thymidine and uracil as a base, respectively. However, it will be understood that the term “ribonucleotide” or “nucleotide” can also refer to a modified nucleotide, as further detailed below, or a surrogate replacement moiety (see, e.g., Table 2). The skilled person is well aware that guanine, cytosine, adenine, and uracil can be replaced by other moieties without substantially altering the base pairing properties of an oligonucleotide comprising a nucleotide bearing such replacement moiety. For example, without limitation, a nucleotide comprising inosine as its base can base pair with nucleotides containing adenine, cytosine, or uracil. Hence, nucleotides containing uracil, guanine, or adenine can be replaced in the nucleotide sequences of dsRNA featured in the invention by a nucleotide containing, for example, inosine. In another example, adenine and cytosine anywhere in the oligonucleotide can be replaced with guanine and uracil, respectively to form G-U Wobble base pairing with the target mRNA. Sequences containing such replacement moieties are suitable for the compositions and methods featured in the invention. 
     The terms “iRNA”, “RNAi agent,” “iRNA agent,”, “RNA interference agent” as used interchangeably herein, refer to an agent that contains RNA as that term is defined herein, and which mediates the targeted cleavage of an RNA transcript via an RNA-induced silencing complex (RISC) pathway. iRNA directs the sequence-specific degradation of mRNA through a process known as RNA interference (RNAi). The iRNA modulates, e.g., inhibits, the expression of C5 in a cell, e.g., a cell within a subject, such as a mammalian subject. 
     In one embodiment, an RNAi agent of the invention includes a single stranded RNA that interacts with a target RNA sequence, e.g., a C5 target mRNA sequence, to direct the cleavage of the target RNA. Without wishing to be bound by theory it is believed that long double stranded RNA introduced into cells is broken down into siRNA by a Type III endonuclease known as Dicer (Sharp et al. (2001)  Genes Dev.  15:485). Dicer, a ribonuclease-III-like enzyme, processes the dsRNA into 19-23 base pair short interfering RNAs with characteristic two base 3′ overhangs (Bernstein, et al., (2001)  Nature  409:363). The siRNAs are then incorporated into an RNA-induced silencing complex (RISC) where one or more helicases unwind the siRNA duplex, enabling the complementary antisense strand to guide target recognition (Nykanen, et al., (2001)  Cell  107:309). Upon binding to the appropriate target mRNA, one or more endonucleases within the RISC cleave the target to induce silencing (Elbashir, et al., (2001)  Genes Dev.  15:188). Thus, in one aspect the invention relates to a single stranded RNA (siRNA) generated within a cell and which promotes the formation of a RISC complex to effect silencing of the target gene, i.e., a C5 gene. Accordingly, the term “siRNA” is also used herein to refer to an RNAi as described above. 
     In another embodiment, the RNAi agent may be a single-stranded siRNA that is introduced into a cell or organism to inhibit a target mRNA. Single-stranded RNAi agents bind to the RISC endonuclease, Argonaute 2, which then cleaves the target mRNA. The single-stranded siRNAs are generally 15-30 nucleotides and are chemically modified. The design and testing of single-stranded siRNAs are described in U.S. Pat. No. 8,101,348 and in Lima et al., (2012)  Cell  150: 883-894, the entire contents of each of which are hereby incorporated herein by reference. Any of the antisense nucleotide sequences described herein may be used as a single-stranded siRNA as described herein or as chemically modified by the methods described in Lima et al., (2012)  Cell  150; :883-894. 
     In another embodiment, an “iRNA” for use in the compositions, uses, and methods of the invention is a double stranded RNA and is referred to herein as a “double stranded RNAi agent,” “double stranded RNA (dsRNA) molecule,” “dsRNA agent,” or “dsRNA”. The term “dsRNA”, refers to a complex of ribonucleic acid molecules, having a duplex structure comprising two anti-parallel and substantially complementary nucleic acid strands, referred to as having “sense” and “antisense” orientations with respect to a target RNA, i.e., a C5 gene. In some embodiments of the invention, a double stranded RNA (dsRNA) triggers the degradation of a target RNA, e.g., an mRNA, through a post-transcriptional gene-silencing mechanism referred to herein as RNA interference or RNAi. 
     In general, the majority of nucleotides of each strand of a dsRNA molecule are ribonucleotides, but as described in detail herein, each or both strands can also include one or more non-ribonucleotides, e.g., a deoxyribonucleotide and/or a modified nucleotide. In addition, as used in this specification, an “RNAi agent” may include ribonucleotides with chemical modifications; an RNAi agent may include substantial modifications at multiple nucleotides. As used herein, the term “modified nucleotide” refers to a nucleotide having, independently, a modified sugar moiety, a modified internucleotide linkage, and/or a modified nucleobase. Thus, the term modified nucleotide encompasses substitutions, additions or removal of, e.g., a functional group or atom, to internucleoside linkages, sugar moieties, or nucleobases. The modifications suitable for use in the agents of the invention include all types of modifications disclosed herein or known in the art. Any such modifications, as used in a siRNA type molecule, are encompassed by “RNAi agent” for the purposes of this specification and claims. The duplex region may be of any length that permits specific degradation of a desired target RNA through a RISC pathway, and may range from about 9 to 36 base pairs in length, e.g., about 15-30 base pairs in length, for example, about 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36 base pairs in length, such as about 15-30, 15-29, 15-28, 15-27, 15-26, 15-25, 15-24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 18-30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-30, 20-29, 20-28, 20-27, 20-26, 20-25, 20-24, 20-23, 20-22, 20-21, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23, or 21-22 base pairs in length. Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the invention. 
     The two strands forming the duplex structure may be different portions of one larger RNA molecule, or they may be separate RNA molecules. Where the two strands are part of one larger molecule, and therefore are connected by an uninterrupted chain of nucleotides between the 3′-end of one strand and the 5′-end of the respective other strand forming the duplex structure, the connecting RNA chain is referred to as a “hairpin loop.” A hairpin loop can comprise at least one unpaired nucleotide. In some embodiments, the hairpin loop can comprise at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 20, at least 23 or more unpaired nucleotides. 
     Where the two substantially complementary strands of a dsRNA are comprised by separate RNA molecules, those molecules need not, but can be covalently connected. Where the two strands are connected covalently by means other than an uninterrupted chain of nucleotides between the 3′-end of one strand and the 5′-end of the respective other strand forming the duplex structure, the connecting structure is referred to as a “linker.” The RNA strands may have the same or a different number of nucleotides. The maximum number of base pairs is the number of nucleotides in the shortest strand of the dsRNA minus any overhangs that are present in the duplex. In addition to the duplex structure, an RNAi may comprise one or more nucleotide overhangs. 
     In one embodiment, an RNAi agent of the invention is a dsRNA of 24-30 nucleotides that interacts with a target RNA sequence, e.g., a C5 target mRNA sequence, to direct the cleavage of the target RNA. Without wishing to be bound by theory, long double stranded RNA introduced into cells is broken down into siRNA by a Type III endonuclease known as Dicer (Sharp et al. (2001)  Genes Dev.  15:485). Dicer, a ribonuclease-III-like enzyme, processes the dsRNA into 19-23 base pair short interfering RNAs with characteristic two base 3′ overhangs (Bernstein, et al., (2001)  Nature  409:363). The siRNAs are then incorporated into an RNA-induced silencing complex (RISC) where one or more helicases unwind the siRNA duplex, enabling the complementary antisense strand to guide target recognition (Nykanen, et al., (2001)  Cell  107:309). Upon binding to the appropriate target mRNA, one or more endonucleases within the RISC cleave the target to induce silencing (Elbashir, et al., (2001)  Genes Dev.  15:188). 
     As used herein, the term “nucleotide overhang” refers to at least one unpaired nucleotide that protrudes from the duplex structure of an iRNA, e.g., a dsRNA. For example, when a 3′-end of one strand of a dsRNA extends beyond the 5′-end of the other strand, or vice versa, there is a nucleotide overhang. A dsRNA can comprise an overhang of at least one nucleotide; alternatively the overhang can comprise at least two nucleotides, at least three nucleotides, at least four nucleotides, at least five nucleotides or more. A nucleotide overhang can comprise or consist of a nucleotide/nucleoside analog, including a deoxynucleotide/nucleoside. The overhang(s) can be on the sense strand, the antisense strand or any combination thereof. Furthermore, the nucleotide(s) of an overhang can be present on the 5′-end, 3′-end or both ends of either an antisense or sense strand of a dsRNA. 
     In one embodiment, the antisense strand of a dsRNA has a 1-10 nucleotide, e.g., a 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotide, overhang at the 3′-end and/or the 5′-end. In one embodiment, the sense strand of a dsRNA has a 1-10 nucleotide, e.g., a 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotide, overhang at the 3′-end and/or the 5′-end. In another embodiment, one or more of the nucleotides in the overhang is replaced with a nucleoside thiophosphate. 
     In certain embodiments, the overhang on the sense strand or the antisense strand, or both, can include extended lengths longer than 10 nucleotides, e.g., 1-30 nucleotides, 2-30 nucleotides, 10-30 nucleotides, or 10-15 nucleotides in length. In certain embodiments, an extended overhang is on the sense strand of the duplex. In certain embodiments, an extended overhang is present on the 3′end of the sense strand of the duplex. In certain embodiments, an extended overhang is present on the 5′end of the sense strand of the duplex. In certain embodiments, an extended overhang is on the antisense strand of the duplex. In certain embodiments, an extended overhang is present on the 3′end of the antisense strand of the duplex. In certain embodiments, an extended overhang is present on the 5′end of the antisense strand of the duplex. In certain embodiments, one or more of the nucleotides in the overhang is replaced with a nucleoside thiophosphate. In certain embodiments, the overhang includes a self-complementary portion such that the overhang is capable of forming a hairpin structure that is stable under physiological conditions. 
     “Blunt” or “blunt end” means that there are no unpaired nucleotides at that end of the double stranded RNAi agent, i.e., no nucleotide overhang. A “blunt ended” RNAi agent is a dsRNA that is double stranded over its entire length, i.e., no nucleotide overhang at either end of the molecule. The RNAi agents of the invention include RNAi agents with nucleotide overhangs at one end (i.e., agents with one overhang and one blunt end) or with nucleotide overhangs at both ends. 
     The term “antisense strand” or “guide strand” refers to the strand of an iRNA, e.g., a dsRNA, which includes a region that is substantially complementary to a target sequence, e.g., a C5 mRNA. As used herein, the term “region of complementarity” refers to the region on the antisense strand that is substantially complementary to a sequence, for example a target sequence, e.g., a C5 nucleotide sequence, as defined herein. Where the region of complementarity is not fully complementary to the target sequence, the mismatches can be in the internal or terminal regions of the molecule. Generally, the most tolerated mismatches are in the terminal regions, e.g., within 5, 4, 3, or 2 nucleotides of the 5′- and/or 3′-terminus of the iRNA. 
     The term “sense strand,” or “passenger strand” as used herein, refers to the strand of an iRNA that includes a region that is substantially complementary to a region of the antisense strand as that term is defined herein. 
     As used herein, the term “cleavage region” refers to a region that is located immediately adjacent to the cleavage site. The cleavage site is the site on the target at which cleavage occurs. In some embodiments, the cleavage region comprises three bases on either end of, and immediately adjacent to, the cleavage site. In some embodiments, the cleavage region comprises two bases on either end of, and immediately adjacent to, the cleavage site. In some embodiments, the cleavage site specifically occurs at the site bound by nucleotides 10 and 11 of the antisense strand, and the cleavage region comprises nucleotides 11, 12 and 13. 
     As used herein, and unless otherwise indicated, the term “complementary,” when used to describe a first nucleotide sequence in relation to a second nucleotide sequence, refers to the ability of an oligonucleotide or polynucleotide comprising the first nucleotide sequence to hybridize and form a duplex structure under certain conditions with an oligonucleotide or polynucleotide comprising the second nucleotide sequence, as will be understood by the skilled person. Such conditions can, for example, be stringent conditions, where stringent conditions can include: 400 mM NaCl, 40 mM PIPES pH 6.4, 1 mM EDTA, 50° C. or 70° C. for 12-16 hours followed by washing (see, e.g., “ Molecular Cloning: A Laboratory Manual , Sambrook, et al. (1989) Cold Spring Harbor Laboratory Press). Other conditions, such as physiologically relevant conditions as can be encountered inside an organism, can apply. The skilled person will be able to determine the set of conditions most appropriate for a test of complementarity of two sequences in accordance with the ultimate application of the hybridized nucleotides. 
     Complementary sequences within an iRNA, e.g., within a dsRNA as described herein, include base-pairing of the oligonucleotide or polynucleotide comprising a first nucleotide sequence to an oligonucleotide or polynucleotide comprising a second nucleotide sequence over the entire length of one or both nucleotide sequences. Such sequences can be referred to as “fully complementary” with respect to each other herein. However, where a first sequence is referred to as “substantially complementary” with respect to a second sequence herein, the two sequences can be fully complementary, or they can form one or more, but generally not more than 5, 4, 3 or 2 mismatched base pairs upon hybridization for a duplex up to 30 base pairs, while retaining the ability to hybridize under the conditions most relevant to their ultimate application, e.g., inhibition of gene expression via a RISC pathway. However, where two oligonucleotides are designed to form, upon hybridization, one or more single stranded overhangs, such overhangs shall not be regarded as mismatches with regard to the determination of complementarity. For example, a dsRNA comprising one oligonucleotide 21 nucleotides in length and another oligonucleotide 23 nucleotides in length, wherein the longer oligonucleotide comprises a sequence of 21 nucleotides that is fully complementary to the shorter oligonucleotide, can yet be referred to as “fully complementary” for the purposes described herein. 
     “Complementary” sequences, as used herein, can also include, or be formed entirely from, non-Watson-Crick base pairs and/or base pairs formed from non-natural and modified nucleotides, in so far as the above requirements with respect to their ability to hybridize are fulfilled. Such non-Watson-Crick base pairs include, but are not limited to, G:U Wobble or Hoogstein base pairing. 
     The terms “complementary,” “fully complementary” and “substantially complementary” herein can be used with respect to the base matching between the sense strand and the antisense strand of a dsRNA, or between the antisense strand of an iRNA agent and a target sequence, as will be understood from the context of their use. 
     As used herein, a polynucleotide that is “substantially complementary to at least part of” a messenger RNA (mRNA) refers to a polynucleotide that is substantially complementary to a contiguous portion of the mRNA of interest (e.g., an mRNA encoding C5). For example, a polynucleotide is complementary to at least a part of a C5 mRNA if the sequence is substantially complementary to a non-interrupted portion of an mRNA encoding C5. 
     Accordingly, in some embodiments, the sense strand polynucleotides and the antisense polynucleotides disclosed herein are fully complementary to a complement component C5 gene sequence. 
     In one embodiment, the antisense polynucleotides disclosed herein are fully complementary to the target complement component C5 sequence. In other embodiments, the antisense polynucleotides disclosed herein are substantially complementary to the target complement component C5 sequence and comprise a contiguous nucleotide sequence which is at least about 80% complementary over its entire length to the equivalent region of the nucleotide sequence of SEQ ID NO:1, or a fragment of SEQ ID NO:1, such as about 85%, about 86%, about 8′7%, about 88%, about 89%, about 90%, about % 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% complementary. 
     In other embodiments, the antisense polynucleotides disclosed herein are substantially complementary to the target complement component C5 sequence and comprise a contiguous nucleotide sequence which is at least about 80% complementary over its entire length to any one of the sense strand nucleotide sequences in any one of Tables 3, 4, 5, 6, 18, 19, 20, 21, and 23, or a fragment of any one of the antisense strand nucleotide sequences in any one of Tables 3, 4, 5, 6, 18, 19, 20, 21, and 23, such as about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about % 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 9′7%, about 98%, or about 99% complementary. 
     In one embodiment, an RNAi agent of the invention includes a sense strand that is substantially complementary to an antisense polynucleotide which, in turn, is complementary to a target complement component C5 sequence and comprises a contiguous nucleotide sequence which is at least about 80% complementary over its entire length to any one of the antisense strand nucleotide sequences in any one of Tables 3, 4, 5, 6, 18, 19, 20, 21, and 23, or a fragment of any one of the antisense strand nucleotide sequences in any one of Tables 3, 4, 5, 6, 18, 19, 20, 21, and 23, such as about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about % 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% complementary. 
     In general, the majority of nucleotides of each strand are ribonucleotides, but as described in detail herein, each or both strands can also include one or more non-ribonucleotides, e.g., a deoxyribonucleotide and/or a modified nucleotide. In addition, an “iRNA” may include ribonucleotides with chemical modifications. Such modifications may include all types of modifications disclosed herein or known in the art. Any such modifications, as used in an iRNA molecule, are encompassed by “iRNA” for the purposes of this specification and claims. 
     In one aspect of the invention, an agent for use in the methods and compositions of the invention is a single-stranded antisense RNA molecule that inhibits a target mRNA via an antisense inhibition mechanism. The single-stranded antisense RNA molecule is complementary to a sequence within the target mRNA. The single-stranded antisense oligonucleotides can inhibit translation in a stoichiometric manner by base pairing to the mRNA and physically obstructing the translation machinery, see Dias, N. et al., (2002)  Mol Cancer Ther  1:347-355. The single-stranded antisense RNA molecule may be about 15 to about 30 nucleotides in length and have a sequence that is complementary to a target sequence. For example, the single-stranded antisense RNA molecule may comprise a sequence that is at least about 15, 16, 17, 18, 19, 20, or more contiguous nucleotides from any one of the antisense sequences described herein. 
     The term “lipid nanoparticle” or “LNP” is a vesicle comprising a lipid layer encapsulating a pharmaceutically active molecule, such as a nucleic acid molecule, e.g., an iRNA or a plasmid from which an iRNA is transcribed. LNPs are described in, for example, U.S. Pat. Nos. 6,858,225, 6,815,432, 8,158,601, and 8,058,069, the entire contents of which are hereby incorporated herein by reference. 
     As used herein, a “subject” is an animal, such as a mammal, including a primate (such as a human, a non-human primate, e.g., a monkey, and a chimpanzee), a non-primate (such as a cow, a pig, a camel, a llama, a horse, a goat, a rabbit, a sheep, a hamster, a guinea pig, a cat, a dog, a rat, a mouse, a horse, and a whale), or a bird (e.g., a duck or a goose). In an embodiment, the subject is a human, such as a human being treated or assessed for a disease, disorder or condition that would benefit from reduction in C5 expression; a human at risk for a disease, disorder or condition that would benefit from reduction in C5 expression; a human having a disease, disorder or condition that would benefit from reduction in C5 expression; and/or human being treated for a disease, disorder or condition that would benefit from reduction in C5 expression as described herein. 
     As used herein, the terms “treating” or “treatment” refer to a beneficial or desired result including, but not limited to, alleviation or amelioration of one or more symptoms associated with unwanted complement pathway activation (e.g., hemolysis and/or chronic inflammation); diminishing the extent of unwanted complement pathway activation; stabilization (i.e., not worsening) of the state of chronic inflammation and/or hemolysis; amelioration or palliation of unwanted complement pathway activation (e.g., chronic inflammation and/or hemolysis) whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival in the absence of treatment. 
     The term “lower” in the context of the level of a complement component C5 in a subject or a disease marker or symptom refers to a statistically significant decrease in such level. The decrease can be, for example, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more and is preferably down to a level accepted as within the range of normal for an individual without such disorder. 
     As used herein, “prevention” or “preventing,” when used in reference to a disease, disorder or condition thereof, that would benefit from a reduction in expression of a C5 gene, refers to a reduction in the likelihood that a subject will develop a symptom associated with such a disease, disorder, or condition, or a reduction in the frequency and/or duration of a symptom associated with such a disease, disorder, or condition, e.g., a symptom of unwanted complement activation, such as a chronic inflammation, hemolysis and/or thrombosis. The likelihood of developing a thrombosis is reduced, for example, when an individual having one or more risk factors for a thrombosis either fails to develop a thrombosis or develops a thrombosis with less severity relative to a population having the same risk factors and not receiving treatment as described herein. The failure to develop a disease, disorder or condition, or the reduction in the development of a symptom associated with such a disease, disorder or condition (e.g., by at least about 10% on a clinically accepted scale for that disease or disorder), or the exhibition of delayed symptoms delayed (e.g., by days, weeks, months or years) is considered effective prevention. 
     As used herein, the term “complement component C5-associated disease” is a disease or disorder that is caused by, or associated with complement activation. Such diseases are typically associated with inflammation and/or immune system activation, e.g., membrane attack complex-mediated lysis, anaphylaxis, and/or hemolysis. Non-limiting examples of complement component C5-associated diseases include paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), asthma, rheumatoid arthritis (RA); antiphospholipid antibody syndrome; lupus nephritis; ischemia-reperfusion injury; typical or infectious hemolytic uremic syndrome (tHUS); dense deposit disease (DDD); neuromyelitis optica (NMO); multifocal motor neuropathy (MMN); multiple sclerosis (MS); macular degeneration (e.g., age-related macular degeneration (AMD)); hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome; thrombotic thrombocytopenic purpura (TTP); spontaneous fetal loss; Pauci-immune vasculitis; epidermolysis bullosa; recurrent fetal loss; pre-eclampsia, traumatic brain injury, myasthenia gravis, cold agglutinin disease, dermatomyositis bullous pemphigoid, Shiga toxin  E. coli -related hemolytic uremic syndrome, C3 nephropathy, anti-neutrophil cytoplasmic antibody-associated vasculitis (e.g., granulomatosis with polyangiitis (previously known as Wegener granulomatosis), Churg-Strauss syndrome, and microscopic polyangiitis), humoral and vascular transplant rejection, graft dysfunction, myocardial infarction (e.g., tissue damage and ischemia in myocardial infarction), an allogenic transplant, sepsis (e.g., poor outcome in sepsis), Coronary artery disease, dermatomyositis, Graves&#39; disease, atherosclerosis, Alzheimer&#39;s disease, systemic inflammatory response sepsis, septic shock, spinal cord injury, glomerulonephritis, Hashimoto&#39;s thyroiditis, type I diabetes, psoriasis, pemphigus, autoimmune hemolytic anemia (AIHA), ITP, Goodpasture syndrome, Degos disease, antiphospholipid syndrome (APS), catastrophic APS (CAPS), a cardiovascular disorder, myocarditis, a cerebrovascular disorder, a peripheral (e.g., musculoskeletal) vascular disorder, a renovascular disorder, a mesenteric/enteric vascular disorder, vasculitis, Henoch-Schönlein purpura nephritis, systemic lupus erythematosus-associated vasculitis, vasculitis associated with rheumatoid arthritis, immune complex vasculitis, Takayasu&#39;s disease, dilated cardiomyopathy, diabetic angiopathy, Kawasaki&#39;s disease (arteritis), venous gas embolus (VGE), and restenosis following stent placement, rotational atherectomy, membraneous nephropathy, Guillain-Barre syndrome, and percutaneous transluminal coronary angioplasty (PTCA) (see, e.g., Holers (2008)  Immunological Reviews  223:300-316; Holers and Thurman (2004)  Molecular Immunology  41:147-152; U.S. Patent Publication No. 20070172483). 
     In one embodiment, a complement component C5-associated disease is paroxysmal nocturnal hemoglobinuria (PNH). The PNH may be classical PNH or PNH in the setting of another bone marrow failure syndrome and/or myelodysplastic syndromes (MDS), e.g., cytopenias. In another embodiment, a complement component C5-associated disease is atypical hemolytic uremic syndrome (aHUS). In another embodiment, a complement component C5-associated disease is neuromyelitis optica (NMO). In yet another embodiment, a complement component C5-associated disease is myasthenia gravis. 
     II. iRNAs of the Invention 
     The present invention provides iRNAs which inhibit the expression of a complement component C5 gene. In one embodiment, the iRNA agent includes double stranded ribonucleic acid (dsRNA) molecules for inhibiting the expression of a C5 gene in a cell, such as a cell within a subject, e.g., a mammal, such as a human having a complement component C5-associated disease, e.g., PNH. The dsRNA includes an antisense strand having a region of complementarity which is complementary to at least a part of an mRNA formed in the expression of a C5 gene. The region of complementarity is about 30 nucleotides or less in length (e.g., about 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, or 18 nucleotides or less in length). Upon contact with a cell expressing the C5 gene, the iRNA inhibits the expression of the C5 gene (e.g., a human, a primate, a non-primate, or a bird C5 gene) by at least about 10% as assayed by, for example, a PCR or branched DNA (bDNA)-based method, or by a protein-based method, such as by immunofluorescence analysis, using, for example, Western Blotting or flowcytometric techniques. 
     A dsRNA includes two RNA strands that are complementary and hybridize to form a duplex structure under conditions in which the dsRNA will be used. One strand of a dsRNA (the antisense strand) includes a region of complementarity that is substantially complementary, and generally fully complementary, to a target sequence. The target sequence can be derived from the sequence of an mRNA formed during the expression of a C5 gene. The other strand (the sense strand) includes a region that is complementary to the antisense strand, such that the two strands hybridize and form a duplex structure when combined under suitable conditions. As described elsewhere herein and as known in the art, the complementary sequences of a dsRNA can also be contained as self-complementary regions of a single nucleic acid molecule, as opposed to being on separate oligonucleotides. 
     Generally, the duplex structure is about 15 to 30 base pairs in length, e.g., about 15-29, 15-28, 15-27, 15-26, 15-25, 15-24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 18-30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-30, 20-29, 20-28, 20-27, 20-26, 20-25, 20-24, 20-23, 20-22, 20-21, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23, or 21-22 base pairs in length. Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the invention. 
     Similarly, the region of complementarity to the target sequence is about 15 to 30 nucleotides in length, e.g., about 15-29, 15-28, 15-27, 15-26, 15-25, 15-24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 18-30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-30, 20-29, 20-28, 20-27, 20-26, 20-25, 20-24, 20-23, 20-22, 20-21, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23, or 21-22 nucleotides in length. Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the invention. 
     In some embodiments, the dsRNA is about 15 to about 20 nucleotides in length, or about 25 to about 30 nucleotides in length. In general, the dsRNA is long enough to serve as a substrate for the Dicer enzyme. For example, it is well-known in the art that dsRNAs longer than about 21-23 nucleotides in length may serve as substrates for Dicer. As the ordinarily skilled person will also recognize, the region of an RNA targeted for cleavage will most often be part of a larger RNA molecule, often an mRNA molecule. Where relevant, a “part” of an mRNA target is a contiguous sequence of an mRNA target of sufficient length to allow it to be a substrate for RNAi-directed cleavage (i.e., cleavage through a RISC pathway). 
     One of skill in the art will also recognize that the duplex region is a primary functional portion of a dsRNA, e.g., a duplex region of about 9 to 36 base pairs, e.g., about 10-36, 11-36, 12-36, 13-36, 14-36, 15-36, 9-35, 10-35, 11-35, 12-35, 13-35, 14-35, 15-35, 9-34, 10-34, 11-34, 12-34, 13-34, 14-34, 15-34, 9-33, 10-33, 11-33, 12-33, 13-33, 14-33, 15-33, 9-32, 10-32, 11-32, 12-32, 13-32, 14-32, 15-32, 9-31, 10-31, 11-31, 12-31, 13-32, 14-31, 15-31, 15-30, 15-29, 15-28, 15-27, 15-26, 15-25, 15-24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 18-30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-30, 20-29, 20-28, 20-27, 20-26, 20-25, 20-24, 20-23, 20-22, 20-21, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23, or 21-22 base pairs. Thus, in one embodiment, to the extent that it becomes processed to a functional duplex, of e.g., 15-30 base pairs, that targets a desired RNA for cleavage, an RNA molecule or complex of RNA molecules having a duplex region greater than 30 base pairs is a dsRNA. Thus, an ordinarily skilled artisan will recognize that in one embodiment, a miRNA is a dsRNA. In another embodiment, a dsRNA is not a naturally occurring miRNA. In another embodiment, an iRNA agent useful to target C5 expression is not generated in the target cell by cleavage of a larger dsRNA. 
     A dsRNA as described herein can further include one or more single-stranded nucleotide overhangs e.g., 1, 2, 3, or 4 nucleotides. dsRNAs having at least one nucleotide overhang can have unexpectedly superior inhibitory properties relative to their blunt-ended counterparts. A nucleotide overhang can comprise or consist of a nucleotide/nucleoside analog, including a deoxynucleotide/nucleoside. The overhang(s) can be on the sense strand, the antisense strand or any combination thereof. Furthermore, the nucleotide(s) of an overhang can be present on the 5′-end, 3′-end or both ends of either an antisense or sense strand of a dsRNA. 
     A dsRNA can be synthesized by standard methods known in the art as further discussed below, e.g., by use of an automated DNA synthesizer, such as are commercially available from, for example, Biosearch, Applied Biosystems, Inc. 
     iRNA compounds of the invention may be prepared using a two-step procedure. First, the individual strands of the double stranded RNA molecule are prepared separately. Then, the component strands are annealed. The individual strands of the siRNA compound can be prepared using solution-phase or solid-phase organic synthesis or both. Organic synthesis offers the advantage that the oligonucleotide strands comprising unnatural or modified nucleotides can be easily prepared. Single-stranded oligonucleotides of the invention can be prepared using solution-phase or solid-phase organic synthesis or both. 
     In one aspect, a dsRNA of the invention includes at least two nucleotide sequences, a sense sequence and an anti-sense sequence. The sense strand is selected from the group of sequences provided in any one of Tables 3, 4, 5, 6, 18, 19, 20, 21, and 23, and the corresponding antisense strand of the sense strand is selected from the group of sequences of any one of Tables 3, 4, 5, 6, 18, 19, 20, 21, and 23. In this aspect, one of the two sequences is complementary to the other of the two sequences, with one of the sequences being substantially complementary to a sequence of an mRNA generated in the expression of a C5 gene. As such, in this aspect, a dsRNA will include two oligonucleotides, where one oligonucleotide is described as the sense strand in any one of Tables 3, 4, 5, 6, 18, 19, 20, 21, and 23, and the second oligonucleotide is described as the corresponding antisense strand of the sense strand in any one of Tables 3, 4, 5, 6, 18, 19, 20, 21, and 23. In one embodiment, the substantially complementary sequences of the dsRNA are contained on separate oligonucleotides. In another embodiment, the substantially complementary sequences of the dsRNA are contained on a single oligonucleotide. 
     It will be understood that, although some of the sequences in Tables 3, 4, 5, 6, 18, 19, 20, 21, and 23 are described as modified and/or conjugated sequences, the RNA of the iRNA of the invention e.g., a dsRNA of the invention, may comprise any one of the sequences set forth in Tables 3, 4, 5, 6, 18, 19, 20, 21, and 23 that is un-modified, un-conjugated, and/or modified and/or conjugated differently than described therein. 
     The skilled person is well aware that dsRNAs having a duplex structure of between about 20 and 23 base pairs, e.g., 21, base pairs have been hailed as particularly effective in inducing RNA interference (Elbashir et al.,  EMBO  2001, 20:6877-6888). However, others have found that shorter or longer RNA duplex structures can also be effective (Chu and Rana (2007)  RNA  14:1714-1719; Kim et al. (2005)  Nat Biotech  23:222-226). In the embodiments described above, by virtue of the nature of the oligonucleotide sequences provided in any one of Tables 3, 4, 5, 6, 18, 19, 20, 21, and 23, dsRNAs described herein can include at least one strand of a length of minimally 21 nucleotides. It can be reasonably expected that shorter duplexes having one of the sequences of any one of Tables 3, 4, 5, 6, 18, 19, 20, 21, and 23 minus only a few nucleotides on one or both ends can be similarly effective as compared to the dsRNAs described above. Hence, dsRNAs having a sequence of at least 15, 16, 17, 18, 19, 20, or more contiguous nucleotides derived from one of the sequences of any one of Tables 3, 4, 5, 6, 18, 19, 20, 21, and 23, and differing in their ability to inhibit the expression of a C5 gene by not more than about 5, 10, 15, 20, 25, or 30% inhibition from a dsRNA comprising the full sequence, are contemplated to be within the scope of the present invention. 
     In addition, the RNAs provided in any one of Tables 3, 4, 5, 6, 18, 19, 20, 21, and 23 identify a site(s) in a C5 transcript that is susceptible to RISC-mediated cleavage. As such, the present invention further features iRNAs that target within one of these sites. As used herein, an iRNA is said to target within a particular site of an RNA transcript if the iRNA promotes cleavage of the transcript anywhere within that particular site. Such an iRNA will generally include at least about 15 contiguous nucleotides from one of the sequences provided in any one of Tables 3, 4, 5, 6, 18, 19, 20, 21, and 23 coupled to additional nucleotide sequences taken from the region contiguous to the selected sequence in a C5 gene. 
     While a target sequence is generally about 15-30 nucleotides in length, there is wide variation in the suitability of particular sequences in this range for directing cleavage of any given target RNA. Various software packages and the guidelines set out herein provide guidance for the identification of optimal target sequences for any given gene target, but an empirical approach can also be taken in which a “window” or “mask” of a given size (as a non-limiting example, 21 nucleotides) is literally or figuratively (including, e.g., in silico) placed on the target RNA sequence to identify sequences in the size range that can serve as target sequences. By moving the sequence “window” progressively one nucleotide upstream or downstream of an initial target sequence location, the next potential target sequence can be identified, until the complete set of possible sequences is identified for any given target size selected. This process, coupled with systematic synthesis and testing of the identified sequences (using assays as described herein or as known in the art) to identify those sequences that perform optimally can identify those RNA sequences that, when targeted with an iRNA agent, mediate the best inhibition of target gene expression. Thus, while the sequences identified, for example, in any one of Tables 3, 4, 5, 6, 18, 19, 20, 21, and 23 represent effective target sequences, it is contemplated that further optimization of inhibition efficiency can be achieved by progressively “walking the window” one nucleotide upstream or downstream of the given sequences to identify sequences with equal or better inhibition characteristics. 
     Further, it is contemplated that for any sequence identified, e.g., in any one of Tables 3, 4, 5, 6, 18, 19, 20, 21, and 23, further optimization could be achieved by systematically either adding or removing nucleotides to generate longer or shorter sequences and testing those sequences generated by walking a window of the longer or shorter size up or down the target RNA from that point. Again, coupling this approach to generating new candidate targets with testing for effectiveness of iRNAs based on those target sequences in an inhibition assay as known in the art and/or as described herein can lead to further improvements in the efficiency of inhibition. Further still, such optimized sequences can be adjusted by, e.g., the introduction of modified nucleotides as described herein or as known in the art, addition or changes in overhang, or other modifications as known in the art and/or discussed herein to further optimize the molecule (e.g., increasing serum stability or circulating half-life, increasing thermal stability, enhancing transmembrane delivery, targeting to a particular location or cell type, increasing interaction with silencing pathway enzymes, increasing release from endosomes) as an expression inhibitor. 
     An iRNA as described herein can contain one or more mismatches to the target sequence. In one embodiment, an iRNA as described herein contains no more than 3 mismatches. If the antisense strand of the iRNA contains mismatches to a target sequence, it is preferable that the area of mismatch is not located in the center of the region of complementarity. If the antisense strand of the iRNA contains mismatches to the target sequence, it is preferable that the mismatch be restricted to be within the last 5 nucleotides from either the 5′- or 3′-end of the region of complementarity. For example, for a 23 nucleotide iRNA agent the strand which is complementary to a region of a C5 gene, generally does not contain any mismatch within the central 13 nucleotides. The methods described herein or methods known in the art can be used to determine whether an iRNA containing a mismatch to a target sequence is effective in inhibiting the expression of a C5 gene. Consideration of the efficacy of iRNAs with mismatches in inhibiting expression of a C5 gene is important, especially if the particular region of complementarity in a C5 gene is known to have polymorphic sequence variation within the population. 
     III. Modified iRNAs of the Invention 
     In one embodiment, the RNA of the iRNA of the invention e.g., a dsRNA, is un-modified, and does not comprise, e.g., chemical modifications and/or conjugations known in the art and described herein. In another embodiment, the RNA of an iRNA of the invention, e.g., a dsRNA, is chemically modified to enhance stability or other beneficial characteristics. In certain embodiments of the invention, substantially all of the nucleotides of an iRNA of the invention are modified. In other embodiments of the invention, all of the nucleotides of an iRNA of the invention are modified. iRNAs of the invention in which “substantially all of the nucleotides are modified” are largely but not wholly modified and can include not more than 5, 4, 3, 2, or 1 unmodified nucleotides. 
     The nucleic acids featured in the invention can be synthesized and/or modified by methods well established in the art, such as those described in “Current protocols in nucleic acid chemistry,” Beaucage, S. L. et al. (Edrs.), John Wiley &amp; Sons, Inc., New York, N.Y., USA, which is hereby incorporated herein by reference. Modifications include, for example, end modifications, e.g., 5′-end modifications (phosphorylation, conjugation, inverted linkages) or 3′-end modifications (conjugation, DNA nucleotides, inverted linkages, etc.); base modifications, e.g., replacement with stabilizing bases, destabilizing bases, or bases that base pair with an expanded repertoire of partners, removal of bases (abasic nucleotides), or conjugated bases; sugar modifications (e.g., at the 2′-position or 4′-position) or replacement of the sugar; and/or backbone modifications, including modification or replacement of the phosphodiester linkages. Specific examples of iRNA compounds useful in the embodiments described herein include, but are not limited to RNAs containing modified backbones or no natural internucleoside linkages. RNAs having modified backbones include, among others, those that do not have a phosphorus atom in the backbone. For the purposes of this specification, and as sometimes referenced in the art, modified RNAs that do not have a phosphorus atom in their internucleoside backbone can also be considered to be oligonucleosides. In some embodiments, a modified iRNA will have a phosphorus atom in its internucleoside backbone. 
     Modified RNA backbones include, for example, phosphorothioates, chiral phosphorothioates, phosphorodithioates, phosphotriesters, aminoalkylphosphotriesters, methyl and other alkyl phosphonates including 3′-alkylene phosphonates and chiral phosphonates, phosphinates, phosphoramidates including 3′-amino phosphoramidate and aminoalkylphosphoramidates, thionophosphoramidates, thionoalkylphosphonates, thionoalkylphosphotriesters, and boranophosphates having normal 3′-5′ linkages, 2′-5′-linked analogs of these, and those having inverted polarity wherein the adjacent pairs of nucleoside units are linked 3′-5′ to 5′-3′ or 2′-5′ to 5′-2′. Various salts, mixed salts and free acid forms are also included. 
     Representative U.S. patents that teach the preparation of the above phosphorus-containing linkages include, but are not limited to, U.S. Pat. Nos. 3,687,808; 4,469,863; 4,476,301; 5,023,243; 5,177,195; 5,188,897; 5,264,423; 5,276,019; 5,278,302; 5,286,717; 5,321,131; 5,399,676; 5,405,939; 5,453,496; 5,455,233; 5,466,677; 5,476,925; 5,519,126; 5,536,821; 5,541,316; 5,550,111; 5,563,253; 5,571,799; 5,587,361; 5,625,050; 6,028,188; 6,124,445; 6,160,109; 6,169,170; 6,172,209; 6,239,265; 6,277,603; 6,326,199; 6,346,614; 6,444,423; 6,531,590; 6,534,639; 6,608,035; 6,683,167; 6,858,715; 6,867,294; 6,878,805; 7,015,315; 7,041,816; 7,273,933; 7,321,029; and U.S. Pat. RE39464, the entire contents of each of which are hereby incorporated herein by reference. 
     Modified RNA backbones that do not include a phosphorus atom therein have backbones that are formed by short chain alkyl or cycloalkyl internucleoside linkages, mixed heteroatoms and alkyl or cycloalkyl internucleoside linkages, or one or more short chain heteroatomic or heterocyclic internucleoside linkages. These include those having morpholino linkages (formed in part from the sugar portion of a nucleoside); siloxane backbones; sulfide, sulfoxide and sulfone backbones; formacetyl and thioformacetyl backbones; methylene formacetyl and thioformacetyl backbones; alkene containing backbones; sulfamate backbones; methyleneimino and methylenehydrazino backbones; sulfonate and sulfonamide backbones; amide backbones; and others having mixed N, O, S and CH 2  component parts. 
     Representative U.S. patents that teach the preparation of the above oligonucleosides include, but are not limited to, U.S. Pat. Nos. 5,034,506; 5,166,315; 5,185,444; 5,214,134; 5,216,141; 5,235,033; 5,64,562; 5,264,564; 5,405,938; 5,434,257; 5,466,677; 5,470,967; 5,489,677; 5,541,307; 5,561,225; 5,596,086; 5,602,240; 5,608,046; 5,610,289; 5,618,704; 5,623,070; 5,663,312; 5,633,360; 5,677,437; and, 5,677,439, the entire contents of each of which are hereby incorporated herein by reference. 
     In other embodiments, suitable RNA mimetics are contemplated for use in iRNAs, in which both the sugar and the internucleoside linkage, i.e., the backbone, of the nucleotide units are replaced with novel groups. The base units are maintained for hybridization with an appropriate nucleic acid target compound. One such oligomeric compound, an RNA mimetic that has been shown to have excellent hybridization properties, is referred to as a peptide nucleic acid (PNA). In PNA compounds, the sugar backbone of an RNA is replaced with an amide containing backbone, in particular an aminoethylglycine backbone. The nucleobases are retained and are bound directly or indirectly to aza nitrogen atoms of the amide portion of the backbone. Representative U.S. patents that teach the preparation of PNA compounds include, but are not limited to, U.S. Pat. Nos. 5,539,082; 5,714,331; and 5,719,262, the entire contents of each of which are hereby incorporated herein by reference. Additional PNA compounds suitable for use in the iRNAs of the invention are described in, for example, in Nielsen et al.,  Science,  1991, 254, 1497-1500. 
     Some embodiments featured in the invention include RNAs with phosphorothioate backbones and oligonucleosides with heteroatom backbones, and in particular —CH 2 —NH—CH 2 —, —CH 2 —N(CH 3 )—O—CH 2 —[known as a methylene (methylimino) or MMI backbone], —CH 2 —O—N(CH 3 )—CH 2 —, —CH 2 —N(CH 3 )—N(CH 3 )—CH 2 — and —N(CH 3 )—CH 2 —CH 2 —[wherein the native phosphodiester backbone is represented as —O—P—O—CH 2 —] of the above-referenced U.S. Pat. No. 5,489,677, and the amide backbones of the above-referenced U.S. Pat. No. 5,602,240. In some embodiments, the RNAs featured herein have morpholino backbone structures of the above-referenced U.S. Pat. No. 5,034,506. 
     Modified RNAs can also contain one or more substituted sugar moieties. The iRNAs, e.g., dsRNAs, featured herein can include one of the following at the 2′-position: OH; F; O-, S-, or N-alkyl; O-, S-, or N-alkenyl; O-, S- or N-alkynyl; or O-alkyl-O-alkyl, wherein the alkyl, alkenyl and alkynyl can be substituted or unsubstituted C 1  to C 10  alkyl or C 2  to C 10  alkenyl and alkynyl. Exemplary suitable modifications include O[(CH 2 ) n O] m CH 3 , O(CH 2 ). n OCH 3 , O(CH 2 ) n NH 2 , O(CH 2 ) n CH 3 , O(CH 2 ) n ONH 2 , and O(CH 2 ) n ON[(CH 2 ) n CH 3 )] 2 , where n and m are from 1 to about 10. In other embodiments, dsRNAs include one of the following at the 2′ position: C 1  to C 10  lower alkyl, substituted lower alkyl, alkaryl, aralkyl, O-alkaryl or O-aralkyl, SH, SCH 3 , OCN, Cl, Br, CN, CF 3 , OCF 3 , SOCH 3 , SO 2 CH 3 , ONO 2 , NO 2 , N 3 , NH 2 , heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, polyalkylamino, substituted silyl, an RNA cleaving group, a reporter group, an intercalator, a group for improving the pharmacokinetic properties of an iRNA, or a group for improving the pharmacodynamic properties of an iRNA, and other substituents having similar properties. In some embodiments, the modification includes a 2′-methoxyethoxy (2′-O—CH 2 CH 2 OCH 3 , also known as 2′-O-(2-methoxyethyl) or 2′-MOE) (Martin et al.,  Helv. Chim. Acta,  1995, 78:486-504) i.e., an alkoxy-alkoxy group. Another exemplary modification is 2′-dimethylaminooxyethoxy, i.e., a O(CH 2 ) 2 ON(CH 3 ) 2  group, also known as 2′-DMAOE, as described in examples herein below, and 2′-dimethylaminoethoxyethoxy (also known in the art as 2′-O-dimethylaminoethoxyethyl or 2′-DMAEOE), i.e., 2′-O—CH 2 —O—CH 2 —N(CH 2 ) 2 . 
     Other modifications include 2′-methoxy (2′-OCH 3 ), 2′-aminopropoxy (2′-OCH 2 CH 2 CH 2 NH 2 ) and 2′-fluoro (2′-F). Similar modifications can also be made at other positions on the RNA of an iRNA, particularly the 3′ position of the sugar on the 3′ terminal nucleotide or in 2′-5′ linked dsRNAs and the 5′ position of 5′ terminal nucleotide. iRNAs can also have sugar mimetics such as cyclobutyl moieties in place of the pentofuranosyl sugar. Representative U.S. patents that teach the preparation of such modified sugar structures include, but are not limited to, U.S. Pat. Nos. 4,981,957; 5,118,800; 5,319,080; 5,359,044; 5,393,878; 5,446,137; 5,466,786; 5,514,785; 5,519,134; 5,567,811; 5,576,427; 5,591,722; 5,597,909; 5,610,300; 5,627,053; 5,639,873; 5,646,265; 5,658,873; 5,670,633; and 5,700,920, certain of which are commonly owned with the instant application. The entire contents of each of the foregoing are hereby incorporated herein by reference. 
     An iRNA can also include nucleobase (often referred to in the art simply as “base”) modifications or substitutions. As used herein, “unmodified” or “natural” nucleobases include the purine bases adenine (A) and guanine (G), and the pyrimidine bases thymine (T), cytosine (C) and uracil (U). Modified nucleobases include other synthetic and natural nucleobases such as deoxy-thymine (dT). 5-methylcytosine (5-me-C), 5-hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-halouracil and cytosine, 5-propynyl uracil and cytosine, 6-azo uracil, cytosine and thymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl anal other 8-substituted adenines and guanines, 5-halo, particularly 5-bromo, 5-trifluoromethyl and other 5-substituted uracils and cytosines, 7-methylguanine and 7-methyladenine, 8-azaguanine and 8-azaadenine, 7-deazaguanine and 7-daazaadenine and 3-deazaguanine and 3-deazaadenine. Further nucleobases include those disclosed in U.S. Pat. No. 3,687,808, those disclosed in Modified Nucleosides in Biochemistry, Biotechnology and Medicine, Herdewijn, P. ed. Wiley-VCH, 2008; those disclosed in The Concise Encyclopedia Of Polymer Science And Engineering, pages 858-859, Kroschwitz, J. L, ed. John Wiley &amp; Sons, 1990, these disclosed by Englisch et al., Angewandte Chemie, International Edition, 1991, 30, 613, and those disclosed by Sanghvi, Y S., Chapter 15, dsRNA Research and Applications, pages 289-302, Crooke, S. T. and Lebleu, B., Ed., CRC Press, 1993. Certain of these nucleobases are particularly useful for increasing the binding affinity of the oligomeric compounds featured in the invention. These include 5-substituted pyrimidines, 6-azapyrimidines and N-2, N-6 and 0-6 substituted purines, including 2-aminopropyladenine, 5-propynyluracil and 5-propynylcytosine. 5-methylcytosine substitutions have been shown to increase nucleic acid duplex stability by 0.6-1.2° C. (Sanghvi, Y. S., Crooke, S. T. and Lebleu, B., Eds., dsRNA Research and Applications, CRC Press, Boca Raton, 1993, pp. 276-278) and are exemplary base substitutions, even more particularly when combined with 2′-O-methoxyethyl sugar modifications. 
     Representative U.S. patents that teach the preparation of certain of the above noted modified nucleobases as well as other modified nucleobases include, but are not limited to, the above noted U.S. Pat. Nos. 3,687,808, 4,845,205; 5,130,30; 5,134,066; 5,175,273; 5,367,066; 5,432,272; 5,457,187; 5,459,255; 5,484,908; 5,502,177; 5,525,711; 5,552,540; 5,587,469; 5,594,121, 5,596,091; 5,614,617; 5,681,941; 5,750,692; 6,015,886; 6,147,200; 6,166,197; 6,222,025; 6,235,887; 6,380,368; 6,528,640; 6,639,062; 6,617,438; 7,045,610; 7,427,672; and 7,495,088, the entire contents of each of which are hereby incorporated herein by reference. 
     The RNA of an iRNA can also be modified to include one or more bicyclic sugar moities. A “bicyclic sugar” is a furanosyl ring modified by the bridging of two atoms. A “bicyclic nucleoside” (“BNA”) is a nucleoside having a sugar moiety comprising a bridge connecting two carbon atoms of the sugar ring, thereby forming a bicyclic ring system. In certain embodiments, the bridge connects the 4′-carbon and the 2′-carbon of the sugar ring. Thus, in some embodiments an agent of the invention may include the RNA of an iRNA can also be modified to include one or more locked nucleic acids (LNA). A locked nucleic acid is a nucleotide having a modified ribose moiety in which the ribose moiety comprises an extra bridge connecting the 2′ and 4′ carbons. In other words, an LNA is a nucleotide comprising a bicyclic sugar moiety comprising a 4′-CH 2 —O-2′ bridge. This structure effectively “locks” the ribose in the 3′-endo structural conformation. The addition of locked nucleic acids to siRNAs has been shown to increase siRNA stability in serum, and to reduce off-target effects (Elmen, J. et al., (2005)  Nucleic Acids Research  33(1):439-447; Mook, O R. et al., (2007)  Mol Canc Ther  6(3):833-843; Grunweller, A. et al., (2003)  Nucleic Acids Research  31(12):3185-3193). 
     Examples of bicyclic nucleosides for use in the polynucleotides of the invention include without limitation nucleosides comprising a bridge between the 4′ and the 2′ ribosyl ring atoms. In certain embodiments, the antisense polynucleotide agents of the invention include one or more bicyclic nucleosides comprising a 4′ to 2′ bridge. Examples of such 4′ to 2′ bridged bicyclic nucleosides, include but are not limited to 4′-(CH2)-O-2′ (LNA); 4′-(CH2)-S-2; 4′-(CH2)2-O-2′ (ENA); 4′-CH(CH3)-O-2′ (also referred to as “constrained ethyl” or “cEt”) and 4′-CH(CH2OCH3)-O-2′ (and analogs thereof; see, e.g., U.S. Pat. No. 7,399,845); 4′-C(CH3)(CH3)-O-2′ (and analogs thereof; see e.g., U.S. Pat. No. 8,278,283); 4′-CH2-N(OCH3)-2′ (and analogs thereof; see e.g., U.S. Pat. No. 8,278,425); 4′-CH2-C—O—N(CH3)-2′ (see, e.g., U.S. Patent Publication No. 2004/0171570); 4′-CH2-N(R)—O-2′, wherein R is H, C1-C12 alkyl, or a protecting group (see, e.g., U.S. Pat. No. 7,427,672); 4′-CH2-C(H)(CH3)-2′ (see, e.g., Chattopadhyaya et al.,  J. Org. Chem.,  2009, 74, 118-134); and 4′-CH2-C(═CH2)-2′ (and analogs thereof; see, e.g., U.S. Pat. No. 8,278,426). The entire contents of each of the foregoing are hereby incorporated herein by reference. 
     Additional representative U.S. patents and US Patent Publications that teach the preparation of locked nucleic acid nucleotides include, but are not limited to, the following: U.S. Pat. Nos. 6,268,490; 6,525,191; 6,670,461; 6,770,748; 6,794,499; 6,998,484; 7,053,207; 7,034,133; 7,084,125; 7,399,845; 7,427,672; 7,569,686; 7,741,457; 8,022,193; 8,030,467; 8,278,425; 8,278,426; 8,278,283; US 2008/0039618; and US 2009/0012281, the entire contents of each of which are hereby incorporated herein by reference. 
     Any of the foregoing bicyclic nucleosides can be prepared having one or more stereochemical sugar configurations including for example α-L-ribofuranose and β-D-ribofuranose (see WO 99/14226). 
     The RNA of an iRNA can also be modified to include one or more constrained ethyl nucleotides. As used herein, a “constrained ethyl nucleotide” or “cEt” is a locked nucleic acid comprising a bicyclic sugar moiety comprising a 4′-CH(CH3)-O-2′ bridge. In one embodiment, a constrained ethyl nucleotide is in the S conformation referred to herein as “S-cEt.” 
     An iRNA of the invention may also include one or more “conformationally restricted nucleotides” (“CRN”). CRN are nucleotide analogs with a linker connecting the C2′ and C4′ carbons of ribose or the C3 and —C5′ carbons of ribose. CRN lock the ribose ring into a stable conformation and increase the hybridization affinity to mRNA. The linker is of sufficient length to place the oxygen in an optimal position for stability and affinity resulting in less ribose ring puckering. 
     Representative publications that teach the preparation of certain of the above noted CRN include, but are not limited to, US Patent Publication No. 2013/0190383; and PCT publication WO 2013/036868, the entire contents of each of which are hereby incorporated herein by reference. 
     One or more of the nucleotides of an iRNA of the invention may also include a hydroxymethyl substituted nucleotide. A “hydroxymethyl substituted nucleotide” is an acyclic 2′-3′-seco-nucleotide, also referred to as an “unlocked nucleic acid” (“UNA”) modification 
     Representative U.S. publications that teach the preparation of UNA include, but are not limited to, U.S. Pat. No. 8,314,227; and US Patent Publication Nos. 2013/0096289; 2013/0011922; and 2011/0313020, the entire contents of each of which are hereby incorporated herein by reference. 
     Potentially stabilizing modifications to the ends of RNA molecules can include N-(acetylaminocaproyl)-4-hydroxyprolinol (Hyp-C6-NHAc), N-(caproyl-4-hydroxyprolinol (Hyp-C6), N-(acetyl-4-hydroxyprolinol (Hyp-NHAc), thymidine-2′-O-deoxythymidine (ether), N-(aminocaproyl)-4-hydroxyprolinol (Hyp-C6-amino), 2-docosanoyl-uridine-3″-phosphate, inverted base dT(idT) and others. Disclosure of this modification can be found in PCT Publication No. WO 2011/005861. 
     A. Modified iRNAs Comprising Motifs of the Invention 
     In certain aspects of the invention, the double stranded RNAi agents of the invention include agents with chemical modifications as disclosed, for example, in U.S. Provisional Application No. 61/561,710, filed on Nov. 18, 2011, or in PCT/US2012/065691, filed on Nov. 16, 2012, the entire contents of each of which are incorporated herein by reference. 
     As shown herein and in Provisional Application No. 61/561,710 or PCT Application No. PCT/US2012/065691, a superior result may be obtained by introducing one or more motifs of three identical modifications on three consecutive nucleotides into a sense strand and/or antisense strand of an RNAi agent, particularly at or near the cleavage site. In some embodiments, the sense strand and antisense strand of the RNAi agent may otherwise be completely modified. The introduction of these motifs interrupts the modification pattern, if present, of the sense and/or antisense strand. The RNAi agent may be optionally conjugated with a GalNAc derivative ligand, for instance on the sense strand. The resulting RNAi agents present superior gene silencing activity. 
     More specifically, it has been surprisingly discovered that when the sense strand and antisense strand of the double stranded RNAi agent are completely modified to have one or more motifs of three identical modifications on three consecutive nucleotides at or near the cleavage site of at least one strand of an RNAi agent, the gene silencing activity of the RNAi agent was superiorly enhanced. 
     Accordingly, the invention provides double stranded RNAi agents capable of inhibiting the expression of a target gene (i.e., a complement component C5 (C5) gene) in vivo. The RNAi agent comprises a sense strand and an antisense strand. Each strand of the RNAi agent may range from 12-30 nucleotides in length. For example, each strand may be between 14-30 nucleotides in length, 17-30 nucleotides in length, 25-30 nucleotides in length, 27-30 nucleotides in length, 17-23 nucleotides in length, 17-21 nucleotides in length, 17-19 nucleotides in length, 19-25 nucleotides in length, 19-23 nucleotides in length, 19-21 nucleotides in length, 21-25 nucleotides in length, or 21-23 nucleotides in length. 
     The sense strand and antisense strand typically form a duplex double stranded RNA (“dsRNA”), also referred to herein as an “RNAi agent.” The duplex region of an RNAi agent may be 12-30 nucleotide pairs in length. For example, the duplex region can be between 14-30 nucleotide pairs in length, 17-30 nucleotide pairs in length, 27-30 nucleotide pairs in length, 17-23 nucleotide pairs in length, 17-21 nucleotide pairs in length, 17-19 nucleotide pairs in length, 19-25 nucleotide pairs in length, 19-23 nucleotide pairs in length, 19-21 nucleotide pairs in length, 21-25 nucleotide pairs in length, or 21-23 nucleotide pairs in length. In another example, the duplex region is selected from 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, and 27 nucleotides in length. 
     In one embodiment, the RNAi agent may contain one or more overhang regions and/or capping groups at the 3′-end, 5′-end, or both ends of one or both strands. The overhang can be 1-6 nucleotides in length, for instance 2-6 nucleotides in length, 1-5 nucleotides in length, 2-5 nucleotides in length, 1-4 nucleotides in length, 2-4 nucleotides in length, 1-3 nucleotides in length, 2-3 nucleotides in length, or 1-2 nucleotides in length. The overhangs can be the result of one strand being longer than the other, or the result of two strands of the same length being staggered. The overhang can form a mismatch with the target mRNA or it can be complementary to the gene sequences being targeted or can be another sequence. The first and second strands can also be joined, e.g., by additional bases to form a hairpin, or by other non-base linkers. 
     In one embodiment, the nucleotides in the overhang region of the RNAi agent can each independently be a modified or unmodified nucleotide including, but no limited to 2′-sugar modified, such as, 2-F, 2′-Omethyl, thymidine (T), 2′-O-methoxyethyl-5-methyluridine (Teo), 2′-O-methoxyethyladenosine (Aeo), —O-methoxyethyl-5-methylcytidine (m5Ceo), and any combinations thereof. For example, TT can be an overhang sequence for either end on either strand. The overhang can form a mismatch with the target mRNA or it can be complementary to the gene sequences being targeted or can be another sequence. 
     The 5′- or 3′-overhangs at the sense strand, antisense strand or both strands of the RNAi agent may be phosphorylated. In some embodiments, the overhang region(s) contains two nucleotides having a phosphorothioate between the two nucleotides, where the two nucleotides can be the same or different. In one embodiment, the overhang is present at the 3′-end of the sense strand, antisense strand, or both strands. In one embodiment, this 3′-overhang is present in the antisense strand. In one embodiment, this 3′-overhang is present in the sense strand. 
     The RNAi agent may contain only a single overhang, which can strengthen the interference activity of the RNAi, without affecting its overall stability. For example, the single-stranded overhang may be located at the 3′-terminal end of the sense strand or, alternatively, at the 3′-terminal end of the antisense strand. The RNAi may also have a blunt end, located at the 5′-end of the antisense strand (or the 3′-end of the sense strand) or vice versa. Generally, the antisense strand of the RNAi has a nucleotide overhang at the 3′-end, and the 5′-end is blunt. While not wishing to be bound by theory, the asymmetric blunt end at the 5′-end of the antisense strand and 3′-end overhang of the antisense strand favor the guide strand loading into RISC process. 
     In one embodiment, the RNAi agent is a double ended bluntmer of 19 nucleotides in length, wherein the sense strand contains at least one motif of three 2′-F modifications on three consecutive nucleotides at positions 7, 8, 9 from the 5′end. The antisense strand contains at least one motif of three 2′-O-methyl modifications on three consecutive nucleotides at positions 11, 12, 13 from the 5′ end. 
     In another embodiment, the RNAi agent is a double ended bluntmer of 20 nucleotides in length, wherein the sense strand contains at least one motif of three 2′-F modifications on three consecutive nucleotides at positions 8, 9, 10 from the 5′end. The antisense strand contains at least one motif of three 2′-O-methyl modifications on three consecutive nucleotides at positions 11, 12, 13 from the 5′ end. 
     In yet another embodiment, the RNAi agent is a double ended bluntmer of 21 nucleotides in length, wherein the sense strand contains at least one motif of three 2′-F modifications on three consecutive nucleotides at positions 9, 10, 11 from the 5′end. The antisense strand contains at least one motif of three 2′-O-methyl modifications on three consecutive nucleotides at positions 11, 12, 13 from the 5′ end. 
     In one embodiment, the RNAi agent comprises a 21 nucleotide sense strand and a 23 nucleotide antisense strand, wherein the sense strand contains at least one motif of three 2′-F modifications on three consecutive nucleotides at positions 9, 10, 11 from the 5′end; the antisense strand contains at least one motif of three 2′-O-methyl modifications on three consecutive nucleotides at positions 11, 12, 13 from the 5′end, wherein one end of the RNAi agent is blunt, while the other end comprises a 2 nucleotide overhang. Preferably, the 2 nucleotide overhang is at the 3′-end of the antisense strand. When the 2 nucleotide overhang is at the 3′-end of the antisense strand, there may be two phosphorothioate internucleotide linkages between the terminal three nucleotides, wherein two of the three nucleotides are the overhang nucleotides, and the third nucleotide is a paired nucleotide next to the overhang nucleotide. In one embodiment, the RNAi agent additionally has two phosphorothioate internucleotide linkages between the terminal three nucleotides at both the 5′-end of the sense strand and at the 5′-end of the antisense strand. In one embodiment, every nucleotide in the sense strand and the antisense strand of the RNAi agent, including the nucleotides that are part of the motifs are modified nucleotides. In one embodiment each residue is independently modified with a 2′-O-methyl or 3′-fluoro, e.g., in an alternating motif. Optionally, the RNAi agent further comprises a ligand (preferably GalNAc3). 
     In one embodiment, the RNAi agent comprises a sense and an antisense strand, wherein the sense strand is 25-30 nucleotide residues in length, wherein starting from the 5′ terminal nucleotide (position 1) positions 1 to 23 of the first strand comprise at least 8 ribonucleotides; the antisense strand is 36-66 nucleotide residues in length and, starting from the 3′ terminal nucleotide, comprises at least 8 ribonucleotides in the positions paired with positions 1-23 of sense strand to form a duplex; wherein at least the 3 ‘ terminal nucleotide of antisense strand is unpaired with sense strand, and up to 6 consecutive 3’ terminal nucleotides are unpaired with sense strand, thereby forming a 3′ single stranded overhang of 1-6 nucleotides; wherein the 5′ terminus of antisense strand comprises from 10-30 consecutive nucleotides which are unpaired with sense strand, thereby forming a 10-30 nucleotide single stranded 5′ overhang; wherein at least the sense strand 5′ terminal and 3′ terminal nucleotides are base paired with nucleotides of antisense strand when sense and antisense strands are aligned for maximum complementarity, thereby forming a substantially duplexed region between sense and antisense strands; and antisense strand is sufficiently complementary to a target RNA along at least 19 ribonucleotides of antisense strand length to reduce target gene expression when the double stranded nucleic acid is introduced into a mammalian cell; and wherein the sense strand contains at least one motif of three 2′-F modifications on three consecutive nucleotides, where at least one of the motifs occurs at or near the cleavage site. The antisense strand contains at least one motif of three 2′-O-methyl modifications on three consecutive nucleotides at or near the cleavage site. 
     In one embodiment, the RNAi agent comprises sense and antisense strands, wherein the RNAi agent comprises a first strand having a length which is at least 25 and at most 29 nucleotides and a second strand having a length which is at most 30 nucleotides with at least one motif of three 2′-O-methyl modifications on three consecutive nucleotides at position 11, 12, 13 from the 5′ end; wherein the 3′ end of the first strand and the 5′ end of the second strand form a blunt end and the second strand is 1-4 nucleotides longer at its 3′ end than the first strand, wherein the duplex region which is at least 25 nucleotides in length, and the second strand is sufficiently complementary to a target mRNA along at least 19 nucleotide of the second strand length to reduce target gene expression when the RNAi agent is introduced into a mammalian cell, and wherein dicer cleavage of the RNAi agent preferentially results in an siRNA comprising the 3′ end of the second strand, thereby reducing expression of the target gene in the mammal. Optionally, the RNAi agent further comprises a ligand. 
     In one embodiment, the sense strand of the RNAi agent contains at least one motif of three identical modifications on three consecutive nucleotides, where one of the motifs occurs at the cleavage site in the sense strand. 
     In one embodiment, the antisense strand of the RNAi agent can also contain at least one motif of three identical modifications on three consecutive nucleotides, where one of the motifs occurs at or near the cleavage site in the antisense strand 
     For an RNAi agent having a duplex region of 17-23 nucleotide in length, the cleavage site of the antisense strand is typically around the 10, 11 and 12 positions from the 5′-end. Thus the motifs of three identical modifications may occur at the 9, 10, 11 positions; 10, 11, 12 positions; 11, 12, 13 positions; 12, 13, 14 positions; or 13, 14, 15 positions of the antisense strand, the count starting from the 1 st  nucleotide from the 5′-end of the antisense strand, or, the count starting from the 1 st  paired nucleotide within the duplex region from the 5′-end of the antisense strand. The cleavage site in the antisense strand may also change according to the length of the duplex region of the RNAi from the 5′-end. 
     The sense strand of the RNAi agent may contain at least one motif of three identical modifications on three consecutive nucleotides at the cleavage site of the strand; and the antisense strand may have at least one motif of three identical modifications on three consecutive nucleotides at or near the cleavage site of the strand. When the sense strand and the antisense strand form a dsRNA duplex, the sense strand and the antisense strand can be so aligned that one motif of the three nucleotides on the sense strand and one motif of the three nucleotides on the antisense strand have at least one nucleotide overlap, i.e., at least one of the three nucleotides of the motif in the sense strand forms a base pair with at least one of the three nucleotides of the motif in the antisense strand. Alternatively, at least two nucleotides may overlap, or all three nucleotides may overlap. 
     In one embodiment, the sense strand of the RNAi agent may contain more than one motif of three identical modifications on three consecutive nucleotides. The first motif may occur at or near the cleavage site of the strand and the other motifs may be a wing modification. The term “wing modification” herein refers to a motif occurring at another portion of the strand that is separated from the motif at or near the cleavage site of the same strand. The wing modification is either adjacent to the first motif or is separated by at least one or more nucleotides. When the motifs are immediately adjacent to each other then the chemistry of the motifs are distinct from each other and when the motifs are separated by one or more nucleotide than the chemistries can be the same or different. Two or more wing modifications may be present. For instance, when two wing modifications are present, each wing modification may occur at one end relative to the first motif which is at or near cleavage site or on either side of the lead motif. 
     Like the sense strand, the antisense strand of the RNAi agent may contain more than one motifs of three identical modifications on three consecutive nucleotides, with at least one of the motifs occurring at or near the cleavage site of the strand. This antisense strand may also contain one or more wing modifications in an alignment similar to the wing modifications that may be present on the sense strand. 
     In one embodiment, the wing modification on the sense strand or antisense strand of the RNAi agent typically does not include the first one or two terminal nucleotides at the 3′-end, 5′-end or both ends of the strand. 
     In another embodiment, the wing modification on the sense strand or antisense strand of the RNAi agent typically does not include the first one or two paired nucleotides within the duplex region at the 3′-end, 5′-end or both ends of the strand. 
     When the sense strand and the antisense strand of the RNAi agent each contain at least one wing modification, the wing modifications may fall on the same end of the duplex region, and have an overlap of one, two or three nucleotides. 
     When the sense strand and the antisense strand of the RNAi agent each contain at least two wing modifications, the sense strand and the antisense strand can be so aligned that two modifications each from one strand fall on one end of the duplex region, having an overlap of one, two or three nucleotides; two modifications each from one strand fall on the other end of the duplex region, having an overlap of one, two or three nucleotides; two modifications one strand fall on each side of the lead motif, having an overlap of one, two or three nucleotides in the duplex region. 
     In one embodiment, every nucleotide in the sense strand and antisense strand of the RNAi agent, including the nucleotides that are part of the motifs, may be modified. Each nucleotide may be modified with the same or different modification which can include one or more alteration of one or both of the non-linking phosphate oxygens and/or of one or more of the linking phosphate oxygens; alteration of a constituent of the ribose sugar, e.g., of the 2′ hydroxyl on the ribose sugar; wholesale replacement of the phosphate moiety with “dephospho” linkers; modification or replacement of a naturally occurring base; and replacement or modification of the ribose-phosphate backbone. 
     As nucleic acids are polymers of subunits, many of the modifications occur at a position which is repeated within a nucleic acid, e.g., a modification of a base, or a phosphate moiety, or a non-linking 0 of a phosphate moiety. In some cases the modification will occur at all of the subject positions in the nucleic acid but in many cases it will not. By way of example, a modification may only occur at a 3′ or 5′ terminal position, may only occur in a terminal region, e.g., at a position on a terminal nucleotide or in the last 2, 3, 4, 5, or 10 nucleotides of a strand. A modification may occur in a double strand region, a single strand region, or in both. A modification may occur only in the double strand region of a RNA or may only occur in a single strand region of a RNA. For example, a phosphorothioate modification at a non-linking 0 position may only occur at one or both termini, may only occur in a terminal region, e.g., at a position on a terminal nucleotide or in the last 2, 3, 4, 5, or 10 nucleotides of a strand, or may occur in double strand and single strand regions, particularly at termini. The 5′ end or ends can be phosphorylated. 
     It may be possible, e.g., to enhance stability, to include particular bases in overhangs, or to include modified nucleotides or nucleotide surrogates, in single strand overhangs, e.g., in a 5′ or 3′ overhang, or in both. For example, it can be desirable to include purine nucleotides in overhangs. In some embodiments all or some of the bases in a 3′ or 5′ overhang may be modified, e.g., with a modification described herein. Modifications can include, e.g., the use of modifications at the 2′ position of the ribose sugar with modifications that are known in the art, e.g., the use of deoxyribonucleotides, 2′-deoxy-2′-fluoro (2′-F) or 2′-O-methyl modified instead of the ribosugar of the nucleobase, and modifications in the phosphate group, e.g., phosphorothioate modifications. Overhangs need not be homologous with the target sequence. 
     In one embodiment, each residue of the sense strand and antisense strand is independently modified with LNA, HNA, CeNA, 2′-methoxyethyl, 2′-O-methyl, 2′-O-allyl, 2′—C-allyl, 2′-deoxy, 2′-hydroxyl, or 2′-fluoro. The strands can contain more than one modification. In one embodiment, each residue of the sense strand and antisense strand is independently modified with 2′-O-methyl or 2′-fluoro. 
     At least two different modifications are typically present on the sense strand and antisense strand. Those two modifications may be the 2′-O-methyl or 2′-fluoro modifications, or others. 
     In one embodiment, the N a  and/or N b  comprise modifications of an alternating pattern. The term “alternating motif” as used herein refers to a motif having one or more modifications, each modification occurring on alternating nucleotides of one strand. The alternating nucleotide may refer to one per every other nucleotide or one per every three nucleotides, or a similar pattern. For example, if A, B and C each represent one type of modification to the nucleotide, the alternating motif can be “ABABABABABAB . . . ,” “AABBAABBAABB . . . ,” “AABAABAABAAB . . . ,” “AAABAAABAAAB . . . ,” “AAABBBAAABBB . . . ,” or “ABCABCABCABC . . . ,” etc. 
     The type of modifications contained in the alternating motif may be the same or different. For example, if A, B, C, D each represent one type of modification on the nucleotide, the alternating pattern, i.e., modifications on every other nucleotide, may be the same, but each of the sense strand or antisense strand can be selected from several possibilities of modifications within the alternating motif such as “ABABAB . . . ”, “ACACAC . . . ” “BDBDBD . . . ” or “CDCDCD . . . ,” etc. 
     In one embodiment, the RNAi agent of the invention comprises the modification pattern for the alternating motif on the sense strand relative to the modification pattern for the alternating motif on the antisense strand is shifted. The shift may be such that the modified group of nucleotides of the sense strand corresponds to a differently modified group of nucleotides of the antisense strand and vice versa. For example, the sense strand when paired with the antisense strand in the dsRNA duplex, the alternating motif in the sense strand may start with “ABABAB” from 5′-3′ of the strand and the alternating motif in the antisense strand may start with “BABABA” from 5′-3′ of the strand within the duplex region. As another example, the alternating motif in the sense strand may start with “AABBAABB” from 5′-3′ of the strand and the alternating motif in the antisense strand may start with “BBAABBAA” from 5′-3′ of the strand within the duplex region, so that there is a complete or partial shift of the modification patterns between the sense strand and the antisense strand. 
     In one embodiment, the RNAi agent comprises the pattern of the alternating motif of 2′-O-methyl modification and 2′-F modification on the sense strand initially has a shift relative to the pattern of the alternating motif of 2′-O-methyl modification and 2′-F modification on the antisense strand initially, i.e., the 2′-O-methyl modified nucleotide on the sense strand base pairs with a 2′-F modified nucleotide on the antisense strand and vice versa. The 1 position of the sense strand may start with the 2′-F modification, and the 1 position of the antisense strand may start with the 2′-O-methyl modification. 
     The introduction of one or more motifs of three identical modifications on three consecutive nucleotides to the sense strand and/or antisense strand interrupts the initial modification pattern present in the sense strand and/or antisense strand. This interruption of the modification pattern of the sense and/or antisense strand by introducing one or more motifs of three identical modifications on three consecutive nucleotides to the sense and/or antisense strand surprisingly enhances the gene silencing activity to the target gene. 
     In one embodiment, when the motif of three identical modifications on three consecutive nucleotides is introduced to any of the strands, the modification of the nucleotide next to the motif is a different modification than the modification of the motif. For example, the portion of the sequence containing the motif is “ . . . N a YYYN b  . . . ,” where “Y” represents the modification of the motif of three identical modifications on three consecutive nucleotide, and “N a ” and “N b ” represent a modification to the nucleotide next to the motif “YYY” that is different than the modification of Y, and where N a  and N b  can be the same or different modifications. Alternatively, N a  and/or N b  may be present or absent when there is a wing modification present. 
     The RNAi agent may further comprise at least one phosphorothioate or methylphosphonate internucleotide linkage. The phosphorothioate or methylphosphonate internucleotide linkage modification may occur on any nucleotide of the sense strand or antisense strand or both strands in any position of the strand. For instance, the internucleotide linkage modification may occur on every nucleotide on the sense strand and/or antisense strand; each internucleotide linkage modification may occur in an alternating pattern on the sense strand and/or antisense strand; or the sense strand or antisense strand may contain both internucleotide linkage modifications in an alternating pattern. The alternating pattern of the internucleotide linkage modification on the sense strand may be the same or different from the antisense strand, and the alternating pattern of the internucleotide linkage modification on the sense strand may have a shift relative to the alternating pattern of the internucleotide linkage modification on the antisense strand. In one embodiment, a double-stranded RNAi agent comprises 6-8phosphorothioate internucleotide linkages. In one embodiment, the antisense strand comprises two phosphorothioate internucleotide linkages at the 5′-terminus and two phosphorothioate internucleotide linkages at the 3′-terminus, and the sense strand comprises at least two phosphorothioate internucleotide linkages at either the 5′-terminus or the 3′-terminus. 
     In one embodiment, the RNAi comprises a phosphorothioate or methylphosphonate internucleotide linkage modification in the overhang region. For example, the overhang region may contain two nucleotides having a phosphorothioate or methylphosphonate internucleotide linkage between the two nucleotides. Internucleotide linkage modifications also may be made to link the overhang nucleotides with the terminal paired nucleotides within the duplex region. For example, at least 2, 3, 4, or all the overhang nucleotides may be linked through phosphorothioate or methylphosphonate internucleotide linkage, and optionally, there may be additional phosphorothioate or methylphosphonate internucleotide linkages linking the overhang nucleotide with a paired nucleotide that is next to the overhang nucleotide. For instance, there may be at least two phosphorothioate internucleotide linkages between the terminal three nucleotides, in which two of the three nucleotides are overhang nucleotides, and the third is a paired nucleotide next to the overhang nucleotide. These terminal three nucleotides may be at the 3′-end of the antisense strand, the 3′-end of the sense strand, the 5′-end of the antisense strand, and/or the 5′ end of the antisense strand. 
     In one embodiment, the 2 nucleotide overhang is at the 3′-end of the antisense strand, and there are two phosphorothioate internucleotide linkages between the terminal three nucleotides, wherein two of the three nucleotides are the overhang nucleotides, and the third nucleotide is a paired nucleotide next to the overhang nucleotide. Optionally, the RNAi agent may additionally have two phosphorothioate internucleotide linkages between the terminal three nucleotides at both the 5′-end of the sense strand and at the 5′-end of the antisense strand. 
     In one embodiment, the RNAi agent comprises mismatch(es) with the target, within the duplex, or combinations thereof. The mismatch may occur in the overhang region or the duplex region. The base pair may be ranked on the basis of their propensity to promote dissociation or melting (e.g., on the free energy of association or dissociation of a particular pairing, the simplest approach is to examine the pairs on an individual pair basis, though next neighbor or similar analysis can also be used). In terms of promoting dissociation: A:U is preferred over G:C; G:U is preferred over G:C; and I:C is preferred over G:C (I=inosine). Mismatches, e.g., non-canonical or other than canonical pairings (as described elsewhere herein) are preferred over canonical (A:T, A:U, G:C) pairings; and pairings which include a universal base are preferred over canonical pairings. 
     In one embodiment, the RNAi agent comprises at least one of the first 1, 2, 3, 4, or 5 base pairs within the duplex regions from the 5′-end of the antisense strand independently selected from the group of: A:U, G:U, I:C, and mismatched pairs, e.g., non-canonical or other than canonical pairings or pairings which include a universal base, to promote the dissociation of the antisense strand at the 5′-end of the duplex. 
     In one embodiment, the nucleotide at the 1 position within the duplex region from the 5′-end in the antisense strand is selected from the group consisting of A, dA, dU, U, and dT. Alternatively, at least one of the first 1, 2 or 3 base pair within the duplex region from the 5′-end of the antisense strand is an AU base pair. For example, the first base pair within the duplex region from the 5′-end of the antisense strand is an AU base pair. 
     In another embodiment, the nucleotide at the 3′-end of the sense strand is deoxy-thymine (dT). In another embodiment, the nucleotide at the 3′-end of the antisense strand is deoxy-thymine (dT). In one embodiment, there is a short sequence of deoxy-thymine nucleotides, for example, two dT nucleotides on the 3′-end of the sense and/or antisense strand. 
     In one embodiment, the sense strand sequence may be represented by formula (I): 
       5′n p -N a -(XXX) i -N b -YYY-N b -(ZZZ) j —N a -n q 3′  (I)
         wherein:       

     i and j are each independently 0 or 1; 
     p and q are each independently 0-6; 
     each N a  independently represents an oligonucleotide sequence comprising 0-25 modified nucleotides, each sequence comprising at least two differently modified nucleotides; 
     each N b  independently represents an oligonucleotide sequence comprising 0-10 modified nucleotides; 
     each n p  and n q  independently represent an overhang nucleotide; 
     wherein Nb and Y do not have the same modification; and 
     XXX, YYY and ZZZ each independently represent one motif of three identical modifications on three consecutive nucleotides. Preferably YYY is all 2′-F modified nucleotides. 
     In one embodiment, the N a  and/or N b  comprise modifications of alternating pattern. 
     In one embodiment, the YYY motif occurs at or near the cleavage site of the sense strand. For example, when the RNAi agent has a duplex region of 17-23 nucleotides in length, the YYY motif can occur at or the vicinity of the cleavage site (e.g.: can occur at positions 6, 7, 8, 7, 8, 9, 8, 9, 10, 9, 10, 11, 10, 11, 12 or 11, 12, 13) of—the sense strand, the count starting from the 1 st  nucleotide, from the 5′-end; or optionally, the count starting at the 1 st  paired nucleotide within the duplex region, from the 5′-end. 
     In one embodiment, i is 1 and j is 0, or i is 0 and j is 1, or both i and j are 1. The sense strand can therefore be represented by the following formulas: 
       5′n p -N a -YYY—N b -ZZZ—N a -n q 3′  (Ib);
 
       5′n p -N a -XXX—N b -YYY—N a -n q 3′  (Ic); or
 
       5′n p -N a -XXX—N b -YYY—N b -ZZZ—N a -n q 3′  (Id).
 
     When the sense strand is represented by formula (Ib), N b  represents an oligonucleotide sequence comprising 0-10, 0-7, 0-5, 0-4, 0-2 or 0 modified nucleotides. Each N a  independently can represent an oligonucleotide sequence comprising 2-20, 2-15, or 2-10 modified nucleotides. 
     When the sense strand is represented as formula (Ic), N b  represents an oligonucleotide sequence comprising 0-10, 0-7, 0-10, 0-7, 0-5, 0-4, 0-2 or 0 modified nucleotides. Each N a  can independently represent an oligonucleotide sequence comprising 2-20, 2-15, or 2-10 modified nucleotides. 
     When the sense strand is represented as formula (Id), each N b  independently represents an oligonucleotide sequence comprising 0-10, 0-7, 0-5, 0-4, 0-2 or 0 modified nucleotides. Preferably, N b  is 0, 1, 2, 3, 4, 5 or 6 Each N a  can independently represent an oligonucleotide sequence comprising 2-20, 2-15, or 2-10 modified nucleotides. 
     Each of X, Y and Z may be the same or different from each other. 
     In other embodiments, i is 0 and j is 0, and the sense strand may be represented by the formula: 
       5′n p -N a -YYY-N a -n q 3′  (Ia).
 
     When the sense strand is represented by formula (Ia), each N a  independently can represent an oligonucleotide sequence comprising 2-20, 2-15, or 2-10 modified nucleotides. In one embodiment, the antisense strand sequence of the RNAi may be represented by formula (II): 
       5′n q′ -N a ′-(Z′Z′Z′) k -N b ′-Y′Y′Y′-N b ′-(X′X′X′) 1 -N′ a -n p ′3′  (II)
 
     wherein: 
     k and l are each independently 0 or 1; 
     p′ and q′ are each independently 0-6; 
     each N a ′ independently represents an oligonucleotide sequence comprising 0-25 modified nucleotides, each sequence comprising at least two differently modified nucleotides; 
     each N b ′ independently represents an oligonucleotide sequence comprising 0-10 modified nucleotides; 
     each n p ′ and n q ′ independently represent an overhang nucleotide; 
     wherein N b ′ and Y′ do not have the same modification; 
     and 
     X′X′X′, Y′Y′Y′ and Z′Z′Z′ each independently represent one motif of three identical modifications on three consecutive nucleotides. 
     In one embodiment, the N a ′ and/or N b ′ comprise modifications of alternating pattern. 
     The Y′Y′Y′ motif occurs at or near the cleavage site of the antisense strand. For example, when the RNAi agent has a duplex region of 17-23 nucleotidein length, the Y′Y′Y′ motif can occur at positions 9, 10, 11; 10, 11, 12; 11, 12, 13; 12, 13, 14; or 13, 14, 15 of the antisense strand, with the count starting from the 1 st  nucleotide, from the 5′-end; or optionally, the count starting at the 1 st  paired nucleotide within the duplex region, from the 5′-end. Preferably, the Y′Y′Y′ motif occurs at positions 11, 12, 13. 
     In one embodiment, Y′Y′Y′ motif is all 2′-OMe modified nucleotides. 
     In one embodiment, k is 1 and l is 0, or k is 0 and l is 1, or both k and l are 1. 
     The antisense strand can therefore be represented by the following formulas: 
       5′n q′ -N a ′-Z′Z′Z′-N b ′-Y′Y′Y′-N a ′-n p ′3′  (IIb);
 
       5′n q′ -N a ′-Y′Y′Y′-N b ′-X′X′X′-n p   ′ 3′  (IIc); or
 
       5′n q′ -N a ′-Z′Z′Z′-N b ′-Y′Y′Y′-N b ′-X′X′X′-N a ′-n p′ 3′  (IId).
 
     When the antisense strand is represented by formula (IIb), N b ′ represents an oligonucleotide sequence comprising 0-10, 0-7, 0-10, 0-7, 0-5, 0-4, 0-2 or 0 modified nucleotides. Each N a ′ independently represents an oligonucleotide sequence comprising 2-20, 2-15, or 2-10 modified nucleotides. 
     When the antisense strand is represented as formula (IIc), N b ′ represents an oligonucleotide sequence comprising 0-10, 0-7, 0-10, 0-7, 0-5, 0-4, 0-2 or 0 modified nucleotides. Each N a ′ independently represents an oligonucleotide sequence comprising 2-20, 2-15, or 2-10 modified nucleotides. 
     When the antisense strand is represented as formula (IId), each N b ′ independently represents an oligonucleotide sequence comprising 0-10, 0-7, 0-10, 0-7, 0-5, 0-4, 0-2 or 0 modified nucleotides. Each N a ′ independently represents an oligonucleotide sequence comprising 2-20, 2-15, or 2-10 modified nucleotides. Preferably, N b  is 0, 1, 2, 3, 4, 5 or 6. 
     In other embodiments, k is 0 and l is 0 and the antisense strand may be represented by the formula: 
       5′n p′ -N a′ -Y′Y′Y′-N a′ -n q′ 3′  (Ia).
 
     When the antisense strand is represented as formula (IIa), each N a ′ independently represents an oligonucleotide sequence comprising 2-20, 2-15, or 2-10 modified nucleotides. 
     Each of X′, Y′ and Z′ may be the same or different from each other. 
     Each nucleotide of the sense strand and antisense strand may be independently modified with LNA, HNA, CeNA, 2′-methoxyethyl, 2′-O-methyl, 2′-O-allyl, 2′-C-allyl, 2′-hydroxyl, or 2′-fluoro. For example, each nucleotide of the sense strand and antisense strand is independently modified with 2′-O-methyl or 2′-fluoro. Each X, Y, Z, X′, Y′ and Z′, in particular, may represent a 2′-O-methyl modification or a 2′-fluoro modification. 
     In one embodiment, the sense strand of the RNAi agent may contain YYY motif occurring at 9, 10 and 11 positions of the strand when the duplex region is 21 nt, the count starting from the 1 st  nucleotide from the 5′-end, or optionally, the count starting at the 1 st  paired nucleotide within the duplex region, from the 5′-end; and Y represents 2′-F modification. The sense strand may additionally contain XXX motif or ZZZ motifs as wing modifications at the opposite end of the duplex region; and XXX and ZZZ each independently represents a 2′-OMe modification or 2′-F modification. 
     In one embodiment the antisense strand may contain Y′Y′Y′ motif occurring at positions 11, 12, 13 of the strand, the count starting from the 1 st  nucleotide from the 5′-end, or optionally, the count starting at the 1 st  paired nucleotide within the duplex region, from the 5′-end; and Y′ represents 2′-O-methyl modification. The antisense strand may additionally contain X′X′X′ motif or Z′Z′Z′ motifs as wing modifications at the opposite end of the duplex region; and X′X′X′ and Z′Z′Z′ each independently represents a 2′-OMe modification or 2′-F modification. 
     The sense strand represented by any one of the above formulas (Ia), (Ib), (Ic), and (Id) forms a duplex with a antisense strand being represented by any one of formulas (IIa), (IIb), (IIc), and (IId), respectively. 
     Accordingly, the RNAi agents for use in the methods of the invention may comprise a sense strand and an antisense strand, each strand having 14 to 30 nucleotides, the RNAi duplex represented by formula (III): 
       sense: 5′n p -N a -(XXX) i -N b -YYY-N b -(ZZZ) j —N a -n q 3′
 
       antisense: 3′n p   ′ -N a   ′ -(X′X′X′) k -N b   ′ -Y′Y′Y′-N b   ′ -(Z′Z′Z′) l -n q   ′ 5′  (III)
 
     wherein: 
     j, k, and l are each independently 0 or 1; 
     p, p′, q, and q′ are each independently 0-6; 
     each N a  and N a ′ independently represents an oligonucleotide sequence comprising 0-25 modified nucleotides, each sequence comprising at least two differently modified nucleotides; 
     each N b  and N b ′ independently represents an oligonucleotide sequence comprising 0-10 modified nucleotides; 
     wherein 
     each n p ′, n p , n q ′, and n q , each of which may or may not be present, independently represents an overhang nucleotide; and 
     XXX, YYY, ZZZ, X′X′X′, Y′Y′Y′, and Z′Z′Z′ each independently represent one motif of three identical modifications on three consecutive nucleotides. 
     In one embodiment, i is 0 and j is 0; or i is 1 and j is 0; or i is 0 and j is 1; or both i and j are 0; or both i and j are 1. In another embodiment, k is 0 and l is 0; or k is 1 and l is 0; k is 0 and l is 1; or both k and l are 0; or both k and l are 1. 
     Exemplary combinations of the sense strand and antisense strand forming a RNAi duplex include the formulas below: 
       5′n p -N a -YYY-N a -n q 3′
 
       3′n p   ′ -N a   ′ -Y′Y′Y′-N a   ′ n q   ′ 5′  (IIIa)
 
       5′n p -N a -YYY-N b -ZZZ-N a -n q 3′
 
       3′n p   ′ -N a   ′ -Y′Y′Y′-N b -Z′Z′Z′—N a ′n q ′5′  (IIIb)
 
       5′n p -N a -XXX-N b -YYY-N a -n q 3′
 
       3′n p   ′ -N a   ′ -X′X′X′-N b ′-Y′Y′Y′-N a   ′ -n q   ′ 5′  (IIIc)
 
       5′n p -N a -XXX-N b -YYY-N b -ZZZ-N a -n q 3′
 
       3′n p   ′ -N a   ′ -X′X′X′-N b   ′ -Y′Y′Y′-N b -Z′Z′Z′-N a -n q   ′ 5′  (IIId)
 
     When the RNAi agent is represented by formula (IIIa), each N a  independently represents an oligonucleotide sequence comprising 2-20, 2-15, or 2-10 modified nucleotides. 
     When the RNAi agent is represented by formula (IIIb), each N b  independently represents an oligonucleotide sequence comprising 1-10, 1-7, 1-5 or 1-4 modified nucleotides. Each N a  independently represents an oligonucleotide sequence comprising 2-20, 2-15, or 2-10 modified nucleotides. 
     When the RNAi agent is represented as formula (IIIc), each N b , N b ′ independently represents an oligonucleotide sequence comprising 0-10, 0-7, 0-10, 0-7, 0-5, 0-4, 0-2 or 0 modified nucleotides. Each N a  independently represents an oligonucleotide sequence comprising 2-20, 2-15, or 2-10 modified nucleotides. 
     When the RNAi agent is represented as formula (IIId), each N b , N b ′ independently represents an oligonucleotide sequence comprising 0-10, 0-7, 0-10, 0-7, 0-5, 0-4, 0-2 or 0 modified nucleotides. Each N a , N a ′ independently represents an oligonucleotide sequence comprising 2-20, 2-15, or 2-10 modified nucleotides. Each of N a , N a ′, N b  and N b , independently comprises modifications of alternating pattern. 
     Each of X, Y and Z in formulas (III), (IIIa), (IIIb), (IIIc), and (IIId) may be the same or different from each other. 
     When the RNAi agent is represented by formula (III), (IIIa), (IIIb), (IIIc), and (IIId), at least one of the Y nucleotides may form a base pair with one of the Y′ nucleotides. Alternatively, at least two of the Y nucleotides form base pairs with the corresponding Y′ nucleotides; or all three of the Y nucleotides all form base pairs with the corresponding Y′ nucleotides. 
     When the RNAi agent is represented by formula (IIIb) or (IIId), at least one of the Z nucleotides may form a base pair with one of the Z′ nucleotides. Alternatively, at least two of the Z nucleotides form base pairs with the corresponding Z′ nucleotides; or all three of the Z nucleotides all form base pairs with the corresponding Z′ nucleotides. 
     When the RNAi agent is represented as formula (IIIc) or (IIId), at least one of the X nucleotides may form a base pair with one of the X′ nucleotides. Alternatively, at least two of the X nucleotides form base pairs with the corresponding X′ nucleotides; or all three of the X nucleotides all form base pairs with the corresponding X′ nucleotides. 
     In one embodiment, the modification on the Y nucleotide is different than the modification on the Y′ nucleotide, the modification on the Z nucleotide is different than the modification on the Z′ nucleotide, and/or the modification on the X nucleotide is different than the modification on the X′ nucleotide. 
     In one embodiment, when the RNAi agent is represented by formula (IIId), the N a  modifications are 2′-O-methyl or 2′-fluoro modifications. In another embodiment, when the RNAi agent is represented by formula (IIId), the N a  modifications are 2′-O-methyl or 2′-fluoro modifications and n p ′&gt;0 and at least one n p ′ is linked to a neighboring nucleotide a via phosphorothioate linkage. In yet another embodiment, when the RNAi agent is represented by formula (IIId), the N a  modifications are 2′-O-methyl or 2′-fluoro modifications, n p ′&gt;0 and at least one n p ′ is linked to a neighboring nucleotide via phosphorothioate linkage, and the sense strand is conjugated to one or more GalNAc derivatives attached through a bivalent or trivalent branched linker (described below). In another embodiment, when the RNAi agent is represented by formula (IIId), the N a  modifications are 2′-O-methyl or 2′-fluoro modifications, n p ′&gt;0 and at least one n p ′ is linked to a neighboring nucleotide via phosphorothioate linkage, the sense strand comprises at least one phosphorothioate linkage, and the sense strand is conjugated to one or more GalNAc derivatives attached through a bivalent or trivalent branched linker. 
     In one embodiment, when the RNAi agent is represented by formula (IIIa), the N a  modifications are 2′-O-methyl or 2′-fluoro modifications, n p ′&gt;0 and at least one n p ′ is linked to a neighboring nucleotide via phosphorothioate linkage, the sense strand comprises at least one phosphorothioate linkage, and the sense strand is conjugated to one or more GalNAc derivatives attached through a bivalent or trivalent branched linker. 
     In one embodiment, the RNAi agent is a multimer containing at least two duplexes represented by formula (III), (IIIa), (IIIb), (IIIc), and (IIId), wherein the duplexes are connected by a linker. The linker can be cleavable or non-cleavable. Optionally, the multimer further comprises a ligand. Each of the duplexes can target the same gene or two different genes; or each of the duplexes can target same gene at two different target sites. 
     In one embodiment, the RNAi agent is a multimer containing three, four, five, six or more duplexes represented by formula (III), (IIIa), (IIIb), (IIIc), and (IIId), wherein the duplexes are connected by a linker. The linker can be cleavable or non-cleavable. Optionally, the multimer further comprises a ligand. Each of the duplexes can target the same gene or two different genes; or each of the duplexes can target same gene at two different target sites. 
     In one embodiment, two RNAi agents represented by formula (III), (IIIa), (IIIb), (IIIc), and (IIId) are linked to each other at the 5′ end, and one or both of the 3′ ends and are optionally conjugated to a ligand. Each of the agents can target the same gene or two different genes; or each of the agents can target same gene at two different target sites. 
     Various publications describe multimeric RNAi agents that can be used in the methods of the invention. Such publications include WO2007/091269, U.S. Pat. No. 7,858,769, WO2010/141511, WO2007/117686, WO2009/014887 and WO2011/031520 the entire contents of each of which are hereby incorporated herein by reference. 
     As described in more detail below, the RNAi agent that contains conjugations of one or more carbohydrate moieties to a RNAi agent can optimize one or more properties of the RNAi agent. In many cases, the carbohydrate moiety will be attached to a modified subunit of the RNAi agent. For example, the ribose sugar of one or more ribonucleotide subunits of a dsRNA agent can be replaced with another moiety, e.g., a non-carbohydrate (preferably cyclic) carrier to which is attached a carbohydrate ligand. A ribonucleotide subunit in which the ribose sugar of the subunit has been so replaced is referred to herein as a ribose replacement modification subunit (RRMS). A cyclic carrier may be a carbocyclic ring system, i.e., all ring atoms are carbon atoms, or a heterocyclic ring system, i.e., one or more ring atoms may be a heteroatom, e.g., nitrogen, oxygen, sulfur. The cyclic carrier may be a monocyclic ring system, or may contain two or more rings, e.g. fused rings. The cyclic carrier may be a fully saturated ring system, or it may contain one or more double bonds. 
     The ligand may be attached to the polynucleotide via a carrier. The carriers include (i) at least one “backbone attachment point,” preferably two “backbone attachment points” and (ii) at least one “tethering attachment point.” A “backbone attachment point” as used herein refers to a functional group, e.g. a hydroxyl group, or generally, a bond available for, and that is suitable for incorporation of the carrier into the backbone, e.g., the phosphate, or modified phosphate, e.g., sulfur containing, backbone, of a ribonucleic acid. A “tethering attachment point” (TAP) in some embodiments refers to a constituent ring atom of the cyclic carrier, e.g., a carbon atom or a heteroatom (distinct from an atom which provides a backbone attachment point), that connects a selected moiety. The moiety can be, e.g., a carbohydrate, e.g. monosaccharide, disaccharide, trisaccharide, tetrasaccharide, oligosaccharide and polysaccharide. Optionally, the selected moiety is connected by an intervening tether to the cyclic carrier. Thus, the cyclic carrier will often include a functional group, e.g., an amino group, or generally, provide a bond, that is suitable for incorporation or tethering of another chemical entity, e.g., a ligand to the constituent ring. 
     The RNAi agents may be conjugated to a ligand via a carrier, wherein the carrier can be cyclic group or acyclic group; preferably, the cyclic group is selected from pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, [1,3]dioxolane, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, tetrahydrofuryl and decalin; preferably, the acyclic group is selected from serinol backbone or diethanolamine backbone. 
     In certain specific embodiments, the RNAi agent for use in the methods of the invention is an agent selected from the group of agents listed in any one of Tables 3, 4, 5, 6, 18, 19, 20, 21, and 23. These agents may further comprise a ligand. 
     IV. iRNAs Conjugated to Ligands 
     Another modification of the RNA of an iRNA of the invention involves chemically linking to the RNA one or more ligands, moieties or conjugates that enhance the activity, cellular distribution or cellular uptake of the iRNA. Such moieties include but are not limited to lipid moieties such as a cholesterol moiety (Letsinger et al.,  Proc. Natl. Acid. Sci. USA,  1989, 86: 6553-6556), cholic acid (Manoharan et al.,  Biorg. Med. Chem. Let.,  1994, 4:1053-1060), a thioether, e.g., beryl-S-tritylthiol (Manoharan et al.,  Ann. N.Y. Acad. Sci.,  1992, 660:306-309; Manoharan et al.,  Biorg. Med. Chem. Let.,  1993, 3:2765-2770), a thiocholesterol (Oberhauser et al.,  Nucl. Acids Res.,  1992, 20:533-538), an aliphatic chain, e.g., dodecandiol or undecyl residues (Saison-Behmoaras et al.,  EMBO J,  1991, 10:1111-1118; Kabanov et al.,  FEBS Lett.,  1990, 259:327-330; Svinarchuk et al.,  Biochimie,  1993, 75:49-54), a phospholipid, e.g., di-hexadecyl-rac-glycerol or triethyl-ammonium 1,2-di-O-hexadecyl-rac-glycero-3-phosphonate (Manoharan et al.,  Tetrahedron Lett.,  1995, 36:3651-3654; Shea et al.,  Nucl. Acids Res.,  1990, 18:3777-3783), a polyamine or a polyethylene glycol chain (Manoharan et al.,  Nucleosides  &amp;  Nucleotides,  1995, 14:969-973), or adamantane acetic acid (Manoharan et al.,  Tetrahedron Lett.,  1995, 36:3651-3654), a palmityl moiety (Mishra et al.,  Biochim. Biophys. Acta,  1995, 1264:229-237), or an octadecylamine or hexylamino-carbonyloxycholesterol moiety (Crooke et al., J.  Pharmacol. Exp. Ther.,  1996, 277:923-937). 
     In one embodiment, a ligand alters the distribution, targeting or lifetime of an iRNA agent into which it is incorporated. In preferred embodiments a ligand provides an enhanced affinity for a selected target, e.g., molecule, cell or cell type, compartment, e.g., a cellular or organ compartment, tissue, organ or region of the body, as, e.g., compared to a species absent such a ligand. Preferred ligands will not take part in duplex pairing in a duplexed nucleic acid. 
     Ligands can include a naturally occurring substance, such as a protein (e.g., human serum albumin (HSA), low-density lipoprotein (LDL), or globulin); carbohydrate (e.g., a dextran, pullulan, chitin, chitosan, inulin, cyclodextrin, N-acetylgalactosamine, or hyaluronic acid); or a lipid. The ligand can also be a recombinant or synthetic molecule, such as a synthetic polymer, e.g., a synthetic polyamino acid. Examples of polyamino acids include polyamino acid is a polylysine (PLL), poly L-aspartic acid, poly L-glutamic acid, styrene-maleic acid anhydride copolymer, poly(L-lactide-co-glycolide) copolymer, divinyl ether-maleic anhydride copolymer, N-(2-hydroxypropyl)methacrylamide copolymer (HMPA), polyethylene glycol (PEG), polyvinyl alcohol (PVA), polyurethane, poly(2-ethylacrylic acid), N-isopropylacrylamide polymers, or polyphosphazine. Example of polyamines include: polyethylenimine, polylysine (PLL), spermine, spermidine, polyamine, pseudopeptide-polyamine, peptidomimetic polyamine, dendrimer polyamine, arginine, amidine, protamine, cationic lipid, cationic porphyrin, quaternary salt of a polyamine, or an alpha helical peptide. 
     Ligands can also include targeting groups, e.g., a cell or tissue targeting agent, e.g., a lectin, glycoprotein, lipid or protein, e.g., an antibody, that binds to a specified cell type such as a kidney cell. A targeting group can be a thyrotropin, melanotropin, lectin, glycoprotein, surfactant protein A, Mucin carbohydrate, multivalent lactose, multivalent galactose, N-acetyl-galactosamine, N-acetyl-gulucoseamine multivalent mannose, multivalent fucose, glycosylated polyaminoacids, multivalent galactose, transferrin, bisphosphonate, polyglutamate, polyaspartate, a lipid, cholesterol, a steroid, bile acid, folate, vitamin B12, vitamin A, biotin, or an RGD peptide or RGD peptide mimetic. 
     Other examples of ligands include dyes, intercalating agents (e.g. acridines), cross-linkers (e.g. psoralene, mitomycin C), porphyrins (TPPC4, texaphyrin, Sapphyrin), polycyclic aromatic hydrocarbons (e.g., phenazine, dihydrophenazine), artificial endonucleases (e.g. EDTA), lipophilic molecules, e.g., cholesterol, cholic acid, adamantane acetic acid, 1-pyrene butyric acid, dihydrotestosterone, 1,3-Bis-O(hexadecyl)glycerol, geranyloxyhexyl group, hexadecylglycerol, borneol, menthol, 1,3-propanediol, heptadecyl group, palmitic acid, myristic acid, O3-(oleoyl)lithocholic acid, O3-(oleoyl)cholenic acid, dimethoxytrityl, or phenoxazine) and peptide conjugates (e.g., antennapedia peptide, Tat peptide), alkylating agents, phosphate, amino, mercapto, PEG (e.g., PEG-40K), MPEG, [MPEG]2, polyamino, alkyl, substituted alkyl, radiolabeled markers, enzymes, haptens (e.g. biotin), transport/absorption facilitators (e.g., aspirin, vitamin E, folic acid), synthetic ribonucleases (e.g., imidazole, bisimidazole, histamine, imidazole clusters, acridine-imidazole conjugates, Eu3+ complexes of tetraazamacrocycles), dinitrophenyl, HRP, or AP. 
     Ligands can be proteins, e.g., glycoproteins, or peptides, e.g., molecules having a specific affinity for a co-ligand, or antibodies e.g., an antibody, that binds to a specified cell type such as a hepatic cell. Ligands can also include hormones and hormone receptors. They can also include non-peptidic species, such as lipids, lectins, carbohydrates, vitamins, cofactors, multivalent lactose, multivalent galactose, N-acetyl-galactosamine, N-acetyl-gulucosamine multivalent mannose, or multivalent fucose. The ligand can be, for example, a lipopolysaccharide, an activator of p38 MAP kinase, or an activator of NF-κB. 
     The ligand can be a substance, e.g., a drug, which can increase the uptake of the iRNA agent into the cell, for example, by disrupting the cell&#39;s cytoskeleton, e.g., by disrupting the cell&#39;s microtubules, microfilaments, and/or intermediate filaments. The drug can be, for example, taxon, vincristine, vinblastine, cytochalasin, nocodazole, japlakinolide, latrunculin A, phalloidin, swinholide A, indanocine, or myoservin. 
     In some embodiments, a ligand attached to an iRNA as described herein acts as a pharmacokinetic modulator (PK modulator). PK modulators include lipophiles, bile acids, steroids, phospholipid analogues, peptides, protein binding agents, PEG, vitamins etc. Exemplary PK modulators include, but are not limited to, cholesterol, fatty acids, cholic acid, lithocholic acid, dialkylglycerides, diacylglyceride, phospholipids, sphingolipids, naproxen, ibuprofen, vitamin E, biotin etc. Oligonucleotides that comprise a number of phosphorothioate linkages are also known to bind to serum protein, thus short oligonucleotides, e.g., oligonucleotides of about 5 bases, 10 bases, 15 bases or 20 bases, comprising multiple of phosphorothioate linkages in the backbone are also amenable to the present invention as ligands (e.g. as PK modulating ligands). In addition, aptamers that bind serum components (e.g. serum proteins) are also suitable for use as PK modulating ligands in the embodiments described herein. 
     Ligand-conjugated oligonucleotides of the invention may be synthesized by the use of an oligonucleotide that bears a pendant reactive functionality, such as that derived from the attachment of a linking molecule onto the oligonucleotide (described below). This reactive oligonucleotide may be reacted directly with commercially-available ligands, ligands that are synthesized bearing any of a variety of protecting groups, or ligands that have a linking moiety attached thereto. 
     The oligonucleotides used in the conjugates of the present invention may be conveniently and routinely made through the well-known technique of solid-phase synthesis. Equipment for such synthesis is sold by several vendors including, for example, Applied Biosystems (Foster City, Calif.). Any other means for such synthesis known in the art may additionally or alternatively be employed. It is also known to use similar techniques to prepare other oligonucleotides, such as the phosphorothioates and alkylated derivatives. 
     In the ligand-conjugated oligonucleotides and ligand-molecule bearing sequence-specific linked nucleosides of the present invention, the oligonucleotides and oligonucleosides may be assembled on a suitable DNA synthesizer utilizing standard nucleotide or nucleoside precursors, or nucleotide or nucleoside conjugate precursors that already bear the linking moiety, ligand-nucleotide or nucleoside-conjugate precursors that already bear the ligand molecule, or non-nucleoside ligand-bearing building blocks. 
     When using nucleotide-conjugate precursors that already bear a linking moiety, the synthesis of the sequence-specific linked nucleosides is typically completed, and the ligand molecule is then reacted with the linking moiety to form the ligand-conjugated oligonucleotide. In some embodiments, the oligonucleotides or linked nucleosides of the present invention are synthesized by an automated synthesizer using phosphoramidites derived from ligand-nucleoside conjugates in addition to the standard phosphoramidites and non-standard phosphoramidites that are commercially available and routinely used in oligonucleotide synthesis. 
     A. Lipid Conjugates 
     In one embodiment, the ligand or conjugate is a lipid or lipid-based molecule. Such a lipid or lipid-based molecule preferably binds a serum protein, e.g., human serum albumin (HSA). An HSA binding ligand allows for distribution of the conjugate to a target tissue, e.g., a non-kidney target tissue of the body. For example, the target tissue can be the liver, including parenchymal cells of the liver. Other molecules that can bind HSA can also be used as ligands. For example, naproxen or aspirin can be used. A lipid or lipid-based ligand can (a) increase resistance to degradation of the conjugate, (b) increase targeting or transport into a target cell or cell membrane, and/or (c) can be used to adjust binding to a serum protein, e.g., HSA. 
     A lipid based ligand can be used to inhibit, e.g., control the binding of the conjugate to a target tissue. For example, a lipid or lipid-based ligand that binds to HSA more strongly will be less likely to be targeted to the kidney and therefore less likely to be cleared from the body. A lipid or lipid-based ligand that binds to HSA less strongly can be used to target the conjugate to the kidney. 
     In a preferred embodiment, the lipid based ligand binds HSA. Preferably, it binds HSA with a sufficient affinity such that the conjugate will be preferably distributed to a non-kidney tissue. However, it is preferred that the affinity not be so strong that the HSA-ligand binding cannot be reversed. 
     In another preferred embodiment, the lipid based ligand binds HSA weakly or not at all, such that the conjugate will be preferably distributed to the kidney. Other moieties that target to kidney cells can also be used in place of or in addition to the lipid based ligand. 
     In another aspect, the ligand is a moiety, e.g., a vitamin, which is taken up by a target cell, e.g., a proliferating cell. These are particularly useful for treating disorders characterized by unwanted cell proliferation, e.g., of the malignant or non-malignant type, e.g., cancer cells. Exemplary vitamins include vitamin A, E, and K. Other exemplary vitamins include are B vitamin, e.g., folic acid, B12, riboflavin, biotin, pyridoxal or other vitamins or nutrients taken up by target cells such as liver cells. Also included are HSA and low density lipoprotein (LDL). 
     B. Cell Permeation Agents 
     In another aspect, the ligand is a cell-permeation agent, preferably a helical cell-permeation agent. Preferably, the agent is amphipathic. An exemplary agent is a peptide such as tat or antennopedia. If the agent is a peptide, it can be modified, including a peptidylmimetic, invertomers, non-peptide or pseudo-peptide linkages, and use of D-amino acids. The helical agent is preferably an alpha-helical agent, which preferably has a lipophilic and a lipophobic phase. 
     The ligand can be a peptide or peptidomimetic. A peptidomimetic (also referred to herein as an oligopeptidomimetic) is a molecule capable of folding into a defined three-dimensional structure similar to a natural peptide. The attachment of peptide and peptidomimetics to iRNA agents can affect pharmacokinetic distribution of the iRNA, such as by enhancing cellular recognition and absorption. The peptide or peptidomimetic moiety can be about 5-50 amino acids long, e.g., about 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 amino acids long. 
     A peptide or peptidomimetic can be, for example, a cell permeation peptide, cationic peptide, amphipathic peptide, or hydrophobic peptide (e.g., consisting primarily of Tyr, Trp or Phe). The peptide moiety can be a dendrimer peptide, constrained peptide or crosslinked peptide. In another alternative, the peptide moiety can include a hydrophobic membrane translocation sequence (MTS). An exemplary hydrophobic MTS-containing peptide is RFGF having the amino acid sequence AAVALLPAVLLALLAP (SEQ ID NO: 9). An RFGF analogue (e.g., amino acid sequence AALLPVLLAAP (SEQ ID NO: 10) containing a hydrophobic MTS can also be a targeting moiety. The peptide moiety can be a “delivery” peptide, which can carry large polar molecules including peptides, oligonucleotides, and protein across cell membranes. For example, sequences from the HIV Tat protein (GRKKRRQRRRPPQ (SEQ ID NO: 11) and the  Drosophila  Antennapedia protein (RQIKIWFQNRRMKWKK (SEQ ID NO: 12) have been found to be capable of functioning as delivery peptides. A peptide or peptidomimetic can be encoded by a random sequence of DNA, such as a peptide identified from a phage-display library, or one-bead-one-compound (OBOC) combinatorial library (Lam et al.,  Nature,  354:82-84, 1991). Examples of a peptide or peptidomimetic tethered to a dsRNA agent via an incorporated monomer unit for cell targeting purposes is an arginine-glycine-aspartic acid (RGD)-peptide, or RGD mimic. A peptide moiety can range in length from about 5 amino acids to about 40 amino acids. The peptide moieties can have a structural modification, such as to increase stability or direct conformational properties. Any of the structural modifications described below can be utilized. 
     An RGD peptide for use in the compositions and methods of the invention may be linear or cyclic, and may be modified, e.g., glycosylated or methylated, to facilitate targeting to a specific tissue(s). RGD-containing peptides and peptidiomimemtics may include D-amino acids, as well as synthetic RGD mimics. In addition to RGD, one can use other moieties that target the integrin ligand. Preferred conjugates of this ligand target PECAM-1 or VEGF. 
     A “cell permeation peptide” is capable of permeating a cell, e.g., a microbial cell, such as a bacterial or fungal cell, or a mammalian cell, such as a human cell. A microbial cell-permeating peptide can be, for example, a α-helical linear peptide (e.g., LL-37 or Ceropin P1), a disulfide bond-containing peptide (e.g., α-defensin, β-defensin or bactenecin), or a peptide containing only one or two dominating amino acids (e.g., PR-39 or indolicidin). A cell permeation peptide can also include a nuclear localization signal (NLS). For example, a cell permeation peptide can be a bipartite amphipathic peptide, such as MPG, which is derived from the fusion peptide domain of HIV-1 gp41 and the NLS of SV40 large T antigen (Simeoni et al.,  Nucl. Acids Res.  31:2717-2724, 2003). 
     C. Carbohydrate Conjugates 
     In some embodiments of the compositions and methods of the invention, an iRNA oligonucleotide further comprises a carbohydrate. The carbohydrate conjugated iRNA are advantageous for the in vivo delivery of nucleic acids, as well as compositions suitable for in vivo therapeutic use, as described herein. As used herein, “carbohydrate” refers to a compound which is either a carbohydrate per se made up of one or more monosaccharide units having at least 6 carbon atoms (which can be linear, branched or cyclic) with an oxygen, nitrogen or sulfur atom bonded to each carbon atom; or a compound having as a part thereof a carbohydrate moiety made up of one or more monosaccharide units each having at least six carbon atoms (which can be linear, branched or cyclic), with an oxygen, nitrogen or sulfur atom bonded to each carbon atom. Representative carbohydrates include the sugars (mono-, di-, tri- and oligosaccharides containing from about 4, 5, 6, 7, 8, or 9 monosaccharide units), and polysaccharides such as starches, glycogen, cellulose and polysaccharide gums. Specific monosaccharides include C5 and above (e.g., C5, C6, C7, or C8) sugars; di- and trisaccharides include sugars having two or three monosaccharide units (e.g., C5, C6, C7, or C8). 
     In one embodiment, a carbohydrate conjugate for use in the compositions and methods of the invention is a monosaccharide. In another embodiment, a carbohydrate conjugate for use in the compositions and methods of the invention is selected from the group consisting of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     In one embodiment, the monosaccharide is an N-acetylgalactosamine, such as 
     
       
         
         
             
             
         
       
     
     Another representative carbohydrate conjugate for use in the embodiments described herein includes, but is not limited to, 
     
       
         
         
             
             
         
       
         
         
           
             (Formula XXIII), when one of X or Y is an oligonucleotide, the other is a hydrogen. 
           
         
       
    
     In certain embodiments of the invention, the GalNAc or GalNAc derivative is attached to an iRNA agent of the invention via a monovalent linker. In some embodiments, the GalNAc or GalNAc derivative is attached to an iRNA agent of the invention via a bivalent linker. In yet other embodiments of the invention, the GalNAc or GalNAc derivative is attached to an iRNA agent of the invention via a trivalent linker. 
     In one embodiment, the double stranded RNAi agents of the invention comprise one GalNAc or GalNAc derivative attached to the iRNA agent. In another embodiment, the double stranded RNAi agents of the invention comprise a plurality (e.g., 2, 3, 4, 5, or 6) GalNAc or GalNAc derivatives, each independently attached to a plurality of nucleotides of the double stranded RNAi agent through a plurality of monovalent linkers. 
     In some embodiments, for example, when the two strands of an iRNA agent of the invention are part of one larger molecule connected by an uninterrupted chain of nucleotides between the 3′-end of one strand and the 5′-end of the respective other strand forming a hairpin loop comprising, a plurality of unpaired nucleotides, each unpaired nucleotide within the hairpin loop may independently comprise a GalNAc or GalNAc derivative attached via a monovalent linker. 
     In some embodiments, the carbohydrate conjugate further comprises one or more additional ligands as described above, such as, but not limited to, a PK modulator and/or a cell permeation peptide. 
     D. Linkers 
     In some embodiments, the conjugate or ligand described herein can be attached to an iRNA oligonucleotide with various linkers that can be cleavable or non-cleavable. 
     The term “linker” or “linking group” means an organic moiety that connects two parts of a compound, e.g., covalently attaches two parts of a compound. Linkers typically comprise a direct bond or an atom such as oxygen or sulfur, a unit such as NR8, C(O), C(O)NH, SO, SO 2 , SO 2 NH or a chain of atoms, such as, but not limited to, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkylarylalkyl, alkylarylalkenyl, alkylarylalkynyl, alkenylarylalkyl, alkenylarylalkenyl, alkenylarylalkynyl, alkynylarylalkyl, alkynylarylalkenyl, alkynylarylalkynyl, alkylheteroarylalkyl, alkylheteroarylalkenyl, alkylheteroarylalkynyl, alkenylheteroarylalkyl, alkenylheteroarylalkenyl, alkenylheteroarylalkynyl, alkynylheteroarylalkyl, alkynylheteroarylalkenyl, alkynylheteroarylalkynyl, alkylheterocyclylalkyl, alkylheterocyclylalkenyl, alkylhererocyclylalkynyl, alkenylheterocyclylalkyl, alkenylheterocyclylalkenyl, alkenylheterocyclylalkynyl, alkynylheterocyclylalkyl, alkynylheterocyclylalkenyl, alkynylheterocyclylalkynyl, alkylaryl, alkenylaryl, alkynylaryl, alkylheteroaryl, alkenylheteroaryl, alkynylhereroaryl, which one or more methylenes can be interrupted or terminated by O, S, S(O), SO 2 , N(R8), C(O), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic; where R8 is hydrogen, acyl, aliphatic or substituted aliphatic. In one embodiment, the linker is between about 1-24 atoms, 2-24, 3-24, 4-24, 5-24, 6-24, 6-18, 7-18, 8-18 atoms, 7-17, 8-17, 6-16, 7-16, or 8-16 atoms. 
     A cleavable linking group is one which is sufficiently stable outside the cell, but which upon entry into a target cell is cleaved to release the two parts the linker is holding together. In a preferred embodiment, the cleavable linking group is cleaved at least about 10 times, 20, times, 30 times, 40 times, 50 times, 60 times, 70 times, 80 times, 90 times or more, or at least about 100 times faster in a target cell or under a first reference condition (which can, e.g., be selected to mimic or represent intracellular conditions) than in the blood of a subject, or under a second reference condition (which can, e.g., be selected to mimic or represent conditions found in the blood or serum). 
     Cleavable linking groups are susceptible to cleavage agents, e.g., pH, redox potential or the presence of degradative molecules. Generally, cleavage agents are more prevalent or found at higher levels or activities inside cells than in serum or blood. Examples of such degradative agents include: redox agents which are selected for particular substrates or which have no substrate specificity, including, e.g., oxidative or reductive enzymes or reductive agents such as mercaptans, present in cells, that can degrade a redox cleavable linking group by reduction; esterases; endosomes or agents that can create an acidic environment, e.g., those that result in a pH of five or lower; enzymes that can hydrolyze or degrade an acid cleavable linking group by acting as a general acid, peptidases (which can be substrate specific), and phosphatases. 
     A cleavable linkage group, such as a disulfide bond can be susceptible to pH. The pH of human serum is 7.4, while the average intracellular pH is slightly lower, ranging from about 7.1-7.3. Endosomes have a more acidic pH, in the range of 5.5-6.0, and lysosomes have an even more acidic pH at around 5.0. Some linkers will have a cleavable linking group that is cleaved at a preferred pH, thereby releasing a cationic lipid from the ligand inside the cell, or into the desired compartment of the cell. 
     A linker can include a cleavable linking group that is cleavable by a particular enzyme. The type of cleavable linking group incorporated into a linker can depend on the cell to be targeted. For example, a liver-targeting ligand can be linked to a cationic lipid through a linker that includes an ester group. Liver cells are rich in esterases, and therefore the linker will be cleaved more efficiently in liver cells than in cell types that are not esterase-rich. Other cell-types rich in esterases include cells of the lung, renal cortex, and testis. 
     Linkers that contain peptide bonds can be used when targeting cell types rich in peptidases, such as liver cells and synoviocytes. 
     In general, the suitability of a candidate cleavable linking group can be evaluated by testing the ability of a degradative agent (or condition) to cleave the candidate linking group. It will also be desirable to also test the candidate cleavable linking group for the ability to resist cleavage in the blood or when in contact with other non-target tissue. Thus, one can determine the relative susceptibility to cleavage between a first and a second condition, where the first is selected to be indicative of cleavage in a target cell and the second is selected to be indicative of cleavage in other tissues or biological fluids, e.g., blood or serum. The evaluations can be carried out in cell free systems, in cells, in cell culture, in organ or tissue culture, or in whole animals. It can be useful to make initial evaluations in cell-free or culture conditions and to confirm by further evaluations in whole animals. In preferred embodiments, useful candidate compounds are cleaved at least about 2, 4, 10, 20, 30, 40, 50, 60, 70, 80, 90, or about 100 times faster in the cell (or under in vitro conditions selected to mimic intracellular conditions) as compared to blood or serum (or under in vitro conditions selected to mimic extracellular conditions). 
     i. Redox Cleavable Linking Groups 
     In one embodiment, a cleavable linking group is a redox cleavable linking group that is cleaved upon reduction or oxidation. An example of reductively cleavable linking group is a disulphide linking group (—S—S—). To determine if a candidate cleavable linking group is a suitable “reductively cleavable linking group,” or for example is suitable for use with a particular iRNA moiety and particular targeting agent one can look to methods described herein. For example, a candidate can be evaluated by incubation with dithiothreitol (DTT), or other reducing agent using reagents know in the art, which mimic the rate of cleavage which would be observed in a cell, e.g., a target cell. The candidates can also be evaluated under conditions which are selected to mimic blood or serum conditions. In one, candidate compounds are cleaved by at most about 10% in the blood. In other embodiments, useful candidate compounds are degraded at least about 2, 4, 10, 20, 30, 40, 50, 60, 70, 80, 90, or about 100 times faster in the cell (or under in vitro conditions selected to mimic intracellular conditions) as compared to blood (or under in vitro conditions selected to mimic extracellular conditions). The rate of cleavage of candidate compounds can be determined using standard enzyme kinetics assays under conditions chosen to mimic intracellular media and compared to conditions chosen to mimic extracellular media. 
     ii. Phosphate-Based Cleavable Linking Groups 
     In another embodiment, a cleavable linker comprises a phosphate-based cleavable linking group. A phosphate-based cleavable linking group is cleaved by agents that degrade or hydrolyze the phosphate group. An example of an agent that cleaves phosphate groups in cells are enzymes such as phosphatases in cells. Examples of phosphate-based linking groups are —O—P(O)(ORk)-O—, —O—P(S)(ORk)-O—, —O—P(S)(SRk)-O—, —S—P(O)(ORk)-O—, —O—P(O)(ORk)-S—, —S—P(O)(ORk)-S—, —O—P(S)(ORk)-S—, —S—P(S)(ORk)-O—, —O—P(O)(Rk)-O—, —O—P(S)(Rk)-O—, —S—P(O)(Rk)-O—, —S—P(S)(Rk)-O—, —S—P(O)(Rk)-S—, —O—P(S)(Rk)-S—. Preferred embodiments are —O—P(O)(OH)—O—, —O—P(S)(OH)—O—, —O—P(S)(SH)—O—, —S—P(O)(OH)—O—, —O—P(O)(OH)—S—, —S—P(O)(OH)—S—, —O—P(S)(OH)—S—, —S—P(S)(OH)—O—, —O—P(O)(H)—O—, —O—P(S)(H)—O—, —S—P(O)(H)—O, —S—P(S)(H)—O—, —S—P(O)(H)—S—, —O—P(S)(H)—S—. A preferred embodiment is —O—P(O)(OH)—O—. These candidates can be evaluated using methods analogous to those described above. 
     iii. Acid Cleavable Linking Groups 
     In another embodiment, a cleavable linker comprises an acid cleavable linking group. An acid cleavable linking group is a linking group that is cleaved under acidic conditions. In preferred embodiments acid cleavable linking groups are cleaved in an acidic environment with a pH of about 6.5 or lower (e.g., about 6.0, 5.75, 5.5, 5.25, 5.0, or lower), or by agents such as enzymes that can act as a general acid. In a cell, specific low pH organelles, such as endosomes and lysosomes can provide a cleaving environment for acid cleavable linking groups. Examples of acid cleavable linking groups include but are not limited to hydrazones, esters, and esters of amino acids. Acid cleavable groups can have the general formula —C═NN—, C(O)O, or —OC(O). A preferred embodiment is when the carbon attached to the oxygen of the ester (the alkoxy group) is an aryl group, substituted alkyl group, or tertiary alkyl group such as dimethyl pentyl or t-butyl. These candidates can be evaluated using methods analogous to those described above. 
     iv. Ester-Based Linking Groups 
     In another embodiment, a cleavable linker comprises an ester-based cleavable linking group. An ester-based cleavable linking group is cleaved by enzymes such as esterases and amidases in cells. Examples of ester-based cleavable linking groups include but are not limited to esters of alkylene, alkenylene and alkynylene groups. Ester cleavable linking groups have the general formula —C(O)O—, or —OC(O)—. These candidates can be evaluated using methods analogous to those described above. 
     v. Peptide-Based Cleaving Groups 
     In yet another embodiment, a cleavable linker comprises a peptide-based cleavable linking group. A peptide-based cleavable linking group is cleaved by enzymes such as peptidases and proteases in cells. Peptide-based cleavable linking groups are peptide bonds formed between amino acids to yield oligopeptides (e.g., dipeptides, tripeptides etc.) and polypeptides. Peptide-based cleavable groups do not include the amide group (—C(O)NH-). The amide group can be formed between any alkylene, alkenylene or alkynelene. A peptide bond is a special type of amide bond formed between amino acids to yield peptides and proteins. The peptide based cleavage group is generally limited to the peptide bond (i.e., the amide bond) formed between amino acids yielding peptides and proteins and does not include the entire amide functional group. Peptide-based cleavable linking groups have the general formula —NHCHRAC(O)NHCHRBC(O)—, where RA and RB are the R groups of the two adjacent amino acids. These candidates can be evaluated using methods analogous to those described above. 
     In one embodiment, an iRNA of the invention is conjugated to a carbohydrate through a linker. Non-limiting examples of iRNA carbohydrate conjugates with linkers of the compositions and methods of the invention include, but are not limited to, 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     when one of X or Y is an oligonucleotide, the other is a hydrogen. 
     In certain embodiments of the compositions and methods of the invention, a ligand is one or more GalNAc (N-acetylgalactosamine) derivatives attached through a bivalent or trivalent branched linker. 
     In one embodiment, a dsRNA of the invention is conjugated to a bivalent or trivalent branched linker selected from the group of structures shown in any of formula (XXXII)-(XXXV): 
     
       
         
         
             
             
         
       
     
     wherein:
 
q2A, q2B, q3A, q3B, q4A, q4B, q5A, q5B and q5C represent independently for each occurrence 0-20 and wherein the repeating unit can be the same or different;
 
P 2A  P 2B , P 3A , P 3B , P 4A , P 4B , P 5A , P 5B , P 5C , T 2A , T 2B , T 3A , T 3B , T 4A , T 4B , T 4A , T 5B , T 5C  are each independently for each occurrence absent, CO, NH, O, S, OC(O), NHC(O), CH 2 , CH 2 NH or CH 2 O;
 
Q 2A , Q 2B , Q 3A , Q 3B , Q 4A , Q 4B , Q 5A , Q 5B , Q 5C  are independently for each occurrence absent, alkylene, substituted alkylene wherein one or more methylenes can be interrupted or terminated by one or more of O, S, S(O), SO 2 , N(R N ), C(R′)═C(R″), C≡C or C(O);
 
R 2A , R 2B , R 3A , R 3B , R 4A , R 4B , R 5A , R 5B , R 5C  are each independently for each occurrence absent, NH, O, S, CH 2 , C(O)O, C(O)NH, NHCH(R a )C(O), —C(O)—CH(R a )—NH—, CO, CH═N—O,
 
     
       
         
         
             
             
         
       
     
     or heterocyclyl; 
     L 2A , L 2B , L 3A , L 3B , L 4A , L 4B , L 5A  L 5B  and L 5C  represent the ligand; i.e. each independently for each occurrence a monosaccharide (such as GalNAc), disaccharide, trisaccharide, tetrasaccharide, oligosaccharide, or polysaccharide; and R a  is H or amino acid side chain. Trivalent conjugating GalNAc derivatives are particularly useful for use with RNAi agents for inhibiting the expression of a target gene, such as those of formula (XXXVI): 
     
       
         
         
             
             
         
       
     
     wherein L 5A , L 5B  and L 5C  represent a monosaccharide, such as GalNAc derivative. 
     Examples of suitable bivalent and trivalent branched linker groups conjugating GalNAc derivatives include, but are not limited to, the structures recited above as formulas II, VII, XI, X, and XIII 
     Representative U.S. patents that teach the preparation of RNA conjugates include, but are not limited to, U.S. Pat. Nos. 4,828,979; 4,948,882; 5,218,105; 5,525,465; 5,541,313; 5,545,730; 5,552,538; 5,578,717, 5,580,731; 5,591,584; 5,109,124; 5,118,802; 5,138,045; 5,414,077; 5,486,603; 5,512,439; 5,578,718; 5,608,046; 4,587,044; 4,605,735; 4,667,025; 4,762,779; 4,789,737; 4,824,941; 4,835,263; 4,876,335; 4,904,582; 4,958,013; 5,082,830; 5,112,963; 5,214,136; 5,082,830; 5,112,963; 5,214,136; 5,245,022; 5,254,469; 5,258,506; 5,262,536; 5,272,250; 5,292,873; 5,317,098; 5,371,241, 5,391,723; 5,416,203, 5,451,463; 5,510,475; 5,512,667; 5,514,785; 5,565,552; 5,567,810; 5,574,142; 5,585,481; 5,587,371; 5,595,726; 5,597,696; 5,599,923; 5,599,928 and 5,688,941; 6,294,664; 6,320,017; 6,576,752; 6,783,931; 6,900,297; 7,037,646; 8,106,022, the entire contents of each of which are hereby incorporated herein by reference. 
     It is not necessary for all positions in a given compound to be uniformly modified, and in fact more than one of the aforementioned modifications can be incorporated in a single compound or even at a single nucleoside within an iRNA. The present invention also includes iRNA compounds that are chimeric compounds. 
     “Chimeric” iRNA compounds or “chimeras,” in the context of this invention, are iRNA compounds, preferably dsRNAs, which contain two or more chemically distinct regions, each made up of at least one monomer unit, i.e., a nucleotide in the case of a dsRNA compound. These iRNAs typically contain at least one region wherein the RNA is modified so as to confer upon the iRNA increased resistance to nuclease degradation, increased cellular uptake, and/or increased binding affinity for the target nucleic acid. An additional region of the iRNA can serve as a substrate for enzymes capable of cleaving RNA:DNA or RNA:RNA hybrids. By way of example, RNase H is a cellular endonuclease which cleaves the RNA strand of an RNA:DNA duplex. Activation of RNase H, therefore, results in cleavage of the RNA target, thereby greatly enhancing the efficiency of iRNA inhibition of gene expression. Consequently, comparable results can often be obtained with shorter iRNAs when chimeric dsRNAs are used, compared to phosphorothioate deoxy dsRNAs hybridizing to the same target region. Cleavage of the RNA target can be routinely detected by gel electrophoresis and, if necessary, associated nucleic acid hybridization techniques known in the art. 
     In certain instances, the RNA of an iRNA can be modified by a non-ligand group. A number of non-ligand molecules have been conjugated to iRNAs in order to enhance the activity, cellular distribution or cellular uptake of the iRNA, and procedures for performing such conjugations are available in the scientific literature. Such non-ligand moieties have included lipid moieties, such as cholesterol (Kubo, T. et al.,  Biochem. Biophys. Res. Comm.,  2007, 365(1):54-61; Letsinger et al.,  Proc. Natl. Acad. Sci. USA,  1989, 86:6553), cholic acid (Manoharan et al.,  Bioorg. Med. Chem. Lett.,  1994, 4:1053), a thioether, e.g., hexyl-S-tritylthiol (Manoharan et al.,  Ann. N.Y. Acad. Sci.,  1992, 660:306; Manoharan et al.,  Bioorg. Med. Chem. Let.,  1993, 3:2765), a thiocholesterol (Oberhauser et al.,  Nucl. Acids Res.,  1992, 20:533), an aliphatic chain, e.g., dodecandiol or undecyl residues (Saison-Behmoaras et al.,  EMBO J.,  1991, 10:111; Kabanov et al.,  FEBS Lett.,  1990, 259:327; Svinarchuk et al.,  Biochimie,  1993, 75:49), a phospholipid, e.g., di-hexadecyl-rac-glycerol or triethylammonium 1,2-di-O-hexadecyl-rac-glycero-3-H-phosphonate (Manoharan et al.,  Tetrahedron Lett.,  1995, 36:3651; Shea et al.,  Nucl. Acids Res.,  1990, 18:3777), a polyamine or a polyethylene glycol chain (Manoharan et al.,  Nucleosides  &amp;  Nucleotides,  1995, 14:969), or adamantane acetic acid (Manoharan et al.,  Tetrahedron Lett.,  1995, 36:3651), a palmityl moiety (Mishra et al.,  Biochim. Biophys. Acta,  1995, 1264:229), or an octadecylamine or hexylamino-carbonyl-oxycholesterol moiety (Crooke et al.,  J. Pharmacol. Exp. Ther.,  1996, 277:923). Representative United States patents that teach the preparation of such RNA conjugates have been listed above. Typical conjugation protocols involve the synthesis of an RNAs bearing an aminolinker at one or more positions of the sequence. The amino group is then reacted with the molecule being conjugated using appropriate coupling or activating reagents. The conjugation reaction can be performed either with the RNA still bound to the solid support or following cleavage of the RNA, in solution phase. Purification of the RNA conjugate by HPLC typically affords the pure conjugate. 
     IV. Delivery of an iRNA of the Invention 
     The delivery of an iRNA of the invention to a cell e.g., a cell within a subject, such as a human subject (e.g., a subject in need thereof, such as a subject having a complement component C5-associated disease) can be achieved in a number of different ways. For example, delivery may be performed by contacting a cell with an iRNA of the invention either in vitro or in vivo. In vivo delivery may also be performed directly by administering a composition comprising an iRNA, e.g., a dsRNA, to a subject. Alternatively, in vivo delivery may be performed indirectly by administering one or more vectors that encode and direct the expression of the iRNA. These alternatives are discussed further below. 
     In general, any method of delivering a nucleic acid molecule (in vitro or in vivo) can be adapted for use with an iRNA of the invention (see e.g., Akhtar S. and Julian R L. (1992)  Trends Cell. Biol.  2(5):139-144 and WO94/02595, which are incorporated herein by reference in their entireties). For in vivo delivery, factors to consider in order to deliver an iRNA molecule include, for example, biological stability of the delivered molecule, prevention of non-specific effects, and accumulation of the delivered molecule in the target tissue. The non-specific effects of an iRNA can be minimized by local administration, for example, by direct injection or implantation into a tissue or topically administering the preparation. Local administration to a treatment site maximizes local concentration of the agent, limits the exposure of the agent to systemic tissues that can otherwise be harmed by the agent or that can degrade the agent, and permits a lower total dose of the iRNA molecule to be administered. Several studies have shown successful knockdown of gene products when an iRNA is administered locally. For example, intraocular delivery of a VEGF dsRNA by intravitreal injection in cynomolgus monkeys (Tolentino, M J., et al (2004)  Retina  24:132-138) and subretinal injections in mice (Reich, S J., et al (2003)  Mol. Vis.  9:210-216) were both shown to prevent neovascularization in an experimental model of age-related macular degeneration. In addition, direct intratumoral injection of a dsRNA in mice reduces tumor volume (Pille, J., et al (2005)  Mol. Ther.  11:267-274) and can prolong survival of tumor-bearing mice (Kim, W J., et al (2006) Mol. Ther.  14:343-350; Li, S., et al (2007)  Mol. Ther.  15:515-523). RNA interference has also shown success with local delivery to the CNS by direct injection (Dorn, G., et al. (2004)  Nucleic Acids  32:e49; Tan, P H., et al (2005)  Gene Ther.  12:59-66; Makimura, H., et al (2002)  BMC Neurosci.  3:18; Shishkina, G T., et al (2004)  Neuroscience  129:521-528; Thakker, E R., et al (2004)  Proc. Natl. Acad. Sci. U.S.A.  101:17270-17275; Akaneya, Y., et al (2005)  J. Neurophysiol.  93:594-602) and to the lungs by intranasal administration (Howard, K A., et al (2006)  Mol. Ther.  14:476-484; Zhang, X., et al (2004)  J. Biol. Chem.  279:10677-10684; Bitko, V., et al (2005)  Nat. Med.  11:50-55). For administering an iRNA systemically for the treatment of a disease, the RNA can be modified or alternatively delivered using a drug delivery system; both methods act to prevent the rapid degradation of the dsRNA by endo- and exo-nucleases in vivo. Modification of the RNA or the pharmaceutical carrier can also permit targeting of the iRNA composition to the target tissue and avoid undesirable off-target effects. iRNA molecules can be modified by chemical conjugation to lipophilic groups such as cholesterol to enhance cellular uptake and prevent degradation. For example, an iRNA directed against ApoB conjugated to a lipophilic cholesterol moiety was injected systemically into mice and resulted in knockdown of apoB mRNA in both the liver and jejunum (Soutschek, J., et al (2004)  Nature  432:173-178). Conjugation of an iRNA to an aptamer has been shown to inhibit tumor growth and mediate tumor regression in a mouse model of prostate cancer (McNamara, J O., et al (2006)  Nat. Biotechnol.  24:1005-1015). In an alternative embodiment, the iRNA can be delivered using drug delivery systems such as a nanoparticle, a dendrimer, a polymer, liposomes, or a cationic delivery system. Positively charged cationic delivery systems facilitate binding of an iRNA molecule (negatively charged) and also enhance interactions at the negatively charged cell membrane to permit efficient uptake of an iRNA by the cell. Cationic lipids, dendrimers, or polymers can either be bound to an iRNA, or induced to form a vesicle or micelle (see e.g., Kim S H., et al (2008)  Journal of Controlled Release  129(2):107-116) that encases an iRNA. The formation of vesicles or micelles further prevents degradation of the iRNA when administered systemically. Methods for making and administering cationic-iRNA complexes are well within the abilities of one skilled in the art (see e.g., Sorensen, D R., et al (2003) J Mol. Biol  327:761-766; Verma, U N., et al (2003)  Clin. Cancer Res.  9:1291-1300; Arnold, A S et al (2007)  J. Hypertens.  25:197-205, which are incorporated herein by reference in their entirety). Some non-limiting examples of drug delivery systems useful for systemic delivery of iRNAs include DOTAP (Sorensen, D R., et al (2003), supra; Verma, U N., et al (2003), supra), Oligofectamine, “solid nucleic acid lipid particles” (Zimmermann, T S., et al (2006)  Nature  441:111-114), cardiolipin (Chien, P Y., et al (2005)  Cancer Gene Ther.  12:321-328; Pal, A., et al (2005)  Int J. Oncol.  26:1087-1091), polyethyleneimine (Bonnet M E., et al (2008)  Pharm. Res. August  16  Epub ahead of print; Aigner , A. (2006)  J. Biomed. Biotechnol.  71659), Arg-Gly-Asp (RGD) peptides (Liu, S. (2006)  Mol. Pharm.  3:472-487), and polyamidoamines (Tomalia, D A., et al (2007)  Biochem. Soc. Trans.  35:61-67; Yoo, H., et al (1999)  Pharm. Res.  16:1799-1804). In some embodiments, an iRNA forms a complex with cyclodextrin for systemic administration. Methods for administration and pharmaceutical compositions of iRNAs and cyclodextrins can be found in U.S. Pat. No. 7,427,605, which is herein incorporated by reference in its entirety. 
     A. Vector encoded iRNAs of the Invention 
     iRNA targeting the C5 gene can be expressed from transcription units inserted into DNA or RNA vectors (see, e.g., Couture, A, et al.,  TIG . (1996), 12:5-10; Skillern, A., et al., International PCT Publication No. WO 00/22113, Conrad, International PCT Publication No. WO 00/22114, and Conrad, U.S. Pat. No. 6,054,299). Expression can be transient (on the order of hours to weeks) or sustained (weeks to months or longer), depending upon the specific construct used and the target tissue or cell type. These transgenes can be introduced as a linear construct, a circular plasmid, or a viral vector, which can be an integrating or non-integrating vector. The transgene can also be constructed to permit it to be inherited as an extrachromosomal plasmid (Gassmann, et al.,  Proc. Natl. Acad. Sci. USA  (1995) 92:1292). 
     The individual strand or strands of an iRNA can be transcribed from a promoter on an expression vector. Where two separate strands are to be expressed to generate, for example, a dsRNA, two separate expression vectors can be co-introduced (e.g., by transfection or infection) into a target cell. Alternatively each individual strand of a dsRNA can be transcribed by promoters both of which are located on the same expression plasmid. In one embodiment, a dsRNA is expressed as inverted repeat polynucleotides joined by a linker polynucleotide sequence such that the dsRNA has a stem and loop structure. 
     iRNA expression vectors are generally DNA plasmids or viral vectors. Expression vectors compatible with eukaryotic cells, preferably those compatible with vertebrate cells, can be used to produce recombinant constructs for the expression of an iRNA as described herein. Eukaryotic cell expression vectors are well known in the art and are available from a number of commercial sources. Typically, such vectors are provided containing convenient restriction sites for insertion of the desired nucleic acid segment. Delivery of iRNA expressing vectors can be systemic, such as by intravenous or intramuscular administration, by administration to target cells ex-planted from the patient followed by reintroduction into the patient, or by any other means that allows for introduction into a desired target cell. 
     iRNA expression plasmids can be transfected into target cells as a complex with cationic lipid carriers (e.g., Oligofectamine) or non-cationic lipid-based carriers (e.g., Transit-TKO™). Multiple lipid transfections for iRNA-mediated knockdowns targeting different regions of a target RNA over a period of a week or more are also contemplated by the invention. Successful introduction of vectors into host cells can be monitored using various known methods. For example, transient transfection can be signaled with a reporter, such as a fluorescent marker, such as Green Fluorescent Protein (GFP). Stable transfection of cells ex vivo can be ensured using markers that provide the transfected cell with resistance to specific environmental factors (e.g., antibiotics and drugs), such as hygromycin B resistance. 
     Viral vector systems which can be utilized with the methods and compositions described herein include, but are not limited to, (a) adenovirus vectors; (b) retrovirus vectors, including but not limited to lentiviral vectors, moloney murine leukemia virus, etc.; (c) adeno-associated virus vectors; (d) herpes simplex virus vectors; (e) SV 40 vectors; (f) polyoma virus vectors; (g) papilloma virus vectors; (h) picornavirus vectors; (i) pox virus vectors such as an orthopox, e.g., vaccinia virus vectors or avipox, e.g. canary pox or fowl pox; and (j) a helper-dependent or gutless adenovirus. Replication-defective viruses can also be advantageous. Different vectors will or will not become incorporated into the cells&#39; genome. The constructs can include viral sequences for transfection, if desired. Alternatively, the construct can be incorporated into vectors capable of episomal replication, e.g. EPV and EBV vectors. Constructs for the recombinant expression of an iRNA will generally require regulatory elements, e.g., promoters, enhancers, etc., to ensure the expression of the iRNA in target cells. Other aspects to consider for vectors and constructs are further described below. 
     Vectors useful for the delivery of an iRNA will include regulatory elements (promoter, enhancer, etc.) sufficient for expression of the iRNA in the desired target cell or tissue. The regulatory elements can be chosen to provide either constitutive or regulated/inducible expression. 
     Expression of the iRNA can be precisely regulated, for example, by using an inducible regulatory sequence that is sensitive to certain physiological regulators, e.g., circulating glucose levels, or hormones (Docherty et al., 1994 , FASEB J.  8:20-24). Such inducible expression systems, suitable for the control of dsRNA expression in cells or in mammals include, for example, regulation by ecdysone, by estrogen, progesterone, tetracycline, chemical inducers of dimerization, and isopropyl-beta-D1-thiogalactopyranoside (IPTG). A person skilled in the art would be able to choose the appropriate regulatory/promoter sequence based on the intended use of the iRNA transgene. 
     Viral vectors that contain nucleic acid sequences encoding an iRNA can be used. For example, a retroviral vector can be used (see Miller et al.,  Meth. Enzymol.  217:581-599 (1993)). These retroviral vectors contain the components necessary for the correct packaging of the viral genome and integration into the host cell DNA. The nucleic acid sequences encoding an iRNA are cloned into one or more vectors, which facilitate delivery of the nucleic acid into a patient. More detail about retroviral vectors can be found, for example, in Boesen et al.,  Biotherapy  6:291-302 (1994), which describes the use of a retroviral vector to deliver the mdr1 gene to hematopoietic stem cells in order to make the stem cells more resistant to chemotherapy. Other references illustrating the use of retroviral vectors in gene therapy are: Clowes et al.,  J. Clin. Invest.  93:644-651 (1994); Kiem et al.,  Blood  83:1467-1473 (1994);  Salmons and Gunzberg, Human Gene Therapy  4:129-141 (1993); and Grossman and Wilson,  Curr. Opin . in Genetics and Devel. 3:110-114 (1993). Lentiviral vectors contemplated for use include, for example, the HIV based vectors described in U.S. Pat. Nos. 6,143,520; 5,665,557; and 5,981,276, which are herein incorporated by reference. 
     Adenoviruses are also contemplated for use in delivery of iRNAs of the invention. Adenoviruses are especially attractive vehicles, e.g., for delivering genes to respiratory epithelia. Adenoviruses naturally infect respiratory epithelia where they cause a mild disease. Other targets for adenovirus-based delivery systems are liver, the central nervous system, endothelial cells, and muscle. Adenoviruses have the advantage of being capable of infecting non-dividing cells. Kozarsky and Wilson,  Current Opinion in Genetics and Development  3:499-503 (1993) present a review of adenovirus-based gene therapy. Bout et al.,  Human Gene Therapy  5:3-10 (1994) demonstrated the use of adenovirus vectors to transfer genes to the respiratory epithelia of rhesus monkeys. Other instances of the use of adenoviruses in gene therapy can be found in Rosenfeld et al.,  Science  252:431-434 (1991); Rosenfeld et al.,  Cell  68:143-155 (1992); Mastrangeli et al.,  J. Clin. Invest.  91:225-234 (1993); PCT Publication WO94/12649; and Wang, et al.,  Gene Therapy  2:775-783 (1995). A suitable AV vector for expressing an iRNA featured in the invention, a method for constructing the recombinant AV vector, and a method for delivering the vector into target cells, are described in Xia H et al. (2002),  Nat. Biotech.  20: 1006-1010. 
     Adeno-associated virus (AAV) vectors may also be used to delivery an iRNA of the invention (Walsh et al.,  Proc. Soc. Exp. Biol. Med.  204:289-300 (1993); U.S. Pat. No. 5,436,146). In one embodiment, the iRNA can be expressed as two separate, complementary single-stranded RNA molecules from a recombinant AAV vector having, for example, either the U6 or H1 RNA promoters, or the cytomegalovirus (CMV) promoter. Suitable AAV vectors for expressing the dsRNA featured in the invention, methods for constructing the recombinant AV vector, and methods for delivering the vectors into target cells are described in Samulski R et al. (1987),  J. Virol.  61: 3096-3101; Fisher K J et al. (1996),  J Virol,  70: 520-532; Samulski R et al. (1989),  J. Virol.  63: 3822-3826; U.S. Pat. Nos. 5,252,479; 5,139,941; International Patent Application No. WO 94/13788; and International patent Application No. WO 93/24641, the entire disclosures of which are herein incorporated by reference. 
     Another viral vector suitable for delivery of an iRNA of the invention is a pox virus such as a vaccinia virus, for example an attenuated vaccinia such as Modified Virus Ankara (MVA) or NYVAC, an avipox such as fowl pox or canary pox. 
     The tropism of viral vectors can be modified by pseudotyping the vectors with envelope proteins or other surface antigens from other viruses, or by substituting different viral capsid proteins, as appropriate. For example, lentiviral vectors can be pseudotyped with surface proteins from vesicular stomatitis virus (VSV), rabies, Ebola, Mokola, and the like. AAV vectors can be made to target different cells by engineering the vectors to express different capsid protein serotypes; see, e.g., Rabinowitz J E et al. (2002),  J Virol  76:791-801, the entire disclosure of which is herein incorporated by reference. 
     The pharmaceutical preparation of a vector can include the vector in an acceptable diluent, or can include a slow release matrix in which the gene delivery vehicle is imbedded. Alternatively, where the complete gene delivery vector can be produced intact from recombinant cells, e.g., retroviral vectors, the pharmaceutical preparation can include one or more cells which produce the gene delivery system. 
     V. Pharmaceutical Compositions of the Invention 
     The present invention also includes pharmaceutical compositions and formulations which include the iRNAs of the invention. In one embodiment, provided herein are pharmaceutical compositions containing an iRNA, as described herein, and a pharmaceutically acceptable carrier. 
     The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human subjects and animal subjects without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. 
     The phrase “pharmaceutically-acceptable carrier” as used herein means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject being treated. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) lubricating agents, such as magnesium state, sodium lauryl sulfate and talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer&#39;s solution; (19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates and/or polyanhydrides; (22) bulking agents, such as polypeptides and amino acids (23) serum component, such as serum albumin, HDL and LDL; and (22) other non-toxic compatible substances employed in pharmaceutical formulations. 
     The pharmaceutical compositions containing the iRNA are useful for treating a disease or disorder associated with the expression or activity of a C5 gene, e.g. a complement component C5-associated disease. Such pharmaceutical compositions are formulated based on the mode of delivery. One example is compositions that are formulated for systemic administration via parenteral delivery, e.g., by subcutaneous (SC) or intravenous (IV) delivery. Another example is compositions that are formulated for direct delivery into the brain parenchyma, e.g., by infusion into the brain, such as by continuous pump infusion. The pharmaceutical compositions of the invention may be administered in dosages sufficient to inhibit expression of a C5 gene. 
     In one embodiment, an iRNA agent of the invention is administered to a subject as a weight-based dose. A “weight-based dose” (e.g., a dose in mg/kg) is a dose of the iRNA agent that will change depending on the subject&#39;s weight. In another embodiment, an iRNA agent is administered to a subject as a fixed dose. A “fixed dose” (e.g., a dose in mg) means that one dose of an iRNA agent is used for all subjects regardless of any specific subject-related factors, such as weight. In one particular embodiment, a fixed dose of an iRNA agent of the invention is based on a predetermined weight or age. 
     In general, a suitable dose of an iRNA of the invention will be in the range of about 0.001 to about 200.0 milligrams per kilogram body weight of the recipient per day, generally in the range of about 1 to 50 mg per kilogram body weight per day. For example, the dsRNA can be administered at about 0.01 mg/kg, about 0.05 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 3 mg/kg, about 10 mg/kg, about 20 mg/kg, about 30 mg/kg, about 40 mg/kg, or about 50 mg/kg per single dose. 
     For example, the dsRNA may be administered at a dose of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or about 10 mg/kg. Values and ranges intermediate to the recited values are also intended to be part of this invention. 
     In another embodiment, the dsRNA is administered at a dose of about 0.1 to about 50 mg/kg, about 0.25 to about 50 mg/kg, about 0.5 to about 50 mg/kg, about 0.75 to about 50 mg/kg, about 1 to about 50 mg/mg, about 1.5 to about 50 mg/kb, about 2 to about 50 mg/kg, about 2.5 to about 50 mg/kg, about 3 to about 50 mg/kg, about 3.5 to about 50 mg/kg, about 4 to about 50 mg/kg, about 4.5 to about 50 mg/kg, about 5 to about 50 mg/kg, about 7.5 to about 50 mg/kg, about 10 to about 50 mg/kg, about 15 to about 50 mg/kg, about 20 to about 50 mg/kg, about 20 to about 50 mg/kg, about 25 to about 50 mg/kg, about 25 to about 50 mg/kg, about 30 to about 50 mg/kg, about 35 to about 50 mg/kg, about 40 to about 50 mg/kg, about 45 to about 50 mg/kg, about 0.1 to about 45 mg/kg, about 0.25 to about 45 mg/kg, about 0.5 to about 45 mg/kg, about 0.75 to about 45 mg/kg, about 1 to about 45 mg/mg, about 1.5 to about 45 mg/kb, about 2 to about 45 mg/kg, about 2.5 to about 45 mg/kg, about 3 to about 45 mg/kg, about 3.5 to about 45 mg/kg, about 4 to about 45 mg/kg, about 4.5 to about 45 mg/kg, about 5 to about 45 mg/kg, about 7.5 to about 45 mg/kg, about 10 to about 45 mg/kg, about 15 to about 45 mg/kg, about 20 to about 45 mg/kg, about 20 to about 45 mg/kg, about 25 to about 45 mg/kg, about 25 to about 45 mg/kg, about 30 to about 45 mg/kg, about 35 to about 45 mg/kg, about 40 to about 45 mg/kg, about 0.1 to about 40 mg/kg, about 0.25 to about 40 mg/kg, about 0.5 to about 40 mg/kg, about 0.75 to about 40 mg/kg, about 1 to about 40 mg/mg, about 1.5 to about 40 mg/kb, about 2 to about 40 mg/kg, about 2.5 to about 40 mg/kg, about 3 to about 40 mg/kg, about 3.5 to about 40 mg/kg, about 4 to about 40 mg/kg, about 4.5 to about 40 mg/kg, about 5 to about 40 mg/kg, about 7.5 to about 40 mg/kg, about 10 to about 40 mg/kg, about 15 to about 40 mg/kg, about 20 to about 40 mg/kg, about 20 to about 40 mg/kg, about 25 to about 40 mg/kg, about 25 to about 40 mg/kg, about 30 to about 40 mg/kg, about 35 to about 40 mg/kg, about 0.1 to about 30 mg/kg, about 0.25 to about 30 mg/kg, about 0.5 to about 30 mg/kg, about 0.75 to about 30 mg/kg, about 1 to about 30 mg/mg, about 1.5 to about 30 mg/kb, about 2 to about 30 mg/kg, about 2.5 to about 30 mg/kg, about 3 to about 30 mg/kg, about 3.5 to about 30 mg/kg, about 4 to about 30 mg/kg, about 4.5 to about 30 mg/kg, about 5 to about 30 mg/kg, about 7.5 to about 30 mg/kg, about 10 to about 30 mg/kg, about 15 to about 30 mg/kg, about 20 to about 30 mg/kg, about 20 to about 30 mg/kg, about 25 to about 30 mg/kg, about 0.1 to about 20 mg/kg, about 0.25 to about 20 mg/kg, about 0.5 to about 20 mg/kg, about 0.75 to about 20 mg/kg, about 1 to about 20 mg/mg, about 1.5 to about 20 mg/kb, about 2 to about 20 mg/kg, about 2.5 to about 20 mg/kg, about 3 to about 20 mg/kg, about 3.5 to about 20 mg/kg, about 4 to about 20 mg/kg, about 4.5 to about 20 mg/kg, about 5 to about 20 mg/kg, about 7.5 to about 20 mg/kg, about 10 to about 20 mg/kg, or about 15 to about 20 mg/kg. Values and ranges intermediate to the recited values are also intended to be part of this invention. 
     For example, the dsRNA may be administered at a dose of about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or about 10 mg/kg. Values and ranges intermediate to the recited values are also intended to be part of this invention. 
     In another embodiment, the dsRNA is administered at a dose of about 0.5 to about 50 mg/kg, about 0.75 to about 50 mg/kg, about 1 to about 50 mg/mg, about 1.5 to about 50 mg/kb, about 2 to about 50 mg/kg, about 2.5 to about 50 mg/kg, about 3 to about 50 mg/kg, about 3.5 to about 50 mg/kg, about 4 to about 50 mg/kg, about 4.5 to about 50 mg/kg, about 5 to about 50 mg/kg, about 7.5 to about 50 mg/kg, about 10 to about 50 mg/kg, about 15 to about 50 mg/kg, about 20 to about 50 mg/kg, about 20 to about 50 mg/kg, about 25 to about 50 mg/kg, about 25 to about 50 mg/kg, about 30 to about 50 mg/kg, about 35 to about 50 mg/kg, about 40 to about 50 mg/kg, about 45 to about 50 mg/kg, about 0.5 to about 45 mg/kg, about 0.75 to about 45 mg/kg, about 1 to about 45 mg/mg, about 1.5 to about 45 mg/kb, about 2 to about 45 mg/kg, about 2.5 to about 45 mg/kg, about 3 to about 45 mg/kg, about 3.5 to about 45 mg/kg, about 4 to about 45 mg/kg, about 4.5 to about 45 mg/kg, about 5 to about 45 mg/kg, about 7.5 to about 45 mg/kg, about 10 to about 45 mg/kg, about 15 to about 45 mg/kg, about 20 to about 45 mg/kg, about 20 to about 45 mg/kg, about 25 to about 45 mg/kg, about 25 to about 45 mg/kg, about 30 to about 45 mg/kg, about 35 to about 45 mg/kg, about 40 to about 45 mg/kg, about 0.5 to about 40 mg/kg, about 0.75 to about 40 mg/kg, about 1 to about 40 mg/mg, about 1.5 to about 40 mg/kb, about 2 to about 40 mg/kg, about 2.5 to about 40 mg/kg, about 3 to about 40 mg/kg, about 3.5 to about 40 mg/kg, about 4 to about 40 mg/kg, about 4.5 to about 40 mg/kg, about 5 to about 40 mg/kg, about 7.5 to about 40 mg/kg, about 10 to about 40 mg/kg, about 15 to about 40 mg/kg, about 20 to about 40 mg/kg, about 20 to about 40 mg/kg, about 25 to about 40 mg/kg, about 25 to about 40 mg/kg, about 30 to about 40 mg/kg, about 35 to about 40 mg/kg, about 0.5 to about 30 mg/kg, about 0.75 to about 30 mg/kg, about 1 to about 30 mg/mg, about 1.5 to about 30 mg/kb, about 2 to about 30 mg/kg, about 2.5 to about 30 mg/kg, about 3 to about 30 mg/kg, about 3.5 to about 30 mg/kg, about 4 to about 30 mg/kg, about 4.5 to about 30 mg/kg, about 5 to about 30 mg/kg, about 7.5 to about 30 mg/kg, about 10 to about 30 mg/kg, about 15 to about 30 mg/kg, about 20 to about 30 mg/kg, about 20 to about 30 mg/kg, about 25 to about 30 mg/kg, about 0.5 to about 20 mg/kg, about 0.75 to about 20 mg/kg, about 1 to about 20 mg/mg, about 1.5 to about 20 mg/kb, about 2 to about 20 mg/kg, about 2.5 to about 20 mg/kg, about 3 to about 20 mg/kg, about 3.5 to about 20 mg/kg, about 4 to about 20 mg/kg, about 4.5 to about 20 mg/kg, about 5 to about 20 mg/kg, about 7.5 to about 20 mg/kg, about 10 to about 20 mg/kg, or about 15 to about 20 mg/kg. In one embodiment, the dsRNA is administered at a dose of about 10 mg/kg to about 30 mg/kg. Values and ranges intermediate to the recited values are also intended to be part of this invention. 
     For example, subjects can be administered, e.g., subcutaneously or intravenously, a single therapeutic amount of iRNA, such as about 0.1, 0.125, 0.15, 0.175, 0.2, 0.225, 0.25, 0.275, 0.3, 0.325, 0.35, 0.375, 0.4, 0.425, 0.45, 0.475, 0.5, 0.525, 0.55, 0.575, 0.6, 0.625, 0.65, 0.675, 0.7, 0.725, 0.75, 0.775, 0.8, 0.825, 0.85, 0.875, 0.9, 0.925, 0.95, 0.975, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 31, 32, 33, 34, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or about 50 mg/kg. Values and ranges intermediate to the recited values are also intended to be part of this invention. 
     In some embodiments, subjects are administered, e.g., subcutaneously or intravenously, multiple doses of a therapeutic amount of iRNA, such as a dose about 0.1, 0.125, 0.15, 0.175, 0.2, 0.225, 0.25, 0.275, 0.3, 0.325, 0.35, 0.375, 0.4, 0.425, 0.45, 0.475, 0.5, 0.525, 0.55, 0.575, 0.6, 0.625, 0.65, 0.675, 0.7, 0.725, 0.75, 0.775, 0.8, 0.825, 0.85, 0.875, 0.9, 0.925, 0.95, 0.975, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 31, 32, 33, 34, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or about 50 mg/kg. A multi-dose regimen may include administration of a therapeutic amount of iRNA daily, such as for two days, three days, four days, five days, six days, seven days, or longer. 
     In other embodiments, subjects are administered, e.g., subcutaneously or intravenously, a repeat dose of a therapeutic amount of iRNA, such as a dose about 0.1, 0.125, 0.15, 0.175, 0.2, 0.225, 0.25, 0.275, 0.3, 0.325, 0.35, 0.375, 0.4, 0.425, 0.45, 0.475, 0.5, 0.525, 0.55, 0.575, 0.6, 0.625, 0.65, 0.675, 0.7, 0.725, 0.75, 0.775, 0.8, 0.825, 0.85, 0.875, 0.9, 0.925, 0.95, 0.975, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 31, 32, 33, 34, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or about 50 mg/kg. A repeat-dose regimine may include administration of a therapeutic amount of iRNA on a regular basis, such as every other day, every third day, every fourth day, twice a week, once a week, every other week, or once a month. 
     In certain embodiments, for example, when a composition of the invention comprises a dsRNA as described herein and a lipid, subjects can be administered a therapeutic amount of iRNA, such as about 0.01 mg/kg to about 5 mg/kg, about 0.01 mg/kg to about 10 mg/kg, about 0.05 mg/kg to about 5 mg/kg, about 0.05 mg/kg to about 10 mg/kg, about 0.1 mg/kg to about 5 mg/kg, about 0.1 mg/kg to about 10 mg/kg, about 0.2 mg/kg to about 5 mg/kg, about 0.2 mg/kg to about 10 mg/kg, about 0.3 mg/kg to about 5 mg/kg, about 0.3 mg/kg to about 10 mg/kg, about 0.4 mg/kg to about 5 mg/kg, about 0.4 mg/kg to about 10 mg/kg, about 0.5 mg/kg to about 5 mg/kg, about 0.5 mg/kg to about 10 mg/kg, about 1 mg/kg to about 5 mg/kg, about 1 mg/kg to about 10 mg/kg, about 1.5 mg/kg to about 5 mg/kg, about 1.5 mg/kg to about 10 mg/kg, about 2 mg/kg to about 2.5 mg/kg, about 2 mg/kg to about 10 mg/kg, about 3 mg/kg to about 5 mg/kg, about 3 mg/kg to about 10 mg/kg, about 3.5 mg/kg to about 5 mg/kg, about 4 mg/kg to about 5 mg/kg, about 4.5 mg/kg to about 5 mg/kg, about 4 mg/kg to about 10 mg/kg, about 4.5 mg/kg to about 10 mg/kg, about 5 mg/kg to about 10 mg/kg, about 5.5 mg/kg to about 10 mg/kg, about 6 mg/kg to about 10 mg/kg, about 6.5 mg/kg to about 10 mg/kg, about 7 mg/kg to about 10 mg/kg, about 7.5 mg/kg to about 10 mg/kg, about 8 mg/kg to about 10 mg/kg, about 8.5 mg/kg to about 10 mg/kg, about 9 mg/kg to about 10 mg/kg, or about 9.5 mg/kg to about 10 mg/kg. Values and ranges intermediate to the recited values are also intended to be part of this invention. 
     For example, the dsRNA may be administered at a dose of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or about 10 mg/kg. Values and ranges intermediate to the recited values are also intended to be part of this invention. 
     In certain embodiments of the invention, for example, when a double stranded RNAi agent includes a modification (e.g., one or more motifs of three identical modifications on three consecutive nucleotides), including one such motif at or near the cleavage site of the agent, six phosphorothioate linkages, and a ligand, such an agent is administered at a dose of about 0.01 to about 0.5 mg/kg, about 0.01 to about 0.4 mg/kg, about 0.01 to about 0.3 mg/kg, about 0.01 to about 0.2 mg/kg, about 0.01 to about 0.1 mg/kg, about 0.01 mg/kg to about 0.09 mg/kg, about 0.01 mg/kg to about 0.08 mg/kg, about 0.01 mg/kg to about 0.07 mg/kg, about 0.01 mg/kg to about 0.06 mg/kg, about 0.01 mg/kg to about 0.05 mg/kg, about 0.02 to about 0.5 mg/kg, about 0.02 to about 0.4 mg/kg, about 0.02 to about 0.3 mg/kg, about 0.02 to about 0.2 mg/kg, about 0.02 to about 0.1 mg/kg, about 0.02 mg/kg to about 0.09 mg/kg, about 0.02 mg/kg to about 0.08 mg/kg, about 0.02 mg/kg to about 0.07 mg/kg, about 0.02 mg/kg to about 0.06 mg/kg, about 0.02 mg/kg to about 0.05 mg/kg, about 0.03 to about 0.5 mg/kg, about 0.03 to about 0.4 mg/kg, about 0.03 to about 0.3 mg/kg, about 0.03 to about 0.2 mg/kg, about 0.03 to about 0.1 mg/kg, about 0.03 mg/kg to about 0.09 mg/kg, about 0.03 mg/kg to about 0.08 mg/kg, about 0.03 mg/kg to about 0.07 mg/kg, about 0.03 mg/kg to about 0.06 mg/kg, about 0.03 mg/kg to about 0.05 mg/kg, about 0.04 to about 0.5 mg/kg, about 0.04 to about 0.4 mg/kg, about 0.04 to about 0.3 mg/kg, about 0.04 to about 0.2 mg/kg, about 0.04 to about 0.1 mg/kg, about 0.04 mg/kg to about 0.09 mg/kg, about 0.04 mg/kg to about 0.08 mg/kg, about 0.04 mg/kg to about 0.07 mg/kg, about 0.04 mg/kg to about 0.06 mg/kg, about 0.05 to about 0.5 mg/kg, about 0.05 to about 0.4 mg/kg, about 0.05 to about 0.3 mg/kg, about 0.05 to about 0.2 mg/kg, about 0.05 to about 0.1 mg/kg, about 0.05 mg/kg to about 0.09 mg/kg, about 0.05 mg/kg to about 0.08 mg/kg, or about 0.05 mg/kg to about 0.07 mg/kg. Values and ranges intermediate to the foregoing recited values are also intended to be part of this invention, e.g., the RNAi agent may be administered to the subject at a dose of about 0.015 mg/kg to about 0.45 mg/kg. 
     For example, the RNAi agent, e.g., RNAi agent in a pharmaceutical composition, may be administered at a dose of about 0.01 mg/kg, 0.0125 mg/kg, 0.015 mg/kg, 0.0175 mg/kg, 0.02 mg/kg, 0.0225 mg/kg, 0.025 mg/kg, 0.0275 mg/kg, 0.03 mg/kg, 0.0325 mg/kg, 0.035 mg/kg, 0.0375 mg/kg, 0.04 mg/kg, 0.0425 mg/kg, 0.045 mg/kg, 0.0475 mg/kg, 0.05 mg/kg, 0.0525 mg/kg, 0.055 mg/kg, 0.0575 mg/kg, 0.06 mg/kg, 0.0625 mg/kg, 0.065 mg/kg, 0.0675 mg/kg, 0.07 mg/kg, 0.0725 mg/kg, 0.075 mg/kg, 0.0775 mg/kg, 0.08 mg/kg, 0.0825 mg/kg, 0.085 mg/kg, 0.0875 mg/kg, 0.09 mg/kg, 0.0925 mg/kg, 0.095 mg/kg, 0.0975 mg/kg, 0.1 mg/kg, 0.125 mg/kg, 0.15 mg/kg, 0.175 mg/kg, 0.2 mg/kg, 0.225 mg/kg, 0.25 mg/kg, 0.275 mg/kg, 0.3 mg/kg, 0.325 mg/kg, 0.35 mg/kg, 0.375 mg/kg, 0.4 mg/kg, 0.425 mg/kg, 0.45 mg/kg, 0.475 mg/kg, or about 0.5 mg/kg. Values intermediate to the foregoing recited values are also intended to be part of this invention. 
     In some embodiments, the RNAi agent is administered as a fixed dose of between about 25 mg to about 900 mg, e.g., between about 25 mg to about 850 mg, between about 25 mg to about 500 mg, between about 25 mg to about 400 mg, between about 25 mg to about 300 mg, between about 50 mg to about 850 mg, between about 50 mg to about 500 mg, between about 50 mg to about 400 mg, between about 50 mg to about 300 mg, between about 100 mg to about 850 mg, between about 100 mg to about 500 mg, between about 100 mg to about 400 mg, between about 100 mg to about 300 mg, between about 200 mg to about 850 mg, between about 200 mg to about 500 mg, between about 200 mg to about 400 mg, between about 200 mg to about 300 mg, between about 100 mg to about 800 mg, between about 100 mg to about 750 mg, between about 100 mg to about 700 mg, between about 100 mg to about 650 mg, between about 100 mg to about 600 mg, between about 100 mg to about 550 mg, between about 100 mg to about 500 mg, between about 200 mg to about 850 mg, between about 200 mg to about 800 mg, between about 200 mg to about 750 mg, between about 200 mg to about 700 mg, between about 200 mg to about 650 mg, between about 200 mg to about 600 mg, between about 200 mg to about 550 mg, between about 200 mg to about 500 mg, between about 300 mg to about 850 mg, between about 300 mg to about 800 mg, between about 300 mg to about 750 mg, between about 300 mg to about 700 mg, between about 300 mg to about 650 mg, between about 300 mg to about 600 mg, between about 300 mg to about 550 mg, between about 300 mg to about 500 mg, between about 400 mg to about 850 mg, between about 400 mg to about 800 mg, between about 400 mg to about 750 mg, between about 400 mg to about 700 mg, between about 400 mg to about 650 mg, between about 400 mg to about 600 mg, between about 400 mg to about 550 mg, or between about 400 mg to about 500 mg. 
     In some embodiments, the RNAi agent is administered as a fixed dose of about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, or about 900 mg. 
     The pharmaceutical composition can be administered by intravenous infusion over a period of time, such as over a 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, and 21, 22, 23, 24, or about a 25 minute period. The administration may be repeated, for example, on a regular basis, such as weekly, biweekly (i.e., every two weeks) for one month, two months, three months, four months or longer. After an initial treatment regimen, the treatments can be administered on a less frequent basis. For example, after administration weekly or biweekly for three months, administration can be repeated once per month, for six months or a year or longer. 
     The pharmaceutical composition can be administered once daily, or the iRNA can be administered as two, three, or more sub-doses at appropriate intervals throughout the day or even using continuous infusion or delivery through a controlled release formulation. In that case, the iRNA contained in each sub-dose must be correspondingly smaller in order to achieve the total daily dosage. The dosage unit can also be compounded for delivery over several days, e.g., using a conventional sustained release formulation which provides sustained release of the iRNA over a several day period. Sustained release formulations are well known in the art and are particularly useful for delivery of agents at a particular site, such as could be used with the agents of the present invention. In this embodiment, the dosage unit contains a corresponding multiple of the daily dose. 
     In other embodiments, a single dose of the pharmaceutical compositions can be long lasting, such that subsequent doses are administered at not more than 3, 4, or 5 day intervals, or at not more than 1, 2, 3, or 4 week intervals. In some embodiments of the invention, a single dose of the pharmaceutical compositions of the invention is administered once per week. In other embodiments of the invention, a single dose of the pharmaceutical compositions of the invention is administered bi-monthly (i.e., every two weeks) for one month, two months, three months, four months or longer. After an initial treatment regimen, the treatments can be administered on a less frequent basis. For example, after administration weekly or biweekly for three months, administration can be repeated once per month, for six months or a year or longer, e.g., administered chronically. 
     The skilled artisan will appreciate that certain factors can influence the dosage and timing required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of a composition can include a single treatment or a series of treatments. Estimates of effective dosages and in vivo half-lives for the individual iRNAs encompassed by the invention can be made using conventional methodologies or on the basis of in vivo testing using an appropriate animal model, as described elsewhere herein. 
     Advances in mouse genetics have generated a number of mouse models for the study of various human diseases, such as a disorder that would benefit from reduction in the expression of C5. Such models can be used for in vivo testing of iRNA, as well as for determining a therapeutically effective dose. Suitable mouse models are known in the art and include, for example, collagen-induced arthritis mouse model (Courtenay, J. S., et al. (1980)  Nature  283, 666-668), myocardial ischemia (Homeister J W and Lucchesi B R (1994)  Annu Rev Pharmacol Toxicol  34:17-40), ovalbumin induced asthma mouse models (e.g., Tomkinson A., et al. (2001).  J. Immunol.  166, 5792-5800), (NZB×NZW)F1, MRL/Fas lpr  (MRL/lpr) and BXSB mouse models (Theofilopoulos, A. N. and Kono, D. H. 1999. Murine lupus models: gene-specific and genome-wide studies. In  Lahita R. G., ed., Systemic Lupus Erythematosus,  3rd edn, p. 145. Academic Press, San Diego, Calif.), mouse aHUS model (Goicoechea de Jorge et al. (2011)  The development of atypical hemolytic uremic syndrome depends on complement C 5 , J Am Soc Nephrol  22: 137-145. 
     The pharmaceutical compositions of the present invention can be administered in a number of ways depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration can be topical (e.g., by a transdermal patch), pulmonary, e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal, oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; subdermal, e.g., via an implanted device; or intracranial, e.g., by intraparenchymal, intrathecal or intraventricular, administration. 
     The iRNA can be delivered in a manner to target a particular tissue, such as the liver (e.g., the hepatocytes of the liver). 
     Pharmaceutical compositions and formulations for topical administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like can be necessary or desirable. Coated condoms, gloves and the like can also be useful. Suitable topical formulations include those in which the iRNAs featured in the invention are in admixture with a topical delivery agent such as lipids, liposomes, fatty acids, fatty acid esters, steroids, chelating agents and surfactants. Suitable lipids and liposomes include neutral (e.g., dioleoylphosphatidyl DOPE ethanolamine, dimyristoylphosphatidyl choline DMPC, distearolyphosphatidyl choline) negative (e.g., dimyristoylphosphatidyl glycerol DMPG) and cationic (e.g., dioleoyltetramethylaminopropyl DOTAP and dioleoylphosphatidyl ethanolamine DOTMA). iRNAs featured in the invention can be encapsulated within liposomes or can form complexes thereto, in particular to cationic liposomes. Alternatively, iRNAs can be complexed to lipids, in particular to cationic lipids. Suitable fatty acids and esters include but are not limited to arachidonic acid, oleic acid, eicosanoic acid, lauric acid, caprylic acid, capric acid, myristic acid, palmitic acid, stearic acid, linoleic acid, linolenic acid, dicaprate, tricaprate, monoolein, dilaurin, glyceryl 1-monocaprate, 1-dodecylazacycloheptan-2-one, an acylcarnitine, an acylcholine, or a C 1-20  alkyl ester (e.g., isopropylmyristate IPM), monoglyceride, diglyceride or pharmaceutically acceptable salt thereof). Topical formulations are described in detail in U.S. Pat. No. 6,747,014, which is incorporated herein by reference. 
     A. iRNA Formulations Comprising Membranous Molecular Assemblies 
     An iRNA for use in the compositions and methods of the invention can be formulated for delivery in a membranous molecular assembly, e.g., a liposome or a micelle. As used herein, the term “liposome” refers to a vesicle composed of amphiphilic lipids arranged in at least one bilayer, e.g., one bilayer or a plurality of bilayers. Liposomes include unilamellar and multilamellar vesicles that have a membrane formed from a lipophilic material and an aqueous interior. The aqueous portion contains the iRNA composition. The lipophilic material isolates the aqueous interior from an aqueous exterior, which typically does not include the iRNA composition, although in some examples, it may. Liposomes are useful for the transfer and delivery of active ingredients to the site of action. Because the liposomal membrane is structurally similar to biological membranes, when liposomes are applied to a tissue, the liposomal bilayer fuses with bilayer of the cellular membranes. As the merging of the liposome and cell progresses, the internal aqueous contents that include the iRNA are delivered into the cell where the iRNA can specifically bind to a target RNA and can mediate RNAi. In some cases the liposomes are also specifically targeted, e.g., to direct the iRNA to particular cell types. 
     A liposome containing a RNAi agent can be prepared by a variety of methods. In one example, the lipid component of a liposome is dissolved in a detergent so that micelles are formed with the lipid component. For example, the lipid component can be an amphipathic cationic lipid or lipid conjugate. The detergent can have a high critical micelle concentration and may be nonionic. Exemplary detergents include cholate, CHAPS, octylglucoside, deoxycholate, and lauroyl sarcosine. The RNAi agent preparation is then added to the micelles that include the lipid component. The cationic groups on the lipid interact with the RNAi agent and condense around the RNAi agent to form a liposome. After condensation, the detergent is removed, e.g., by dialysis, to yield a liposomal preparation of RNAi agent. 
     If necessary a carrier compound that assists in condensation can be added during the condensation reaction, e.g., by controlled addition. For example, the carrier compound can be a polymer other than a nucleic acid (e.g., spermine or spermidine). pH can also adjusted to favor condensation. 
     Methods for producing stable polynucleotide delivery vehicles, which incorporate a polynucleotide/cationic lipid complex as structural components of the delivery vehicle, are further described in, e.g., WO 96/37194, the entire contents of which are incorporated herein by reference. Liposome formation can also include one or more aspects of exemplary methods described in Felgner, P. L. et al.,  Proc. Natl. Acad. Sci., USA  8:7413-7417, 1987; U.S. Pat. Nos. 4,897,355; 5,171,678; Bangham, et al.  M Mol. Biol.  23:238, 1965; Olson, et al.  Biochim. Biophys. Acta  557:9, 1979; Szoka, et al.  Proc. Natl. Acad. Sci.  75: 4194, 1978; Mayhew, et al.  Biochim. Biophys. Acta  775:169, 1984; Kim, et al.  Biochim. Biophys. Acta  728:339, 1983; and Fukunaga, et al.  Endocrinol.  115:757, 1984. Commonly used techniques for preparing lipid aggregates of appropriate size for use as delivery vehicles include sonication and freeze-thaw plus extrusion (see, e.g., Mayer, et al.  Biochim. Biophys. Acta  858:161, 1986). Microfluidization can be used when consistently small (50 to 200 nm) and relatively uniform aggregates are desired (Mayhew, et al.  Biochim. Biophys. Acta  775:169, 1984). These methods are readily adapted to packaging RNAi agent preparations into liposomes. 
     Liposomes fall into two broad classes. Cationic liposomes are positively charged liposomes which interact with the negatively charged nucleic acid molecules to form a stable complex. The positively charged nucleic acid/liposome complex binds to the negatively charged cell surface and is internalized in an endosome. Due to the acidic pH within the endosome, the liposomes are ruptured, releasing their contents into the cell cytoplasm (Wang et al.,  Biochem. Biophys. Res. Commun.,  1987, 147, 980-985). 
     Liposomes which are pH-sensitive or negatively-charged, entrap nucleic acids rather than complex with it. Since both the nucleic acid and the lipid are similarly charged, repulsion rather than complex formation occurs. Nevertheless, some nucleic acid is entrapped within the aqueous interior of these liposomes. pH-sensitive liposomes have been used to deliver nucleic acids encoding the thymidine kinase gene to cell monolayers in culture. Expression of the exogenous gene was detected in the target cells (Zhou et al.,  Journal of Controlled Release,  1992, 19, 269-274). 
     One major type of liposomal composition includes phospholipids other than naturally-derived phosphatidylcholine. Neutral liposome compositions, for example, can be formed from dimyristoyl phosphatidylcholine (DMPC) or dipalmitoyl phosphatidylcholine (DPPC). Anionic liposome compositions generally are formed from dimyristoyl phosphatidylglycerol, while anionic fusogenic liposomes are formed primarily from dioleoyl phosphatidylethanolamine (DOPE). Another type of liposomal composition is formed from phosphatidylcholine (PC) such as, for example, soybean PC, and egg PC. Another type is formed from mixtures of phospholipid and/or phosphatidylcholine and/or cholesterol. 
     Examples of other methods to introduce liposomes into cells in vitro and in vivo include U.S. Pat. Nos. 5,283,185; 5,171,678; WO 94/00569; WO 93/24640; WO 91/16024; Felgner, J. Biol. Chem. 269:2550, 1994; Nabel, Proc. Natl. Acad. Sci. 90:11307, 1993; Nabel, Human Gene Ther. 3:649, 1992; Gershon, Biochem. 32:7143, 1993; and Strauss EMBO J. 11:417, 1992. 
     Non-ionic liposomal systems have also been examined to determine their utility in the delivery of drugs to the skin, in particular systems comprising non-ionic surfactant and cholesterol. Non-ionic liposomal formulations comprising Novasome™ I (glyceryl dilaurate/cholesterol/polyoxyethylene-10-stearyl ether) and Novasome™ II (glyceryl distearate/cholesterol/polyoxyethylene-10-stearyl ether) were used to deliver cyclosporin-A into the dermis of mouse skin. Results indicated that such non-ionic liposomal systems were effective in facilitating the deposition of cyclosporine A into different layers of the skin (Hu et al.  S.T.P.Pharma. Sci.,  1994, 4(6) 466). 
     Liposomes also include “sterically stabilized” liposomes, a term which, as used herein, refers to liposomes comprising one or more specialized lipids that, when incorporated into liposomes, result in enhanced circulation lifetimes relative to liposomes lacking such specialized lipids. Examples of sterically stabilized liposomes are those in which part of the vesicle-forming lipid portion of the liposome (A) comprises one or more glycolipids, such as monosialoganglioside G M1 , or (B) is derivatized with one or more hydrophilic polymers, such as a polyethylene glycol (PEG) moiety. While not wishing to be bound by any particular theory, it is thought in the art that, at least for sterically stabilized liposomes containing gangliosides, sphingomyelin, or PEG-derivatized lipids, the enhanced circulation half-life of these sterically stabilized liposomes derives from a reduced uptake into cells of the reticuloendothelial system (RES) (Allen et al.,  FEBS Letters,  1987, 223, 42; Wu et al.,  Cancer Research,  1993, 53, 3765). 
     Various liposomes comprising one or more glycolipids are known in the art. Papahadjopoulos et al. ( Ann. N.Y. Acad. Sci.,  1987, 507, 64) reported the ability of monosialoganglioside G Ml , galactocerebroside sulfate and phosphatidylinositol to improve blood half-lives of liposomes. These findings were expounded upon by Gabizon et al. ( Proc. Natl. Acad. Sci. U.S.A.,  1988, 85, 6949). U.S. Pat. No. 4,837,028 and WO 88/04924, both to Allen et al., disclose liposomes comprising (1) sphingomyelin and (2) the ganglioside G Ml  or a galactocerebroside sulfate ester. U.S. Pat. No. 5,543,152 (Webb et al.) discloses liposomes comprising sphingomyelin. Liposomes comprising 1,2-sn-dimyristoylphosphatidylcholine are disclosed in WO 97/13499 (Lim et al). 
     In one embodiment, cationic liposomes are used. Cationic liposomes possess the advantage of being able to fuse to the cell membrane. Non-cationic liposomes, although not able to fuse as efficiently with the plasma membrane, are taken up by macrophages in vivo and can be used to deliver RNAi agents to macrophages. 
     Further advantages of liposomes include: liposomes obtained from natural phospholipids are biocompatible and biodegradable; liposomes can incorporate a wide range of water and lipid soluble drugs; liposomes can protect encapsulated RNAi agents in their internal compartments from metabolism and degradation (Rosoff, in “Pharmaceutical Dosage Forms,” Lieberman, Rieger and Banker (Eds.), 1988, volume 1, p. 245). Important considerations in the preparation of liposome formulations are the lipid surface charge, vesicle size and the aqueous volume of the liposomes. 
     A positively charged synthetic cationic lipid, N-[1-(2,3-dioleyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA) can be used to form small liposomes that interact spontaneously with nucleic acid to form lipid-nucleic acid complexes which are capable of fusing with the negatively charged lipids of the cell membranes of tissue culture cells, resulting in delivery of RNAi agent (see, e.g., Felgner, P. L. et al.,  Proc. Natl. Acad. Sci., USA  8:7413-7417, 1987 and U.S. Pat. No. 4,897,355 for a description of DOTMA and its use with DNA). 
     A DOTMA analogue, 1,2-bis(oleoyloxy)-3-(trimethylammonia)propane (DOTAP) can be used in combination with a phospholipid to form DNA-complexing vesicles. Lipofectin™ Bethesda Research Laboratories, Gaithersburg, Md.) is an effective agent for the delivery of highly anionic nucleic acids into living tissue culture cells that comprise positively charged DOTMA liposomes which interact spontaneously with negatively charged polynucleotides to form complexes. When enough positively charged liposomes are used, the net charge on the resulting complexes is also positive. Positively charged complexes prepared in this way spontaneously attach to negatively charged cell surfaces, fuse with the plasma membrane, and efficiently deliver functional nucleic acids into, for example, tissue culture cells. Another commercially available cationic lipid, 1,2-bis(oleoyloxy)-3,3-(trimethylammonia)propane (“DOTAP”) (Boehringer Mannheim, Indianapolis, Ind.) differs from DOTMA in that the oleoyl moieties are linked by ester, rather than ether linkages. 
     Other reported cationic lipid compounds include those that have been conjugated to a variety of moieties including, for example, carboxyspermine which has been conjugated to one of two types of lipids and includes compounds such as 5-carboxyspermylglycine dioctaoleoylamide (“DOGS”) (Transfectam™, Promega, Madison, Wis.) and dipalmitoylphosphatidylethanolamine 5-carboxyspermyl-amide (“DPPES”) (see, e.g., U.S. Pat. No. 5,171,678). 
     Another cationic lipid conjugate includes derivatization of the lipid with cholesterol (“DC-Chol”) which has been formulated into liposomes in combination with DOPE (See, Gao, X. and Huang, L.,  Biochim. Biophys. Res. Commun.  179:280, 1991). Lipopolylysine, made by conjugating polylysine to DOPE, has been reported to be effective for transfection in the presence of serum (Zhou, X. et al.,  Biochim. Biophys. Acta  1065:8, 1991). For certain cell lines, these liposomes containing conjugated cationic lipids, are said to exhibit lower toxicity and provide more efficient transfection than the DOTMA-containing compositions. Other commercially available cationic lipid products include DMRIE and DMRIE-HP (Vical, La Jolla, Calif.) and Lipofectamine (DOSPA) (Life Technology, Inc., Gaithersburg, Md.). Other cationic lipids suitable for the delivery of oligonucleotides are described in WO 98/39359 and WO 96/37194. 
     Liposomal formulations are particularly suited for topical administration, liposomes present several advantages over other formulations. Such advantages include reduced side effects related to high systemic absorption of the administered drug, increased accumulation of the administered drug at the desired target, and the ability to administer RNAi agent into the skin. In some implementations, liposomes are used for delivering RNAi agent to epidermal cells and also to enhance the penetration of RNAi agent into dermal tissues, e.g., into skin. For example, the liposomes can be applied topically. Topical delivery of drugs formulated as liposomes to the skin has been documented (see, e.g., Weiner et al.,  Journal of Drug Targeting,  1992, vol. 2, 405-410 and du Plessis et al.,  Antiviral Research,  18, 1992, 259-265; Mannino, R. J. and Fould-Fogerite, S., Biotechniques 6:682-690, 1988; Itani, T. et al.  Gene  56:267-276. 1987; Nicolau, C. et al.  Meth. Enz.  149:157-176, 1987; Straubinger, R. M. and Papahadjopoulos, D.  Meth. Enz.  101:512-527, 1983; Wang, C. Y. and Huang,  L., Proc. Natl. Acad. Sci. USA  84:7851-7855, 1987). 
     Non-ionic liposomal systems have also been examined to determine their utility in the delivery of drugs to the skin, in particular systems comprising non-ionic surfactant and cholesterol. Non-ionic liposomal formulations comprising Novasome I (glyceryl dilaurate/cholesterol/polyoxyethylene-10-stearyl ether) and Novasome II (glyceryl distearate/cholesterol/polyoxyethylene-10-stearyl ether) were used to deliver a drug into the dermis of mouse skin. Such formulations with RNAi agent are useful for treating a dermatological disorder. 
     Liposomes that include iRNA can be made highly deformable. Such deformability can enable the liposomes to penetrate through pore that are smaller than the average radius of the liposome. For example, transfersomes are a type of deformable liposomes. Transferosomes can be made by adding surface edge activators, usually surfactants, to a standard liposomal composition. Transfersomes that include RNAi agent can be delivered, for example, subcutaneously by infection in order to deliver RNAi agent to keratinocytes in the skin. In order to cross intact mammalian skin, lipid vesicles must pass through a series of fine pores, each with a diameter less than 50 nm, under the influence of a suitable transdermal gradient. In addition, due to the lipid properties, these transferosomes can be self-optimizing (adaptive to the shape of pores, e.g., in the skin), self-repairing, and can frequently reach their targets without fragmenting, and often self-loading. 
     Other formulations amenable to the present invention are described in U.S. provisional application Ser. No. 61/018,616, filed Jan. 2, 2008; 61/018,611, filed Jan. 2, 2008; 61/039,748, filed Mar. 26, 2008; 61/047,087, filed Apr. 22, 2008 and 61/051,528, filed May 8, 2008. PCT application no PCT/US2007/080331, filed Oct. 3, 2007 also describes formulations that are amenable to the present invention. 
     Transfersomes are yet another type of liposomes, and are highly deformable lipid aggregates which are attractive candidates for drug delivery vehicles. Transfersomes can be described as lipid droplets which are so highly deformable that they are easily able to penetrate through pores which are smaller than the droplet. Transfersomes are adaptable to the environment in which they are used, e.g., they are self-optimizing (adaptive to the shape of pores in the skin), self-repairing, frequently reach their targets without fragmenting, and often self-loading. To make transfersomes it is possible to add surface edge-activators, usually surfactants, to a standard liposomal composition. Transfersomes have been used to deliver serum albumin to the skin. The transfersome-mediated delivery of serum albumin has been shown to be as effective as subcutaneous injection of a solution containing serum albumin. 
     Surfactants find wide application in formulations such as emulsions (including microemulsions) and liposomes. The most common way of classifying and ranking the properties of the many different types of surfactants, both natural and synthetic, is by the use of the hydrophile/lipophile balance (HLB). The nature of the hydrophilic group (also known as the “head”) provides the most useful means for categorizing the different surfactants used in formulations (Rieger, in “Pharmaceutical Dosage Forms”, Marcel Dekker, Inc., New York, N.Y., 1988, p. 285). 
     If the surfactant molecule is not ionized, it is classified as a nonionic surfactant. Nonionic surfactants find wide application in pharmaceutical and cosmetic products and are usable over a wide range of pH values. In general their HLB values range from 2 to about 18 depending on their structure. Nonionic surfactants include nonionic esters such as ethylene glycol esters, propylene glycol esters, glyceryl esters, polyglyceryl esters, sorbitan esters, sucrose esters, and ethoxylated esters. Nonionic alkanolamides and ethers such as fatty alcohol ethoxylates, propoxylated alcohols, and ethoxylated/propoxylated block polymers are also included in this class. The polyoxyethylene surfactants are the most popular members of the nonionic surfactant class. 
     If the surfactant molecule carries a negative charge when it is dissolved or dispersed in water, the surfactant is classified as anionic. Anionic surfactants include carboxylates such as soaps, acyl lactylates, acyl amides of amino acids, esters of sulfuric acid such as alkyl sulfates and ethoxylated alkyl sulfates, sulfonates such as alkyl benzene sulfonates, acyl isethionates, acyl taurates and sulfosuccinates, and phosphates. The most important members of the anionic surfactant class are the alkyl sulfates and the soaps. 
     If the surfactant molecule carries a positive charge when it is dissolved or dispersed in water, the surfactant is classified as cationic. Cationic surfactants include quaternary ammonium salts and ethoxylated amines. The quaternary ammonium salts are the most used members of this class. 
     If the surfactant molecule has the ability to carry either a positive or negative charge, the surfactant is classified as amphoteric. Amphoteric surfactants include acrylic acid derivatives, substituted alkylamides, N-alkylbetaines and phosphatides. 
     The use of surfactants in drug products, formulations and in emulsions has been reviewed (Rieger, in “Pharmaceutical Dosage Forms”, Marcel Dekker, Inc., New York, N.Y., 1988, p. 285). 
     The iRNA for use in the methods of the invention can also be provided as micellar formulations. “Micelles” are defined herein as a particular type of molecular assembly in which amphipathic molecules are arranged in a spherical structure such that all the hydrophobic portions of the molecules are directed inward, leaving the hydrophilic portions in contact with the surrounding aqueous phase. The converse arrangement exists if the environment is hydrophobic. 
     A mixed micellar formulation suitable for delivery through transdermal membranes may be prepared by mixing an aqueous solution of the siRNA composition, an alkali metal C 8  to C 22  alkyl sulphate, and a micelle forming compounds. Exemplary micelle forming compounds include lecithin, hyaluronic acid, pharmaceutically acceptable salts of hyaluronic acid, glycolic acid, lactic acid, chamomile extract, cucumber extract, oleic acid, linoleic acid, linolenic acid, monoolein, monooleates, monolaurates, borage oil, evening of primrose oil, menthol, trihydroxy oxo cholanyl glycine and pharmaceutically acceptable salts thereof, glycerin, polyglycerin, lysine, polylysine, triolein, polyoxyethylene ethers and analogues thereof, polidocanol alkyl ethers and analogues thereof, chenodeoxycholate, deoxycholate, and mixtures thereof. The micelle forming compounds may be added at the same time or after addition of the alkali metal alkyl sulphate. Mixed micelles will form with substantially any kind of mixing of the ingredients but vigorous mixing in order to provide smaller size micelles. 
     In one method a first micellar composition is prepared which contains the siRNA composition and at least the alkali metal alkyl sulphate. The first micellar composition is then mixed with at least three micelle forming compounds to form a mixed micellar composition. In another method, the micellar composition is prepared by mixing the siRNA composition, the alkali metal alkyl sulphate and at least one of the micelle forming compounds, followed by addition of the remaining micelle forming compounds, with vigorous mixing. 
     Phenol and/or m-cresol may be added to the mixed micellar composition to stabilize the formulation and protect against bacterial growth. Alternatively, phenol and/or m-cresol may be added with the micelle forming ingredients. An isotonic agent such as glycerin may also be added after formation of the mixed micellar composition. 
     For delivery of the micellar formulation as a spray, the formulation can be put into an aerosol dispenser and the dispenser is charged with a propellant. The propellant, which is under pressure, is in liquid form in the dispenser. The ratios of the ingredients are adjusted so that the aqueous and propellant phases become one, i.e., there is one phase. If there are two phases, it is necessary to shake the dispenser prior to dispensing a portion of the contents, e.g., through a metered valve. The dispensed dose of pharmaceutical agent is propelled from the metered valve in a fine spray. 
     Propellants may include hydrogen-containing chlorofluorocarbons, hydrogen-containing fluorocarbons, dimethyl ether and diethyl ether. In certain embodiments, HFA 134a (1,1,1,2 tetrafluoroethane) may be used. 
     The specific concentrations of the essential ingredients can be determined by relatively straightforward experimentation. For absorption through the oral cavities, it is often desirable to increase, e.g., at least double or triple, the dosage for through injection or administration through the gastrointestinal tract. 
     B. Lipid particles 
     iRNAs, e.g., dsRNAs of in the invention may be fully encapsulated in a lipid formulation, e.g., a LNP, or other nucleic acid-lipid particle. 
     As used herein, the term “LNP” refers to a stable nucleic acid-lipid particle. LNPs typically contain a cationic lipid, a non-cationic lipid, and a lipid that prevents aggregation of the particle (e.g., a PEG-lipid conjugate). LNPs are extremely useful for systemic applications, as they exhibit extended circulation lifetimes following intravenous (i.v.) injection and accumulate at distal sites (e.g., sites physically separated from the administration site). LNPs include “pSPLP,” which include an encapsulated condensing agent-nucleic acid complex as set forth in PCT Publication No. WO 00/03683. The particles of the present invention typically have a mean diameter of about 50 nm to about 150 nm, more typically about 60 nm to about 130 nm, more typically about 70 nm to about 110 nm, most typically about 70 nm to about 90 nm, and are substantially nontoxic. In addition, the nucleic acids when present in the nucleic acid-lipid particles of the present invention are resistant in aqueous solution to degradation with a nuclease. Nucleic acid-lipid particles and their method of preparation are disclosed in, e.g., U.S. Pat. Nos. 5,976,567; 5,981,501; 6,534,484; 6,586,410; 6,815,432; U.S. Publication No. 2010/0324120 and PCT Publication No. WO 96/40964. 
     In one embodiment, the lipid to drug ratio (mass/mass ratio) (e.g., lipid to dsRNA ratio) will be in the range of from about 1:1 to about 50:1, from about 1:1 to about 25:1, from about 3:1 to about 15:1, from about 4:1 to about 10:1, from about 5:1 to about 9:1, or about 6:1 to about 9:1. Ranges intermediate to the above recited ranges are also contemplated to be part of the invention. 
     The cationic lipid can be, for example, N,N-dioleyl-N,N-dimethylammonium chloride (DODAC), N,N-distearyl-N,N-dimethylammonium bromide (DDAB), N-(I-(2,3-dioleoyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTAP), N-(I-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTMA), N,N-dimethyl-2,3-dioleyloxy)propylamine (DODMA), 1,2-DiLinoleyloxy-N,N-dimethylaminopropane (DLinDMA), 1,2-Dilinolenyloxy-N,N-dimethylaminopropane (DLenDMA), 1,2-Dilinoleylcarbamoyloxy-3-dimethylaminopropane (DLin-C-DAP), 1,2-Dilinoleyoxy-3-(dimethylamino)acetoxypropane (DLin-DAC), 1,2-Dilinoleyoxy-3-morpholinopropane (DLin-MA), 1,2-Dilinoleoyl-3-dimethylaminopropane (DLinDAP), 1,2-Dilinoleylthio-3-dimethylaminopropane (DLin-S-DMA), 1-Linoleoyl-2-linoleyloxy-3-dimethylaminopropane (DLin-2-DMAP), 1,2-Dilinoleyloxy-3-trimethylaminopropane chloride salt (DLin-TMA.Cl), 1,2-Dilinoleoyl-3-trimethylaminopropane chloride salt (DLin-TAP.Cl), 1,2-Dilinoleyloxy-3-(N-methylpiperazino)propane (DLin-MPZ), or 3-(N,N-Dilinoleylamino)-1,2-propanediol (DLinAP), 3-(N,N-Dioleylamino)-1,2-propanedio (DOAP), 1,2-Dilinoleyloxo-3-(2-N,N-dimethylamino)ethoxypropane (DLin-EG-DMA), 1,2-Dilinolenyloxy-N,N-dimethylaminopropane (DLinDMA), 2,2-Dilinoleyl-4-dimethylaminomethyl-[1,3]-dioxolane (DLin-K-DMA) or analogs thereof, (3aR,5s,6aS)-N,N-dimethyl-2,2-di((9Z,12Z)-octadeca-9,12-dienyl)tetrahydro-3aH-cyclopenta[d][1,3]dioxol-5-amine (ALN100), (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl 4-(dimethylamino)butanoate (MC3), 1,1′-(2-(4-(2-((2-(bis(2-hydroxydodecyl)amino)ethyl)(2-hydroxydodecyl)amino)ethyl)piperazin-1-yl)ethylazanediyl)didodecan-2-ol (Tech G1), or a mixture thereof. The cationic lipid can comprise from about 20 mol % to about 50 mol % or about 40 mol % of the total lipid present in the particle. 
     In another embodiment, the compound 2,2-Dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane can be used to prepare lipid-siRNA nanoparticles. Synthesis of 2,2-Dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane is described in U.S. provisional patent application No. 61/107,998 filed on Oct. 23, 2008, which is herein incorporated by reference. 
     In one embodiment, the lipid-siRNA particle includes 40% 2, 2-Dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane: 10% DSPC: 40% Cholesterol: 10% PEG-C-DOMG (mole percent) with a particle size of 63.0±20 nm and a 0.027 siRNA/Lipid Ratio. 
     The ionizable/non-cationic lipid can be an anionic lipid or a neutral lipid including, but not limited to, di stearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylglycerol (DOPG), dipalmitoylphosphatidylglycerol (DPPG), dioleoyl-phosphatidylethanolamine (DOPE), palmitoyloleoylphosphatidylcholine (POPC), palmitoyloleoylphosphatidylethanolamine (POPE), dioleoyl-phosphatidylethanolamine 4-(N-maleimidomethyl)-cyclohexane-l-carboxylate (DOPE-mal), dipalmitoyl phosphatidyl ethanolamine (DPPE), dimyristoylphosphoethanolamine (DMPE), distearoyl-phosphatidyl-ethanolamine (DSPE), 16-O-monomethyl PE, 16-O-dimethyl PE, 18-1-trans PE, 1-stearoyl-2-oleoyl-phosphatidyethanolamine (SOPE), cholesterol, or a mixture thereof. The non-cationic lipid can be from about 5 mol % to about 90 mol %, about 10 mol %, or about 58 mol % if cholesterol is included, of the total lipid present in the particle. The conjugated lipid that inhibits aggregation of particles can be, for example, a polyethyleneglycol (PEG)-lipid including, without limitation, a PEG-diacylglycerol (DAG), a PEG-dialkyloxypropyl (DAA), a PEG-phospholipid, a PEG-ceramide (Cer), or a mixture thereof. The PEG-DAA conjugate can be, for example, a PEG-dilauryloxypropyl (Ci 2 ), a PEG-dimyristyloxypropyl (Ci 4 ), a PEG-dipalmityloxypropyl (Ci 6 ), or a PEG-distearyloxypropyl (C]8). The conjugated lipid that prevents aggregation of particles can be from 0 mol % to about 20 mol % or about 2 mol % of the total lipid present in the particle. 
     In some embodiments, the nucleic acid-lipid particle further includes cholesterol at, e.g., about 10 mol % to about 60 mol % or about 48 mol % of the total lipid present in the particle. 
     In one embodiment, the lipidoid ND98.4HCl (MW 1487) (see U.S. patent application Ser. No. 12/056,230, filed Mar. 26, 2008, which is incorporated herein by reference), Cholesterol (Sigma-Aldrich), and PEG-Ceramide C16 (Avanti Polar Lipids) can be used to prepare lipid-dsRNA nanoparticles (i.e., LNP01 particles). Stock solutions of each in ethanol can be prepared as follows: ND98, 133 mg/ml; Cholesterol, 25 mg/ml, PEG-Ceramide C16, 100 mg/ml. The ND98, Cholesterol, and PEG-Ceramide C16 stock solutions can then be combined in a, e.g., 42:48:10 molar ratio. The combined lipid solution can be mixed with aqueous dsRNA (e.g., in sodium acetate pH 5) such that the final ethanol concentration is about 35-45% and the final sodium acetate concentration is about 100-300 mM. Lipid-dsRNA nanoparticles typically form spontaneously upon mixing. Depending on the desired particle size distribution, the resultant nanoparticle mixture can be extruded through a polycarbonate membrane (e.g., 100 nm cut-off) using, for example, a thermobarrel extruder, such as Lipex Extruder (Northern Lipids, Inc). In some cases, the extrusion step can be omitted. Ethanol removal and simultaneous buffer exchange can be accomplished by, for example, dialysis or tangential flow filtration. Buffer can be exchanged with, for example, phosphate buffered saline (PBS) at about pH 7, e.g., about pH 6.9, about pH 7.0, about pH 7.1, about pH 7.2, about pH 7.3, or about pH 7.4. 
     
       
         
         
             
             
         
       
     
     LNP01 formulations are described, e.g., in International Application Publication No. WO 2008/042973, which is hereby incorporated by reference. 
     Additional exemplary lipid-dsRNA formulations are described in Table 1. 
                                 TABLE 1                           cationic lipid/non-cationic               lipid/cholesterol/PEG-lipid conjugate           Ionizable/Cationic Lipid   Lipid:siRNA ratio                                                SNALP-1   1,2-Dilinolenyloxy-N,N-dimethylaminopropane   DLinDMA/DPPC/Cholesterol/PEG-cDMA           (DLinDMA)   (57.1/7.1/34.4/1.4)               lipid:siRNA~7:1       2-XTC   2,2-Dilinoleyl-4-dimethylaminoethyl-[1,3]-   XTC/DPPC/Cholesterol/PEG-cDMA           dioxolane (XTC)   57.1/7.1/34.4/1.4               lipid:siRNA~7:1       LNP05   2,2-Dilinoleyl-4-dimethylaminoethyl-[1,3]-   XTC/DSPC/Cholesterol/PEG-DMG           dioxolane (XTC)   57.5/7.5/31.5/3.5               lipid:siRNA~6:1       LNP06   2,2-Dilinoleyl-4-dimethylaminoethyl-[1,3]-   XTC/DSPC/Cholesterol/PEG-DMG           dioxolane (XTC)   57.5/7.5/31.5/3.5               lipid:siRNA~11:1       LNP07   2,2-Dilinoleyl-4-dimethylaminoethyl-[1,3]-   XTC/DSPC/Cholesterol/PEG-DMG           dioxolane (XTC)   60/7.5/31/1.5,               lipid:siRNA~6:1       LNP08   2,2-Dilinoleyl-4-dimethylaminoethyl-[1,3]-   XTC/DSPC/Cholesterol/PEG-DMG           dioxolane (XTC)   60/7.5/31/1.5,               lipid:siRNA~11:1       LNP09   2,2-Dilinoleyl-4-dimethylaminoethyl-[1,3]-   XTC/DSPC/Cholesterol/PEG-DMG           dioxolane (XTC)   50/10/38.5/1.5               Lipid:siRNA 10:1       LNP10   (3aR,5s,6aS)-N,N-dimethyl-2,2-di((9Z,12Z)-   ALN100/DSPC/Cholesterol/PEG-DMG           octadeca-9,12-dienyl)tetrahydro-3aH-   50/10/38.5/1.5           cyclopenta[d][1,3]dioxol-5-amine (ALN100)   Lipid:siRNA 10:1       LNP11   (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-   MC-3/DSPC/Cholesterol/PEG-DMG           tetraen-19-yl 4-(dimethylamino)butanoate   50/10/38.5/1.5           (MC3)   Lipid:siRNA 10:1       LNP12   1,1′-(2-(4-(2-((2-(bis(2-   Tech G1/DSPC/Cholesterol/PEG-DMG           hydroxydodecyl)amino)ethyl)(2-   50/10/38.5/1.5           hydroxydodecyl)amino)ethyl)piperazin-1-   Lipid:siRNA 10:1           yl)ethylazanediyl)didodecan-2-ol (Tech G1)       LNP13   XTC   XTC/DSPC/Chol/PEG-DMG               50/10/38.5/1.5               Lipid:siRNA: 33:1       LNP14   MC3   MC3/DSPC/Chol/PEG-DMG               40/15/40/5               Lipid:siRNA: 11:1       LNP15   MC3   MC3/DSPC/Chol/PEG-DSG/GalNAc-PEG-DSG               50/10/35/4.5/0.5               Lipid:siRNA: 11:1       LNP16   MC3   MC3/DSPC/Chol/PEG-DMG               50/10/38.5/1.5               Lipid:siRNA: 7:1       LNP17   MC3   MC3/DSPC/Chol/PEG-DSG               50/10/38.5/1.5               Lipid:siRNA: 10:1       LNP18   MC3   MC3/DSPC/Chol/PEG-DMG               50/10/38.5/1.5               Lipid:siRNA: 12:1       LNP19   MC3   MC3/DSPC/Chol/PEG-DMG               50/10/35/5               Lipid:siRNA: 8:1       LNP20   MC3   MC3/DSPC/Chol/PEG-DPG               50/10/38.5/1.5               Lipid:siRNA: 10:1       LNP21   C12-200   C12-200/DSPC/Chol/PEG-DSG               50/10/38.5/1.5               Lipid:siRNA: 7:1       LNP22   XTC   XTC/DSPC/Chol/PEG-DSG               50/10/38.5/1.5               Lipid:siRNA: 10:1                    
DSPC: distearoylphosphatidylcholine
 
DPPC: dipalmitoylphosphatidylcholine
 
PEG-DMG: PEG-didimyristoyl glycerol (C14-PEG, or PEG-C14) (PEG with avg mol wt of 2000)
 
PEG-DSG: PEG-distyryl glycerol (C18-PEG, or PEG-C18) (PEG with avg mol wt of 2000)
 
PEG-cDMA: PEG-carbamoyl-1,2-dimyristyloxypropylamine (PEG with avg mol wt of 2000)
 
SNALP (1,2-Dilinolenyloxy-N,N-dimethylaminopropane (DLinDMA)) comprising formulations are described in International Publication No. WO2009/127060, filed Apr. 15, 2009, which is hereby incorporated by reference.
 
     XTC comprising formulations are described, e.g., in U.S. Provisional Ser. No. 61/148,366, filed Jan. 29, 2009; U.S. Provisional Ser. No. 61/156,851, filed Mar. 2, 2009; U.S. Provisional Serial No. filed Jun. 10, 2009; U.S. Provisional Ser. No. 61/228,373, filed Jul. 24, 2009; U.S. Provisional Ser. No. 61/239,686, filed Sep. 3, 2009, and International Application No. PCT/US2010/022614, filed Jan. 29, 2010, which are hereby incorporated by reference. 
     MC3 comprising formulations are described, e.g., in U.S. Publication No. 2010/0324120, filed Jun. 10, 2010, the entire contents of which are hereby incorporated by reference. 
     ALNY-100 comprising formulations are described, e.g., International patent application number PCT/US09/63933, filed on Nov. 10, 2009, which is hereby incorporated by reference. 
     C12-200 comprising formulations are described in U.S. Provisional Ser. No. 61/175,770, filed May 5, 2009 and International Application No. PCT/US10/33777, filed May 5, 2010, which are hereby incorporated by reference. 
     Synthesis of ionizable/cationic lipids 
     Any of the compounds, e.g., cationic lipids and the like, used in the nucleic acid-lipid particles of the invention can be prepared by known organic synthesis techniques, including the methods described in more detail in the Examples. All substituents are as defined below unless indicated otherwise. 
     “Alkyl” means a straight chain or branched, noncyclic or cyclic, saturated aliphatic hydrocarbon containing from 1 to 24 carbon atoms. Representative saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, and the like; while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and the like. Representative saturated cyclic alkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; while unsaturated cyclic alkyls include cyclopentenyl and cyclohexenyl, and the like. 
     “Alkenyl” means an alkyl, as defined above, containing at least one double bond between adjacent carbon atoms. Alkenyls include both cis and trans isomers. Representative straight chain and branched alkenyls include ethylenyl, propylenyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, and the like. 
     “Alkynyl” means any alkyl or alkenyl, as defined above, which additionally contains at least one triple bond between adjacent carbons. Representative straight chain and branched alkynyls include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1 butynyl, and the like. 
     “Acyl” means any alkyl, alkenyl, or alkynyl wherein the carbon at the point of attachment is substituted with an oxo group, as defined below. For example, —C(═O)alkyl, —C(═O)alkenyl, and —C(═O)alkynyl are acyl groups. 
     “Heterocycle” means a 5- to 7-membered monocyclic, or 7- to 10-membered bicyclic, heterocyclic ring which is either saturated, unsaturated, or aromatic, and which contains from 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the nitrogen and sulfur heteroatoms can be optionally oxidized, and the nitrogen heteroatom can be optionally quaternized, including bicyclic rings in which any of the above heterocycles are fused to a benzene ring. The heterocycle can be attached via any heteroatom or carbon atom. Heterocycles include heteroaryls as defined below. Heterocycles include morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperizinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like. 
     The terms “optionally substituted alkyl”, “optionally substituted alkenyl”, “optionally substituted alkynyl”, “optionally substituted acyl”, and “optionally substituted heterocycle” means that, when substituted, at least one hydrogen atom is replaced with a substituent. In the case of an oxo substituent (═O) two hydrogen atoms are replaced. In this regard, substituents include oxo, halogen, heterocycle, —CN,—ORx, —NRxRy, —NRxC(═O)Ry, —NRxSO2Ry, —C(═O)Rx, —C(═O)ORx, —C(═O)NRxRy, —SOnRx and —SOnNRxRy, wherein n is 0, 1 or 2, Rx and Ry are the same or different and independently hydrogen, alkyl or heterocycle, and each of said alkyl and heterocycle substituents can be further substituted with one or more of oxo, halogen, —OH, —CN, alkyl, —ORx, heterocycle, —NRxRy, —NRxC(═O)Ry, —NRxSO2Ry, —C(═O)Rx, —C(═O)ORx, —C(═O)NRxRy, —SOnRx and —SOnNRxRy. 
     “Halogen” means fluoro, chloro, bromo and iodo. 
     In some embodiments, the methods of the invention can require the use of protecting groups. Protecting group methodology is well known to those skilled in the art (see, for example, Protective Groups in Organic Synthesis, Green, T. W. et al., Wiley-Interscience, New York City, 1999). Briefly, protecting groups within the context of this invention are any group that reduces or eliminates unwanted reactivity of a functional group. A protecting group can be added to a functional group to mask its reactivity during certain reactions and then removed to reveal the original functional group. In some embodiments an “alcohol protecting group” is used. An “alcohol protecting group” is any group which decreases or eliminates unwanted reactivity of an alcohol functional group. Protecting groups can be added and removed using techniques well known in the art. 
     Synthesis of Formula A 
     In some embodiments, nucleic acid-lipid particles of the invention are formulated using a cationic lipid of formula A: 
     
       
         
         
             
             
         
       
     
     where R1 and R2 are independently alkyl, alkenyl or alkynyl, each can be optionally substituted, and R3 and R4 are independently lower alkyl or R3 and R4 can be taken together to form an optionally substituted heterocyclic ring. In some embodiments, the cationic lipid is XTC (2,2-Dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane). In general, the lipid of formula A above can be made by the following Reaction Schemes 1 or 2, wherein all substituents are as defined above unless indicated otherwise. 
     
       
         
         
             
             
         
       
     
     Lipid A, where R1 and R2 are independently alkyl, alkenyl or alkynyl, each can be optionally substituted, and R3 and R4 are independently lower alkyl or R3 and R4 can be taken together to form an optionally substituted heterocyclic ring, can be prepared according to Scheme 1. Ketone 1 and bromide 2 can be purchased or prepared according to methods known to those of ordinary skill in the art. Reaction of 1 and 2 yields ketal 3. Treatment of ketal 3 with amine 4 yields lipids of formula A. The lipids of formula A can be converted to the corresponding ammonium salt with an organic salt of formula 5, where X is anion counter ion selected from halogen, hydroxide, phosphate, sulfate, or the like. 
     
       
         
         
             
             
         
       
     
     Alternatively, the ketone 1 starting material can be prepared according to Scheme 2. Grignard reagent 6 and cyanide 7 can be purchased or prepared according to methods known to those of ordinary skill in the art. Reaction of 6 and 7 yields ketone 1. Conversion of ketone 1 to the corresponding lipids of formula A is as described in Scheme 1. 
     Synthesis of MC3 
     Preparation of DLin-M-C3-DMA (i.e., (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl 4-(dimethylamino)butanoate) was as follows. A solution of (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-ol (0.53 g), 4-N,N-dimethylaminobutyric acid hydrochloride (0.51 g), 4-N,N-dimethylaminopyridine (0.61 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.53 g) in dichloromethane (5 mL) was stirred at room temperature overnight. The solution was washed with dilute hydrochloric acid followed by dilute aqueous sodium bicarbonate. The organic fractions were dried over anhydrous magnesium sulphate, filtered and the solvent removed on a rotovap. The residue was passed down a silica gel column (20 g) using a 1-5% methanol/dichloromethane elution gradient. Fractions containing the purified product were combined and the solvent removed, yielding a colorless oil (0.54 g). Synthesis of ALNY-100 
     Synthesis of ketal 519 [ALNY-100] was performed using the following scheme 3: 
     
       
         
         
             
             
         
       
     
     Synthesis of 515 
     To a stirred suspension of LiA1H4 (3.74 g, 0.09852 mol) in 200 ml anhydrous THF in a two neck RBF (1 L), was added a solution of 514 (10 g, 0.04926 mol) in 70 mL of THF slowly at 0° C. under nitrogen atmosphere. After complete addition, reaction mixture was warmed to room temperature and then heated to reflux for 4 h. Progress of the reaction was monitored by TLC. After completion of reaction (by TLC) the mixture was cooled to 0° C. and quenched with careful addition of saturated Na2SO4 solution. Reaction mixture was stirred for 4 h at room temperature and filtered off. Residue was washed well with THF. The filtrate and washings were mixed and diluted with 400 mL dioxane and 26 mL conc. HCl and stirred for 20 minutes at room temperature. The volatilities were stripped off under vacuum to furnish the hydrochloride salt of 515 as a white solid. Yield: 7.12 g 1H-NMR (DMSO, 400 MHz): δ =9.34 (broad, 2H), 5.68 (s, 2H), 3.74 (m, 1H), 2.66-2.60 (m, 2H), 2.50-2.45 (m, 5H). 
     Synthesis of 516 
     To a stirred solution of compound 515 in 100 mL dry DCM in a 250 mL two neck RBF, was added NEt3 (37.2 mL, 0.2669 mol) and cooled to 0° C. under nitrogen atmosphere. After a slow addition of N-(benzyloxy-carbonyloxy)-succinimide (20 g, 0.08007 mol) in 50 mL dry DCM, reaction mixture was allowed to warm to room temperature. After completion of the reaction (2-3 h by TLC) mixture was washed successively with 1N HCl solution (1×100 mL) and saturated NaHCO 3  solution (1×50 mL). The organic layer was then dried over anhyd. Na2SO4 and the solvent was evaporated to give crude material which was purified by silica gel column chromatography to get 516 as sticky mass. Yield: 11 g (89%). 1H-NMR (CDCl3, 400 MHz): δ =7.36-7.27 (m, 5H), 5.69 (s, 2H), 5.12 (s, 2H), 4.96 (br., 1H) 2.74 (s, 3H), 2.60 (m, 2H), 2.30-2.25 (m, 2H). LC-MS [M+H]-232.3 (96.94%). 
     Synthesis of 517A and 517B 
     The cyclopentene 516 (5 g, 0.02164 mol) was dissolved in a solution of 220 mL acetone and water (10:1) in a single neck 500 mL RBF and to it was added N-methyl morpholine-N-oxide (7.6 g, 0.06492 mol) followed by 4.2 mL of 7.6% solution of OsO4 (0.275 g, 0.00108 mol) in tert-butanol at room temperature. After completion of the reaction (˜3 h), the mixture was quenched with addition of solid Na2SO3 and resulting mixture was stirred for 1.5 h at room temperature. Reaction mixture was diluted with DCM (300 mL) and washed with water (2×100 mL) followed by saturated NaHCO 3 (1×50 mL) solution, water (1×30 mL) and finally with brine (1×50 mL). Organic phase was dried over an.Na2SO4 and solvent was removed in vacuum. Silica gel column chromatographic purification of the crude material was afforded a mixture of diastereomers, which were separated by prep HPLC. Yield: −6 g crude 
     517A—Peak-1 (white solid), 5.13 g (96%). 1H-NMR (DMSO, 400 MHz): δ=7.39-7.31 (m, 5H), 5.04 (s, 2H), 4.78-4.73 (m, 1H), 4.48-4.47 (d, 2H), 3.94-3.93 (m, 2H), 2.71 (s, 3H), 1.72-1.67 (m, 4H). LC-MS-[M+H]-266.3, [M+NH 4 +]-283.5 present, HPLC-97.86%. Stereochemistry confirmed by X-ray. 
     Synthesis of 518 
     Using a procedure analogous to that described for the synthesis of compound 505, compound 518 (1.2 g, 41%) was obtained as a colorless oil. 1H-NMR (CDCl3, 400 MHz): δ =7.35-7.33 (m, 4H), 7.30-7.27 (m, 1H), 5.37-5.27 (m, 8H), 5.12 (s, 2H), 4.75 (m, 1H), 4.58-4.57 (m, 2H), 2.78-2.74 (m, 7H), 2.06-2.00 (m, 8H), 1.96-1.91 (m, 2H), 1.62 (m, 4H), 1.48 (m, 2H), 1.37-1.25 (br m, 36H), 0.87 (m, 6H). HPLC-98.65%. 
     General Procedure for the Synthesis of Compound 519 
     A solution of compound 518 (1 eq) in hexane (15 mL) was added in a drop-wise fashion to an ice-cold solution of LAH in THF (1 M, 2 eq). After complete addition, the mixture was heated at 40° C. over 0.5 h then cooled again on an ice bath. The mixture was carefully hydrolyzed with saturated aqueous Na2SO4 then filtered through celite and reduced to an oil. Column chromatography provided the pure 519 (1.3 g, 68%) which was obtained as a colorless oil. 13C NMR 6=130.2, 130.1 (×2), 127.9 (×3), 112.3, 79.3, 64.4, 44.7, 38.3, 35.4, 31.5, 29.9 (×2), 29.7, 29.6 (×2), 29.5 (×3), 29.3 (×2), 27.2 (×3), 25.6, 24.5, 23.3, 226, 14.1; Electrospray MS (+ve): Molecular weight for C44H80NO2 (M+H)+Calc. 654.6, Found 654.6. 
     Formulations prepared by either the standard or extrusion-free method can be characterized in similar manners. For example, formulations are typically characterized by visual inspection. They should be whitish translucent solutions free from aggregates or sediment. Particle size and particle size distribution of lipid-nanoparticles can be measured by light scattering using, for example, a Malvern Zetasizer Nano ZS (Malvern, USA). Particles should be about 20-300 nm, such as 40-100 nm in size. The particle size distribution should be unimodal. The total dsRNA concentration in the formulation, as well as the entrapped fraction, is estimated using a dye exclusion assay. A sample of the formulated dsRNA can be incubated with an RNA-binding dye, such as Ribogreen (Molecular Probes) in the presence or absence of a formulation disrupting surfactant, e.g., 0.5% Triton-X100. The total dsRNA in the formulation can be determined by the signal from the sample containing the surfactant, relative to a standard curve. The entrapped fraction is determined by subtracting the “free” dsRNA content (as measured by the signal in the absence of surfactant) from the total dsRNA content. Percent entrapped dsRNA is typically &gt;85%. For SNALP formulation, the particle size is at least 30 nm, at least 40 nm, at least 50 nm, at least 60 nm, at least 70 nm, at least 80 nm, at least 90 nm, at least 100 nm, at least 110 nm, and at least 120 nm. The suitable range is typically about at least 50 nm to about at least 110 nm, about at least 60 nm to about at least 100 nm, or about at least 80 nm to about at least 90 nm. 
     Compositions and formulations for oral administration include powders or granules, microparticulates, nanoparticulates, suspensions or solutions in water or non-aqueous media, capsules, gel capsules, sachets, tablets or minitablets. Thickeners, flavoring agents, diluents, emulsifiers, dispersing aids or binders can be desirable. In some embodiments, oral formulations are those in which dsRNAs featured in the invention are administered in conjunction with one or more penetration enhancer surfactants and chelators. Suitable surfactants include fatty acids and/or esters or salts thereof, bile acids and/or salts thereof. Suitable bile acids/salts include chenodeoxycholic acid (CDCA) and ursodeoxychenodeoxycholic acid (UDCA), cholic acid, dehydrocholic acid, deoxycholic acid, glucholic acid, glycholic acid, glycodeoxycholic acid, taurocholic acid, taurodeoxycholic acid, sodium tauro-24,25-dihydro-fusidate and sodium glycodihydrofusidate. Suitable fatty acids include arachidonic acid, undecanoic acid, oleic acid, lauric acid, caprylic acid, capric acid, myristic acid, palmitic acid, stearic acid, linoleic acid, linolenic acid, dicaprate, tricaprate, monoolein, dilaurin, glyceryl 1-monocaprate, 1-dodecylazacycloheptan-2-one, an acylcarnitine, an acylcholine, or a monoglyceride, a diglyceride or a pharmaceutically acceptable salt thereof (e.g., sodium). In some embodiments, combinations of penetration enhancers are used, for example, fatty acids/salts in combination with bile acids/salts. One exemplary combination is the sodium salt of lauric acid, capric acid and UDCA. Further penetration enhancers include polyoxyethylene-9-lauryl ether, polyoxyethylene-20-cetyl ether. DsRNAs featured in the invention can be delivered orally, in granular form including sprayed dried particles, or complexed to form micro or nanoparticles. DsRNA complexing agents include poly-amino acids; polyimines; polyacrylates; polyalkylacrylates, polyoxethanes, polyalkylcyanoacrylates; cationized gelatins, albumins, starches, acrylates, polyethyleneglycols (PEG) and starches; polyalkylcyanoacrylates; DEAE-derivatized polyimines, pollulans, celluloses and starches. Suitable complexing agents include chitosan, N-trimethylchitosan, poly-L-lysine, polyhistidine, polyornithine, polyspermines, protamine, polyvinylpyridine, polythiodiethylaminomethylethylene P(TDAE), polyaminostyrene (e.g., p-amino), poly(methylcyanoacrylate), poly(ethylcyanoacrylate), poly(butylcyanoacrylate), poly(isobutylcyanoacrylate), poly(isohexylcynaoacrylate), DEAE-methacrylate, DEAE-hexylacrylate, DEAE-acrylamide, DEAE-albumin and DEAE-dextran, polymethylacrylate, polyhexylacrylate, poly(D,L-lactic acid), poly(DL-lactic-co-glycolic acid (PLGA), alginate, and polyethyleneglycol (PEG). Oral formulations for dsRNAs and their preparation are described in detail in U.S. Pat. No. 6,887,906, US Publn. No. 20030027780, and U.S. Pat. No. 6,747,014, each of which is incorporated herein by reference. 
     Compositions and formulations for parenteral, intraparenchymal (into the brain), intrathecal, intraventricular or intrahepatic administration can include sterile aqueous solutions which can also contain buffers, diluents and other suitable additives such as, but not limited to, penetration enhancers, carrier compounds and other pharmaceutically acceptable carriers or excipients. 
     Pharmaceutical compositions of the present invention include, but are not limited to, solutions, emulsions, and liposome-containing formulations. These compositions can be generated from a variety of components that include, but are not limited to, preformed liquids, self-emulsifying solids and self-emulsifying semisolids. Particularly preferred are formulations that target the liver when treating hepatic disorders such as hepatic carcinoma. 
     The pharmaceutical formulations of the present invention, which can conveniently be presented in unit dosage form, can be prepared according to conventional techniques well known in the pharmaceutical industry. Such techniques include the step of bringing into association the active ingredients with the pharmaceutical carrier(s) or excipient(s). In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product. 
     The compositions of the present invention can be formulated into any of many possible dosage forms such as, but not limited to, tablets, capsules, gel capsules, liquid syrups, soft gels, suppositories, and enemas. The compositions of the present invention can also be formulated as suspensions in aqueous, non-aqueous or mixed media. Aqueous suspensions can further contain substances which increase the viscosity of the suspension including, for example, sodium carboxymethylcellulose, sorbitol and/or dextran. The suspension can also contain stabilizers. 
     C. Additional Formulations 
     i. Emulsions 
     The compositions of the present invention can be prepared and formulated as emulsions. Emulsions are typically heterogeneous systems of one liquid dispersed in another in the form of droplets usually exceeding 0.1 μm in diameter (see e.g., Ansel&#39;s Pharmaceutical Dosage Forms and Drug Delivery Systems, Allen, L V., Popovich N G., and Ansel H C., 2004, Lippincott Williams &amp; Wilkins (8th ed.), New York, N.Y.; Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 199; Rosoff, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., Volume 1, p. 245; Block in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 2, p. 335; Higuchi et al., in Remington&#39;s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 1985, p. 301). Emulsions are often biphasic systems comprising two immiscible liquid phases intimately mixed and dispersed with each other. In general, emulsions can be of either the water-in-oil (w/o) or the oil-in-water (o/w) variety. When an aqueous phase is finely divided into and dispersed as minute droplets into a bulk oily phase, the resulting composition is called a water-in-oil (w/o) emulsion. Alternatively, when an oily phase is finely divided into and dispersed as minute droplets into a bulk aqueous phase, the resulting composition is called an oil-in-water (o/w) emulsion. Emulsions can contain additional components in addition to the dispersed phases, and the active drug which can be present as a solution in either the aqueous phase, oily phase or itself as a separate phase. Pharmaceutical excipients such as emulsifiers, stabilizers, dyes, and anti-oxidants can also be present in emulsions as needed. Pharmaceutical emulsions can also be multiple emulsions that are comprised of more than two phases such as, for example, in the case of oil-in-water-in-oil (o/w/o) and water-in-oil-in-water (w/o/w) emulsions. Such complex formulations often provide certain advantages that simple binary emulsions do not. Multiple emulsions in which individual oil droplets of an o/w emulsion enclose small water droplets constitute a w/o/w emulsion. Likewise a system of oil droplets enclosed in globules of water stabilized in an oily continuous phase provides an o/w/o emulsion. 
     Emulsions are characterized by little or no thermodynamic stability. Often, the dispersed or discontinuous phase of the emulsion is well dispersed into the external or continuous phase and maintained in this form through the means of emulsifiers or the viscosity of the formulation. Either of the phases of the emulsion can be a semisolid or a solid, as is the case of emulsion-style ointment bases and creams. Other means of stabilizing emulsions entail the use of emulsifiers that can be incorporated into either phase of the emulsion. Emulsifiers can broadly be classified into four categories: synthetic surfactants, naturally occurring emulsifiers, absorption bases, and finely dispersed solids (see e.g., Ansel&#39;s Pharmaceutical Dosage Forms and Drug Delivery Systems, Allen, L V., Popovich N G., and Ansel H C., 2004, Lippincott Williams &amp; Wilkins (8th ed.), New York, N.Y.; Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 199). 
     Synthetic surfactants, also known as surface active agents, have found wide applicability in the formulation of emulsions and have been reviewed in the literature (see e.g., Ansel&#39;s Pharmaceutical Dosage Forms and Drug Delivery Systems, Allen, L V., Popovich N G., and Ansel H C., 2004, Lippincott Williams &amp;  Wilkins  (8th ed.), New York, N.Y.; Rieger, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 285; Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), Marcel Dekker, Inc., New York, N.Y., 1988, volume 1, p. 199). Surfactants are typically amphiphilic and comprise a hydrophilic and a hydrophobic portion. The ratio of the hydrophilic to the hydrophobic nature of the surfactant has been termed the hydrophile/lipophile balance (HLB) and is a valuable tool in categorizing and selecting surfactants in the preparation of formulations. Surfactants can be classified into different classes based on the nature of the hydrophilic group: nonionic, anionic, cationic and amphoteric (see e.g., Ansel&#39;s Pharmaceutical Dosage Forms and Drug Delivery Systems, Allen, L V., Popovich N G., and Ansel H C., 2004, Lippincott Williams &amp; Wilkins (8th ed.), New York, N.Y. Rieger, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 285). 
     Naturally occurring emulsifiers used in emulsion formulations include lanolin, beeswax, phosphatides, lecithin and acacia. Absorption bases possess hydrophilic properties such that they can soak up water to form w/o emulsions yet retain their semisolid consistencies, such as anhydrous lanolin and hydrophilic petrolatum. Finely divided solids have also been used as good emulsifiers especially in combination with surfactants and in viscous preparations. These include polar inorganic solids, such as heavy metal hydroxides, nonswelling clays such as bentonite, attapulgite, hectorite, kaolin, montmorillonite, colloidal aluminum silicate and colloidal magnesium aluminum silicate, pigments and nonpolar solids such as carbon or glyceryl tristearate. 
     A large variety of non-emulsifying materials are also included in emulsion formulations and contribute to the properties of emulsions. These include fats, oils, waxes, fatty acids, fatty alcohols, fatty esters, humectants, hydrophilic colloids, preservatives and antioxidants (Block, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 335; Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 199). 
     Hydrophilic colloids or hydrocolloids include naturally occurring gums and synthetic polymers such as polysaccharides (for example, acacia, agar, alginic acid, carrageenan, guar gum, karaya gum, and tragacanth), cellulose derivatives (for example, carboxymethylcellulose and carboxypropylcellulose), and synthetic polymers (for example, carbomers, cellulose ethers, and carboxyvinyl polymers). These disperse or swell in water to form colloidal solutions that stabilize emulsions by forming strong interfacial films around the dispersed-phase droplets and by increasing the viscosity of the external phase. 
     Since emulsions often contain a number of ingredients such as carbohydrates, proteins, sterols and phosphatides that can readily support the growth of microbes, these formulations often incorporate preservatives. Commonly used preservatives included in emulsion formulations include methyl paraben, propyl paraben, quaternary ammonium salts, benzalkonium chloride, esters of p-hydroxybenzoic acid, and boric acid. Antioxidants are also commonly added to emulsion formulations to prevent deterioration of the formulation. Antioxidants used can be free radical scavengers such as tocopherols, alkyl gallates, butylated hydroxyanisole, butylated hydroxytoluene, or reducing agents such as ascorbic acid and sodium metabisulfite, and antioxidant synergists such as citric acid, tartaric acid, and lecithin. 
     The application of emulsion formulations via dermatological, oral and parenteral routes and methods for their manufacture have been reviewed in the literature (see e.g., Ansel&#39;s Pharmaceutical Dosage Forms and Drug Delivery Systems, Allen, L V., Popovich N G., and Ansel H C., 2004, Lippincott Williams &amp; Wilkins (8th ed.), New York, N.Y.; Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 199). Emulsion formulations for oral delivery have been very widely used because of ease of formulation, as well as efficacy from an absorption and bioavailability standpoint (see e.g., Ansel&#39;s Pharmaceutical Dosage Forms and Drug Delivery Systems, Allen, L V., Popovich N G., and Ansel H C., 2004, Lippincott Williams &amp; Wilkins (8th ed.), New York, N.Y.; Rosoff, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 245; Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 199). Mineral-oil base laxatives, oil-soluble vitamins and high fat nutritive preparations are among the materials that have commonly been administered orally as o/w emulsions. 
     ii. Microemulsions 
     In one embodiment of the present invention, the compositions of iRNAs and nucleic acids are formulated as microemulsions. A microemulsion can be defined as a system of water, oil and amphiphile which is a single optically isotropic and thermodynamically stable liquid solution (see e.g., Ansel&#39;s Pharmaceutical Dosage Forms and Drug Delivery Systems, Allen, L V., Popovich N G., and Ansel H C., 2004, Lippincott Williams &amp; Wilkins (8th ed.), New York, N.Y.; Rosoff, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 245). Typically microemulsions are systems that are prepared by first dispersing an oil in an aqueous surfactant solution and then adding a sufficient amount of a fourth component, generally an intermediate chain-length alcohol to form a transparent system. Therefore, microemulsions have also been described as thermodynamically stable, isotropically clear dispersions of two immiscible liquids that are stabilized by interfacial films of surface-active molecules (Leung and Shah, in: Controlled Release of Drugs: Polymers and Aggregate Systems, Rosoff, M., Ed., 1989, VCH Publishers, New York, pages 185-215). Microemulsions commonly are prepared via a combination of three to five components that include oil, water, surfactant, cosurfactant and electrolyte. Whether the microemulsion is of the water-in-oil (w/o) or an oil-in-water (o/w) type is dependent on the properties of the oil and surfactant used and on the structure and geometric packing of the polar heads and hydrocarbon tails of the surfactant molecules (Schott, in Remington&#39;s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 1985, p. 271). 
     The phenomenological approach utilizing phase diagrams has been extensively studied and has yielded a comprehensive knowledge, to one skilled in the art, of how to formulate microemulsions (see e.g., Ansel&#39;s Pharmaceutical Dosage Forms and Drug Delivery Systems, Allen, L V., Popovich N G., and Ansel H C., 2004, Lippincott Williams &amp; Wilkins (8th ed.), New York, N.Y.; Rosoff, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 245; Block, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 335). Compared to conventional emulsions, microemulsions offer the advantage of solubilizing water-insoluble drugs in a formulation of thermodynamically stable droplets that are formed spontaneously. 
     Surfactants used in the preparation of microemulsions include, but are not limited to, ionic surfactants, non-ionic surfactants, Brij 96, polyoxyethylene oleyl ethers, polyglycerol fatty acid esters, tetraglycerol monolaurate (ML310), tetraglycerol monooleate (MO310), hexaglycerol monooleate (PO310), hexaglycerol pentaoleate (PO500), decaglycerol monocaprate (MCA750), decaglycerol monooleate (MO750), decaglycerol sequioleate (SO750), decaglycerol decaoleate (DA0750), alone or in combination with cosurfactants. The cosurfactant, usually a short-chain alcohol such as ethanol, 1-propanol, and 1-butanol, serves to increase the interfacial fluidity by penetrating into the surfactant film and consequently creating a disordered film because of the void space generated among surfactant molecules. Microemulsions can, however, be prepared without the use of cosurfactants and alcohol-free self-emulsifying microemulsion systems are known in the art. The aqueous phase can typically be, but is not limited to, water, an aqueous solution of the drug, glycerol, PEG300, PEG400, polyglycerols, propylene glycols, and derivatives of ethylene glycol. The oil phase can include, but is not limited to, materials such as Captex 300, Captex 355, Capmul MCM, fatty acid esters, medium chain (C8-C12) mono, di, and tri-glycerides, polyoxyethylated glyceryl fatty acid esters, fatty alcohols, polyglycolized glycerides, saturated polyglycolized C8-C10 glycerides, vegetable oils and silicone oil. 
     Microemulsions are particularly of interest from the standpoint of drug solubilization and the enhanced absorption of drugs. Lipid based microemulsions (both o/w and w/o) have been proposed to enhance the oral bioavailability of drugs, including peptides (see e.g., U.S. Pat. Nos. 6,191,105; 7,063,860; 7,070,802; 7,157,099; Constantinides et al., Pharmaceutical Research, 1994, 11, 1385-1390; Ritschel, Meth. Find. Exp. Clin. Pharmacol., 1993, 13, 205). Microemulsions afford advantages of improved drug solubilization, protection of drug from enzymatic hydrolysis, possible enhancement of drug absorption due to surfactant-induced alterations in membrane fluidity and permeability, ease of preparation, ease of oral administration over solid dosage forms, improved clinical potency, and decreased toxicity (see e.g., U.S. Pat. Nos. 6,191,105; 7,063,860; 7,070,802; 7,157,099; Constantinides et al., Pharmaceutical Research, 1994, 11, 1385; Ho et al., J. Pharm. Sci., 1996, 85, 138-143). Often microemulsions can form spontaneously when their components are brought together at ambient temperature. This can be particularly advantageous when formulating thermolabile drugs, peptides or iRNAs. Microemulsions have also been effective in the transdermal delivery of active components in both cosmetic and pharmaceutical applications. It is expected that the microemulsion compositions and formulations of the present invention will facilitate the increased systemic absorption of iRNAs and nucleic acids from the gastrointestinal tract, as well as improve the local cellular uptake of iRNAs and nucleic acids. 
     Microemulsions of the present invention can also contain additional components and additives such as sorbitan monostearate (Grill 3), Labrasol, and penetration enhancers to improve the properties of the formulation and to enhance the absorption of the iRNAs and nucleic acids of the present invention. Penetration enhancers used in the microemulsions of the present invention can be classified as belonging to one of five broad categories—surfactants, fatty acids, bile salts, chelating agents, and non-chelating non-surfactants (Lee et al.,  Critical Reviews in Therapeutic Drug Carrier Systems,  1991, p. 92). Each of these classes has been discussed above. 
     iii. Microparticles 
     an RNAi agent of the invention may be incorporated into a particle, e.g., a microparticle. Microparticles can be produced by spray-drying, but may also be produced by other methods including lyophilization, evaporation, fluid bed drying, vacuum drying, or a combination of these techniques. 
     iv. Penetration Enhancers 
     In one embodiment, the present invention employs various penetration enhancers to effect the efficient delivery of nucleic acids, particularly iRNAs, to the skin of animals. Most drugs are present in solution in both ionized and nonionized forms. However, usually only lipid soluble or lipophilic drugs readily cross cell membranes. It has been discovered that even non-lipophilic drugs can cross cell membranes if the membrane to be crossed is treated with a penetration enhancer. In addition to aiding the diffusion of non-lipophilic drugs across cell membranes, penetration enhancers also enhance the permeability of lipophilic drugs. 
     Penetration enhancers can be classified as belonging to one of five broad categories, i.e., surfactants, fatty acids, bile salts, chelating agents, and non-chelating non-surfactants (see e.g., Malmsten, M. Surfactants and polymers in drug delivery, Informa Health Care, New York, N.Y., 2002; Lee et al.,  Critical Reviews in Therapeutic Drug Carrier Systems,  1991, p. 92). Each of the above mentioned classes of penetration enhancers are described below in greater detail. 
     Surfactants (or “surface-active agents”) are chemical entities which, when dissolved in an aqueous solution, reduce the surface tension of the solution or the interfacial tension between the aqueous solution and another liquid, with the result that absorption of iRNAs through the mucosa is enhanced. In addition to bile salts and fatty acids, these penetration enhancers include, for example, sodium lauryl sulfate, polyoxyethylene-9-lauryl ether and polyoxyethylene-20-cetyl ether) (see e.g., Malmsten, M. Surfactants and polymers in drug delivery, Informa Health Care, New York, N.Y., 2002; Lee et al.,  Critical Reviews in Therapeutic Drug Carrier Systems,  1991, p. 92); and perfluorochemical emulsions, such as FC-43. Takahashi et al.,  J. Pharm. Pharmacol.,  1988, 40, 252). 
     Various fatty acids and their derivatives which act as penetration enhancers include, for example, oleic acid, lauric acid, capric acid (n-decanoic acid), myristic acid, palmitic acid, stearic acid, linoleic acid, linolenic acid, dicaprate, tricaprate, monoolein (1-monooleoyl-rac-glycerol), dilaurin, caprylic acid, arachidonic acid, glycerol 1-monocaprate, 1-dodecylazacycloheptan-2-one, acylcarnitines, acylcholines, C 1 -20 alkyl esters thereof (e.g., methyl, isopropyl and t-butyl), and mono- and di-glycerides thereof (i.e., oleate, laurate, caprate, myristate, palmitate, stearate, linoleate, etc.) (see e.g., Touitou, E., et al. Enhancement in Drug Delivery, CRC Press, Danvers, Mass., 2006; Lee et al., Critical Reviews in Therapeutic Drug Carrier Systems, 1991, p. 92; Muranishi, Critical Reviews in Therapeutic Drug Carrier Systems, 1990, 7, 1-33; El Hariri et al.,  J. Pharm. Pharmacol.,  1992, 44, 651-654). 
     The physiological role of bile includes the facilitation of dispersion and absorption of lipids and fat-soluble vitamins (see e.g., Malmsten, M. Surfactants and polymers in drug delivery, Informa Health Care, New York, N.Y., 2002; Brunton, Chapter 38 in: Goodman &amp; Gilman&#39;s The Pharmacological Basis of Therapeutics, 9th Ed., Hardman et al. Eds., McGraw-Hill, New York, 1996, pp. 934-935). Various natural bile salts, and their synthetic derivatives, act as penetration enhancers. Thus the term “bile salts” includes any of the naturally occurring components of bile as well as any of their synthetic derivatives. Suitable bile salts include, for example, cholic acid (or its pharmaceutically acceptable sodium salt, sodium cholate), dehydrocholic acid (sodium dehydrocholate), deoxycholic acid (sodium deoxycholate), glucholic acid (sodium glucholate), glycholic acid (sodium glycocholate), glycodeoxycholic acid (sodium glycodeoxycholate), taurocholic acid (sodium taurocholate), taurodeoxycholic acid (sodium taurodeoxycholate), chenodeoxycholic acid (sodium chenodeoxycholate), ursodeoxycholic acid (UDCA), sodium tauro-24,25-dihydro-fusidate (STDHF), sodium glycodihydrofusidate and polyoxyethylene-9-lauryl ether (POE) (see e.g., Malmsten, M. Surfactants and polymers in drug delivery, Informa Health Care, New York, N.Y., 2002; Lee et al., Critical Reviews in Therapeutic Drug Carrier Systems, 1991, page 92; Swinyard, Chapter 39 In: Remington&#39;s Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, Pa., 1990, pages 782-783; Muranishi, Critical Reviews in Therapeutic Drug Carrier Systems, 1990, 7, 1-33; Yamamoto et al.,  J. Pharm. Exp. Ther.,  1992, 263, 25; Yamashita et al.,  J. Pharm. Sci.,  1990, 79, 579-583). 
     Chelating agents, as used in connection with the present invention, can be defined as compounds that remove metallic ions from solution by forming complexes therewith, with the result that absorption of iRNAs through the mucosa is enhanced. With regards to their use as penetration enhancers in the present invention, chelating agents have the added advantage of also serving as DNase inhibitors, as most characterized DNA nucleases require a divalent metal ion for catalysis and are thus inhibited by chelating agents (Jarrett,  J. Chromatogr.,  1993, 618, 315-339). Suitable chelating agents include but are not limited to disodium ethylenediaminetetraacetate (EDTA), citric acid, salicylates (e.g., sodium salicylate, 5-methoxysalicylate and homovanilate), N-acyl derivatives of collagen, laureth-9 and N-amino acyl derivatives of beta-diketones (enamines)(see e.g., Katdare, A. et al., Excipient development for pharmaceutical, biotechnology, and drug delivery, CRC Press, Danvers, Mass., 2006; Lee et al., Critical Reviews in Therapeutic Drug Carrier Systems, 1991, page 92; Muranishi, Critical Reviews in Therapeutic Drug Carrier Systems, 1990, 7, 1-33; Buur et al.,  J. Control Rel.,  1990, 14, 43-51). 
     As used herein, non-chelating non-surfactant penetration enhancing compounds can be defined as compounds that demonstrate insignificant activity as chelating agents or as surfactants but that nonetheless enhance absorption of iRNAs through the alimentary mucosa (see e.g., Muranishi, Critical Reviews in Therapeutic Drug Carrier Systems, 1990, 7, 1-33). This class of penetration enhancers includes, for example, unsaturated cyclic ureas, 1-alkyl- and 1-alkenylazacyclo-alkanone derivatives (Lee et al., Critical Reviews in Therapeutic Drug Carrier Systems, 1991, page 92); and non-steroidal anti-inflammatory agents such as diclofenac sodium, indomethacin and phenylbutazone (Yamashita et al.,  J. Pharm. Pharmacol.,  1987, 39, 621-626). 
     Agents that enhance uptake of iRNAs at the cellular level can also be added to the pharmaceutical and other compositions of the present invention. For example, cationic lipids, such as lipofectin (Junichi et al, U.S. Pat. No. 5,705,188), cationic glycerol derivatives, and polycationic molecules, such as polylysine (Lollo et al., PCT Application WO 97/30731), are also known to enhance the cellular uptake of dsRNAs. Examples of commercially available transfection reagents include, for example Lipofectamine™ (Invitrogen; Carlsbad, Calif.), Lipofectamine 2000™ (Invitrogen; Carlsbad, Calif.), 293Fectin™ (Invitrogen; Carlsbad, Calif.), Cellfectin™ (Invitrogen; Carlsbad, Calif.), DMRIE-C™ (Invitrogen; Carlsbad, Calif.), FreeStyle™ MAX (Invitrogen; Carlsbad, Calif.), Lipofectamine™ 2000 CD (Invitrogen; Carlsbad, Calif.), Lipofectamine™ (Invitrogen; Carlsbad, Calif.), RNAiMAX (Invitrogen; Carlsbad, Calif.), Oligofectamine™ (Invitrogen; Carlsbad, Calif.), Optifect™ (Invitrogen; Carlsbad, Calif.), X-tremeGENE Q2 Transfection Reagent (Roche; Grenzacherstrasse, Switzerland), DOTAP Liposomal Transfection Reagent (Grenzacherstrasse, Switzerland), DOSPER Liposomal Transfection Reagent (Grenzacherstrasse, Switzerland), or Fugene (Grenzacherstrasse, Switzerland), Transfectam® Reagent (Promega; Madison, Wis.), TransFast™ Transfection Reagent (Promega; Madison, Wis.), Tfx™-20 Reagent (Promega; Madison, Wis.), Tfx™-50 Reagent (Promega; Madison, Wis.), DreamFect™ (OZ Biosciences; Marseille, France), EcoTransfect (OZ Biosciences; Marseille, France), TransPass&#39; D1 Transfection Reagent (New England Biolabs; Ipswich, Mass., USA), LyoVec™/LipoGen™ (Invitrogen; San Diego, Calif., USA), PerFectin Transfection Reagent (Genlantis; San Diego, Calif., USA), NeuroPORTER Transfection Reagent (Genlantis; San Diego, Calif., USA), GenePORTER Transfection reagent (Genlantis; San Diego, Calif., USA), GenePORTER 2 Transfection reagent (Genlantis; San Diego, Calif., USA), Cytofectin Transfection Reagent (Genlantis; San Diego, Calif., USA), BaculoPORTER Transfection Reagent (Genlantis; San Diego, Calif., USA), TroganPORTER™ transfection Reagent (Genlantis; San Diego, Calif., USA), RiboFect (Bioline; Taunton, Mass., USA), PlasFect (Bioline; Taunton, Mass., USA), UniFECTOR (B-Bridge International; Mountain View, Calif., USA), SureFECTOR (B-Bridge International; Mountain View, Calif., USA), or HiFect™ (B-Bridge International, Mountain View, Calif., USA), among others. 
     Other agents can be utilized to enhance the penetration of the administered nucleic acids, including glycols such as ethylene glycol and propylene glycol, pyrrols such as 2-pyrrol, azones, and terpenes such as limonene and menthone. 
     v. Carriers 
     Certain compositions of the present invention also incorporate carrier compounds in the formulation. As used herein, “carrier compound” or “carrier” can refer to a nucleic acid, or analog thereof, which is inert (i.e., does not possess biological activity per se) but is recognized as a nucleic acid by in vivo processes that reduce the bioavailability of a nucleic acid having biological activity by, for example, degrading the biologically active nucleic acid or promoting its removal from circulation. The coadministration of a nucleic acid and a carrier compound, typically with an excess of the latter substance, can result in a substantial reduction of the amount of nucleic acid recovered in the liver, kidney or other extracirculatory reservoirs, presumably due to competition between the carrier compound and the nucleic acid for a common receptor. For example, the recovery of a partially phosphorothioate dsRNA in hepatic tissue can be reduced when it is coadministered with polyinosinic acid, dextran sulfate, polycytidic acid or 4-acetamido-4′isothiocyano-stilbene-2,2′-disulfonic acid (Miyao et al., DsRNA Res. Dev., 1995, 5, 115-121; Takakura et al., DsRNA &amp; Nucl. Acid Drug Dev., 1996, 6, 177-183. 
     vi. Excipients 
     In contrast to a carrier compound, a “pharmaceutical carrier” or “excipient” is a pharmaceutically acceptable solvent, suspending agent or any other pharmacologically inert vehicle for delivering one or more nucleic acids to an animal. The excipient can be liquid or solid and is selected, with the planned manner of administration in mind, so as to provide for the desired bulk, consistency, etc., when combined with a nucleic acid and the other components of a given pharmaceutical composition. Typical pharmaceutical carriers include, but are not limited to, binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose, etc.); fillers (e.g., lactose and other sugars, microcrystalline cellulose, pectin, gelatin, calcium sulfate, ethyl cellulose, polyacrylates or calcium hydrogen phosphate, etc.); lubricants (e.g., magnesium stearate, talc, silica, colloidal silicon dioxide, stearic acid, metallic stearates, hydrogenated vegetable oils, corn starch, polyethylene glycols, sodium benzoate, sodium acetate, etc.); disintegrants (e.g., starch, sodium starch glycolate, etc.); and wetting agents (e.g., sodium lauryl sulphate, etc). 
     Pharmaceutically acceptable organic or inorganic excipients suitable for non-parenteral administration which do not deleteriously react with nucleic acids can also be used to formulate the compositions of the present invention. Suitable pharmaceutically acceptable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose, polyvinylpyrrolidone and the like. 
     Formulations for topical administration of nucleic acids can include sterile and non-sterile aqueous solutions, non-aqueous solutions in common solvents such as alcohols, or solutions of the nucleic acids in liquid or solid oil bases. The solutions can also contain buffers, diluents and other suitable additives. Pharmaceutically acceptable organic or inorganic excipients suitable for non-parenteral administration which do not deleteriously react with nucleic acids can be used. 
     Suitable pharmaceutically acceptable excipients include, but are not limited to, water, salt solutions, alcohol, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose, polyvinylpyrrolidone and the like. 
     vii. Other Components 
     The compositions of the present invention can additionally contain other adjunct components conventionally found in pharmaceutical compositions, at their art-established usage levels. Thus, for example, the compositions can contain additional, compatible, pharmaceutically-active materials such as, for example, antipruritics, astringents, local anesthetics or anti-inflammatory agents, or can contain additional materials useful in physically formulating various dosage forms of the compositions of the present invention, such as dyes, flavoring agents, preservatives, antioxidants, opacifiers, thickening agents and stabilizers. However, such materials, when added, should not unduly interfere with the biological activities of the components of the compositions of the present invention. The formulations can be sterilized and, if desired, mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like which do not deleteriously interact with the nucleic acid(s) of the formulation. 
     Aqueous suspensions can contain substances which increase the viscosity of the suspension including, for example, sodium carboxymethylcellulose, sorbitol and/or dextran. The suspension can also contain stabilizers. 
     In some embodiments, pharmaceutical compositions featured in the invention include (a) one or more iRNA compounds and (b) one or more agents which function by a non-RNAi mechanism and which are useful in treating a hemolytic disorder. Examples of such agents include, but are not limited to an anti-inflammatory agent, anti-steatosis agent, anti-viral, and/or anti-fibrosis agent. In addition, other substances commonly used to protect the liver, such as silymarin, can also be used in conjunction with the iRNAs described herein. Other agents useful for treating liver diseases include telbivudine, entecavir, and protease inhibitors such as telaprevir and other disclosed, for example, in Tung et al., U.S. Application Publication Nos. 2005/0148548, 2004/0167116, and 2003/0144217; and in Hale et al., U.S. Application Publication No. 2004/0127488. 
     Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50. Compounds that exhibit high therapeutic indices are preferred. 
     The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of compositions featured herein in the invention lies generally within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage can vary within this range depending upon the dosage form employed and the route of administration utilized. For any compound used in the methods featured in the invention, the therapeutically effective dose can be estimated initially from cell culture assays. A dose can be formulated in animal models to achieve a circulating plasma concentration range of the compound or, when appropriate, of the polypeptide product of a target sequence (e.g., achieving a decreased concentration of the polypeptide) that includes the IC50 (i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma can be measured, for example, by high performance liquid chromatography. 
     In addition to their administration, as discussed above, the iRNAs featured in the invention can be administered in combination with other known agents effective in treatment of pathological processes mediated by C5 expression. In any event, the administering physician can adjust the amount and timing of iRNA administration on the basis of results observed using standard measures of efficacy known in the art or described herein. 
     VI. Methods For Inhibiting C5 Expression 
     The present invention provides methods of inhibiting expression of C5 in a cell. The methods include contacting a cell with an RNAi agent, e.g., a double stranded RNAi agent, in an amount effective to inhibit expression of the C5 in the cell, thereby inhibiting expression of the C5 in the cell. 
     Contacting of a cell with a double stranded RNAi agent may be done in vitro or in vivo. Contacting a cell in vivo with the RNAi agent includes contacting a cell or group of cells within a subject, e.g., a human subject, with the RNAi agent. Combinations of in vitro and in vivo methods of contacting are also possible. Contacting may be direct or indirect, as discussed above. Furthermore, contacting a cell may be accomplished via a targeting ligand, including any ligand described herein or known in the art. In preferred embodiments, the targeting ligand is a carbohydrate moiety, e.g., a GalNAc 3  ligand, or any other ligand that directs the RNAi agent to a site of interest, e.g., the liver of a subject. 
     The term “inhibiting,” as used herein, is used interchangeably with “reducing,” “silencing,” “downregulating” and other similar terms, and includes any level of inhibition. 
     The phrase “inhibiting expression of a C5” is intended to refer to inhibition of expression of any C5 gene (such as, e.g., a mouse C5 gene, a rat C5 gene, a monkey C5 gene, or a human C5 gene) as well as variants or mutants of a C5 gene. Thus, the C5 gene may be a wild-type C5 gene, a mutant C5 gene, or a transgenic C5 gene in the context of a genetically manipulated cell, group of cells, or organism. 
     “Inhibiting expression of a C5 gene” includes any level of inhibition of a C5 gene, e.g., at least partial suppression of the expression of a C5 gene. The expression of the C5 gene may be assessed based on the level, or the change in the level, of any variable associated with C5 gene expression, e.g., C5 mRNA level, C5 protein level, or for example, CH 50  activity as a measure of total hemolytic complement, AH 50  to measure the hemolytic activity of the alternate pathway of complement, and/or lactate dehydrogenase (LDH) levels as a measure of intravascular hemolysis, and/or hemoglobin levels. Levels of C5a, C5 b, and soluble C5 b-9 complex may also be measured to assess C5 expression. This level may be assessed in an individual cell or in a group of cells, including, for example, a sample derived from a subject. 
     Inhibition may be assessed by a decrease in an absolute or relative level of one or more variables that are associated with C5 expression compared with a control level. The control level may be any type of control level that is utilized in the art, e.g., a pre-dose baseline level, or a level determined from a similar subject, cell, or sample that is untreated or treated with a control (such as, e.g., buffer only control or inactive agent control). 
     In some embodiments of the methods of the invention, expression of a C5 gene is inhibited by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%. at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%. 
     Inhibition of the expression of a C5 gene may be manifested by a reduction of the amount of mRNA expressed by a first cell or group of cells (such cells may be present, for example, in a sample derived from a subject) in which a C5 gene is transcribed and which has or have been treated (e.g., by contacting the cell or cells with an RNAi agent of the invention, or by administering an RNAi agent of the invention to a subject in which the cells are or were present) such that the expression of a C5 gene is inhibited, as compared to a second cell or group of cells substantially identical to the first cell or group of cells but which has not or have not been so treated (control cell(s)). In preferred embodiments, the inhibition is assessed by expressing the level of mRNA in treated cells as a percentage of the level of mRNA in control cells, using the following formula: 
     
       
         
           
             
               
                 
                   
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     Alternatively, inhibition of the expression of a C5 gene may be assessed in terms of a reduction of a parameter that is functionally linked to C5 gene expression, e.g., C5 protein expression, hepcidin gene or protein expression, or iron levels in tissues or serum. C5 gene silencing may be determined in any cell expressing C5, either constitutively or by genomic engineering, and by any assay known in the art. The liver is the major site of C5 expression. Other significant sites of expression include the kidneys and the uterus. 
     Inhibition of the expression of a C5 protein may be manifested by a reduction in the level of the C5 protein that is expressed by a cell or group of cells (e.g., the level of protein expressed in a sample derived from a subject). As explained above for the assessment of mRNA suppression, the inhibition of protein expression levels in a treated cell or group of cells may similarly be expressed as a percentage of the level of protein in a control cell or group of cells. 
     A control cell or group of cells that may be used to assess the inhibition of the expression of a C5 gene includes a cell or group of cells that has not yet been contacted with an RNAi agent of the invention. For example, the control cell or group of cells may be derived from an individual subject (e.g., a human or animal subject) prior to treatment of the subject with an RNAi agent. 
     The level of C5 mRNA that is expressed by a cell or group of cells may be determined using any method known in the art for assessing mRNA expression. In one embodiment, the level of expression of C5 in a sample is determined by detecting a transcribed polynucleotide, or portion thereof, e.g., mRNA of the C5 gene. RNA may be extracted from cells using RNA extraction techniques including, for example, using acid phenol/guanidine isothiocyanate extraction (RNAzol B; Biogenesis), RNeasy RNA preparation kits (Qiagen) or PAXgene (PreAnalytix, Switzerland). Typical assay formats utilizing ribonucleic acid hybridization include nuclear run-on assays, RT-PCR, RNase protection assays (Melton et al.,  Nuc. Acids Res.  12:7035), Northern blotting, in situ hybridization, and microarray analysis. 
     In one embodiment, the level of expression of C5 is determined using a nucleic acid probe. The term “probe”, as used herein, refers to any molecule that is capable of selectively binding to a specific C5. Probes can be synthesized by one of skill in the art, or derived from appropriate biological preparations. Probes may be specifically designed to be labeled. Examples of molecules that can be utilized as probes include, but are not limited to, RNA, DNA, proteins, antibodies, and organic molecules. 
     Isolated mRNA can be used in hybridization or amplification assays that include, but are not limited to, Southern or Northern analyses, polymerase chain reaction (PCR) analyses and probe arrays. One method for the determination of mRNA levels involves contacting the isolated mRNA with a nucleic acid molecule (probe) that can hybridize to C5 mRNA. In one embodiment, the mRNA is immobilized on a solid surface and contacted with a probe, for example by running the isolated mRNA on an agarose gel and transferring the mRNA from the gel to a membrane, such as nitrocellulose. In an alternative embodiment, the probe(s) are immobilized on a solid surface and the mRNA is contacted with the probe(s), for example, in an Affymetrix gene chip array. A skilled artisan can readily adapt known mRNA detection methods for use in determining the level of C5 mRNA. 
     An alternative method for determining the level of expression of C5 in a sample involves the process of nucleic acid amplification and/or reverse transcriptase (to prepare cDNA) of for example mRNA in the sample, e.g., by RT-PCR (the experimental embodiment set forth in Mullis, 1987, U.S. Pat. No. 4,683,202), ligase chain reaction (Barany (1991)  Proc. Natl . Acad. Sci. USA 88:189-193), self sustained sequence replication (Guatelli et al. (1990)  Proc. Natl . Acad. Sci. USA 87:1874-1878), transcriptional amplification system (Kwoh et al. (1989)  Proc. Natl . Acad. Sci. USA 86:1173-1177), Q-Beta Replicase (Lizardi et al. (1988) Bio/Technology 6:1197), rolling circle replication (Lizardi et al., U.S. Pat. No. 5,854,033) or any other nucleic acid amplification method, followed by the detection of the amplified molecules using techniques well known to those of skill in the art. These detection schemes are especially useful for the detection of nucleic acid molecules if such molecules are present in very low numbers. In particular aspects of the invention, the level of expression of C5 is determined by quantitative fluorogenic RT-PCR (i.e., the TaqMan™ System). 
     The expression levels of C5 mRNA may be monitored using a membrane blot (such as used in hybridization analysis such as Northern, Southern, dot, and the like), or microwells, sample tubes, gels, beads or fibers (or any solid support comprising bound nucleic acids). See U.S. Pat. Nos. 5,770,722, 5,874,219, 5,744,305, 5,677,195 and 5,445,934, which are incorporated herein by reference. The determination of C5 expression level may also comprise using nucleic acid probes in solution. 
     In preferred embodiments, the level of mRNA expression is assessed using branched DNA (bDNA) assays or real time PCR (qPCR). The use of these methods is described and exemplified in the Examples presented herein. 
     The level of C5 protein expression may be determined using any method known in the art for the measurement of protein levels. Such methods include, for example, electrophoresis, capillary electrophoresis, high performance liquid chromatography (HPLC), thin layer chromatography (TLC), hyperdiffusion chromatography, fluid or gel precipitin reactions, absorption spectroscopy, a colorimetric assays, spectrophotometric assays, flow cytometry, immunodiffusion (single or double), immunoelectrophoresis, Western blotting, radioimmunoassay (RIA), enzyme-linked immunosorbent assays (ELISAs), immunofluorescent assays, electrochemiluminescence assays, and the like. 
     The term “sample” as used herein refers to a collection of similar fluids, cells, or tissues isolated from a subject, as well as fluids, cells, or tissues present within a subject. Examples of biological fluids include blood, serum and serosal fluids, plasma, lymph, urine, cerebrospinal fluid, saliva, ocular fluids, and the like. Tissue samples may include samples from tissues, organs or localized regions. For example, samples may be derived from particular organs, parts of organs, or fluids or cells within those organs. In certain embodiments, samples may be derived from the liver (e.g., whole liver or certain segments of liver or certain types of cells in the liver, such as, e.g., hepatocytes). In preferred embodiments, a “sample derived from a subject” refers to blood or plasma drawn from the subject. In further embodiments, a “sample derived from a subject” refers to liver tissue derived from the subject. 
     In some embodiments of the methods of the invention, the RNAi agent is administered to a subject such that the RNAi agent is delivered to a specific site within the subject. The inhibition of expression of C5 may be assessed using measurements of the level or change in the level of C5 mRNA or C5 protein in a sample derived from fluid or tissue from the specific site within the subject. In preferred embodiments, the site is the liver. The site may also be a subsection or subgroup of cells from any one of the aforementioned sites. The site may also include cells that express a particular type of receptor. 
     The phrase “contacting a cell with an RNAi agent,” such as a dsRNA, as used herein, includes contacting a cell by any possible means. Contacting a cell with an RNAi agent includes contacting a cell in vitro with the iRNA or contacting a cell in vivo with the iRNA. The contacting may be done directly or indirectly. Thus, for example, the RNAi agent may be put into physical contact with the cell by the individual performing the method, or alternatively, the RNAi agent may be put into a situation that will permit or cause it to subsequently come into contact with the cell. 
     Contacting a cell in vitro may be done, for example, by incubating the cell with the RNAi agent. Contacting a cell in vivo may be done, for example, by injecting the RNAi agent into or near the tissue where the cell is located, or by injecting the RNAi agent into another area, e.g., the bloodstream or the subcutaneous space, such that the agent will subsequently reach the tissue where the cell to be contacted is located. For example, the RNAi agent may contain and/or be coupled to a ligand, e.g., GalNAc3, that directs the RNAi agent to a site of interest, e.g., the liver. Combinations of in vitro and in vivo methods of contacting are also possible. For example, a cell may also be contacted in vitro with an RNAi agent and subsequently transplanted into a subject. 
     In one embodiment, contacting a cell with an iRNA includes “introducing” or “delivering the iRNA into the cell” by facilitating or effecting uptake or absorption into the cell. Absorption or uptake of an iRNA can occur through unaided diffusive or active cellular processes, or by auxiliary agents or devices. Introducing an iRNA into a cell may be in vitro and/or in vivo. For example, for in vivo introduction, iRNA can be injected into a tissue site or administered systemically. In vivo delivery can also be done by a beta-glucan delivery system, such as those described in U.S. Pat. Nos. 5,032,401 and 5,607,677, and U.S. Publication No. 2005/0281781, the entire contents of which are hereby incorporated herein by reference. In vitro introduction into a cell includes methods known in the art such as electroporation and lipofection. Further approaches are described herein below and/or are known in the art. 
     VII. Methods for Treating or Preventing a Complement Component C5-Associated Disorder 
     The present invention also provides therapeutic and prophylactic methods which include administering to a subject having a complement component C5-associated disease, e.g., PNH, aHUS, neuromyelitis optica (NMO), or myasthenia gravis, an iRNA agent, pharmaceutical compositions comprising an iRNA agent, or vector comprising an iRNA of the invention. In some aspects of the invention, the methods further include administering to the subject an additional therapeutic agent, such as an anti-complement component C5 antibody, or antigen-binding fragment thereof (e.g., eculizumab). 
     In one aspect, the present invention provides methods of treating a subject having a disorder that would benefit from reduction in C5 expression, e.g., a complement component C5-associated disease, e.g., PNH, aHUS, neuromyelitis optica (NMO), or myasthenia gravis. The treatment methods (and uses) of the invention include administering to the subject, e.g., a human, a therapeutically effective amount of an iRNA agent targeting a C5 gene or a pharmaceutical composition comprising an iRNA agent targeting a C5 gene, thereby treating the subject having a disorder that would benefit from reduction in C5 expression. 
     In another aspect, the present invention provides methods of treating a subject having a disorder that would benefit from reduction in C5 expression, e.g., a complement component C5-associated disease, e.g., PNH, aHUS, neuromyelitis optica (NMO), or myasthenia gravis, which include administering to the subject, e.g., a human, a therapeutically effective amount of an iRNA agent targeting a C5 gene or a pharmaceutical composition comprising an iRNA agent targeting a C5 gene, and an additional therapeutic agent, such as an anti-complement component C5 antibody, or antigen-binding fragment thereof (e.g., eculizumab), thereby treating the subject having a disorder that would benefit from reduction in C5 expression. 
     In one aspect, the invention provides methods of preventing at least one symptom in a subject having a disorder that would benefit from reduction in C5 expression, e.g., a complement component C5-associated disease, e.g., PNH, aHUS, neuromyelitis optica (NMO), or myasthenia gravis. The methods include administering to the subject a prohpylactically effective amount of the iRNA agent, e.g., dsRNA, or vector of the invention, thereby preventing at least one symptom in the subject having a disorder that would benefit from reduction in C5 expression. For example, the invention provides methods for preventing hemolysis in a subject suffering from a disorder that would benefit from reduction in C5 expression, e.g., a complement component C5-associated disease, e.g., PNH, aHUS, neuromyelitis optica (NMO), or myasthenia gravis. 
     In another aspect, the invention provides methods of preventing at least one symptom in a subject having a disorder that would benefit from reduction in C5 expression, e.g., a complement component C5-associated disease, e.g., PNH, aHUS, neuromyelitis optica (NMO), or myasthenia gravis. The methods include administering to the subject a prohpylactically effective amount of the iRNA agent, e.g., dsRNA, or vector of the invention, and an additional therapeutic agent, such as an anti-complement component C5 antibody, or antigen-binding fragment thereof (e.g., eculizumab), thereby preventing at least one symptom in the subject having a disorder that would benefit from reduction in C5 expression. 
     “Therapeutically effective amount,” as used herein, is intended to include the amount of an RNAi agent or anti-complement component C5 antibody, or antigen-binding fragment thereof (e.g., eculizumab), that, when administered to a subject having a complement component C5-associated disease, is sufficient to effect treatment of the disease (e.g., by diminishing, ameliorating or maintaining the existing disease or one or more symptoms of disease). The “therapeutically effective amount” may vary depending on the RNAi agent or antibody, or antigen-binding fragment thereof, how the agent is administered, the disease and its severity and the history, age, weight, family history, genetic makeup, the types of preceding or concomitant treatments, if any, and other individual characteristics of the subject to be treated. 
     “Prophylactically effective amount,” as used herein, is intended to include the amount of an iRNA agent or anti-complement component C5 antibody, or antigen-binding fragment thereof (e.g., eculizumab), that, when administered to a subject having a complement component C5-associate disease but not yet (or currently) experiencing or displaying symptoms of the disease, and/or a subject at risk of developing a complement component C5-associated disease, e.g., a subject having a graft and/or transplant, e.g., a sensitized or allogenic recipient, a subject having sepsis, and/or a subject having a myocardial infarction, is sufficient to prevent or ameliorate the disease or one or more symptoms of the disease. Ameliorating the disease includes slowing the course of the disease or reducing the severity of later-developing disease. The “prophylactically effective amount” may vary depending on the iRNA agent or anti-complement component C5 antibody, or antigen-binding fragment thereof, how the agent or anti-complement component C5 antibody, or antigen-binding fragment thereof, is administered, the degree of risk of disease, and the history, age, weight, family history, genetic makeup, the types of preceding or concomitant treatments, if any, and other individual characteristics of the patient to be treated. 
     A “therapeutically effective amount” or “prophylactically effective amount” also includes an amount of an RNAi agent or anti-complement component C5 antibody, or antigen-binding fragment thereof (e.g., eculizumab), that produces some desired local or systemic effect at a reasonable benefit/risk ratio applicable to any treatment. iRNA agents employed in the methods of the present invention may be administered in a sufficient amount to produce a reasonable benefit/risk ratio applicable to such treatment. 
     In another aspect, the present invention provides uses of a therapeutically effective amount of an iRNA agent of the invention for treating a subject, e.g., a subject that would benefit from a reduction and/or inhibition of C5 expression. 
     In another aspect, the present invention provides uses of a therapeutically effective amount of an iRNA agent of the invention and an additional therapeutic agent, such as an anti-complement component C5 antibody, or antigen-binding fragment thereof (e.g., eculizumab), for treating a subject, e.g., a subject that would benefit from a reduction and/or inhibition of C5 expression. 
     In yet another aspect, the present invention provides use of an iRNA agent, e.g., a dsRNA, of the invention targeting a C5 gene or a pharmaceutical composition comprising an iRNA agent targeting a C5 gene in the manufacture of a medicament for treating a subject, e.g., a subject that would benefit from a reduction and/or inhibition of C5 expression, such as a subject having a disorder that would benefit from reduction in C5 expression, e.g., a complement component C5-associated disease, e.g., PNH, aHUS, neuromyelitis optica (NMO), or myasthenia gravis. 
     In another aspect, the present invention provides uses of an iRNA agent, e.g., a dsRNA, of the invention targeting a C5 gene or a pharmaceutical composition comprising an iRNA agent targeting a C5 gene in the manufacture of a medicament for use in combination with an additional therapeutic agent, such as an anti-complement component C5 antibody, or antigen-binding fragment thereof (e.g., eculizumab), for treating a subject, e.g., a subject that would benefit from a reduction and/or inhibition of C5 expression, e.g., a complement component C5-associated disease, e.g., PNH, aHUS, neuromyelitis optica (NMO), or myasthenia gravis. 
     In another aspect, the invention provides uses of an iRNA, e.g., a dsRNA, of the invention for preventing at least one symptom in a subject suffering from a disorder that would benefit from a reduction and/or inhibition of C5 expression, such as a complement component C5-associated disease, e.g., PNH, aHUS, neuromyelitis optica (NMO), or myasthenia gravis. 
     In yet another aspect, the invention provides uses of an iRNA agent, e.g., a dsRNA, of the invention, and an additional therapeutic agent, such as an anti-complement component C5 antibody, or antigen-binding fragment thereof (e.g., eculizumab), for preventing at least one symptom in a subject suffering from a disorder that would benefit from a reduction and/or inhibition of C5 expression, such as a complement component C5-associated disease, e.g., PNH, aHUS, neuromyelitis optica (NMO), or myasthenia gravis. 
     In a further aspect, the present invention provides uses of an iRNA agent of the invention in the manufacture of a medicament for preventing at least one symptom in a subject suffering from a disorder that would benefit from a reduction and/or inhibition of C5 expression, such as a a complement component C5-associated disease, e.g., PNH, aHUS, neuromyelitis optica (NMO), or myasthenia gravis. 
     In a further aspect, the present invention provides uses of an iRNA agent of the invention in the manufacture of a medicament for use in combination with an additional therapeutic agent, such as an anti-complement component C5 antibody, or antigen-binding fragment thereof (e.g., eculizumab), for preventing at least one symptom in a subject suffering from a disorder that would benefit from a reduction and/or inhibition of C5 expression, such as a complement component C5-associated disease, e.g., PNH, aHUS, neuromyelitis optica (NMO), or myasthenia gravis. 
     In one embodiment, an iRNA agent targeting C5 is administered to a subject having a complement component C5-associated disease such that C5 levels, e.g., in a cell, tissue, blood, urine or other tissue or fluid of the subject are reduced by at least about 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 62%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least about 99% or more and, subsequently, an additional therapeutic (as described below) is administered to the subject. 
     The additional therapeutic may be an anti-complement component C5 antibody, or antigen-binding fragment or derivative thereof. In one embodiment, the anti-complement component C5 antibody is eculizumab (SOLIRIS®), or antigen-binding fragment or derivative thereof. Eculizumab is a humanized monoclonal IgG2/4, kappa light chain antibody that specifically binds complement component C5 with high affinity and inhibits cleavage of C5 to C5a and C5 b, thereby inhibiting the generation of the terminal complement complex C5 b-9. Eculizumab is described in U.S. Pat. No. 6,355,245, the entire contents of which are incorporated herein by reference. 
     The methods of the invention comprising administration of an iRNA agent of the invention and eculizumab to a subject may further comprise administration of a meningococcal vaccine to the subject. 
     The additional therapeutic, e.g., eculizumab and/or a meningococcal vaccine, may be administered to the subject at the same time as the iRNA agent targeting C5 or at a different time. 
     Moreover, the additional therapeutic, e.g., eculizumab, may be administered to the subject in the same formulation as the iRNA agent targeting C5 or in a different formulation as the iRNA agent targeting C5. 
     In one embodiment, a dsRNA agent is administered to the subject before the anti-complement component C5 antibody, or antigen-binding fragment thereof, is administered to the subject. In one embodiment, the dsRNA agent is administered to the subject first for a period of time sufficient to reduce the levels of complement component C5 in the subject. 
     Eculizumab dosage regimens are described in, for example, the product insert for eculizumab (SOLIRIS®) and in U.S. Patent Application No. 2012/0225056, the entire contents of each of which are incorporated herein by reference. In exemplary methods of the invention for treating a complement component C5-associated disease, e.g., PNH, aHUS, neuromyelitis optica (NMO), or myasthenia gravis, an iRNA agent targeting C5 is administered (e.g., subcutaneously) to the subject first, such that the C5 levels in the subject are reduced (e.g., by at least about 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 62%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least about 99% or more) and subsequently eculizumab is administered at doses lower than the ones described in the product insert for SOLIRIS®. For example, eculizumab may be administered to the subject weekly at a dose less than about 600 mg for 4 weeks followed by a fifth dose at about one week later of less than about 900 mg, followed by a dose less than about 900 mg about every two weeks thereafter. Eculizumab may also be administered to the subject weekly at a dose less than about 900 mg for 4 weeks followed by a fifth dose at about one week later of less than about 1200 mg, followed by a dose less than about 1200 mg about every two weeks thereafter. If the subject is less than 18 years of age, eculizumab may be administered to the subject weekly at a dose less than about 900 mg for 4 weeks followed by a fifth dose at about one week later of less than about 1200 mg, followed by a dose less than about 1200 mg about every two weeks thereafter; or if the subject is less than 18 years of age, eculizumab may be administered to the subject weekly at a dose less than about 600 mg for 2 weeks followed by a third dose at about one week later of less than about 900 mg, followed by a dose less than about 900 mg about every two weeks thereafter; or if the subject is less than 18 years of age, eculizumab may be administered to the subject weekly at a dose less than about 600 mg for 2 weeks followed by a third dose at about one week later of less than about 600 mg, followed by a dose less than about 600 mg about every two weeks thereafter; or if the subject is less than 18 years of age, eculizumab may be administered to the subject weekly at a dose less than about 600 mg for 1 week followed by a second dose at about one week later of less than about 300 mg, followed by a dose less than about 300 mg about every two weeks thereafter; or if the subject is less than 18 years of age, eculizumab may be administered to the subject weekly at a dose less than about 300 mg for 1 week followed by a second dose at about one week later of less than about 300 mg, followed by a dose less than about 300 mg about every two weeks thereafter. If the subject is receiving plamapheresis or plasma exchange, eculizumab may be administered to the subject at a dose less than about 300 mg (e.g., if the most recent does of eculizumab was about 300 mg) or less than about 600 mg (e.g., if the most recent does of eculizumab was about 600 mg or more). If the subject is receiving plasma infusion, eculizumab may be administered to the subject at a dose less than about 300 mg (e.g., if the most recent does of eculizumab was about 300 mg or more). The lower doses of eculizumab allow for either subcutaneous or intravenous administration of eculizumab. 
     In the combination therapies of the present invention comprising eculizumab, the effective amount of eculizumab to treat the subject may be reduced. 
     In one embodiment of the combination therapies of the present invention comprising eculizumab, eculizumab may be administered to the subject, e.g., subcutaneously, at a dose of about 0.01 mg/kg to about 10 mg/kg, or about 5 mg/kg to about 10 mg/kg, or about 0.5 mg/kg to about 15 mg/kg. For example, eculizumab may be administered to the subject, e.g., subcutaneously, at a dose of 0.5 mg/kg, 1 mg/kg, 1.5 mg/kg, 2 mg/kg, 2.5 mg/kg, 3 mg/kg, 3.5 mg/kg, 4 mg/kg, 4.5 mg/kg, 5 mg/kg, 5.5 mg/kg, 6 mg/kg, 6.5 mg/kg, 7 mg/kg, 7.5 mg/kg, 8 mg/kg, 8.5 mg/kg, 9 mg/kg, 9.5 mg/kg, 10 mg/kg, 10.5 mg/kg, 11 mg/kg, 11.5 mg/kg, 12 mg/kg, 12.5 mg/kg, 13 mg/kg, 13.5 mg/kg, 14 mg/kg, 14.5 mg/kg, or 15 mg/kg. 
     In one embodiment of the combination therapies of the present invention comprising eculizumab, the lactate dehydrogenase (LDH) serum levels in the treated subject are less than about 1.5 times the upper limit of normal range. 
     The methods and uses of the invention include administering a composition described herein such that expression of the target C5 gene is decreased, such as for about 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 18, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, or about 80 hours. In one embodiment, expression of the target C5 gene is decreased for an extended duration, e.g., at least about two, three, four, five, six, seven days or more, e.g., about one week, two weeks, three weeks, or about four weeks or longer. 
     Administration of the dsRNA according to the methods and uses of the invention may result in a reduction of the severity, signs, symptoms, and/or markers of such diseases or disorders in a patient with a complement component C5-associated disease. By “reduction” in this context is meant a statistically significant decrease in such level. The reduction can be, for example, at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or about 100%. 
     Efficacy of treatment or prevention of disease can be assessed, for example by measuring disease progression, disease remission, symptom severity, reduction in pain, quality of life, dose of a medication required to sustain a treatment effect, level of a disease marker or any other measurable parameter appropriate for a given disease being treated or targeted for prevention. It is well within the ability of one skilled in the art to monitor efficacy of treatment or prevention by measuring any one of such parameters, or any combination of parameters. For example, efficacy of treatment of a hemolytic disorder may be assessed, for example, by periodic monitoring of LDH and CH 50  levels. Comparisons of the later readings with the initial readings provide a physician an indication of whether the treatment is effective. It is well within the ability of one skilled in the art to monitor efficacy of treatment or prevention by measuring any one of such parameters, or any combination of parameters. In connection with the administration of an iRNA targeting C5 or pharmaceutical composition thereof, “effective against” a complement component C5-associated disease indicates that administration in a clinically appropriate manner results in a beneficial effect for at least a statistically significant fraction of patients, such as improvement of symptoms, a cure, a reduction in disease, extension of life, improvement in quality of life, or other effect generally recognized as positive by medical doctors familiar with treating a complement component C5-associated disease and the related causes. 
     A treatment or preventive effect is evident when there is a statistically significant improvement in one or more parameters of disease status, or by a failure to worsen or to develop symptoms where they would otherwise be anticipated. As an example, a favorable change of at least 10% in a measurable parameter of disease, and preferably at least 20%, 30%, 40%, 50% or more can be indicative of effective treatment. Efficacy for a given iRNA drug or formulation of that drug can also be judged using an experimental animal model for the given disease as known in the art. When using an experimental animal model, efficacy of treatment is evidenced when a statistically significant reduction in a marker or symptom is observed. 
     Alternatively, the efficacy can be measured by a reduction in the severity of disease as determined by one skilled in the art of diagnosis based on a clinically accepted disease severity grading scale, as but one example the Rheumatoid Arthritis Severity Scale (RASS). Any positive change resulting in e.g., lessening of severity of disease measured using the appropriate scale, represents adequate treatment using an iRNA or iRNA formulation as described herein. 
     Subjects can be administered a therapeutic amount of iRNA, such as about 0.01 mg/kg, 0.02 mg/kg, 0.03 mg/kg, 0.04 mg/kg, 0.05 mg/kg, 0.1 mg/kg, 0.15 mg/kg, 0.2 mg/kg, 0.25 mg/kg, 0.3 mg/kg, 0.35 mg/kg, 0.4 mg/kg, 0.45 mg/kg, 0.5 mg/kg, 0.55 mg/kg, 0.6 mg/kg, 0.65 mg/kg, 0.7 mg/kg, 0.75 mg/kg, 0.8 mg/kg, 0.85 mg/kg, 0.9 mg/kg, 0.95 mg/kg, 1.0 mg/kg, 1.1 mg/kg, 1.2 mg/kg, 1.3 mg/kg, 1.4 mg/kg, 1.5 mg/kg, 1.6 mg/kg, 1.7 mg/kg, 1.8 mg/kg, 1.9 mg/kg, 2.0 mg/kg, 2.1 mg/kg, 2.2 mg/kg, 2.3 mg/kg, 2.4 mg/kg, 2.5 mg/kg dsRNA, 2.6 mg/kg dsRNA, 2.7 mg/kg dsRNA, 2.8 mg/kg dsRNA, 2.9 mg/kg dsRNA, 3.0 mg/kg dsRNA, 3.1 mg/kg dsRNA, 3.2 mg/kg dsRNA, 3.3 mg/kg dsRNA, 3.4 mg/kg dsRNA, 3.5 mg/kg dsRNA, 3.6 mg/kg dsRNA, 3.7 mg/kg dsRNA, 3.8 mg/kg dsRNA, 3.9 mg/kg dsRNA, 4.0 mg/kg dsRNA, 4.1 mg/kg dsRNA, 4.2 mg/kg dsRNA, 4.3 mg/kg dsRNA, 4.4 mg/kg dsRNA, 4.5 mg/kg dsRNA, 4.6 mg/kg dsRNA, 4.7 mg/kg dsRNA, 4.8 mg/kg dsRNA, 4.9 mg/kg dsRNA, 5.0 mg/kg dsRNA, 5.1 mg/kg dsRNA, 5.2 mg/kg dsRNA, 5.3 mg/kg dsRNA, 5.4 mg/kg dsRNA, 5.5 mg/kg dsRNA, 5.6 mg/kg dsRNA, 5.7 mg/kg dsRNA, 5.8 mg/kg dsRNA, 5.9 mg/kg dsRNA, 6.0 mg/kg dsRNA, 6.1 mg/kg dsRNA, 6.2 mg/kg dsRNA, 6.3 mg/kg dsRNA, 6.4 mg/kg dsRNA, 6.5 mg/kg dsRNA, 6.6 mg/kg dsRNA, 6.7 mg/kg dsRNA, 6.8 mg/kg dsRNA, 6.9 mg/kg dsRNA, 7.0 mg/kg dsRNA, 7.1 mg/kg dsRNA, 7.2 mg/kg dsRNA, 7.3 mg/kg dsRNA, 7.4 mg/kg dsRNA, 7.5 mg/kg dsRNA, 7.6 mg/kg dsRNA, 7.7 mg/kg dsRNA, 7.8 mg/kg dsRNA, 7.9 mg/kg dsRNA, 8.0 mg/kg dsRNA, 8.1 mg/kg dsRNA, 8.2 mg/kg dsRNA, 8.3 mg/kg dsRNA, 8.4 mg/kg dsRNA, 8.5 mg/kg dsRNA, 8.6 mg/kg dsRNA, 8.7 mg/kg dsRNA, 8.8 mg/kg dsRNA, 8.9 mg/kg dsRNA, 9.0 mg/kg dsRNA, 9.1 mg/kg dsRNA, 9.2 mg/kg dsRNA, 9.3 mg/kg dsRNA, 9.4 mg/kg dsRNA, 9.5 mg/kg dsRNA, 9.6 mg/kg dsRNA, 9.7 mg/kg dsRNA, 9.8 mg/kg dsRNA, 9.9 mg/kg dsRNA, 9.0 mg/kg dsRNA, 10 mg/kg dsRNA, 15 mg/kg dsRNA, 20 mg/kg dsRNA, 25 mg/kg dsRNA, 30 mg/kg dsRNA, 35 mg/kg dsRNA, 40 mg/kg dsRNA, 45 mg/kg dsRNA, or about 50 mg/kg dsRNA. Values and ranges intermediate to the recited values are also intended to be part of this invention. 
     In certain embodiments, for example, when a composition of the invention comprises a dsRNA as described herein and a lipid, subjects can be administered a therapeutic amount of iRNA, such as about 0.01 mg/kg to about 5 mg/kg, about 0.01 mg/kg to about 10 mg/kg, about 0.05 mg/kg to about 5 mg/kg, about 0.05 mg/kg to about 10 mg/kg, about 0.1 mg/kg to about 5 mg/kg, about 0.1 mg/kg to about 10 mg/kg, about 0.2 mg/kg to about 5 mg/kg, about 0.2 mg/kg to about 10 mg/kg, about 0.3 mg/kg to about 5 mg/kg, about 0.3 mg/kg to about 10 mg/kg, about 0.4 mg/kg to about 5 mg/kg, about 0.4 mg/kg to about 10 mg/kg, about 0.5 mg/kg to about 5 mg/kg, about 0.5 mg/kg to about 10 mg/kg, about 1 mg/kg to about 5 mg/kg, about 1 mg/kg to about 10 mg/kg, about 1.5 mg/kg to about 5 mg/kg, about 1.5 mg/kg to about 10 mg/kg, about 2 mg/kg to about 2.5 mg/kg, about 2 mg/kg to about 10 mg/kg, about 3 mg/kg to about 5 mg/kg, about 3 mg/kg to about 10 mg/kg, about 3.5 mg/kg to about 5 mg/kg, about 4 mg/kg to about 5 mg/kg, about 4.5 mg/kg to about 5 mg/kg, about 4 mg/kg to about 10 mg/kg, about 4.5 mg/kg to about 10 mg/kg, about 5 mg/kg to about 10 mg/kg, about 5.5 mg/kg to about 10 mg/kg, about 6 mg/kg to about 10 mg/kg, about 6.5 mg/kg to about 10 mg/kg, about 7 mg/kg to about 10 mg/kg, about 7.5 mg/kg to about 10 mg/kg, about 8 mg/kg to about 10 mg/kg, about 8.5 mg/kg to about 10 mg/kg, about 9 mg/kg to about 10 mg/kg, or about 9.5 mg/kg to about 10 mg/kg. Values and ranges intermediate to the recited values are also intended to be part of this invention. 
     For example, the dsRNA may be administered at a dose of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or about 10 mg/kg. Values and ranges intermediate to the recited values are also intended to be part of this invention. 
     In other embodiments, for example, when a composition of the invention comprises a dsRNA as described herein and an N-acetylgalactosamine, subjects can be administered a therapeutic amount of iRNA, such as a dose of about 0.1 to about 50 mg/kg, about 0.25 to about 50 mg/kg, about 0.5 to about 50 mg/kg, about 0.75 to about 50 mg/kg, about 1 to about 50 mg/mg, about 1.5 to about 50 mg/kb, about 2 to about 50 mg/kg, about 2.5 to about 50 mg/kg, about 3 to about 50 mg/kg, about 3.5 to about 50 mg/kg, about 4 to about 50 mg/kg, about 4.5 to about 50 mg/kg, about 5 to about 50 mg/kg, about 7.5 to about 50 mg/kg, about 10 to about 50 mg/kg, about 15 to about 50 mg/kg, about 20 to about 50 mg/kg, about 20 to about 50 mg/kg, about 25 to about 50 mg/kg, about 25 to about 50 mg/kg, about 30 to about 50 mg/kg, about 35 to about 50 mg/kg, about 40 to about 50 mg/kg, about 45 to about 50 mg/kg, about 0.1 to about 45 mg/kg, about 0.25 to about 45 mg/kg, about 0.5 to about 45 mg/kg, about 0.75 to about 45 mg/kg, about 1 to about 45 mg/mg, about 1.5 to about 45 mg/kb, about 2 to about 45 mg/kg, about 2.5 to about 45 mg/kg, about 3 to about 45 mg/kg, about 3.5 to about 45 mg/kg, about 4 to about 45 mg/kg, about 4.5 to about 45 mg/kg, about 5 to about 45 mg/kg, about 7.5 to about 45 mg/kg, about 10 to about 45 mg/kg, about 15 to about 45 mg/kg, about 20 to about 45 mg/kg, about 20 to about 45 mg/kg, about 25 to about 45 mg/kg, about 25 to about 45 mg/kg, about 30 to about 45 mg/kg, about 35 to about 45 mg/kg, about 40 to about 45 mg/kg, about 0.1 to about 40 mg/kg, about 0.25 to about 40 mg/kg, about 0.5 to about 40 mg/kg, about 0.75 to about 40 mg/kg, about 1 to about 40 mg/mg, about 1.5 to about 40 mg/kb, about 2 to about 40 mg/kg, about 2.5 to about 40 mg/kg, about 3 to about 40 mg/kg, about 3.5 to about 40 mg/kg, about 4 to about 40 mg/kg, about 4.5 to about 40 mg/kg, about 5 to about 40 mg/kg, about 7.5 to about 40 mg/kg, about 10 to about 40 mg/kg, about 15 to about 40 mg/kg, about 20 to about 40 mg/kg, about 20 to about 40 mg/kg, about 25 to about 40 mg/kg, about 25 to about 40 mg/kg, about 30 to about 40 mg/kg, about 35 to about 40 mg/kg, about 0.1 to about 30 mg/kg, about 0.25 to about 30 mg/kg, about 0.5 to about 30 mg/kg, about 0.75 to about 30 mg/kg, about 1 to about 30 mg/mg, about 1.5 to about 30 mg/kb, about 2 to about 30 mg/kg, about 2.5 to about 30 mg/kg, about 3 to about 30 mg/kg, about 3.5 to about 30 mg/kg, about 4 to about 30 mg/kg, about 4.5 to about 30 mg/kg, about 5 to about 30 mg/kg, about 7.5 to about 30 mg/kg, about 10 to about 30 mg/kg, about 15 to about 30 mg/kg, about 20 to about 30 mg/kg, about 20 to about 30 mg/kg, about 25 to about 30 mg/kg, about 0.1 to about 20 mg/kg, about 0.25 to about 20 mg/kg, about 0.5 to about 20 mg/kg, about 0.75 to about 20 mg/kg, about 1 to about 20 mg/mg, about 1.5 to about 20 mg/kb, about 2 to about 20 mg/kg, about 2.5 to about 20 mg/kg, about 3 to about 20 mg/kg, about 3.5 to about 20 mg/kg, about 4 to about 20 mg/kg, about 4.5 to about 20 mg/kg, about 5 to about 20 mg/kg, about 7.5 to about 20 mg/kg, about 10 to about 20 mg/kg, or about 15 to about 20 mg/kg. In one embodiment, when a composition of the invention comprises a dsRNA as described herein and an N-acetylgalactosamine, subjects can be administered a therapeutic amount of about 10 to about 30 mg/kg of dsRNA. Values and ranges intermediate to the recited values are also intended to be part of this invention. 
     For example, subjects can be administered a therapeutic amount of iRNA, such as about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 31, 32, 33, 34, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or about 50 mg/kg. Values and ranges intermediate to the recited values are also intended to be part of this invention. 
     In some embodiments, the RNAi agent is administered as a fixed dose of between about 25 mg to about 900 mg, e.g., between about 25 mg to about 850 mg, between about 25 mg to about 500 mg, between about 25 mg to about 400 mg, between about 25 mg to about 300 mg, between about 50 mg to about 850 mg, between about 50 mg to about 500 mg, between about 50 mg to about 400 mg, between about 50 mg to about 300 mg, between about 100 mg to about 850 mg, between about 100 mg to about 500 mg, between about 100 mg to about 400 mg, between about 100 mg to about 300 mg, between about 200 mg to about 850 mg, between about 200 mg to about 500 mg, between about 200 mg to about 400 mg, between about 200 mg to about 300 mg, between about 100 mg to about 800 mg, between about 100 mg to about 750 mg, between about 100 mg to about 700 mg, between about 100 mg to about 650 mg, between about 100 mg to about 600 mg, between about 100 mg to about 550 mg, between about 100 mg to about 500 mg, between about 200 mg to about 850 mg, between about 200 mg to about 800 mg, between about 200 mg to about 750 mg, between about 200 mg to about 700 mg, between about 200 mg to about 650 mg, between about 200 mg to about 600 mg, between about 200 mg to about 550 mg, between about 200 mg to about 500 mg, between about 300 mg to about 850 mg, between about 300 mg to about 800 mg, between about 300 mg to about 750 mg, between about 300 mg to about 700 mg, between about 300 mg to about 650 mg, between about 300 mg to about 600 mg, between about 300 mg to about 550 mg, between about 300 mg to about 500 mg, between about 400 mg to about 850 mg, between about 400 mg to about 800 mg, between about 400 mg to about 750 mg, between about 400 mg to about 700 mg, between about 400 mg to about 650 mg, between about 400 mg to about 600 mg, between about 400 mg to about 550 mg, or between about 400 mg to about 500 mg. 
     In some embodiments, the RNAi agent is administered as a fixed dose of about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, or about 900 mg. 
     The iRNA can be administered by intravenous infusion over a period of time, such as over a 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or about a 25 minute period. The administration may be repeated, for example, on a regular basis, such as weekly, biweekly (i.e., every two weeks) for one month, two months, three months, four months or longer. After an initial treatment regimen, the treatments can be administered on a less frequent basis. For example, after administration weekly or biweekly for three months, administration can be repeated once per month, for six months or a year or longer. 
     Administration of the iRNA can reduce C5 levels, e.g., in a cell, tissue, blood, urine or other compartment of the patient by at least about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least about 99% or more. 
     Before administration of a full dose of the iRNA, patients can be administered a smaller dose, such as a 5% infusion, and monitored for adverse effects, such as an allergic reaction. In another example, the patient can be monitored for unwanted immunostimulatory effects, such as increased cytokine (e.g., TNF-alpha or INF-alpha) levels. 
     Owing to the inhibitory effects on C5 expression, a composition according to the invention or a pharmaceutical composition prepared therefrom can enhance the quality of life. 
     An iRNA of the invention may be administered in “naked” form, or as a “free iRNA.” A naked iRNA is administered in the absence of a pharmaceutical composition. The naked iRNA may be in a suitable buffer solution. The buffer solution may comprise acetate, citrate, prolamine, carbonate, or phosphate, or any combination thereof. In one embodiment, the buffer solution is phosphate buffered saline (PBS). The pH and osmolarity of the buffer solution containing the iRNA can be adjusted such that it is suitable for administering to a subject. 
     Alternatively, an iRNA of the invention may be administered as a pharmaceutical composition, such as a dsRNA liposomal formulation. 
     Subjects that would benefit from a reduction and/or inhibition of C5 gene expression are those having a complement component C5-associated disease or disorder as described herein. In one embodiment, a subject having a complement component C5-associated disease has paroxysmal nocturnal hemoglobinuria (PNH). In another embodiment, a subject having a complement component C5-associated disease has asthma. In another embodiment, a subject having a complement component C5-associated disease has rheumatoid arthritis. In yet another embodiment, a subject having a complement component C5-associated disease has systemic lupus erythmatosis. In one embodiment, a subject having a complement component C5-associated disease has glomerulonephritis. In another embodiment, a subject having a complement component C5-associated disease has psoriasis. In yet another embodiment, a subject having a complement component C5-associated disease has dermatomyositis bullous pemphigoid. In one embodiment, a subject having a complement component C5-associated disease has atypical hemolytic uremic syndrome. In another embodiment, a subject having a complement component C5-associated disease has Shiga toxin  E. coli -related hemolytic uremic syndrome. In another embodiment, a subject having a complement component C5-associated disease has myasthenia gravis. In yet another embodiment, a subject having a complement component C5-associated disease has neuromyelistis optica. In one embodiment, a subject having a complement component C5-associated disease has dense deposit disease. In one embodiment, a subject having a complement component C5-associated disease has C3 neuropathy. In another embodiment, a subject having a complement component C5-associated disease has age-related macular degeneration. In another embodiment, a subject having a complement component C5-associated disease has cold agglutinin disease. In one embodiment, a subject having a complement component C5-associated disease has anti-neutrophil cytoplasmic antibody-associated vasculitis. In another embodiment, a subject having a complement component C5-associated disease has humoral and vascular transplant rejection. In one embodiment, a subject having a complement component C5-associated disease has graft dysfunction. In one embodiment, a subject having a complement component C5-associated disease has had a myocardial infarction. In another embodiment, a subject having a complement component C5-associated disease is a sensitized recipient of a transplant. In yet another embodiment, a subject having a complement component C5-associated disease has sepsis. 
     In one embodiment, a subject having a complement component C5-associated disease, e.g., PNH, aHUS, neuromyelitis optica (NMO), or myasthenia gravis is an incomplete responder or non-responder to anti-complement component C5 antibody (e.g., eculizumab) therapy. For example, an incomplete responder or non-responder may be transfusion dependent due to chronic persistent extravascular hemolysis. The subject may be CD55 deficient. A “non-responder” to anti-complement component C5 antibody (e.g., eculizumab) therapy is a subject failing at least to have a hematologic response after 6 to 8 weeks of therapy, e.g., a subject that remains transfusion dependent. In one embodiment, an incomplete responder or non-responder to anti-complement component C5 antibody (e.g., eculizumab) therapy is a subject who is receiving a label dose of eculizumab and who is either experiencing ongoing uncontrolled intravascular hemolysis resulting in LDH&gt;1.5×ULN or one or more of the following: any clinical PNH symptoms (e.g., fatigue, abdominal pain, dyspnea, dysphagia or rectile dysfunction); remains transfusion dependent; remains anemic with HGB&lt;10 g/dL; develops a major vascular event (e.g., thrombosis). 
     Treatment of a subject that would benefit from a reduction and/or inhibition of C5 gene expression includes therapeutic and prophylactic (e.g., the subject is to undergo sensitized (or allogenic) transplant surgery) treatment. 
     The invention further provides methods and uses of an iRNA agent or a pharmaceutical composition thereof (including methods and uses of an iRNA agent or a pharmaceutical composition comprising an iRNA agent and an anti-complement component C5 antibody, or antigen-binding fragment thereof) for treating a subject that would benefit from reduction and/or inhibition of C5 expression, e.g., a subject having a complement component C5-associated disease, in combination with other pharmaceuticals and/or other therapeutic methods, e.g., with known pharmaceuticals and/or known therapeutic methods, such as, for example, those which are currently employed for treating these disorders. For example, in certain embodiments, an iRNA targeting C5 is administered in combination with, e.g., an agent useful in treating a complement component C5-associated disease as described elsewhere herein. 
     For example, additional therapeutics and therapeutic methods suitable for treating a subject that would benefit from reduction in C5 expression, e.g., a subject having a complement component C5-associated disease, include plasmaphoresis, thrombolytic therapy (e.g., streptokinase), antiplatelet agents, folic acid, corticosteroids; immunosuppressive agents; estrogens, methotrexate, 6-MP, azathioprine sulphasalazine, mesalazine, olsalazine, chloroquinine/hydroxychloroquine, pencillamine, aurothiomalate (intramuscular and oral), azathioprine, cochicine, corticosteroids (oral, inhaled and local injection), beta-2 adrenoreceptor agonists (salbutamol, terbutaline, salmeteral), xanthines (theophylline, aminophylline), cromoglycate, nedocromil, ketotifen, ipratropium and oxitropium, cyclosporin, FK506, rapamycin, mycophenolate mofetil, leflunomide, NSAIDs, for example, ibuprofen, corticosteroids such as prednisolone, phosphodiesterase inhibitors, adensosine agonists, antithrombotic agents, complement inhibitors, adrenergic agents, agents which interfere with signalling by proinflammatory cytokines, such as TNF-α or IL-1 (e.g., IRAK, NIK, IKK, p38 or MAP kinase inhibitors), IL-10 converting enzyme inhibitors, TNFα converting enzyme (TACE) inhibitors, T-cell signalling inhibitors, such as kinase inhibitors, metalloproteinase inhibitors, sulfasalazine, azathioprine, 6-mercaptopurines, angiotensin converting enzyme inhibitors, soluble cytokine receptors and derivatives thereof (e.g., soluble p55 or p75 TNF receptors and the derivatives p75TNFRIgG (Enbrel™ and p55TNFRIgG (Lenercept)), sIL-1RI, sIL-1RII, and sIL-6R), antiinflammatory cytokines (e.g., IL-4, IL-10, IL-11, IL-13 and TGFβ), celecoxib, folic acid, hydroxychloroquine sulfate, rofecoxib, etanercept, infliximonoclonal antibody, naproxen, valdecoxib, sulfasalazine, methylprednisolone, meloxicam, methylprednisolone acetate, gold sodium thiomalate, aspirin, triamcinolone acetonide, propoxyphene napsylate/apap, folate, nabumetone, diclofenac, piroxicam, etodolac, diclofenac sodium, oxaprozin, oxycodone hcl, hydrocodone bitartrate/apap, diclofenac sodium/misoprostol, fentanyl, anakinra, human recombinant, tramadol hcl, salsalate, sulindac, cyanocobalamin/fa/pyridoxine, acetaminophen, alendronate sodium, prednisolone, morphine sulfate, lidocaine hydrochloride, indomethacin, glucosamine sulf/chondroitin, amitriptyline hcl, sulfadiazine, oxycodone hcl/acetaminophen, olopatadine hcl, misoprostol, naproxen sodium, omeprazole, cyclophosphamide, rituximonoclonal antibody, IL-1 TRAP, MRA, CTLA4-IG, IL-18 BP, anti-IL-18, Anti-IL15, BIRB-796, SCIO-469, VX-702, AMG-548, VX-740, Roflumilast, IC-485, CDC-801, Mesopram, cyclosporine, cytokine suppressive anti-inflammatory drug(s) (CSAIDs); CDP-571/BAY-10-3356 (humanized anti-TNFα antibody; Celltech/Bayer); cA2/infliximonoclonal antibody (chimeric anti-TNFα antibody; Centocor); 75 kdTNFR-IgG/etanercept (75 kD TNF receptor-IgG fusion protein; Immunex; see e.g., (1994) Arthr. Rheum. 37: 5295; (1996) J. Invest. Med. 44: 235A); 55 kdTNF-IgG (55 kD TNF receptor-IgG fusion protein; Hoffmann-LaRoche); IDEC-CE9.1/SB 210396 (non-depleting primatized anti-CD4 antibody; IDEC/SmithKline; see e.g., (1995) Arthr. Rheum. 38: S185); DAB 486-IL-2 and/or DAB 389-IL-2 (IL-2 fusion proteins; Seragen; see e.g., (1993) Arthrit. Rheum. 36: 1223); Anti-Tac (humanized anti-IL-2Ra; Protein Design Labs/Roche); IL-4 (anti-inflammatory cytokine; DNAX/Schering); IL-10 (SCH 52000; recombinant IL-10, anti-inflammatory cytokine; DNAX/Schering); IL-4; IL-10 and/or IL-4 agonists (e.g., agonist antibodies); IL-1RA (IL-1 receptor antagonist; Synergen/Amgen); anakinra (Kineret®)/Amgen); TNF-bp/s-TNF (soluble TNF binding protein; see e.g., (1996) Arthr. Rheum. 39(9 (supplement)): 5284; (1995) Amer. J. Physiol.-Heart and Circ. Physiol. 268: 37-42); R973401 (phosphodiesterase Type IV inhibitor; see e.g., (1996) Arthr. Rheum. 39(9 (supplement): S282); MK-966 (COX-2 Inhibitor; see e.g., (1996) Arthr. Rheum. 39(9 (supplement): S81); Iloprost (see e.g., (1996) Arthr. Rheum. 39(9 (supplement): S82); methotrexate; thalidomide (see e.g., (1996) Arthr. Rheum. 39(9 (supplement): 5282) and thalidomide-related drugs (e.g., Celgen); leflunomide (anti-inflammatory and cytokine inhibitor; see e.g., (1996) Arthr. Rheum. 39(9 (supplement): 5131; (1996) Inflamm. Res. 45: 103-107); tranexamic acid (inhibitor of plasminogen activation; see e.g., (1996) Arthr. Rheum. 39(9 (supplement): S284); T-614 (cytokine inhibitor; see e.g., (1996) Arthr. Rheum. 39(9 (supplement): S282); prostaglandin E1 (see e.g., (1996) Arthr. Rheum. 39(9 (supplement): S282); Tenidap (non-steroidal anti-inflammatory drug; see e.g., (1996) Arthr. Rheum. 39(9 (supplement): S280); Naproxen (non-steroidal anti-inflammatory drug; see e.g., (1996) Neuro. Report 7: 1209-1213); Meloxicam (non-steroidal anti-inflammatory drug); Ibuprofen (non-steroidal anti-inflammatory drug); Piroxicam (non-steroidal anti-inflammatory drug); Diclofenac (non-steroidal anti-inflammatory drug); Indomethacin (non-steroidal anti-inflammatory drug); Sulfasalazine (see e.g., (1996) Arthr. Rheum. 39(9 (supplement): S281); Azathioprine (see e.g., (1996) Arthr. Rheum. 39(9 (supplement): S281); ICE inhibitor (inhibitor of the enzyme interleukin-1β converting enzyme); zap-70 and/or lck inhibitor (inhibitor of the tyrosine kinase zap-70 or lck); VEGF inhibitor and/or VEGF-R inhibitor (inhibitors of vascular endothelial cell growth factor or vascular endothelial cell growth factor receptor; inhibitors of angiogenesis); corticosteroid anti-inflammatory drugs (e.g., SB203580); TNF-convertase inhibitors; anti-IL-12 antibodies; anti-IL-18 antibodies; interleukin-11 (see e.g., (1996) Arthr. Rheum. 39(9 (supplement): S296); interleukin-13 (see e.g., (1996) Arthr. Rheum. 39(9 (supplement): S308); interleukin-1β inhibitors (see e.g., (1996) Arthr. Rheum. 39(9 (supplement): S120); gold; penicillamine; chloroquine; chlorambucil; hydroxychloroquine; cyclosporine; cyclophosphamide; total lymphoid irradiation; anti-thymocyte globulin; anti-CD4 antibodies; CD5-toxins; orally-administered peptides and collagen; lobenzarit disodium; Cytokine Regulating Agents (CRAs) HP228 and HP466 (Houghten Pharmaceuticals, Inc.); ICAM-1 antisense phosphorothioate oligo-deoxynucleotides (ISIS 2302; Isis Pharmaceuticals, Inc.); soluble complement receptor 1 (TP10; T Cell Sciences, Inc.); prednisone; orgotein; glycosaminoglycan polysulphate; minocycline; anti-IL2R antibodies; marine and botanical lipids (fish and plant seed fatty acids; see e.g., DeLuca et al. (1995) Rheum. Dis. Clin. North Am. 21: 759-777); auranofin; phenylbutazone; meclofenamic acid; flufenamic acid; intravenous immune globulin; zileuton; azaribine; mycophenolic acid (RS-61443); tacrolimus (FK-506); sirolimus (rapamycin); amiprilose (therafectin); cladribine (2-chlorodeoxyadenosine); methotrexate; bcl-2 inhibitors (see Bruncko, M. et al. (2007)  J. Med. Chem.  50(4): 641-662); antivirals and immune-modulating agents, small molecule inhibitor of KDR, small molecule inhibitor of Tie-2; methotrexate; prednisone; celecoxib; folic acid; hydroxychloroquine sulfate; rofecoxib; etanercept; infliximonoclonal antibody; leflunomide; naproxen; valdecoxib; sulfasalazine; methylprednisolone; ibuprofen; meloxicam; methylprednisolone acetate; gold sodium thiomalate; aspirin; azathioprine; triamcinolone acetonide; propxyphene napsylate/apap; folate; nabumetone; diclofenac; piroxicam; etodolac; diclofenac sodium; oxaprozin; oxycodone hcl; hydrocodone bitartrate/apap; diclofenac sodium/misoprostol; fentanyl; anakinra, human recombinant; tramadol hcl; salsalate; sulindac; cyanocobalamin/fa/pyridoxine; acetaminophen; alendronate sodium; prednisolone; morphine sulfate; lidocaine hydrochloride; indomethacin; glucosamine sulfate/chondroitin; cyclosporine; amitriptyline hcl; sulfadiazine; oxycodone hcl/acetaminophen; olopatadine hcl; misoprostol; naproxen sodium; omeprazole; mycophenolate mofetil; cyclophosphamide; rituximonoclonal antibody; IL-1 TRAP; MRA; CTLA4-IG; IL-18 BP; IL-12/23; anti-IL 18; anti-IL 15; BIRB-796; SC10-469; VX-702; AMG-548; VX-740; Roflumilast; IC-485; CDC-801; mesopram, albuterol, salmeterol/fluticasone, montelukast sodium, fluticasone propionate, budesonide, prednisone, salmeterol xinafoate, levalbuterol hcl, albuterol sulfate/ipratropium, prednisolone sodium phosphate, triamcinolone acetonide, beclomethasone dipropionate, ipratropium bromide, azithromycin, pirbuterol acetate, prednisolone, theophylline anhydrous, methylprednisolone sodium succinate, clarithromycin, zafirlukast, formoterol fumarate, influenza virus vaccine, methylprednisolone, amoxicillin trihydrate, flunisolide, allergy injection, cromolyn sodium, fexofenadine hydrochloride, flunisolide/menthol, amoxicillin/clavulanate, levofloxacin, inhaler assist device, guaifenesin, dexamethasone sodium phosphate, moxifloxacin hcl, doxycycline hyclate, guaifenesin/d-methorphan, p-ephedrine/cod/chlorphenir, gatifloxacin, cetirizine hydrochloride, mometasone furoate, salmeterol xinafoate, benzonatate, cephalexin, pe/hydrocodone/chlorphenir, cetirizine hcl/pseudoephed, phenylephrine/cod/promethazine, codeine/promethazine, cefprozil, dexamethasone, guaifenesin/pseudoephedrine, chlorpheniramine/hydrocodone, nedocromil sodium, terbutaline sulfate, epinephrine, methylprednisolone, metaproterenol sulfate, aspirin, nitroglycerin, metoprolol tartrate, enoxaparin sodium, heparin sodium, clopidogrel bisulfate, carvedilol, atenolol, morphine sulfate, metoprolol succinate, warfarin sodium, lisinopril, isosorbide mononitrate, digoxin, furosemide, simvastatin, ramipril, tenecteplase, enalapril maleate, torsemide, retavase, losartan potassium, quinapril hcl/mag carb, bumetanide, alteplase, enalaprilat, amiodarone hydrochloride, tirofiban hcl m-hydrate, diltiazem hydrochloride, captopril, irbesartan, valsartan, propranolol hydrochloride, fosinopril sodium, lidocaine hydrochloride, eptifibatide, cefazolin sodium, atropine sulfate, aminocaproic acid, spironolactone, interferon, sotalol hydrochloride, potassium chloride, docusate sodium, dobutamine hcl, alprazolam, pravastatin sodium, atorvastatin calcium, midazolam hydrochloride, meperidine hydrochloride, isosorbide dinitrate, epinephrine, dopamine hydrochloride, bivalirudin, rosuvastatin, ezetimibe/simvastatin, avasimibe, and cariporide. 
     The iRNA agent (and/or an anti-complement component C5 antibody) and an additional therapeutic agent and/or treatment may be administered at the same time and/or in the same combination, e.g., parenterally, or the additional therapeutic agent can be administered as part of a separate composition or at separate times and/or by another method known in the art or described herein. 
     In one embodiment, a subject is administered an initial dose and one or more maintenance doses of an RNAi agent. The maintenance dose or doses can be the same or lower than the initial dose, e.g., one-half of the initial dose. A maintenance regimen can include treating the subject with a dose or doses ranging from about 10 mg to about 900 mg, e.g., about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, or about 900 mg per week. The maintenance doses are, for example, administered no more than once every 7 days, once every 10 days, once every 14 days, once every 21 days, or once every 30 days. Further, the treatment regimen may last for a period of time which will vary depending upon the nature of the particular disease, its severity and the overall condition of the patient. 
     The present invention also provides methods of using an iRNA agent of the invention and/or a composition containing an iRNA agent of the invention to reduce and/or inhibit complement component C5 expression in a cell. In other aspects, the present invention provides an iRNA of the invention and/or a composition comprising an iRNA of the invention for use in reducing and/or inhibiting C5 expression in a cell. In yet other aspects, use of an iRNA of the invention and/or a composition comprising an iRNA of the invention for the manufacture of a medicament for reducing and/or inhibiting C5 expression in a cell are provided. 
     The methods and uses include contacting the cell with an iRNA, e.g., a dsRNA, of the invention and maintaining the cell for a time sufficient to obtain degradation of the mRNA transcript of a C5 gene, thereby inhibiting expression of the C5 gene in the cell. 
     Reduction in gene expression can be assessed by any methods known in the art. For example, a reduction in the expression of C5 may be determined by determining the mRNA expression level of C5 using methods routine to one of ordinary skill in the art, e.g., Northern blotting, qRT-PCR, by determining the protein level of C5 using methods routine to one of ordinary skill in the art, such as Western blotting, immunological techniques, flow cytometry methods, ELISA, and/or by determining a biological activity of C5, such as CH 50  or AH 50  hemolysis assay, and/or by determining the biological activity of one or more molecules associated with the complement system, e.g., C5 products, such as C5a and C5 b (or, in an in vivo setting, e.g., hemolysis). 
     In the methods and uses of the invention the cell may be contacted in vitro or in vivo, i.e., the cell may be within a subject. In embodiments of the invention in which the cell is within a subject, the methods may include further contacting the cell with an anti-complement component C5 antibody, e.g., eculizumab. 
     A cell suitable for treatment using the methods of the invention may be any cell that expresses a C5 gene. A cell suitable for use in the methods and uses of the invention may be a mammalian cell, e.g., a primate cell (such as a human cell or a non-human primate cell, e.g., a monkey cell or a chimpanzee cell), a non-primate cell (such as a cow cell, a pig cell, a camel cell, a llama cell, a horse cell, a goat cell, a rabbit cell, a sheep cell, a hamster, a guinea pig cell, a cat cell, a dog cell, a rat cell, a mouse cell, a lion cell, a tiger cell, a bear cell, or a buffalo cell), a bird cell (e.g., a duck cell or a goose cell), or a whale cell. In one embodiment, the cell is a human cell, e.g., a human liver cell. 
     C5 expression may be inhibited in the cell by at least about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or about 100%. 
     The in vivo methods and uses of the invention may include administering to a subject a composition containing an iRNA, where the iRNA includes a nucleotide sequence that is complementary to at least a part of an RNA transcript of the C5 gene of the mammal to be treated. When the organism to be treated is a mammal such as a human, the composition can be administered by any means known in the art including, but not limited to subcutaneous, intravenous, oral, intraperitoneal, or parenteral routes, including intracranial (e.g., intraventricular, intraparenchymal and intrathecal), intramuscular, transdermal, airway (aerosol), nasal, rectal, and topical (including buccal and sublingual) administration. In certain embodiments, the compositions are administered by subcutaneous or intravenous infusion or injection. 
     In some embodiments, the administration is via a depot injection. A depot injection may release the iRNA in a consistent way over a prolonged time period. Thus, a depot injection may reduce the frequency of dosing needed to obtain a desired effect, e.g., a desired inhibition of C5, or a therapeutic or prophylactic effect. A depot injection may also provide more consistent serum concentrations. Depot injections may include subcutaneous injections or intramuscular injections. In preferred embodiments, the depot injection is a subcutaneous injection. 
     In some embodiments, the administration is via a pump. The pump may be an external pump or a surgically implanted pump. In certain embodiments, the pump is a subcutaneously implanted osmotic pump. In other embodiments, the pump is an infusion pump. An infusion pump may be used for intravenous, subcutaneous, arterial, or epidural infusions. In preferred embodiments, the infusion pump is a subcutaneous infusion pump. In other embodiments, the pump is a surgically implanted pump that delivers the iRNA to the liver. 
     The mode of administration may be chosen based upon whether local or systemic treatment is desired and based upon the area to be treated. The route and site of administration may be chosen to enhance targeting. 
     In one aspect, the present invention also provides methods for inhibiting the expression of a C5 gene in a mammal, e.g., a human. The present invention also provides a composition comprising an iRNA, e.g., a dsRNA, that targets a C5 gene in a cell of a mammal for use in inhibiting expression of the C5 gene in the mammal. In another aspect, the present invention provides use of an iRNA, e.g., a dsRNA, that targets a C5 gene in a cell of a mammal in the manufacture of a medicament for inhibiting expression of the C5 gene in the mammal. 
     The methods and uses include administering to the mammal, e.g., a human, a composition comprising an iRNA, e.g., a dsRNA, that targets a C5 gene in a cell of the mammal and maintaining the mammal for a time sufficient to obtain degradation of the mRNA transcript of the C5 gene, thereby inhibiting expression of the C5 gene in the mammal. In some embodiment, the methods further comprise administering an anti-complement component C5 antibody, e.g., eculizumab, to the subject. 
     Reduction in gene expression can be assessed by any methods known it the art and by methods, e.g. qRT-PCR, described herein. Reduction in protein production can be assessed by any methods known it the art and by methods, e.g., ELISA or Western blotting, described herein. In one embodiment, a puncture liver biopsy sample serves as the tissue material for monitoring the reduction in C5 gene and/or protein expression. In another embodiment, a blood sample serves as the tissue material for monitoring the reduction in C5 gene and/or protein expression. In other embodiments, inhibition of the expression of a C5 gene is monitored indirectly by, for example, determining the expression and/or activity of a gene in a C5 pathway, including, for example, C5a, C5 b, and soluble C5 b-9 (see, e.g.,  FIG. 1 ). For example, the activity of CD59 may be monitored to determine the inhibition of expression of a C5 gene. CH 50 , AH 50 , clot formation and/or serum lactate dehydrogenase (LDH), in a sample, e.g., a blood or liver sample, may also be measured. Suitable assays are further described in the Examples section below. 
     Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the iRNAs and methods featured in the invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. 
     EXAMPLES 
     Example 1. IRNA Synthesis 
     Source of Reagents 
     Where the source of a reagent is not specifically given herein, such reagent can be obtained from any supplier of reagents for molecular biology at a quality/purity standard for application in molecular biology. 
     Transcripts siRNA design was carried out to identify siRNAs targeting human, rhesus ( Macaca mulatta ), mouse, and rat C5 transcripts annotated in the NCBI Gene database (http://www.ncbi.nlm.nih.gov/gene/). Design used the following transcripts from the NCBI RefSeq collection: Human—NM_001735.2; Rhesus—XM_001095750.2; Mouse—NM_010406.2; Rat—XM_345342.4. SiRNA duplexes were designed in several separate batches, including but not limited to batches containing duplexes matching human and rhesus transcripts only; human, rhesus, and mouse transcripts only; human, rhesus, mouse, and rat transcripts only; and mouse and rat transcripts only. All siRNA duplexes were designed that shared 100% identity with the listed human transcript and other species transcripts considered in each design batch (above). 
     siRNA Design, Specificity, and Efficacy Prediction 
     The predicted specificity of all possible 19mers was predicted from each sequence. Candidate 19mers were then selected that lacked repeats longer than 7 nucleotides. These 2971 candidate human/rhesus, 142 human/rhesus/mouse, 54 human/rhesus/mouse/rat, and 807 mouse/rat siRNAs were used in comprehensive searches against the appropriate transcriptomes (defined as the set of NM_ and XM_records within the human, rhesus, dog, mouse, or rat NCBI Refseq sets) using an exhaustive “brute-force” algorithm implemented in the python script ‘BruteForce.py’. The script next parsed the transcript-oligo alignments to generate a score based on the position and number of mismatches between the siRNA and any potential ‘off-target’ transcript. The off-target score is weighted to emphasize differences in the ‘seed’ region of siRNAs, in positions 2-9 from the 5′-end of the molecule. 
     Each oligo-transcript pair from the brute-force search was given a mismatch score by summing the individual mismatch scores; mismatches in the position 2-9 were counted as 2.8, mismatches in the cleavage site positions 10-11 were counted as 1.2, and mismatches in region 12-19 counted as 1.0. An additional off-target prediction was carried out by comparing the frequency of heptamers and octomers derived from 3 distinct, seed-derived hexamers of each oligo. The hexamers from positions 2-7 relative to the 5′ start were used to create 2 heptamers and one octamer. Heptamer1′ was created by adding a 3′-A to the hexamer; heptamer2 was created by adding a 5′-A to the hexamer; the octomer was created by adding an A to both 5′- and 3′-ends of the hexamer. The frequency of octamers and heptamers in the human, rhesus, mouse, or rat 3′-UTRome (defined as the subsequence of the transcriptome from NCBI&#39;s Refseq database where the end of the coding region, the ‘CDS’, is clearly defined) was pre-calculated. The octamer frequency was normalized to the heptamer frequency using the median value from the range of octamer frequencies. A ‘mirSeedScore’ was then calculated by calculating the sum of ((3× normalized octamer count)+(2× heptamer2 count)+(1× heptamer1 count)). 
     Both siRNAs strands were assigned to a category of specificity according to the calculated scores: a score above 3 qualifies as highly specific, equal to 3 as specific and between 2.2 and 2.8 as moderately specific. The duplexes were sorted by the specificity of the antisense strand and those duplexes whose antisense oligos lacked GC at the first position, lacked G at both positions 13 and 14, and had 3 or more Us or As in the seed region were selected. 
     For GalNaC-conjugated duplexes, sense 21mer and antisense 23mer oligos were designed by extending antisense 19mers (described above) to 23 nucleotides of target-complementary sequence. All species transcripts included in the design batch were checked for complementarity. Only 23mers that preserved 100% sequence complementarity in at least 2 species were used. For each duplex, the sense 21mer was specified as the reverse complement of the first 21 nucleotides of the antisense strand. 
     siRNA sequence selection 
     A total of 23 sense and 23 antisense derived human/rhesus, 6 sense and 6 antisense human/rhesus/mouse, 6 sense and 6 antisense derived human/rhesus/mouse/mouse/rat, and 13 sense and 13 antisense derived mouse/rat siRNA 19mer oligos were synthesized and formed into duplexes. 
     The above 19mer sets were extended to 21/23mer duplexes for GalNac conjugate design and re-classified according to their new species matches. Twenty-seven sense and 27 antisense derived human/rhesus, 1 sense and 1 sense derived human/rhesus/mouse, 3 sense and 3 antisense derived human/rhesus/rat, 4 sense and 4 antisense derived human/rhesus/mouse/rat, and 13 sense and 13 antisense derived mouse/rat 21mer (sense) and 23mer (antisense) oligos were synthesized and formed into duplexes. 
     A detailed list of C5 sense and antisense strand sequences is shown in Tables 3-6. 
     siRNA Synthesis 
     General Small and Medium Scale RNA Synthesis Procedure 
     RNA oligonucleotides were synthesized at scales between 0.2-500 μmol using commercially available 5′-O-(4,4′-dimethoxytrityl)-2′-O-t-butyldimethylsilyl-3′-O-(2-cyanoethyl-N,N-diisopropyl)phosphoramidite monomers of uridine, 4-N-acetylcytidine, 6-N-benzoyladenosine and 2-N-isobutyrylguanosine and the corresponding 2′-O-methyl and 2′-fluoro phosphoramidites according to standard solid phase oligonucleotide synthesis protocols. The amidite solutions were prepared at 0.1-0.15 M concentration and 5-ethylthio-1H-tetrazole (0.25-0.6 M in acetonitrile) was used as the activator. Phosphorothioate backbone modifications were introduced during synthesis using 0.2 M phenylacetyl disulfide (PADS) in lutidine:acetonitrile (1:1) (v;v) or 0.1 M 3-(dimethylaminomethylene)amino-3H-1,2,4-dithiazole-5-thione (DDTT) in pyridine for the oxidation step. After completion of synthesis, the sequences were cleaved from the solid support and deprotected using methylamine followed by triethylamine.3HF to remove any 2′-O-t-butyldimethylsilyl protecting groups present. 
     For synthesis scales between 5-500 μmol and fully 2′ modified sequences (2′-fluoro and/or 2′-O-methyl or combinations thereof) the oligonucleotides where deprotected using 3:1 (v/v) ethanol and concentrated (28-32%) aqueous ammonia either at 35° C. 16 h or 55° C. for 5.5 h. Prior to ammonia deprotection the oligonucleotides where treated with 0.5 M piperidine in acetonitrile for 20 min on the solid support. The crude oligonucleotides were analyzed by LC-MS and anion-exchange HPLC (IEX-HPLC). Purification of the oligonucleotides was carried out by IEX HPLC using: 20 mM phosphate, 10%-15% ACN, pH=8.5 (buffer A) and 20 mM phosphate, 10%-15% ACN, 1 M NaBr, pH=8.5 (buffer B). Fractions were analyzed for purity by analytical HPLC. The product-containing fractions with suitable purity were pooled and concentrated on a rotary evaporator prior to desalting. The samples were desalted by size exclusion chromatography and lyophilized to dryness. Equal molar amounts of sense and antisense strands were annealed in 1×PBS buffer to prepare the corresponding siRNA duplexes. 
     For small scales (0.2-1 μmol), synthesis was performed on a MerMade 192 synthesizer in a 96 well format. In case of fully 2′-modified sequences (2′-fluoro and/or 2′-O-methyl or combinations thereof) the oligonucleotides where deprotected using methylamine at room temperature for 30-60 min followed by incubation at 60° C. for 30 min or using 3:1 (v/v) ethanol and concentrated (28-32%) aqueous ammonia at room temperature for 30-60 min followed by incubation at 40° C. for 1.5 hours. The crude oligonucleotides were then precipitated in a solution of acetonitrile:acetone (9:1) and isolated by centrifugation and decanting the supernatant. The crude oligonucleotide pellet was re-suspended in 20 mM NaOAc buffer and analyzed by LC-MS and anion exchange HPLC. The crude oligonucleotide sequences were desalted in 96 deep well plates on a 5 mL HiTrap Sephadex G25 column (GE Healthcare). In each well about 1.5 mL samples corresponding to an individual sequence was collected. These purified desalted oligonucleotides were analyzed by LC-MS and anion exchange chromatography. Duplexes were prepared by annealing equimolar amounts of sense and antisense sequences on a Tecan robot. Concentration of duplexes was adjusted to 10 μM in 1×PBS buffer. 
     Synthesis of GalNAc-Conjugated Oligonucleotides for In Vivo Analysis 
     Oligonucleotides conjugated with GalNAc ligand at their 3′-terminus were synthesized at scales between 0.2-500 μmol using a solid support pre-loaded with a Y-shaped linker bearing a 4,4′-dimethoxytrityl (DMT)-protected primary hydroxy group for oligonucleotide synthesis and a GalNAc ligand attached through a tether. 
     For synthesis of GalNAc conjugates in the scales between 5-500 μmol the above synthesis protocol for RNA was followed with the following adaptions: For polystyrene-based synthesis supports 5% dichloroacetic acid in toluene was used for DMT-cleavage during synthesis. Cleavage from the support and deprotection was performed as described above. Phosphorothioate-rich sequences (usually &gt;5 phorphorothioates) were synthesized without removing the final 5′-DMT group (“DMT-on”) and, after cleavage and deprotection as described above, purified by reverse phase HPLC using 50 mM ammonium acetate in water (buffer A) and 50 mM ammoniumacetate in 80% acetonitrile (buffer B). Fractions were analyzed for purity by analytical HPLC and/or LC-MS. The product-containing fractions with suitable purity were pooled and concentrated on a rotary evaporator. The DMT-group was removed using 20%-25% acetic acid in water until completion. The samples were desalted by size exclusion chromatography and lyophilized to dryness. Equal molar amounts of sense and antisense strands were annealed in 1×PBS buffer to prepare the corresponding siRNA duplexes. 
     For small scale synthesis of GalNAc conjugates (0.2-1 μmol), including sequences with multiple phosphorothioate linkages, the protocols described above for synthesis of RNA or fully 2′-F/2′-OMe-containing sequences on MerMade platform were applied. Synthesis was performed on pre-packed columns containing GalNAc-functionalized controlled pore glass support. 
     Example 2. In Vitro Screening 
     Cell Culture and Transfections 
     Hep3B cells (ATCC, Manassas, Va.) were grown to near confluence at 37° C. in an atmosphere of 5% CO2 in Eagle&#39;s Minimum Essential Medium (ATCC) supplemented with 10% FBS, streptomycin, and glutamine (ATCC) before being released from the plate by trypsinization. Cells were washed and re-suspended at 0.25×10 6  cells/ml. During transfections, cells were plated onto a 96-well plate with about 20,000 cells per well. 
     Primary mouse hepatocytes (PMH) were freshly isolated from a C57BL/6 female mouse (Charles River Labortories International, Inc. Willmington, Mass.) less than 1 hour prior to transfections and grown in primary hepatocyte media. Cells were resuspended at 0.11×10 6  cells/ml in InVitroGRO CP Rat (plating) medium (Celsis In Vitro Technologies, catalog number S01494). During transfections, cells were plated onto a BD BioCoat 96 well collagen plate (BD, 356407) at 10,000 cells per well and incubated at 37° C. in an atmosphere of 5% CO 2 . 
     Cryopreserved Primary Cynomolgus Hepatocytes (Celsis In Vitro Technologies, M003055-P) were thawed at 37° C. water bath immediately prior to usage and re-suspended at 0.26×10 6  cells/ml in InVitroGRO CP (plating) medium (Celsis In Vitro Technologies, catalog number Z99029). During transfections, cells were plated onto a BD BioCoat 96 well collagen plate (BD, 356407) at 25,000 cells per well and incubated at 37° C. in an atmosphere of 5% CO 2 . 
     For Hep3B, PMH, and primary Cynomolgus hepatocytes, transfection was carried out by adding 14.8 μl of Opti-MEM plus 0.2 μl of Lipofectamine RNAiMax per well (Invitrogen, Carlsbad Calif. catalog number 13778-150) to 5 μl of each siRNA duplex to an individual well in a 96-well plate. The mixture was then incubated at room temperature for 20 minutes. Eighty μ1 of complete growth media without antibiotic containing the appropriate cell number were then added to the siRNA mixture. Cells were incubated for 24 hours prior to RNA purification. 
     Single dose experiments were performed at 10 nM and 0.1 nM final duplex concentration for GalNAc modified sequences or at 1 nM and 0.01 nM final duplex concentration for all other sequences. Dose response experiments were done at 3, 1, 0.3, 0.1, 0.037, 0.0123, 0.00412, and 0.00137 nM final duplex concentration for primary mouse hepatocytes and at 3, 1, 0.3, 0.1, 0.037, 0.0123, 0.00412, 0.00137, 0.00046, 0.00015, 0.00005, and 0.000017 nM final duplex concentration for Hep3B cells. 
     Free Uptake Transfection 
     Free uptake experiments were performed by adding 10 μl of siRNA duplexes in PBS per well into a 96 well plate. Ninety μ1 of complete growth media containing appropriate cell number for the cell type was then added to the siRNA. Cells were incubated for 24 hours prior to RNA purification. Single dose experiments were performed at 500 nM and 5 nM final duplex concentration and dose response experiments were done at 1000, 333, 111, 37, 12.3, 4.12, 1.37, 0.46 nM final duplex concentration. 
     Total RNA isolation using DYNABEADS mRNA Isolation Kit (Invitrogen, part #: 610-12) 
     Cells were harvested and lysed in 150 μl of Lysis/Binding Buffer then mixed for 5 minutes at 850 rpm using an Eppendorf Thermomixer (the mixing speed was the same throughout the process). Ten microliters of magnetic beads and 80 μl Lysis/Binding Buffer mixture were added to a round bottom plate and mixed for 1 minute. Magnetic beads were captured using a magnetic stand and the supernatant was removed without disturbing the beads. After removing the supernatant, the lysed cells were added to the remaining beads and mixed for 5 minutes. After removing the supernatant, magnetic beads were washed 2 times with 150 μl Wash Buffer A and mixed for 1 minute. The beads were captured again and the supernatant was removed. The beads were then washed with 150 μl Wash Buffer B, captured and the supernatant was removed. The beads were next washed with 150 μl Elution Buffer, captured and the supernatant removed. Finally, the beads were allowed to dry for 2 minutes. After drying, 50 μl of Elution Buffer was added and mixed for 5 minutes at 70° C. The beads were captured on magnet for 5 minutes. Forty-five μ1 of supernatant was removed and added to another 96 well plate. 
     cDNA synthesis using ABI High capacity cDNA reverse transcription kit (Applied Biosystems, Foster City, Calif., Cat #4368813) 
     A master mix of 2 μl 10× Buffer, 0.8 μl 25×dNTPs, 2 μl Random primers, 1 μl Reverse Transcriptase, 1 μl RNase inhibitor and 3.2 μl of H 2 O per reaction as prepared. Equal volumes master mix and RNA were mixed for a final volume of 12 μl for in vitro screened or 20 μl for in vivo screened samples. cDNA was generated using a Bio-Rad C-1000 or S-1000 thermal cycler (Hercules, Calif.) through the following steps: 25° C. for 10 minutes, 37° C. for 120 minutes, 85° C. for 5 seconds, and 4° C. hold. 
     Real Time PCR 
     Two μl of cDNA were added to a master mix containing 2 μl of H 2 O, 0.5 μl GAPDH TaqMan Probe (Life Technologies catalog number 4326317E for Hep3B cells, catalog number 352339E for primary mouse hepatocytes or custom probe for cynomolgus primary hepatocytes), 0.5 μl C5 TaqMan probe (Life Technologies c catalog number Hs00156197_m1 for Hep3B cells or mm00439275_m1 for Primary Mouse Hepatoctyes or custom probe for cynomolgus primary hepatocytes) and 5 μl Lightcycler 480 probe master mix (Roche catalog number 04887301001) per well in a 384 well plates (Roche catalog number 04887301001). Real time PCR was performed in an Roche LC480 Real Time PCR system (Roche) using the ΔΔCt(RQ) assay. For in vitro screening, each duplex was tested with two biological replicates unless otherwise noted and each Real Time PCR was performed in duplicate technical replicates. For in vivo screening, each duplex was tested in one or more experiments (3 mice per group) and each Real Time PCR was run in duplicate technical replicates. 
     To calculate relative fold change in C5 mRNA levels, real time data were analyzed using the ΔΔCt method and normalized to assays performed with cells transfected with 10 nM AD-1955, or mock transfected cells. IC 50 s were calculated using a 4 parameter fit model using XLFit and normalized to cells transfected with AD-1955 over the same dose range, or to its own lowest dose. 
     The sense and antisense sequences of AD-1955 are: 
     
       
         
           
               
               
            
               
                   
                 SENSE: 
               
               
                   
                 (SEQ ID NO: 13) 
               
               
                   
                 cuuAcGcuGAGuAcuucGAdTsdT; 
               
               
                   
                   
               
               
                   
                 ANTISENSE: 
               
               
                   
                 (SEQ ID NO: 14) 
               
               
                   
                 UCGAAGuACUcAGCGuAAGdTsdT. 
               
            
           
         
       
     
     Table 7 shows the results of a single dose screen in Hep3B cells transfected with the indicated GalNAC conjugated modified iRNAs. Data are expressed as percent of message remaining relative to untreated cells. 
     Table 8 shows the results of a single dose transfection screen in primary mouse hepatocytes transfected with the indicated GalNAC conjugated modified iRNAs. Data are expressed as percent of message remaining relative to untreated cells. 
     Table 9 shows the results of a single dose free uptake screen in primary Cynomolgus hepatocytes with the indicated GalNAC conjugated modified iRNAs. Data are expressed as percent of message remaining relative to untreated cells. 
     Table 10 shows the results of a single dose free uptake screen in primary mouse hepatocytes with the indicated GalNAC conjugated modified iRNAs. Data are expressed as percent of message remaining relative to untreated cells. 
     Table 11 shows the dose response of a free uptake screen in primary Cynomolgus hepatocytes with the indicated GalNAC conjugated modified iRNAs. The indicated IC50 values represent the IC50 values relative to untreated cells. 
     Table 12 shows the dose response of a free uptake screen in primary mouse hepatocytes with the indicated GalNAC conjugated modified iRNAs. The indicated IC50 values represent the IC50 values relative to untreated cells. 
     Table 13 shows the results of a single dose screen in Hep3B cells transfected with the indicated modified and unmodified iRNAs. Data are expressed as percent of message remaining relative to untreated cells. The 0.01 nM dose was a single biological transfection and the 1 nM dose was a duplicate biological transfection. 
     Table 14 shows the results of a single dose screen in primary mouse hepatocytes transfected with the indicated modified and unmodified iRNAs. Data are expressed as percent of message remaining relative to untreated cells. 
     Table 15 shows the dose response in Hep3B cells transfected with the indicated modified and unmodified iRNAs. The indicated IC 50  values represent the IC 50  values relative to untreated cells. 
     Table 16 shows the dose response in primary mouse hepatocytes transfected with the indicated modified and unmodified iRNAs. The indicated IC 50  values represent the IC 50  values relative to untreated cells. 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Abbreviations of nucleotide monomers used in nucleic 
               
               
                 acid sequence representation. It will be understood 
               
               
                 that these monomers, when present in an oligonucleotide, 
               
               
                 are mutually linked by 5′-3′-phosphodiester bonds. 
               
            
           
           
               
               
            
               
                 Abbreviation 
                 Nucleotide(s) 
               
               
                   
               
               
                 A 
                 Adenosine-3′-phosphate 
               
               
                 Af 
                 2′-fluoroadenosine-3′-phosphate 
               
               
                 Afs 
                 2′-fluoroadenosine-3′-phosphorothioate 
               
               
                 As 
                 adenosine-3′-phosphorothioate 
               
               
                 C 
                 cytidine-3′-phosphate 
               
               
                 Cf 
                 2′-fluorocytidine-3′-phosphate 
               
               
                 Cfs 
                 2′-fluorocytidine-3′-phosphorothioate 
               
               
                 Cs 
                 cytidine-3′-phosphorothioate 
               
               
                 G 
                 guanosine-3′-phosphate 
               
               
                 Gf 
                 2′-fluoroguanosine-3′-phosphate 
               
               
                 Gfs 
                 2′-fluoroguanosine-3′-phosphorothioate 
               
               
                 Gs 
                 guanosine-3′-phosphorothioate 
               
               
                 T 
                 5′-methyluridine-3′-phosphate 
               
               
                 Tf 
                 2′-fluoro-5-methyluridine-3′-phosphate 
               
               
                 Tfs 
                 2′-fluoro-5-methyluridine-3′-phosphorothioate 
               
               
                 Ts 
                 5-methyluridine-3′-phosphorothioate 
               
               
                 U 
                 Uridine-3′-phosphate 
               
               
                 Uf 
                 2′-fluorouridine-3′-phosphate 
               
               
                 Ufs 
                 2′-fluorouridine-3′-phosphorothioate 
               
               
                 Us 
                 uridine-3′-phosphorothioate 
               
               
                 N 
                 any nucleotide (G, A, C, T or U) 
               
               
                 a 
                 2′-O-methyladenosine-3′-phosphate 
               
               
                 as 
                 2′-O-methyladenosine-3′-phosphorothioate 
               
               
                 c 
                 2′-O-methylcytidine-3′-phosphate 
               
               
                 cs 
                 2′-O-methylcytidine-3′-phosphorothioate 
               
               
                 g 
                 2′-O-methylguanosine-3′-phosphate 
               
               
                 gs 
                 2′-O-methylguanosine-3′-phosphorothioate 
               
               
                 t 
                 2′-O-methyl-5-methyluridine-3′-phosphate 
               
               
                 ts 
                 2′-O-methyl-5-methyluridine-3′-phosphorothioate 
               
               
                 u 
                 2′-O-methyluridine-3′-phosphate 
               
               
                 us 
                 2′-O-methyluridine-3′-phosphorothioate 
               
               
                 s 
                 phosphorothioate linkage 
               
               
                 L96 
                 N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol 
               
               
                   
                 Hyp-(GalNAc-alkyl)3 
               
               
                 (dt) 
                 deoxy-thymine 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Unmodified Sense and Antisense Strand Sequences of C5 dsRNAs 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                 SEQ 
                   
                   
                 SEQ 
                   
               
               
                   
                 Sense 
                 Sense Unmodified 
                 ID 
                   
                 Antisense 
                 ID 
                   
               
               
                 Duplex ID 
                 strand 
                 Sequence 
                 NO: 
                 Antisense 
                 Unmodified Sequence 
                 NO: 
               
               
                   
               
               
                 AD-58093.1 2   
                 A-118310.1 
                 AAUAACUCACUAUAAUUACUU 
                 15 
                 A-118311.1 
                 AAGUAAUUAUAGUGAGUUAUUUU 
                  66 
                 NM_001735.2_ 
               
               
                  UM 3   
                   
                   
                   
                   
                   
                   
                 1517-1539_as 
               
               
                   
               
               
                 AD-58099.1 
                 A-118312.1 
                 UGACAAAAUAACUCACUAUAA 
                 16 
                 A-118313.1 
                 UUAUAGUGAGUUAUUUUGUCAAU 
                  67 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 1511-1533_as 
               
               
                   
               
               
                 AD-58105.1 
                 A-118314.1 
                 CUUCCUCUGGAAAUUGGCCUU 
                 17 
                 A-118315.1 
                 AAGGCCAAUUUCCAGAGGAAGCA 
                  68 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 2733-2755_as 
               
               
                   
               
               
                 AD-58111.1 
                 A-118316.1 
                 GACAAAAUAACUCACUAUAAU 
                 18 
                 A-118317.1 
                 AUUAUAGUGAGUUAUUUUGUCAA 
                  69 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 1512-1534_as 
               
               
                   
               
               
                 AD-58117.1 
                 A-118318.1 
                 UCCUCUGGAAAUUGGCCUUCA 
                 19 
                 A-118319.1 
                 UGAAGGCCAAUUUCCAGAGGAAG 
                  70 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 2735-2757_as 
               
               
                   
               
               
                 AD-58123.1 
                 A-118320.1 
                 AAGCAAGAUAUUUUUAUAAUA 
                 20 
                 A-118321.1 
                 UAUUAUAAAAAUAUCUUGCUUUU 
                  71 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 784-806_as 
               
               
                   
               
               
                 AD-58129.1 
                 A-118322.1 
                 AAAAUGUUUUUGUCAAGUACA 
                 21 
                 A-118323.1 
                 UGUACUUGACAAAAACAUUUUCU 
                  72 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 4744-4766_as 
               
               
                   
               
               
                 AD-58088.1 
                 A-118324.1 
                 AUUUAAACAACAAGUACCUUU 
                 22 
                 A-118325.1 
                 AAAGGUACUUGUUGUUUAAAUCU 
                  73 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 982-1004_as 
               
               
                   
               
               
                 AD-58094.1 
                 A-118326.1 
                 AUUCAGAAAGUCUGUGAAGGA 
                 23 
                 A-118327.1 
                 UCCUUCACAGACUUUCUGAAUUU 
                  74 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 4578-4600_as 
               
               
                   
               
               
                 AD-58100.1 
                 A-118328.1 
                 ACACUGAAGCAUUUGAUGCAA 
                 24 
                 A-118329.1 
                 UUGCAUCAAAUGCUUCAGUGUAU 
                  75 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 169-191_as 
               
               
                   
               
               
                 AD-58106.1 
                 A-118330.1 
                 GCAGUUCUGUGUUAAAAUGUC 
                 25 
                 A-118331.1 
                 GACAUUUUAACACAGAACUGCAU 
                  76 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 2591-2613_as 
               
               
                   
               
               
                 AD-58112.1 
                 A-118332.1 
                 AGGAUUUUGAGUGUAAAAGGA 
                 26 
                 A-118333.1 
                 UCCUUUUACACUCAAAAUCCUUU 
                  77 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 2955-2977_as 
               
               
                   
               
               
                 AD-58118.1 
                 A-118334.1 
                 AAUGAUGAACCUUGUAAAGAA 
                 27 
                 A-118335.1 
                 UUCUUUACAAGGUUCAUCAUUUU 
                  78 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 2025-2047_as 
               
               
                   
               
               
                 AD-58124.1 
                 A-118336.1 
                 AUCAUUGGAACAUUUUUCAUU 
                 28 
                 A-118337.1 
                 AAUGAAAAAUGUUCCAAUGAUUU 
                  79 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 3118-3140_as 
               
               
                   
               
               
                 AD-58130.1 
                 A-118338.1 
                 AGCCAGAAAUUCGGAGUUAUU 
                 29 
                 A-118339.1 
                 AAUAACUCCGAAUUUCUGGCUUG 
                  80 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 2317-2339_as 
               
               
                   
               
               
                 AD-58089.1 
                 A-118340.1 
                 UCCCUGGGAGAUAAAACUCAC 
                 30 
                 A-118341.1 
                 GUGAGUUUUAUCUCCCAGGGAAA 
                  81 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 3618-3640_as 
               
               
                   
               
               
                 AD-58095.1 
                 A-118342.1 
                 GAAAAUGAUGAACCUUGUAAA 
                 31 
                 A-118343.1 
                 UUUACAAGGUUCAUCAUUUUCUU 
                  82 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 2022-2044_as 
               
               
                   
               
               
                 AD-58101.1 
                 A-118344.1 
                 AUUGCUCAAGUCACAUUUGAU 
                 32 
                 A-118345.1 
                 AUCAAAUGUGACUUGAGCAAUUC 
                  83 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 918-940 as 
               
               
                   
               
               
                 AD-58107.1 
                 A-118346.1 
                 GAGAUUGCAUAUGCUUAUAAA 
                 33 
                 A-118347.1 
                 UUUAUAAGCAUAUGCAAUCUCUG 
                  84 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 4698-4720_as 
               
               
                   
               
               
                 AD-58113.1 
                 A-118348.1 
                 GUUAUCCUGAUAAAAAAUUUA 
                 34 
                 A-118349.1 
                 UAAAUUUUUUAUCAGGAUAACUU 
                  85 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 205-227_as 
               
               
                   
               
               
                 AD-58119.1 
                 A-118350.1 
                 AGGAAGUUUGCAGCUUUUAUU 
                 35 
                 A-118351.1 
                 AAUAAAAGCUGCAAACUUCCUCA 
                  86 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 4147-4169_as 
               
               
                   
               
               
                 AD-58125.1 
                 A-118352.1 
                 GAAGAAAUUGAUCAUAUUGGA 
                 36 
                 A-118353.1 
                 UCCAAUAUGAUCAAUUUCUUCUA 
                  87 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 555-577_as 
               
               
                   
               
               
                 AD-58131.1 
                 A-118354.1 
                 AUCCUGAUAAAAAAUUUAGUU 
                 37 
                 A-118355.1 
                 AACUAAAUUUUUUAUCAGGAUAA 
                  88 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 208-230_as 
               
               
                   
               
               
                 AD-58090.1 
                 A-118356.1 
                 UGGAAAAGAAAUCUUAGUAAA 
                 38 
                 A-118357.1 
                 UUUACUAAGAUUUCUUUUCCAAA 
                  89 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 2786-2808_as 
               
               
                   
               
               
                 AD-58096.1 
                 A-118358.1 
                 UCUUAUCAAAGUAUAAACAUU 
                 39 
                 A-118359.1 
                 AAUGUUUAUACUUUGAUAAGAUG 
                  90 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 1596-1618_as 
               
               
                   
               
               
                 AD-58102.1 
                 A-118360.1 
                 UCCCUACAAACUGAAUUUGGU 
                 40 
                 A-118361.1 
                 ACCAAAUUCAGUUUGUAGGGAGA 
                  91 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 1082-1104_as 
               
               
                   
               
               
                 AD-58108.1 
                 A-118362.1 
                 CAGGAGCAAACAUAUGUCAUU 
                 41 
                 A-118363.1 
                 AAUGACAUAUGUUUGCUCCUGUC 
                  92 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 87-109_as 
               
               
                   
               
               
                 AD-58114.1 
                 A-118364.1 
                 ACAUGUAACAACUGUAGUUCA 
                 42 
                 A-118365.1 
                 UGAACUACAGUUGUUACAUGUAC 
                  93 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 4109-4131_as 
               
               
                   
               
               
                 AD-58120.1 
                 A-118366.1 
                 CAGGAAAUCAUUGGAACAUUU 
                 43 
                 A-118367.1 
                 AAAUGUUCCAAUGAUUUCCUGUU 
                  94 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 3112-3134_as 
               
               
                   
               
               
                 AD-58126.1 
                 A-118368.1 
                 UUUAAGAAUUUUGAAAUUACU 
                 44 
                 A-118369.1 
                 AGUAAUUUCAAAAUUCUUAAAGU 
                  95 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 759-781_as 
               
               
                   
               
               
                 AD-58132.1 
                 A-118370.1 
                 UAUUCUGCAACUGAAUUCGAU 
                 45 
                 A-118371.1 
                 AUCGAAUUCAGUUGCAGAAUAAC 
                  96 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 4412-4434_as 
               
               
                   
               
               
                 AD-58091.1 
                 A-118372.1 
                 GCCCUUGGAAAGAGUAUUUCA 
                 46 
                 A-118373.1 
                 UGAAAUACUCUUUCCAAGGGCUU 
                  97 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 1886-1908_as 
               
               
                   
               
               
                 AD-58097.1 
                 A-118374.1 
                 CCUGAUAAAAAAUUUAGUUAC 
                 47 
                 A-118375.1 
                 GUAACUAAAUUUUUUAUCAGGAU 
                  98 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 210-232_as 
               
               
                   
               
               
                 AD-58103.1 
                 A-118376.1 
                 CCCUUGGAAAGAGUAUUUCAA 
                 48 
                 A-118377.1 
                 UUGAAAUACUCUUUCCAAGGGCU 
                  99 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 1887-1909_as 
               
               
                   
               
               
                 AD-58121.1 
                 A-118382.1 
                 UGCAGAUCAAACACAAUUUCA 
                 49 
                 A-118383.1 
                 UGAAAUUGUGUUUGAUCUGCAGA 
                 100 
                 NM_010406.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 4943-4965_as 
               
               
                   
               
               
                 AD-58133.1 
                 A-118386.1 
                 CAGAUCAAACACAAUUUCAGU 
                 50 
                 A-118387.1 
                 ACUGAAAUUGUGUUUGAUCUGCA 
                 101 
                 NM_010406.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 4945-4967_as 
               
               
                   
               
               
                 AD-58116.1 
                 A-118396.1 
                 GUUCCGGAUAUUUGAACUUUU 
                 51 
                 A-118397.1 
                 AAAAGUUCAAAUAUCCGGAACCG 
                 102 
                 NM_010406.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 4500-4522_as 
               
               
                   
               
               
                 AD-58644.1 
                 A-119328.1 
                 AUUUAAACAACAAGUACCUUU 
                 52 
                 A-119329.1 
                 AAAGGUACUUGUUGUUUAAAUCU 
                 103 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 982-1004_as 
               
               
                   
               
               
                 AD-58651.1 
                 A-119328.2 
                 AUUUAAACAACAAGUACCUUU 
                 53 
                 A-119339.1 
                 AAAGGUACUUGUUGUUUAAAUCU 
                 104 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 982-1004_as 
               
               
                   
               
               
                 AD-58641.1 
                 A-119322.1 
                 UGACAAAAUAACUCACUAUAA 
                 54 
                 A-119323.1 
                 UUAUAGUGAGUUAUUUUGUCAAU 
                 105 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 1511-1533_as 
               
               
                   
               
               
                 AD-58648.1 
                 A-119322.2 
                 UGACAAAAUAACUCACUAUAA 
                 55 
                 A-119336.1 
                 UUAUAGUGAGUUAUUUUGUCAAU 
                 106 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 1511-1533_as 
               
               
                   
               
               
                 AD-58642.1 
                 A-119324.1 
                 GACAAAAUAACUCACUAUAAU 
                 56 
                 A-119325.1 
                 AUUAUAGUGAGUUAUUUUGUCAA 
                 107 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 1512-1534_as 
               
               
                   
               
               
                 AD-58649.1 
                 A-119324.2 
                 GACAAAAUAACUCACUAUAAU 
                 57 
                 A-119337.1 
                 AUUAUAGUGAGUUAUUUUGUCAA 
                 108 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 1512-1534_as 
               
               
                   
               
               
                 AD-58647.1 
                 A-119334.1 
                 GUUCCGGAUAUUUGAACUUUU 
                 58 
                 A-119335.1 
                 AAAAGUUCAAAUAUCCGGAACCG 
                 109 
                 NM_010406.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 4500-4522_as 
               
               
                   
               
               
                 AD-58654.1 
                 A-119334.2 
                 GUUCCGGAUAUUUGAACUUUU 
                 59 
                 A-119342.1 
                 AAAAGUUCAAAUAUCCGGAACCG 
                 110 
                 NM_010406.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 4500-4522_as 
               
               
                   
               
               
                 AD-58645.1 
                 A-119330.1 
                 UGCAGAUCAAACACAAUUUCA 
                 60 
                 A-119331.1 
                 UGAAAUUGUGUUUGAUCUGCAGA 
                 111 
                 NM_010406.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 4943-4965_as 
               
               
                   
               
               
                 AD-58652.1 
                 A-119330.2 
                 UGCAGAUCAAACACAAUUUCA 
                 61 
                 A-119340.1 
                 UGAAAUUGUGUUUGAUCUGCAGA 
                 112 
                 NM_010406.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 4943-4965_as 
               
               
                   
               
               
                 AD-58643.1 
                 A-119326.1 
                 AAGCAAGAUAUUUUUAUAAUA 
                 62 
                 A-119327.1 
                 UAUUAUAAAAAUAUCUUGCUUUU 
                 113 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 784-806_as 
               
               
                   
               
               
                 AD-58650.1 
                 A-119326.2 
                 AAGCAAGAUAUUUUUAUAAUA 
                 63 
                 A-119338.1 
                 UAUUAUAAAAAUAUCUUGCUUUU 
                 114 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 784-806_as 
               
               
                   
               
               
                 AD-58646.1 
                 A-119332.1 
                 CAGAUCAAACACAAUUUCAGU 
                 64 
                 A-119333.1 
                 ACUGAAAUUGUGUUUGAUCUGCA 
                 115 
                 NM_010406.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 4945-4967_as 
               
               
                   
               
               
                 AD-58653.1 
                 A-119332.2 
                 CAGAUCAAACACAAUUUCAGU 
                 65 
                 A-119341.1 
                 ACUGAAAUUGUGUUUGAUCUGCA 
                 116 
                 NM_010406.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 4945-4967_as 
               
               
                   
               
               
                   1 The Species Oligo name reflects the GenBank record (e.g., NM_001735.2) and the position in the nucleotide 
               
               
                 sequence of the GenBank record (e.g, 1517-1539) that the antisense strand targets. 
               
               
                   2 The number following the decimal point refers to the lot number. 
               
               
                   3 UM = unmodified 
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                 TABLE 4 
               
               
                   
               
               
                   
                   
                   
                 SEQ 
                   
                   
                 SEQ 
                 Species_ 
               
               
                   
                 Sense 
                   
                 ID 
                   
                   
                 ID 
                 Oligo 
               
               
                 Duplex ID 
                 strand 
                 Sense sequence 
                 NO: 
                 Antisense 
                 Antisense sequence 
                 NO: 
                 name 4   
               
               
                   
               
             
            
               
                 AD-58093.1 
                 A-118310.1 
                 AfaUfaAfcUfcAfCfUfa 
                 117 
                 A-118311.1 
                 aAfgUfaAfuUfaUfaguGfaGfu 
                 168 
                   
               
               
                   
                   
                 UfaAfuUfaCfuUfL96 
                   
                   
                 UfaUfusUfsu 
                   
                   
               
               
                   
               
               
                 AD-58099.1 
                 A-118312.1 
                 UfgAfcAfaAfaUfAfAfc 
                 118 
                 A-118313.1 
                 uUfaUfaGfuGfaGfuuaUfuUfu 
                 169 
                   
               
               
                   
                   
                 UfcAfcUfaUfaAfL96 
                   
                   
                 GfuCfasAfsu 
                   
                   
               
               
                   
               
               
                 AD-58105.1 
                 A-118314.1 
                 CfuUfcCfuCfuGfGfAfa 
                 119 
                 A-118315.1 
                 aAfgGfcCfaAfuUfuccAfgAfg 
                 170 
                   
               
               
                   
                   
                 AfuUfgGfcCfuUfL96 
                   
                   
                 GfaAfgsCfsa 
                   
                   
               
               
                   
               
               
                 AD-58111.1 
                 A-118316.1 
                 GfaCfaAfaAfuAfAfCfu 
                 120 
                 A-118317.1 
                 aUfuAfuAfgUfgAfguuAfuUfu 
                 171 
                   
               
               
                   
                   
                 CfaCfuAfuAfaUfL96 
                   
                   
                 UfgUfcsAfsa 
                   
                   
               
               
                   
               
               
                 AD-58117.1 
                 A-118318.1 
                 UfcCfuCfuGfgAfAfAfu 
                 121 
                 A-118319.1 
                 uGfaAfgGfcCfaAfuuuCfcAfg 
                 172 
                   
               
               
                   
                   
                 UfgGfcCfuUfcAfL96 
                   
                   
                 AfgGfasAfsg 
                   
                   
               
               
                   
               
               
                 AD-58123.1 
                 A-118320.1 
                 AfaGfcAfaGfaUfAfUfu 
                 122 
                 A-118321.1 
                 uAfuUfaUfaAfaAfauaUfcUfu 
                 173 
                   
               
               
                   
                   
                 UfuUfaUfaAfuAfL96 
                   
                   
                 GfcUfusUfsu 
                   
                   
               
               
                   
               
               
                 AD-58129.1 
                 A-118322.1 
                 AfaAfaUfgUfuUfUfUfg 
                 123 
                 A-118323.1 
                 uGfuAfcUfuGfaCfaaaAfaCfa 
                 174 
                   
               
               
                   
                   
                 UfcAfaGfuAfcAfL96 
                   
                   
                 UfuUfusCfsu 
                   
                   
               
               
                   
               
               
                 AD-58088.1 
                 A-118324.1 
                 AfuUfuAfaAfcAfAfCfa 
                 124 
                 A-118325.1 
                 aAfaGfgUfaCfuUfguuGfuUfu 
                 175 
                   
               
               
                   
                   
                 AfgUfaCfcUfuUfL96 
                   
                   
                 AfaAfusCfsu 
                   
                   
               
               
                   
               
               
                 AD-58094.1 
                 A-118326.1 
                 AfuUfcAfgAfaAfGfUfc 
                 125 
                 A-118327.1 
                 uCfcUfuCfaCfaGfacuUfuCfu 
                 176 
                   
               
               
                   
                   
                 UfgUfgAfaGfgAfL96 
                   
                   
                 GfaAfusUfsu 
                   
                   
               
               
                   
               
               
                 AD-58100.1 
                 A-118328.1 
                 AfcAfcUfgAfaGfCfAfu 
                 126 
                 A-118329.1 
                 uUfgCfaUfcAfaAfugcUfuCfa 
                 177 
                   
               
               
                   
                   
                 UfuGfaUfgCfaAfL96 
                   
                   
                 GfuGfusAfsu 
                   
                   
               
               
                   
               
               
                 AD-58106.1 
                 A-118330.1 
                 GfcAfgUfuCfuGfUfGfu 
                 127 
                 A-118331.1 
                 gAfcAfuUfuUfaAfcacAfgAfa 
                 178 
                   
               
               
                   
                   
                 UfaAfaAfuGfuCfL96 
                   
                   
                 CfuGfcsAfsu 
                   
                   
               
               
                   
               
               
                 AD-58112.1 
                 A-118332.1 
                 AfgGfaUfuUfuGfAfGfu 
                 128 
                 A-118333.1 
                 uCfcUfuUfuAfcAfcucAfaAfa 
                 179 
                   
               
               
                   
                   
                 GfuAfaAfaGfgAfL96 
                   
                   
                 UfcCfusUfsu 
                   
                   
               
               
                   
               
               
                 AD-58118.1 
                 A-118334.1 
                 AfaUfgAfuGfaAfCfCfu 
                 129 
                 A-118335.1 
                 uUfcUfuUfaCfaAfgguUfcAfu 
                 180 
                   
               
               
                   
                   
                 UfgUfaAfaGfaAfL96 
                   
                   
                 CfaUfusUfsu 
                   
                   
               
               
                   
               
               
                 AD-58124.1 
                 A-118336.1 
                 AfuCfaUfuGfgAfAfCfa 
                 130 
                 A-118337.1 
                 aAfuGfaAfaAfaUfguuCfcAfa 
                 181 
                   
               
               
                   
                   
                 UfuUfuUfcAfuUfL96 
                   
                   
                 UfgAfusUfsu 
                   
                   
               
               
                   
               
               
                 AD-58130.1 
                 A-118338.1 
                 AfgCfcAfgAfaAfUfUfc 
                 131 
                 A-118339.1 
                 aAfuAfaCfuCfcGfaauUfuCfu 
                 182 
                   
               
               
                   
                   
                 GfgAfgUfuAfuUfL96 
                   
                   
                 GfgCfusUfsg 
                   
                   
               
               
                   
               
               
                 AD-58089.1 
                 A-118340.1 
                 UfcCfcUfgGfgAfGfAfu 
                 132 
                 A-118341.1 
                 gUfgAfgUfuUfuAfucuCfcCfa 
                 183 
                   
               
               
                   
                   
                 AfaAfaCfuCfaCfL96 
                   
                   
                 GfgGfasAfsa 
                   
                   
               
               
                   
               
               
                 AD-58095.1 
                 A-118342.1 
                 GfaAfaAfuGfaUfGfAfa 
                 133 
                 A-118343.1 
                 uUfuAfcAfaGfgUfucaUfcAfu 
                 184 
                   
               
               
                   
                   
                 CfcUfuGfuAfaAfL96 
                   
                   
                 UfuUfcsUfsu 
                   
                   
               
               
                   
               
               
                 AD-58101.1 
                 A-118344.1 
                 AfuUfgCfuCfaAfGfUfc 
                 134 
                 A-118345.1 
                 aUfcAfaAfuGfuGfacuUfgAfg 
                 185 
                   
               
               
                   
                   
                 AfcAfuUfuGfaUfL96 
                   
                   
                 CfaAfusUfsc 
                   
                   
               
               
                   
               
               
                 AD-58107.1 
                 A-118346.1 
                 GfaGfaUfuGfcAfUfAfu 
                 135 
                 A-118347.1 
                 uUfuAfuAfaGfcAfuauGfcAfa 
                 186 
                   
               
               
                   
                   
                 GfcUfuAfuAfaAfL96 
                   
                   
                 UfcUfcsUfsg 
                   
                   
               
               
                   
               
               
                 AD-58113.1 
                 A-118348.1 
                 GfuUfaUfcCfuGfAfUfa 
                 136 
                 A-118349.1 
                 uAfaAfuUfuUfuUfaucAfgGfa 
                 187 
                   
               
               
                   
                   
                 AfaAfaAfuUfuAfL96 
                   
                   
                 UfaAfcsUfsu 
                   
                   
               
               
                   
               
               
                 AD-58119.1 
                 A-118350.1 
                 AfgGfaAfgUfuUfGfCfa 
                 137 
                 A-118351.1 
                 aAfuAfaAfaGfcUfgcaAfaCfu 
                 188 
                   
               
               
                   
                   
                 GfcUfuUfuAfuUfL96 
                   
                   
                 UfcCfusCfsa 
                   
                   
               
               
                   
               
               
                 AD-58125.1 
                 A-118352.1 
                 GfaAfgAfaAfuUfGfAfu 
                 138 
                 A-118353.1 
                 uCfcAfaUfaUfgAfucaAfuUfu 
                 189 
                   
               
               
                   
                   
                 CfaUfaUfuGfgAfL96 
                   
                   
                 CfuUfcsUfsa 
                   
                   
               
               
                   
               
               
                 AD-58131.1 
                 A-118354.1 
                 AfuCfcUfgAfuAfAfAfa 
                 139 
                 A-118355.1 
                 aAfcUfaAfaUfuUfuuuAfuCfa 
                 190 
                   
               
               
                   
                   
                 AfaUfuUfaGfuUfL96 
                   
                   
                 GfgAfusAfsa 
                   
                   
               
               
                   
               
               
                 AD-58090.1 
                 A-118356.1 
                 UfgGfaAfaAfgAfAfAfu 
                 140 
                 A-118357.1 
                 uUfuAfcUfaAfgAfuuuCfuUfu 
                 191 
                   
               
               
                   
                   
                 CfuUfaGfuAfaAfL96 
                   
                   
                 UfcCfasAfsa 
                   
                   
               
               
                   
               
               
                 AD-58096.1 
                 A-118358.1 
                 UfcUfuAfuCfaAfAfGfu 
                 141 
                 A-118359.1 
                 aAfuGfuUfuAfuAfcuuUfgAfu 
                 192 
                   
               
               
                   
                   
                 AfuAfaAfcAfuUfL96 
                   
                   
                 AfaGfasUfsg 
                   
                   
               
               
                   
               
               
                 AD-58102.1 
                 A-118360.1 
                 UfcCfcUfaCfaAfAfCfu 
                 142 
                 A-118361.1 
                 aCfcAfaAfuUfcAfguuUfgUfa 
                 193 
                   
               
               
                   
                   
                 GfaAfuUfuGfgUfL96 
                   
                   
                 GfgGfasGfsa 
                   
                   
               
               
                   
               
               
                 AD-58108.1 
                 A-118362.1 
                 CfaGfgAfgCfaAfAfCfa 
                 143 
                 A-118363.1 
                 aAfuGfaCfaUfaUfguuUfgCfu 
                 194 
                   
               
               
                   
                   
                 UfaUfgUfcAfuUfL96 
                   
                   
                 CfcUfgsUfsc 
                   
                   
               
               
                   
               
               
                 AD-58114.1 
                 A-118364.1 
                 AfcAfuGfuAfaCfAfAfc 
                 144 
                 A-118365.1 
                 uGfaAfcUfaCfaGfuugUfuAfc 
                 195 
                   
               
               
                   
                   
                 UfgUfaGfuUfcAfL96 
                   
                   
                 AfuGfusAfsc 
                   
                   
               
               
                   
               
               
                 AD-58120.1 
                 A-118366.1 
                 CfaGfgAfaAfuCfAfUfu 
                 145 
                 A-118367.1 
                 aAfaUfgUfuCfcAfaugAfuUfu 
                 196 
                   
               
               
                   
                   
                 GfgAfaCfaUfuUfL96 
                   
                   
                 CfcUfgsUfsu 
                   
                   
               
               
                   
               
               
                 AD-58126.1 
                 A-118368.1 
                 UfuUfaAfgAfaUfUfUfu 
                 146 
                 A-118369.1 
                 aGfuAfaUfuUfcAfaaaUfuCfu 
                 197 
                   
               
               
                   
                   
                 GfaAfaUfuAfcUfL96 
                   
                   
                 UfaAfasGfsu 
                   
                   
               
               
                   
               
               
                 AD-58132.1 
                 A-118370.1 
                 UfaUfuCfuGfcAfAfCfu 
                 147 
                 A-118371.1 
                 aUfcGfaAfuUfcAfguuGfcAfg 
                 198 
                   
               
               
                   
                   
                 GfaAfuUfcGfaUfL96 
                   
                   
                 AfaUfasAfsc 
                   
                   
               
               
                   
               
               
                 AD-58091.1 
                 A-118372.1 
                 GfcCfcUfuGfgAfAfAfg 
                 148 
                 A-118373.1 
                 uGfaAfaUfaCfuCfuuuCfcAfa 
                 199 
                   
               
               
                   
                   
                 AfgUfaUfuUfcAfL96 
                   
                   
                 GfgGfcsUfsu 
                   
                   
               
               
                   
               
               
                 AD-58097.1 
                 A-118374.1 
                 CfcUfgAfuAfaAfAfAfa 
                 149 
                 A-118375.1 
                 gUfaAfcUfaAfaUfuuuUfuAfu 
                 200 
                   
               
               
                   
                   
                 UfuUfaGfuUfaCfL96 
                   
                   
                 CfaGfgsAfsu 
                   
                   
               
               
                   
               
               
                 AD-58103.1 
                 A-118376.1 
                 CfcCfuUfgGfaAfAfGfa 
                 150 
                 A-118377.1 
                 uUfgAfaAfuAfcUfcuuUfcCfa 
                 201 
                   
               
               
                   
                   
                 GfuAfuUfuCfaAfL96 
                   
                   
                 AfgGfgsCfsu 
                   
                   
               
               
                   
               
               
                 AD-58121.1 
                 A-118382.1 
                 UfgCfaGfaUfcAfAfAfc 
                 151 
                 A-118383.1 
                 uGfaAfaUfuGfuGfuuuGfaUfc 
                 202 
                   
               
               
                   
                   
                 AfcAfaUfuUfcAfL96 
                   
                   
                 UfgCfasGfsa 
                   
                   
               
               
                   
               
               
                 AD-58133.1 
                 A-118386.1 
                 CfaGfaUfcAfaAfCfAfc 
                 152 
                 A-118387.1 
                 aCfuGfaAfaUfuGfuguUfuGfa 
                 203 
                   
               
               
                   
                   
                 AfaUfuUfcAfgUfL96 
                   
                   
                 UfcUfgsCfsa 
                   
                   
               
               
                   
               
               
                 AD-58116.1 
                 A-118396.1 
                 GfuUfcCfgGfaUfAfUfu 
                 153 
                 A-118397.1 
                 aAfaAfgUfuCfaAfauaUfcCfg 
                 204 
                   
               
               
                   
                   
                 UfgAfaCfuUfuUfL96 
                   
                   
                 GfaAfcsCfsg 
                   
                   
               
               
                   
               
               
                 AD-58644.1 
                 A-119328.1 
                 AfsusUfuAfaAfcAfAfC 
                 154 
                 A-119329.1 
                 asAfsaGfgUfaCfuUfguuGfuU 
                 205 
                   
               
               
                   
                   
                 faAfgUfaCfcUfuUfL96 
                   
                   
                 fuAfaAfuscsu 
                   
                   
               
               
                   
               
               
                 AD-58651.1 
                 A-119328.2 
                 AfsusUfuAfaAfcAfAfC 
                 155 
                 A-119339.1 
                 asAfsaGfsgUfsaCfsuUfsguu 
                 206 
                   
               
               
                   
                   
                 faAfgUfaCfcUfuUfL96 
                   
                   
                 GfsuUfsuAfsaAfsuscsu 
                   
                   
               
               
                   
               
               
                 AD-58641.1 
                 A-119322.1 
                 UfsgsAfcAfaAfaUfAfA 
                 156 
                 A-119323.1 
                 usUfsaUfaGfuGfaGfuuaUfuU 
                 207 
                   
               
               
                   
                   
                 fcUfcAfcUfaUfaAfL96 
                   
                   
                 fuGfuCfasasu 
                   
                   
               
               
                   
               
               
                 AD-58648.1 
                 A-119322.2 
                 UfsgsAfcAfaAfaUfAfA 
                 157 
                 A-119336.1 
                 usUfsaUfsaGfsuGfsaGfsuua 
                 208 
                   
               
               
                   
                   
                 fcUfcAfcUfaUfaAfL96 
                   
                   
                 UfsuUfsuGfsuCfsasasu 
                   
                   
               
               
                   
               
               
                 AD-58642.1 
                 A-119324.1 
                 GfsasCfaAfaAfuAfAfC 
                 158 
                 A-119325.1 
                 asUfsuAfuAfgUfgAfguuAfuU 
                 209 
                   
               
               
                   
                   
                 fuCfaCfuAfuAfaUfL96 
                   
                   
                 fuUfgUfcsasa 
                   
                   
               
               
                   
               
               
                 AD-58649.1 
                 A-119324.2 
                 GfsasCfaAfaAfuAfAfC 
                 159 
                 A-119337.1 
                 asUfsuAfsuAfsgUfsgAfsguu 
                 210 
                   
               
               
                   
                   
                 fuCfaCfuAfuAfaUfL96 
                   
                   
                 AfsuUfsuUfsgUfscsasa 
                   
                   
               
               
                   
               
               
                 AD-58647.1 
                 A-119334.1 
                 GfsusUfcCfgGfaUfAfU 
                 160 
                 A-119335.1 
                 asAfsaAfgUfuCfaAfauaUfcC 
                 211 
                   
               
               
                   
                   
                 fuUfgAfaCfuUfuUfL96 
                   
                   
                 fgGfaAfcscsg 
                   
                   
               
               
                   
               
               
                 AD-58654.1 
                 A-119334.2 
                 GfsusUfcCfgGfaUfAfU 
                 161 
                 A-119342.1 
                 asAfsaAfsgUfsuCfsaAfsaua 
                 212 
                   
               
               
                   
                   
                 fuUfgAfaCfuUfuUfL96 
                   
                   
                 UfscCfsgGfsaAfscscsg 
                   
                   
               
               
                   
               
               
                 AD-58645.1 
                 A-119330.1 
                 UfsgsCfaGfaUfcAfAfA 
                 162 
                 A-119331.1 
                 usGfsaAfaUfuGfuGfuuuGfaU 
                 213 
                   
               
               
                   
                   
                 fcAfcAfaUfuUfcAfL96 
                   
                   
                 fcUfgCfasgsa 
                   
                   
               
               
                   
               
               
                 AD-58652.1 
                 A-119330.2 
                 UfsgsCfaGfaUfcAfAfA 
                 163 
                 A-119340.1 
                 usGfsaAfsaUfsuGfsuGfsuuu 
                 214 
                   
               
               
                   
                   
                 fcAfcAfaUfuUfcAfL96 
                   
                   
                 GfsaUfscUfsgCfsasgsa 
                   
                   
               
               
                   
               
               
                 AD-58643.1 
                 A-119326.1 
                 AfsasGfcAfaGfaUfAfU 
                 164 
                 A-119327.1 
                 usAfsuUfaUfaAfaAfauaUfcU 
                 215 
                   
               
               
                   
                   
                 fuUfuUfaUfaAfuAfL96 
                   
                   
                 fuGfcUfususu 
                   
                   
               
               
                   
               
               
                 AD-58650.1 
                 A-119326.2 
                 AfsasGfcAfaGfaUfAfU 
                 165 
                 A-119338.1 
                 usAfsuUfsaUfsaAfsaAfsaua 
                 216 
                   
               
               
                   
                   
                 fuUfuUfaUfaAfuAfL96 
                   
                   
                 UfscUfsuGfscUfsususu 
                   
                   
               
               
                   
               
               
                 AD-58646.1 
                 A-119332.1 
                 CfsasGfaUfcAfaAfCfA 
                 166 
                 A-119333.1 
                 asCfsuGfaAfaUfuGfuguUfuG 
                 217 
                   
               
               
                   
                   
                 fcAfaUfuUfcAfgUfL96 
                   
                   
                 faUfcUfgscsa 
                   
                   
               
               
                   
               
               
                 AD-58653.1 
                 A-119332.2 
                 CfsasGfaUfcAfaAfCfA 
                 167 
                 A-119341.1 
                 asCfsuGfsaAfsaUfsuGfsugu 
                 218 
                   
               
               
                   
                   
                 fcAfaUfuUfcAfgUfL96 
                   
                   
                 UfsuGfsaUfscUfsgscsa 
               
               
                   
               
               
                   4 The Species Oligo name and the position in the nucleotide sequence of the GenBank record that the 
               
               
                 antisense strand targets correspond to those shown in Table 3. 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 Unmodified Sense and Antisense Strand Sequences of C5 dsRNAs 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                 SEQ 
                   
                   
                 SEQ 
                   
               
               
                   
                 Sense 
                 Sense Unmodified 
                 ID 
                   
                 Antisense 
                 ID 
                 Species_ 
               
               
                 Duplex ID 
                 strand 
                 Sequence 
                 NO: 
                 Antisense 
                 Unmodifed Sequence 
                 NO: 
                 Oligo name 
               
               
                   
               
               
                 AD-58143.1 
                 A-118423.1 
                 CACUAUAAUUACUUGAUUU 
                 219 
                 A-118424.1 
                 AAAUCAAGUAAUUAUAGUG 
                 302 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 1522-1540_as 
               
               
                   
               
               
                 AD-58149.1 
                 A-118425.1 
                 UAACUCACUAUAAUUACUU 
                 220 
                 A-118426.1 
                 AAGUAAUUAUAGUGAGUUA 
                 303 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 1517-1535_as 
               
               
                   
               
               
                 AD-8155.1 
                 A-118427.1 
                 ACAAAAUAACUCACUAUAA 
                 221 
                 A-118428.1 
                 UUAUAGUGAGUUAUUUUGU 
                 304 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 1511-1529_as 
               
               
                   
               
               
                 AD-58161.1 
                 A-118429.1 
                 UCCUCUGGAAAUUGGCCUU 
                 222 
                 A-118430.1 
                 AAGGCCAAUUUCCAGAGGA 
                 305 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 2733-2751_as 
               
               
                   
               
               
                 AD-58167.1 
                 A-118431.1 
                 CAAAAUAACUCACUAUAAU 
                 223 
                 A-118432.1 
                 AUUAUAGUGAGUUAUUUUG 
                 306 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 1512-1530_as 
               
               
                   
               
               
                 AD-58173.1 
                 A-118433.1 
                 CUCUGGAAAUUGGCCUUCA 
                 224 
                 A-118434.1 
                 UGAAGGCCAAUUUCCAGAG 
                 307 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 2735-2753_as 
               
               
                   
               
               
                 AD-58179.1 
                 A-118435.1 
                 GCAAGAUAUUUUUAUAAUA 
                 225 
                 A-118436.1 
                 UAUUAUAAAAAUAUCUUGC 
                 308 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 784-802_as 
               
               
                   
               
               
                 AD-58185.1 
                 A-118437.1 
                 AAUGUUUUUGUCAAGUACA 
                 226 
                 A-118438.1 
                 UGUACUUGACAAAAACAUU 
                 309 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 4744-4762_as 
               
               
                   
               
               
                 AD-58144.1 
                 A-118439.1 
                 UUAAACAACAAGUACCUUU 
                 227 
                 A-118440.1 
                 AAAGGUACUUGUUGUUUAA 
                 310 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 982-1000_as 
               
               
                   
               
               
                 AD-58150.1 
                 A-118441.1 
                 UCAGAAAGUCUGUGAAGGA 
                 228 
                 A-118442.1 
                 UCCUUCACAGACUUUCUGA 
                 311 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 4578-4596_as 
               
               
                   
               
               
                 AD-58156.1 
                 A-118443.1 
                 ACUGAAGCAUUUGAUGCAA 
                 229 
                 A-118444.1 
                 UUGCAUCAAAUGCUUCAGU 
                 312 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 169-187_as 
               
               
                   
               
               
                 AD-58162.1 
                 A-118445.1 
                 AGUUCUGUGUUAAAAUGUC 
                 230 
                 A-118446.1 
                 GACAUUUUAACACAGAACU 
                 313 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 2591-2609_as 
               
               
                   
               
               
                 AD-58168.1 
                 A-118447.1 
                 GAUUUUGAGUGUAAAAGGA 
                 231 
                 A-118448.1 
                 UCCUUUUACACUCAAAAUC 
                 314 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 2955-2973_as 
               
               
                   
               
               
                 AD-58174.1 
                 A-118449.1 
                 UGAUGAACCUUGUAAAGAA 
                 232 
                 A-118450.1 
                 UUCUUUACAAGGUUCAUCA 
                 315 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 2025-2043_as 
               
               
                   
               
               
                 AD-58180.1 
                 A-118451.1 
                 CAUUGGAACAUUUUUCAUU 
                 233 
                 A-118452.1 
                 AAUGAAAAAUGUUCCAAUG 
                 316 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 3118-3136_as 
               
               
                   
               
               
                 AD-58186.1 
                 A-118453.1 
                 CCAGAAAUUCGGAGUUAUU 
                 234 
                 A-118454.1 
                 AAUAACUCCGAAUUUCUGG 
                 317 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 2317-2335_as 
               
               
                   
               
               
                 AD-58145.1 
                 A-118455.1 
                 CCUGGGAGAUAAAACUCAC 
                 235 
                 A-118456.1 
                 GUGAGUUUUAUCUCCCAGG 
                 318 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 3618-3636_as 
               
               
                   
               
               
                 AD-58151.1 
                 A-118457.1 
                 AAAUGAUGAACCUUGUAAA 
                 236 
                 A-118458.1 
                 UUUACAAGGUUCAUCAUUU 
                 319 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 2022-2040_as 
               
               
                   
               
               
                 AD-58157.1 
                 A-118459.1 
                 UGCUCAAGUCACAUUUGAU 
                 237 
                 A-118460.1 
                 AUCAAAUGUGACUUGAGCA 
                 320 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 918-936_as 
               
               
                   
               
               
                 AD-58163.1 
                 A-118461.1 
                 GAUUGCAUAUGCUUAUAAA 
                 238 
                 A-118462.1 
                 UUUAUAAGCAUAUGCAAUC 
                 321 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 4698-4716_as 
               
               
                   
               
               
                 AD-58169.1 
                 A-118463.1 
                 UAUCCUGAUAAAAAAUUUA 
                 239 
                 A-118464.1 
                 UAAAUUUUUUAUCAGGAUA 
                 322 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 205-223_as 
               
               
                   
               
               
                 AD-58175.1 
                 A-118465.1 
                 GAAGUUUGCAGCUUUUAUU 
                 240 
                 A-118466.1 
                 AAUAAAAGCUGCAAACUUC 
                 323 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 4147-4165_as 
               
               
                   
               
               
                 AD-58181.1 
                 A-118467.1 
                 AGAAAUUGAUCAUAUUGGA 
                 241 
                 A-118468.1 
                 UCCAAUAUGAUCAAUUUCU 
                 324 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 555-573_as 
               
               
                   
               
               
                 AD-58187.1 
                 A-118469.1 
                 CCUGAUAAAAAAUUUAGUU 
                 242 
                 A-118470.1 
                 AACUAAAUUUUUUAUCAGG 
                 325 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 208-226_as 
               
               
                   
               
               
                 AD-58146.1 
                 A-118471.1 
                 GAAAAGAAAUCUUAGUAAA 
                 243 
                 A-118472.1 
                 UUUACUAAGAUUUCUUUUC 
                 326 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 2786-2804_as 
               
               
                   
               
               
                 AD-58152.1 
                 A-118473.1 
                 UUAUCAAAGUAUAAACAUU 
                 244 
                 A-118474.1 
                 AAUGUUUAUACUUUGAUAA 
                 327 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 1596-1614_as 
               
               
                   
               
               
                 AD-58158.1 
                 A-118475.1 
                 CCUACAAACUGAAUUUGGU 
                 245 
                 A-118476.1 
                 ACCAAAUUCAGUUUGUAGG 
                 328 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 1082-1100_as 
               
               
                   
               
               
                 AD-58164.1 
                 A-118477.1 
                 GGAGCAAACAUAUGUCAUU 
                 246 
                 A-118478.1 
                 AAUGACAUAUGUUUGCUCC 
                 329 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 87-105_as 
               
               
                   
               
               
                 AD-58171.1 
                 A-118479.1 
                 AUGUAACAACUGUAGUUCA 
                 247 
                 A-118480.1 
                 UGAACUACAGUUGUUACAU 
                 330 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 4109-4127_as 
               
               
                   
               
               
                 AD-58176.1 
                 A-118481.1 
                 GGAAAUCAUUGGAACAUUU 
                 248 
                 A-118482.1 
                 AAAUGUUCCAAUGAUUUCC 
                 331 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 3112-3130_as 
               
               
                   
               
               
                 AD-58182.1 
                 A-118483.1 
                 UAAGAAUUUUGAAAUUACU 
                 249 
                 A-118484.1 
                 AGUAAUUUCAAAAUUCUUA 
                 332 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 759-777_as 
               
               
                   
               
               
                 AD-58188.1 
                 A-118485.1 
                 UUCUGCAACUGAAUUCGAU 
                 250 
                 A-118486.1 
                 AUCGAAUUCAGUUGCAGAA 
                 333 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 4412-4430_as 
               
               
                   
               
               
                 AD-58147.1 
                 A-118487.1 
                 CCUUGGAAAGAGUAUUUCA 
                 251 
                 A-118488.1 
                 UGAAAUACUCUUUCCAAGG 
                 334 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 1886-1904_as 
               
               
                   
               
               
                 AD-58153.1 
                 A-118489.1 
                 UGAUAAAAAAUUUAGUUAC 
                 252 
                 A-118490.1 
                 GUAACUAAAUUUUUUAUCA 
                 335 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 210-228_as 
               
               
                   
               
               
                 AD-58159.1 
                 A-118491.1 
                 CUUGGAAAGAGUAUUUCAA 
                 253 
                 A-118492.1 
                 UUGAAAUACUCUUUCCAAG 
                 336 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 1887-1905_as 
               
               
                   
               
               
                 AD-58190.1 
                 A-118519.1 
                 CACUAUAAUUACUUGAUUU 
                 254 
                 A-118520.1 
                 AAAUCAAGUAAUUAUAGUG 
                 337 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                 1522-1540_as 
               
               
                   
               
               
                 AD-58196.1 
                 A-118521.1 
                 UAACUCACUAUAAUUACUU 
                 255 
                 A-118522.1 
                 AAGUAAUUAUAGUGAGUUA 
                 338 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58202.1 
                 A-118523.1 
                 ACAAAAUAACUCACUAUAA 
                 256 
                 A-118524.1 
                 UUAUAGUGAGUUAUUUUGU 
                 339 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58208.1 
                 A-118525.1 
                 UCCUCUGGAAAUUGGCCUU 
                 257 
                 A-118526.1 
                 AAGGCCAAUUUCCAGAGGA 
                 340 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58214.1 
                 A-118527.1 
                 CAAAAUAACUCACUAUAAU 
                 258 
                 A-118528.1 
                 AUUAUAGUGAGUUAUUUUG 
                 341 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58220.1 
                 A-118529.1 
                 CUCUGGAAAUUGGCCUUCA 
                 259 
                 A-118530.1 
                 UGAAGGCCAAUUUCCAGAG 
                 342 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58226.1 
                 A-118531.1 
                 GCAAGAUAUUUUUAUAAUA 
                 260 
                 A-118532.1 
                 UAUUAUAAAAAUAUCUUGC 
                 343 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58231.1 
                 A-118533.1 
                 AAUGUUUUUGUCAAGUACA 
                 261 
                 A-118534.1 
                 UGUACUUGACAAAAACAUU 
                 344 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-59191.1 
                 A-118535.1 
                 UUAAACAACAAGUACCUUU 
                 262 
                 A-118536.1 
                 AAAGGUACUUGUUGUUUAA 
                 345 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58197.1 
                 A-118537.1 
                 UCAGAAAGUCUGUGAAGGA 
                 263 
                 A-118538.1 
                 UCCUUCACAGACUUUCUGA 
                 346 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58203.1 
                 A-118539.1 
                 ACUGAAGCAUUUGAUGCAA 
                 264 
                 A-118540.1 
                 UUGCAUCAAAUGCUUCAGU 
                 347 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58209.1 
                 A-118541.1 
                 AGUUCUGUGUUAAAAUGUC 
                 265 
                 A-118542.1 
                 GACAUUUUAACACAGAACU 
                 348 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58233.1 
                 A-118564.1 
                 CACUAUAAUUACUUGAUUU 
                 266 
                 A-118566.1 
                 AAAUCAAGUAAUUAUAGUG 
                 349 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58193.1 
                 A-118567.1 
                 UAACUCACUAUAAUUACUU 
                 267 
                 A-118568.1 
                 AAGUAAUUAUAGUGAGUUA 
                 350 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58199.1 
                 A-118569.1 
                 ACAAAAUAACUCACUAUAA 
                 268 
                 A-118570.1 
                 UUAUAGUGAGUUAUUUUGU 
                 351 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58205.1 
                 A-118571.1 
                 UCCUCUGGAAAUUGGCCUU 
                 269 
                 A-118572.1 
                 AAGGCCAAUUUCCAGAGGA 
                 352 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58211.1 
                 A-118573.1 
                 CAAAAUAACUCACUAUAAU 
                 270 
                 A-118574.1 
                 AUUAUAGUGAGUUAUUUUG 
                 353 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58217.1 
                 A-118575.1 
                 CUCUGGAAAUUGGCCUUCA 
                 271 
                 A-118576.1 
                 UGAAGGCCAAUUUCCAGAG 
                 354 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58223.1 
                 A-118577.1 
                 GCAAGAUAUUUUUAUAAUA 
                 272 
                 A-118578.1 
                 UAUUAUAAAAAUAUCUUGC 
                 355 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58229.1 
                 A-118579.1 
                 AAUGUUUUUGUCAAGUACA 
                 273 
                 A-118580.1 
                 UGUACUUGACAAAAACAUU 
                 356 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58234.1 
                 A-118581.1 
                 UUAAACAACAAGUACCUUU 
                 274 
                 A-118582.1 
                 AAAGGUACUUGUUGUUUAA 
                 357 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58194.1 
                 A-118583.1 
                 UCAGAAAGUCUGUGAAGGA 
                 275 
                 A-118584.1 
                 UCCUUCACAGACUUUCUGA 
                 358 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58200.1 
                 A-118585.1 
                 ACUGAAGCAUUUGAUGCAA 
                 276 
                 A-118586.1 
                 UUGCAUCAAAUGCUUCAGU 
                 359 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58206.1 
                 A-118587.1 
                 AGUUCUGUGUUAAAAUGUC 
                 277 
                 A-118588.1 
                 GACAUUUUAACACAGAACU 
                 360 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58236.1 
                 A-118423.2 
                 CACUAUAAUUACUUGAUUU 
                 278 
                 A-118644.1 
                 AAAUCAAGUAAUUAUAGUG 
                 361 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58242.1 
                 A-118425.2 
                 UAACUCACUAUAAUUACUU 
                 279 
                 A-118645.1 
                 AAGUAAUUAUAGUGAGUUA 
                 362 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58248.1 
                 A-118427.2 
                 ACAAAAUAACUCACUAUAA 
                 280 
                 A-118646.1 
                 UUAUAGUGAGUUAUUUUGU 
                 363 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58254.1 
                 A-118429.2 
                 UCCUCUGGAAAUUGGCCUU 
                 281 
                 A-118647.1 
                 AAGGCCAAUUUCCAGAGGA 
                 364 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58260.1 
                 A-118431.2 
                 CAAAAUAACUCACUAUAAU 
                 282 
                 A-118648.1 
                 AUUAUAGUGAGUUAUUUUG 
                 365 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58266.1 
                 A-118433.2 
                 CUCUGGAAAUUGGCCUUCA 
                 283 
                 A-118649.1 
                 UGAAGGCCAAUUUCCAGAG 
                 366 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58272.1 
                 A-118435.2 
                 GCAAGAUAUUUUUAUAAUA 
                 284 
                 A-118650.1 
                 UAUUAUAAAAAUAUCUUGC 
                 367 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58277.1 
                 A-118437.2 
                 AAUGUUUUUGUCAAGUACA 
                 285 
                 A-118651.1 
                 UGUACUUGACAAAAACAUU 
                 368 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58237.1 
                 A-118439.2 
                 UUAAACAACAAGUACCUUU 
                 286 
                 A-118652.1 
                 AAAGGUACUUGUUGUUUAA 
                 369 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58243.1 
                 A-118441.2 
                 UCAGAAAGUCUGUGAAGGA 
                 287 
                 A-118653.1 
                 UCCUUCACAGACUUUCUGA 
                 370 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58249.1 
                 A-118443.2 
                 ACUGAAGCAUUUGAUGCAA 
                 288 
                 A-118654.1 
                 UUGCAUCAAAUGCUUCAGU 
                 371 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58255.1 
                 A-118445.2 
                 AGUUCUGUGUUAAAAUGUC 
                 289 
                 A-118655.1 
                 GACAUUUUAACACAGAACU 
                 372 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58279.1 
                 A-118423.3 
                 CACUAUAAUUACUUGAUUU 
                 290 
                 A-118667.1 
                 AAAUCAAGUAAUUAUAGUG 
                 373 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58239.1 
                 A-118425.3 
                 UAACUCACUAUAAUUACUU 
                 291 
                 A-118668.1 
                 AAGUAAUUAUAGUGAGUUA 
                 374 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58245.1 
                 A-118427.3 
                 ACAAAAUAACUCACUAUAA 
                 292 
                 A-118669.1 
                 UUAUAGUGAGUUAUUUUGU 
                 375 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58251.1 
                 A-118429.3 
                 UCCUCUGGAAAUUGGCCUU 
                 293 
                 A-118670.1 
                 AAGGCCAAUUUCCAGAGGA 
                 376 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58257.1 
                 A-118431.3 
                 CAAAAUAACUCACUAUAAU 
                 294 
                 A-118671.1 
                 AUUAUAGUGAGUUAUUUUG 
                 377 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58263.1 
                 A-118433.3 
                 CUCUGGAAAUUGGCCUUCA 
                 295 
                 A-118672.1 
                 UGAAGGCCAAUUUCCAGAG 
                 378 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58269.1 
                 A-118435.3 
                 GCAAGAUAUUUUUAUAAUA 
                 296 
                 A-118673.1 
                 UAUUAUAAAAAUAUCUUGC 
                 379 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58275.1 
                 A-118437.3 
                 AAUGUUUUUGUCAAGUACA 
                 297 
                 A-118674.1 
                 UGUACUUGACAAAAACAUU 
                 380 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58280.1 
                 A-118439.3 
                 UUAAACAACAAGUACCUUU 
                 298 
                 A-118675.1 
                 AAAGGUACUUGUUGUUUAA 
                 381 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58240.1 
                 A-118441.3 
                 UCAGAAAGUCUGUGAAGGA 
                 299 
                 A-118676.1 
                 UCCUUCACAGACUUUCUGA 
                 382 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58246.1 
                 A-118443.3 
                 ACUGAAGCAUUUGAUGCAA 
                 300 
                 A-118677.1 
                 UUGCAUCAAAUGCUUCAGU 
                 383 
                 NM_001735.2_ 
               
               
                 UM 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58252.1 
                 A-118445.3 
                 AGUUCUGUGUUAAAAUGUC 
                 301 
                 A-118678.1 
                 GACAUUUUAACACAGAACU 
                 384 
                 NM_001735.2_ 
               
               
                 UM 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 Modified Sense and Antisense Strand SequencesofC5 dsRNAs 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                 SEQ 
                   
                   
                 SEQ 
                 Species_ 
               
               
                   
                 Sense 
                   
                 ID 
                   
                   
                 ID 
                 Oligo 
               
               
                 Duplex ID 
                 strand 
                 Sense Sequence 
                 NO: 
                 Antisense 
                 Antisense sequence 
                 NO: 
                 name 5   
               
               
                   
               
               
                 AD-58143.1 
                 A-118423.1 
                 cAcuAuAAuuAcuuGAuuudTsdT 
                 385 
                 A-118424.1 
                 AAAUcAAGuAAUuAuAGUGdTsdT 
                 468 
                   
               
               
                   
               
               
                 AD-58149.1 
                 A-118425.1 
                 uAAcucAcuAuAAuuAcuudTsdT 
                 386 
                 A-118426.1 
                 AAGuAAUuAuAGUGAGUuAdTsdT 
                 469 
                   
               
               
                   
               
               
                 AD-58155.1 
                 A-118427.1 
                 AcAAAAuAAcucAcuAuAAdTsdT 
                 387 
                 A-118428.1 
                 UuAuAGUGAGUuAUUUUGUdTsdT 
                 470 
                   
               
               
                   
               
               
                 AD-58161.1 
                 A-118429.1 
                 uccucuGGAAAuuGGccuudTsdT 
                 388 
                 A-118430.1 
                 AAGGCcAAUUUCcAGAGGAdTsdT 
                 471 
                   
               
               
                   
               
               
                 AD-58167.1 
                 A-118431.1 
                 cAAAAuAAcucAcuAuAAudTsdT 
                 389 
                 A-118432.1 
                 AUuAuAGUGAGUuAUUUUGdTsdT 
                 472 
                   
               
               
                   
               
               
                 AD-58173.1 
                 A-118433.1 
                 cucuGGAAAuuGGccuucAdTsdT 
                 390 
                 A-118434.1 
                 UGAAGGCcAAUUUCcAGAGdTsdT 
                 473 
                   
               
               
                   
               
               
                 AD-58179.1 
                 A-118435.1 
                 GcAAGAuAuuuuuAuAAuAdTsdT 
                 391 
                 A-118436.1 
                 uAUuAuAAAAAuAUCUUGCdTsdT 
                 474 
                   
               
               
                   
               
               
                 AD-58185.1 
                 A-118437.1 
                 AAuGuuuuuGucAAGuAcAdTsdT 
                 392 
                 A-118438.1 
                 UGuACUUGAcAAAAAcAUUdTsdT 
                 475 
                   
               
               
                   
               
               
                 AD-58144.1 
                 A-118439.1 
                 uuAAAcAAcAAGuAccuuudTsdT 
                 393 
                 A-118440.1 
                 AAAGGuACUUGUUGUUuAAdTsdT 
                 476 
                   
               
               
                   
               
               
                 AD-58150.1 
                 A-118441.1 
                 ucAGAAAGucuGuGAAGGAdTsdT 
                 394 
                 A-118442.1 
                 UCCUUcAcAGACUUUCUGAdTsdT 
                 477 
                   
               
               
                   
               
               
                 AD-58156.1 
                 A-118443.1 
                 AcuGAAGcAuuuGAuGcAAdTsdT 
                 395 
                 A-118444.1 
                 UUGcAUcAAAUGCUUcAGUdTsdT 
                 478 
                   
               
               
                   
               
               
                 AD-58162.1 
                 A-118445.1 
                 AGuucuGuGuuAAAAuGucdTsdT 
                 396 
                 A-118446.1 
                 GAcAUUUuAAcAcAGAACUdTsdT 
                 479 
                   
               
               
                   
               
               
                 AD-58168.1 
                 A-118447.1 
                 GAuuuuGAGuGuAAAAGGAdTsdT 
                 397 
                 A-118448.1 
                 UCCUUUuAcACUcAAAAUCdTsdT 
                 480 
                   
               
               
                   
               
               
                 AD-58174.1 
                 A-118449.1 
                 uGAuGAAccuuGuAAAGAAdTsdT 
                 398 
                 A-118450.1 
                 UUCUUuAcAAGGUUcAUcAdTsdT 
                 481 
                   
               
               
                   
               
               
                 AD-58180.1 
                 A-118451.1 
                 cAuuGGAAcAuuuuucAuudTsdT 
                 399 
                 A-118452.1 
                 AAUGAAAAAUGUUCcAAUGdTsdT 
                 482 
                   
               
               
                   
               
               
                 AD-58186.1 
                 A-118453.1 
                 ccAGAAAuucGGAGuuAuudTsdT 
                 400 
                 A-118454.1 
                 AAuAACUCCGAAUUUCUGGdTsdT 
                 483 
                   
               
               
                   
               
               
                 AD-58145.1 
                 A-118455.1 
                 ccuGGGAGAuAAAAcucAcdTsdT 
                 401 
                 A-118456.1 
                 GUGAGUUUuAUCUCCcAGGdTsdT 
                 484 
                   
               
               
                   
               
               
                 AD-58151.1 
                 A-118457.1 
                 AAAuGAuGAAccuuGuAAAdTsdT 
                 402 
                 A-118458.1 
                 UUuAcAAGGUUcAUcAUUUdTsdT 
                 485 
                   
               
               
                   
               
               
                 AD-58157.1 
                 A-118459.1 
                 uGcucAAGucAcAuuuGAudTsdT 
                 403 
                 A-118460.1 
                 AUcAAAUGUGACUUGAGcAdTsdT 
                 486 
                   
               
               
                   
               
               
                 AD-58163.1 
                 A-118461.1 
                 GAuuGcAuAuGcuuAuAAAdTsdT 
                 404 
                 A-118462.1 
                 UUuAuAAGcAuAUGcAAUCdTsdT 
                 487 
                   
               
               
                   
               
               
                 AD-58169.1 
                 A-118463.1 
                 uAuccuGAuAAAAAAuuuAdTsdT 
                 405 
                 A-118464.1 
                 uAAAUUUUUuAUcAGGAuAdTsdT 
                 488 
                   
               
               
                   
               
               
                 AD-58175.1 
                 A-118465.1 
                 GAAGuuuGcAGcuuuuAuudTsdT 
                 406 
                 A-118466.1 
                 AAuAAAAGCUGcAAACUUCdTsdT 
                 489 
                   
               
               
                   
               
               
                 AD-58181.1 
                 A-118467.1 
                 AGAAAuuGAucAuAuuGGAdTsdT 
                 407 
                 A-118468.1 
                 UCcAAuAUGAUcAAUUUCUdTsdT 
                 490 
                   
               
               
                   
               
               
                 AD-58187.1 
                 A-118469.1 
                 ccuGAuAAAAAAuuuAGuudTsdT 
                 408 
                 A-118470.1 
                 AACuAAAUUUUUuAUcAGGdTsdT 
                 491 
                   
               
               
                   
               
               
                 AD-58146.1 
                 A-118471.1 
                 GAAAAGAAAucuuAGuAAAdTsdT 
                 409 
                 A-118472.1 
                 UUuACuAAGAUUUCUUUUCdTsdT 
                 492 
                   
               
               
                   
               
               
                 AD-58152.1 
                 A-118473.1 
                 uuAucAAAGuAuAAAcAuudTsdT 
                 410 
                 A-118474.1 
                 AAUGUUuAuACUUUGAuAAdTsdT 
                 493 
                   
               
               
                   
               
               
                 AD-58158.1 
                 A-118475.1 
                 ccuAcAAAcuGAAuuuGGudTsdT 
                 411 
                 A-118476.1 
                 ACcAAAUUcAGUUUGuAGGdTsdT 
                 494 
                   
               
               
                   
               
               
                 AD-58164.1 
                 A-118477.1 
                 GGAGcAAAcAuAuGucAuudTsdT 
                 412 
                 A-118478.1 
                 AAUGAcAuAUGUUUGCUCCdTsdT 
                 495 
                   
               
               
                   
               
               
                 AD-58170.1 
                 A-118479.1 
                 AuGuAAcAAcuGuAGuucAdTsdT 
                 413 
                 A-118480.1 
                 UGAACuAcAGUUGUuAcAUdTsdT 
                 496 
                   
               
               
                   
               
               
                 AD-58176.1 
                 A-118481.1 
                 GGAAAucAuuGGAAcAuuudTsdT 
                 414 
                 A-118482.1 
                 AAAUGUUCcAAUGAUUUCCdTsdT 
                 497 
                   
               
               
                   
               
               
                 AD-58182.1 
                 A-118483.1 
                 uAAGAAuuuuGAAAuuAcudTsdT 
                 415 
                 A-118484.1 
                 AGuAAUUUcAAAAUUCUuAdTsdT 
                 498 
                   
               
               
                   
               
               
                 AD-58188.1 
                 A-118485.1 
                 uucuGcAAcuGAAuucGAudTsdT 
                 416 
                 A-118486.1 
                 AUCGAAUUcAGUUGcAGAAdTsdT 
                 499 
                   
               
               
                   
               
               
                 AD-58147.1 
                 A-118487.1 
                 ccuuGGAAAGAGuAuuucAdTsdT 
                 417 
                 A-118488.1 
                 UGAAAuACUCUUUCcAAGGdTsdT 
                 500 
                   
               
               
                   
               
               
                 AD-58153.1 
                 A-118489.1 
                 uGAuAAAAAAuuuAGuuAcdTsdT 
                 418 
                 A-118490.1 
                 GuAACuAAAUUUUUuAUcAdTsdT 
                 501 
                   
               
               
                   
               
               
                 AD-58159.1 
                 A-118491.1 
                 cuuGGAAAGAGuAuuucAAdTsdT 
                 419 
                 A-118492.1 
                 UUGAAAuACUCUUUCcAAGdTsdT 
                 502 
                   
               
               
                   
               
               
                 AD-58190.1 
                 A-118519.1 
                 CACUAUAAUUACUUGAUUUdTdT 
                 420 
                 A-118520.1 
                 AAAUCAAGUAAUUAUAGUGdTdT 
                 503 
                   
               
               
                   
               
               
                 AD-58196.1 
                 A-118521.1 
                 UAACUCACUAUAAUUACUUdTdT 
                 421 
                 A-118522.1 
                 AAGUAAUUAUAGUGAGUUAdTdT 
                 504 
                   
               
               
                   
               
               
                 AD-58202.1 
                 A-118523.1 
                 ACAAAAUAACUCACUAUAAdTdT 
                 422 
                 A-118524.1 
                 UUAUAGUGAGUUAUUUUGUdTdT 
                 505 
                   
               
               
                   
               
               
                 AD-58208.1 
                 A-118525.1 
                 UCCUCUGGAAAUUGGCCUUdTdT 
                 423 
                 A-118526.1 
                 AAGGCCAAUUUCCAGAGGAdTdT 
                 506 
                   
               
               
                   
               
               
                 AD-58214.1 
                 A-118527.1 
                 CAAAAUAACUCACUAUAAUdTdT 
                 424 
                 A-118528.1 
                 AUUAUAGUGAGUUAUUUUGdTdT 
                 507 
                   
               
               
                   
               
               
                 AD-58220.1 
                 A-118529.1 
                 CUCUGGAAAUUGGCCUUCAdTdT 
                 425 
                 A-118530.1 
                 UGAAGGCCAAUUUCCAGAGdTdT 
                 508 
                   
               
               
                   
               
               
                 AD-58226.1 
                 A-118531.1 
                 GCAAGAUAUUUUUAUAAUAdTdT 
                 426 
                 A-118532.1 
                 UAUUAUAAAAAUAUCUUGCdTdT 
                 509 
                   
               
               
                   
               
               
                 AD-58231.1 
                 A-118533.1 
                 AAUGUUUUUGUCAAGUACAdTdT 
                 427 
                 A-118534.1 
                 UGUACUUGACAAAAACAUUdTdT 
                 510 
                   
               
               
                   
               
               
                 AD-58191.1 
                 A-118535.1 
                 UUAAACAACAAGUACCUUUdTdT 
                 428 
                 A-118536.1 
                 AAAGGUACUUGUUGUUUAAdTdT 
                 511 
                   
               
               
                   
               
               
                 AD-58197.1 
                 A-118537.1 
                 UCAGAAAGUCUGUGAAGGAdTdT 
                 429 
                 A-118538.1 
                 UCCUUCACAGACUUUCUGAdTdT 
                 512 
                   
               
               
                   
               
               
                 AD-58203.1 
                 A-118539.1 
                 ACUGAAGCAUUUGAUGCAAdTdT 
                 430 
                 A-118540.1 
                 UUGCAUCAAAUGCUUCAGUdTdT 
                 513 
                   
               
               
                   
               
               
                 AD-58209.1 
                 A-118541.1 
                 AGUUCUGUGUUAAAAUGUCdTdT 
                 431 
                 A-118542.1 
                 GACAUUUUAACACAGAACUdTdT 
                 514 
                   
               
               
                   
               
               
                 AD-58233.1 
                 A-118565.1 
                 CfACfUfAUfAAUfUfACfUfUf 
                 432 
                 A-118566.1 
                 AAAUCfAAGUfAAUUfAUfAGUGd 
                 515 
                   
               
               
                   
                   
                 GAUfUfUfdTsdT 
                   
                   
                 TsdT 
                   
                   
               
               
                   
               
               
                 AD-58193.1 
                 A-118567.1 
                 UfAACfUiCfACfUfAUfAAUfU 
                 433 
                 A-118568.1 
                 AAGUfAAUUfAUfAGUGAGUUfAd 
                 516 
                   
               
               
                   
                   
                 fACfUfUfdTsdT 
                   
                   
                 TsdT 
                   
                   
               
               
                   
               
               
                 AD-58199.1 
                 A-118569.1 
                 ACfAAAAUfAACfUfCfACfUfA 
                 434 
                 A-118570.1 
                 UUfAUfAGUGAGUUfAUUUUGUdT 
                 517 
                   
               
               
                   
                   
                 UfAAdTsdT 
                   
                   
                 sdT 
                   
                   
               
               
                   
               
               
                 AD-58205.1 
                 A-118571.1 
                 UfCfCfUfCfUfGGAAAUfUfGG 
                 435 
                 A-118572.1 
                 AAGGCCfAAUUUCCfAGAGGAdTs 
                 518 
                   
               
               
                   
                   
                 CfCfUfUfdTsdT 
                   
                   
                 dT 
                   
                   
               
               
                   
               
               
                 AD-58211.1 
                 A-118573.1 
                 CfAAAAUfAACfUfCfACfUfAU 
                 436 
                 A-118574.1 
                 AUUfAUfAGUGAGUUfAUUUUGdT 
                 519 
                   
               
               
                   
                   
                 fAAUfdTsdT 
                   
                   
                 sdT 
                   
                   
               
               
                   
               
               
                 AD-58217.1 
                 A-118575.1 
                 CfUfCfUfGGAAAUfUfGGCfCf 
                 437 
                 A-118576.1 
                 UGAAGGCCfAAUUUCCfAGAGdTs 
                 520 
                   
               
               
                   
                   
                 UfUfCfAdTsdT 
                   
                   
                 dT 
                   
                   
               
               
                   
               
               
                 AD-58223.1 
                 A-118577.1 
                 GCfAAGAUfAUfUfUfUfUfAUf 
                 438 
                 A-118578.1 
                 UfAUUfAUfAAAAAUfAUCUUGCd 
                 521 
                   
               
               
                   
                   
                 AAUfAdTsdT 
                   
                   
                 TsdT 
                   
                   
               
               
                   
               
               
                 AD-58229.1 
                 A-118579.1 
                 AAUfGUfUfUfUfUfGUfCfAAG 
                 439 
                 A-118580.1 
                 UGUfACUUGACfAAAAACfAUUdT 
                 522 
                   
               
               
                   
                   
                 UfACfAdTsdT 
                   
                   
                 sdT 
                   
                   
               
               
                   
               
               
                 AD-58234.1 
                 A-118581.1 
                 UfUfAAACfAACfAAGUfACfCf 
                 440 
                 A-118582.1 
                 AAAGGUfACUUGUUGUUUfAAdTs 
                 523 
                   
               
               
                   
                   
                 UfUfUfdTsdT 
                   
                   
                 dT 
                   
                   
               
               
                   
               
               
                 AD-58194.1 
                 A-118583.1 
                 UfCfAGAAAGUfCfUfGUfGAAG 
                 441 
                 A-118584.1 
                 UCCUUCfACfAGACUUUCUGAdTs 
                 524 
                   
               
               
                   
                   
                 GAdTsdT 
                   
                   
                 dT 
                   
                   
               
               
                   
               
               
                 AD-58200.1 
                 A-118585.1 
                 ACfUfGAAGCfAUfUfUfGAUfG 
                 442 
                 A-118586.1 
                 UUGCfAUCfAAAUGCUUCfAGUdT 
                 525 
                   
               
               
                   
                   
                 CfAAdTsdT 
                   
                   
                 sdT 
                   
                   
               
               
                   
               
               
                 AD-58206.1 
                 A-118587.1 
                 AGUfUfCfUfGUfGUfUfAAAAU 
                 443 
                 A-118588.1 
                 GACfAUUUUfAACfACfAGAACUd 
                 526 
                   
               
               
                   
                   
                 fGUfCfdTsdT 
                   
                   
                 TsdT 
                   
                   
               
               
                   
               
               
                 AD-58236.1 
                 A-118423.2 
                 cAcuAuAAuuAcuuGAuuudTsdT 
                 444 
                 A-118644.1 
                 AAAUcAAGuAAUuAuAGuGdTsdT 
                 527 
                   
               
               
                   
               
               
                 AD-58242.1 
                 A-118425.2 
                 uAAcucAcuAuAAuuAcuudTsdT 
                 445 
                 A-118645.1 
                 AAGuAAUuAuAGuGAGUuAdTsdT 
                 528 
                   
               
               
                   
               
               
                 AD-58248.1 
                 A-118427.2 
                 AcAAAAuAAcucAcuAuAAdTsdT 
                 446 
                 A-118646.1 
                 UuAuAGuGAGUuAuUuuGUdTsdT 
                 529 
                   
               
               
                   
               
               
                 AD-58254.1 
                 A-118429.2 
                 uccucuGGAAAuuGGccuudTsdT 
                 447 
                 A-118647.1 
                 AAGGCcAAuUUCcAGAGGAdTsdT 
                 530 
                   
               
               
                   
               
               
                 AD-58260.1 
                 A-118431.2 
                 cAAAAuAAcucAcuAuAAudTsdT 
                 448 
                 A-118648.1 
                 AUuAuAGuGAGUuAuUuuGdTsdT 
                 531 
                   
               
               
                   
               
               
                 AD-58266.1 
                 A-118433.2 
                 cucuGGAAAuuGGccuucAdTsdT 
                 449 
                 A-118649.1 
                 uGAAGGCcAAuUUCcAGAGdTsdT 
                 532 
                   
               
               
                   
               
               
                 AD-58272.1 
                 A-118435.2 
                 GcAAGAuAuuuuuAuAAuAdTsdT 
                 450 
                 A-118650.1 
                 uAUuAuAAAAAuAUCuuGCdTsdT 
                 533 
                   
               
               
                   
               
               
                 AD-58277.1 
                 A-118437.2 
                 AAuGuuuuuGucAAGuAcAdTsdT 
                 451 
                 A-118651.1 
                 uGuACuuGAcAAAAAcAuUdTsdT 
                 534 
                   
               
               
                   
               
               
                 AD-58237.1 
                 A-118439.2 
                 uuAAAcAAcAAGuAccuuudTsdT 
                 452 
                 A-118652.1 
                 AAAGGuACuuGuuGuUuAAdTsdT 
                 535 
                   
               
               
                   
               
               
                 AD-58243.1 
                 A-118441.2 
                 ucAGAAAGucuGuGAAGGAdTsdT 
                 453 
                 A-118653.1 
                 UCCuUcAcAGACuUUCuGAdTsdT 
                 536 
                   
               
               
                   
               
               
                 AD-58249.1 
                 A-118443.2 
                 AcuGAAGcAuuuGAuGcAAdTsdT 
                 454 
                 A-118654.1 
                 uuGcAUcAAAuGCuUcAGUdTsdT 
                 537 
                   
               
               
                   
               
               
                 AD-58255.1 
                 A-118445.2 
                 AGuucuGuGuuAAAAuGucdTsdT 
                 455 
                 A-118655.1 
                 GAcAuUUuAAcAcAGAACUdTsdT 
                 538 
                   
               
               
                   
               
               
                 AD-58279.1 
                 A-118423.3 
                 cAcuAuAAuuAcuuGAuuudTsdT 
                 456 
                 A-118667.1 
                 AAAUCAAGuAAuuAuAgugdTsdT 
                 539 
                   
               
               
                   
               
               
                 AD-58239.1 
                 A-118425.3 
                 uAAcucAcuAuAAuuAcuudTsdT 
                 457 
                 A-118668.1 
                 AAGuAAuUAuAGuGAGuuadTsdT 
                 540 
                   
               
               
                   
               
               
                 AD-58245.1 
                 A-118427.3 
                 AcAAAAuAAcucAcuAuAAdTsdT 
                 458 
                 A-118669.1 
                 UuAuAGuGAGuuAuuuugudTsdT 
                 541 
                   
               
               
                   
               
               
                 AD-58251.1 
                 A-118429.3 
                 uccucuGGAAAuuGGccuudTsdT 
                 459 
                 A-118670.1 
                 AAGGCCAAuUuCCAGAggadTsdT 
                 542 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 C5 single dose screen in Hep3B cells 
               
               
                 with GalNAC conjugated iRNAs 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                 10 nM 
                 0.1 nM 
                 10 nM 
                 0.1 nM 
               
               
                   
                 Duplex ID 
                 AVG 
                 AVG 
                 STDEV 
                 STDEV 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 AD-58093.1 
                 15.62 
                 21.60 
                 7.48 
                 6.52 
               
               
                   
                 AD-58099.1 
                 9.07 
                 14.70 
                 1.18 
                 4.65 
               
               
                   
                 AD-58105.1 
                 36.71 
                 60.23 
                 5.07 
                 19.83 
               
               
                   
                 AD-58111.1 
                 11.83 
                 22.78 
                 3.51 
                 12.75 
               
               
                   
                 AD-58117.1 
                 12.43 
                 33.46 
                 2.00 
                 23.56 
               
               
                   
                 AD-58123.1 
                 8.05 
                 15.18 
                 2.89 
                 7.94 
               
               
                   
                 AD-58129.1 
                 10.77 
                 40.06 
                 1.30 
                 19.66 
               
               
                   
                 AD-58088.1 
                 6.55 
                 16.40 
                 1.24 
                 4.58 
               
               
                   
                 AD-58094.1 
                 19.59 
                 40.68 
                 7.64 
                 12.30 
               
               
                   
                 AD-58100.1 
                 10.92 
                 20.12 
                 0.74 
                 8.38 
               
               
                   
                 AD-58106.1 
                 10.97 
                 37.23 
                 2.49 
                 19.95 
               
               
                   
                 AD-58112.1 
                 13.24 
                 29.32 
                 2.90 
                 14.08 
               
               
                   
                 AD-58118.1 
                 6.63 
                 15.23 
                 0.54 
                 5.72 
               
               
                   
                 AD-58124.1 
                 7.17 
                 13.00 
                 1.44 
                 6.48 
               
               
                   
                 AD-58130.1 
                 10.38 
                 17.92 
                 2.36 
                 6.92 
               
               
                   
                 AD-58089.1 
                 8.81 
                 30.67 
                 2.91 
                 10.53 
               
               
                   
                 AD-58095.1 
                 8.72 
                 14.66 
                 1.04 
                 3.37 
               
               
                   
                 AD-58101.1 
                 8.17 
                 19.36 
                 1.30 
                 5.69 
               
               
                   
                 AD-58107.1 
                 4.84 
                 18.10 
                 1.66 
                 7.21 
               
               
                   
                 AD-58113.1 
                 8.78 
                 14.62 
                 1.77 
                 7.89 
               
               
                   
                 AD-58119.1 
                 8.90 
                 15.01 
                 0.91 
                 7.35 
               
               
                   
                 AD-58125.1 
                 11.13 
                 17.04 
                 2.61 
                 9.03 
               
               
                   
                 AD-58131.1 
                 13.50 
                 40.14 
                 1.08 
                 12.07 
               
               
                   
                 AD-58090.1 
                 7.90 
                 21.57 
                 2.95 
                 6.61 
               
               
                   
                 AD-58096.1 
                 8.02 
                 16.56 
                 1.54 
                 6.68 
               
               
                   
                 AD-58102.1 
                 12.40 
                 27.93 
                 1.83 
                 11.78 
               
               
                   
                 AD-58108.1 
                 12.02 
                 15.07 
                 2.88 
                 5.74 
               
               
                   
                 AD-58114.1 
                 11.86 
                 25.05 
                 1.48 
                 9.46 
               
               
                   
                 AD-58120.1 
                 7.65 
                 10.57 
                 0.58 
                 3.56 
               
               
                   
                 AD-58126.1 
                 8.45 
                 15.39 
                 2.08 
                 7.42 
               
               
                   
                 AD-58132.1 
                 8.50 
                 19.26 
                 2.52 
                 9.38 
               
               
                   
                 AD-58091.1 
                 8.68 
                 18.05 
                 2.95 
                 6.62 
               
               
                   
                 AD-58097.1 
                 9.31 
                 23.02 
                 0.67 
                 10.10 
               
               
                   
                 AD-58103.1 
                 8.53 
                 17.23 
                 2.90 
                 7.27 
               
               
                   
                 AD-1955 
                 57.41 
                 81.16 
                 10.76 
                 5.29 
               
               
                   
                 Mock 
                 78.61 
                 75.97 
                 5.70 
                 2.76 
               
               
                   
                 Untreated 
                 100 
                 100 
                 6.13 
                 5.98 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 8 
               
             
            
               
                   
               
               
                 C5 single dose transfection screen in primary 
               
               
                 mouse hepatocytes with GalNAC conjugated iRNAs 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                 10 nM 
                 0.1 nM 
                 10 nM 
                 0.1 nM 
               
               
                   
                 Duplex ID 
                 AVG 
                 AVG 
                 STDEV 
                 STDEV 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 AD-58093.1 
                 1.53 
                 1.65 
                 0.17 
                 0.25 
               
               
                   
                 AD-58099.1 
                 1.65 
                 1.50 
                 0.61 
                 0.22 
               
               
                   
                 AD-58105.1 
                 11.20 
                 46.95 
                 0.08 
                 3.89 
               
               
                   
                 AD-58111.1 
                 2.49 
                 2.13 
                 0.26 
                 0.20 
               
               
                   
                 AD-58117.1 
                 3.57 
                 31.91 
                 0.93 
                 0.62 
               
               
                   
                 AD-58123.1 
                 4.29 
                 2.97 
                 0.11 
                 2.22 
               
               
                   
                 AD-58129.1 
                 1.19 
                 8.53 
                 0.23 
                 0.72 
               
               
                   
                 AD-58088.1 
                 0.84 
                 1.34 
                 0.68 
                 0.07 
               
               
                   
                 AD-58094.1 
                 11.34 
                 66.82 
                 0.17 
                 3.01 
               
               
                   
                 AD-58100.1 
                 2.78 
                 1.51 
                 0.43 
                 0.33 
               
               
                   
                 AD-58106.1 
                 6.79 
                 52.91 
                 4.42 
                 6.78 
               
               
                   
                 AD-58121.1 
                 1.94 
                 2.15 
                 0.04 
                 0.91 
               
               
                   
                 AD-58133.1 
                 1.74 
                 3.25 
                 0.19 
                 1.64 
               
               
                   
                 AD-58116.1 
                 1.76 
                 2.21 
                 1.27 
                 0.78 
               
               
                   
                 AD-1955 
                 87.39 
                 91.71 
                 5.77 
                 4.68 
               
               
                   
                 Mock 
                 79.67 
                 89.02 
                 1.51 
                 3.91 
               
               
                   
                 Untreated 
                 100 
                 100 
                 6.39 
                 13.11 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 9 
               
             
            
               
                   
               
               
                 C5 single dose screen in primary Cynomolgus 
               
               
                 hepatocytes with GalNAC conjugated iRNAs 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                 500 nM 
                 5 nM 
                 500 nM 
                 5 nM 
               
               
                   
                 Duplex ID 
                 AVG 
                 AVG 
                 STDEV 
                 STDEV 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 AD-58093.1 
                 63.94 
                 83.09 
                 2.14 
                 12.65 
               
               
                   
                 AD-58099.1 
                 61.34 
                 85.85 
                 12.32 
                 21.95 
               
               
                   
                 AD-58105.1 
                 91.98 
                 97.57 
                 6.09 
                 11.48 
               
               
                   
                 AD-58111.1 
                 71.27 
                 92.28 
                 1.93 
                 12.72 
               
               
                   
                 AD-58117.1 
                 73.42 
                 88.82 
                 3.24 
                 11.08 
               
               
                   
                 AD-58123.1 
                 75.14 
                 73.06 
                 7.72 
                 9.71 
               
               
                   
                 AD-58129.1 
                 81.66 
                 90.62 
                 2.13 
                 4.77 
               
               
                   
                 AD-58088.1 
                 53.63 
                 87.03 
                 5.93 
                 19.86 
               
               
                   
                 AD-58094.1 
                 89.62 
                 93.65 
                 0.87 
                 14.76 
               
               
                   
                 AD-58100.1 
                 79.56 
                 96.70 
                 4.31 
                 1.10 
               
               
                   
                 AD-58106.1 
                 116.24 
                 125.99 
                 14.28 
                 40.65 
               
               
                   
                 AD-58112.1 
                 97.19 
                 107.81 
                 N/A 
                 3.13 
               
               
                   
                 AD-58118.1 
                 67.40 
                 97.38 
                 5.28 
                 22.64 
               
               
                   
                 AD-58124.1 
                 58.04 
                 96.14 
                 8.72 
                 10.64 
               
               
                   
                 AD-58130.1 
                 84.19 
                 88.65 
                 10.50 
                 4.34 
               
               
                   
                 AD-58089.1 
                 83.83 
                 83.44 
                 1.91 
                 12.26 
               
               
                   
                 AD-58095.1 
                 58.53 
                 78.02 
                 15.07 
                 12.45 
               
               
                   
                 AD-58101.1 
                 76.68 
                 76.73 
                 3.95 
                 6.35 
               
               
                   
                 AD-58107.1 
                 57.37 
                 86.78 
                 14.71 
                 2.99 
               
               
                   
                 AD-58113.1 
                 37.79 
                 71.10 
                 8.27 
                 7.76 
               
               
                   
                 AD-58119.1 
                 36.77 
                 83.16 
                 3.42 
                 9.66 
               
               
                   
                 AD-58125.1 
                 72.40 
                 96.53 
                 4.46 
                 4.96 
               
               
                   
                 AD-58131.1 
                 95.58 
                 101.69 
                 10.17 
                 2.21 
               
               
                   
                 AD-58090.1 
                 56.37 
                 75.00 
                 3.21 
                 4.97 
               
               
                   
                 AD-58096.1 
                 44.33 
                 57.99 
                 11.46 
                 25.17 
               
               
                   
                 AD-58102.1 
                 95.46 
                 89.35 
                 0.83 
                 1.76 
               
               
                   
                 AD-58108.1 
                 41.54 
                 56.41 
                 8.41 
                 0.14 
               
               
                   
                 AD-58114.1 
                 88.32 
                 101.88 
                 20.02 
                 30.29 
               
               
                   
                 AD-58120.1 
                 37.34 
                 56.41 
                 0.73 
                 2.14 
               
               
                   
                 AD-58126.1 
                 84.97 
                 105.90 
                 2.39 
                 7.96 
               
               
                   
                 AD-58132.1 
                 81.55 
                 85.12 
                 12.93 
                 8.94 
               
               
                   
                 AD-58091.1 
                 78.88 
                 84.60 
                 44.66 
                 17.40 
               
               
                   
                 AD-58097.1 
                 106.06 
                 98.16 
                 13.74 
                 3.14 
               
               
                   
                 AD-58103.1 
                 57.21 
                 89.46 
                 6.40 
                 5.93 
               
               
                   
                 Untreated 
                 100 
                 100 
                 8.77 
                 10.33 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 10 
               
             
            
               
                   
               
               
                 C5 single dose free uptake screen in primary mouse 
               
               
                 hepatocytes with GalNAC conjugated iRNAs 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                 500 nM 
                 5 nM 
                 500 nM 
                 5 nM 
               
               
                   
                 Duplex ID 
                 AVG 
                 AVG 
                 STDEV 
                 STDEV 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 AD-58093.1 
                 31.62 
                 64.91 
                 7.13 
                 8.39 
               
               
                   
                 AD-58099.1 
                 9.46 
                 29.63 
                 1.29 
                 5.66 
               
               
                   
                 AD-58105.1 
                 84.77 
                 96.41 
                 5.22 
                 1.89 
               
               
                   
                 AD-58111.1 
                 17.35 
                 50.95 
                 1.21 
                 3.16 
               
               
                   
                 AD-58117.1 
                 94.95 
                 139.52 
                 15.43 
                 43.39 
               
               
                   
                 AD-58123.1 
                 13.07 
                 44.58 
                 2.11 
                 3.49 
               
               
                   
                 AD-58129.1 
                 68.87 
                 85.04 
                 2.62 
                 4.42 
               
               
                   
                 AD-58088.1 
                 17.61 
                 48.22 
                 2.22 
                 3.40 
               
               
                   
                 AD-58094.1 
                 95.92 
                 104.23 
                 4.16 
                 6.53 
               
               
                   
                 AD-58100.1 
                 34.92 
                 61.71 
                 1.30 
                 2.15 
               
               
                   
                 AD-58106.1 
                 85.26 
                 107.53 
                 2.30 
                 3.38 
               
               
                   
                 AD-58121.1 
                 12.88 
                 43.76 
                 1.41 
                 1.28 
               
               
                   
                 AD-58133.1 
                 20.97 
                 42.76 
                 0.24 
                 0.11 
               
               
                   
                 AD-58116.1 
                 8.35 
                 38.04 
                 1.35 
                 1.40 
               
               
                   
                 Untreated 
                 100.00 
                 100.00 
                 3.85 
                 4.38 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 11 
               
             
            
               
                   
               
               
                 IC 50  data in primary Cynomolgus hepatocytes 
               
               
                 with GalNAC conjugated iRNAs 
               
            
           
           
               
               
               
               
            
               
                   
                 Duplex ID 
                 IC 50  (nM) 
                 STDEV 
               
               
                   
                   
               
            
           
           
               
               
               
               
            
               
                   
                 AD-58099.1 
                 3.131 
                 1.141 
               
               
                   
                 AD-58111.1 
                 12.750 
                 5.280 
               
               
                   
                 AD-58123.1 
                 0.679 
                 7.587 
               
               
                   
                 AD-58088.1 
                 0.218 
                 3.487 
               
               
                   
                 AD-58113.1 
                 7.296 
                 3.540 
               
               
                   
                 AD-58119.1 
                 33.240 
                 14.740 
               
               
                   
                 AD-58096.1 
                 10.380 
                 4.199 
               
               
                   
                 AD-58108.1 
                 0.953 
                 10.080 
               
               
                   
                 AD-58120.1 
                 36.170 
                 88.070 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 12 
               
             
            
               
                   
               
               
                 IC 50  data in primary mouse hepatocytes 
               
               
                 with GalNAC conjugated iRNAs 
               
            
           
           
               
               
               
               
            
               
                   
                 Duplex ID 
                 IC 50  (nM) 
                 STDEV 
               
               
                   
                   
               
            
           
           
               
               
               
               
            
               
                   
                 AD-58099 
                 3.777 
                 0.122 
               
               
                   
                 AD-58111 
                 0.622 
                 2.421 
               
               
                   
                 AD-58123 
                 0.549 
                 1.626 
               
               
                   
                 AD-58088 
                 9.513 
                 2.588 
               
               
                   
                 AD-58121 
                 2.169 
                 1.176 
               
               
                   
                 AD-58133 
                 3.802 
                 1.006 
               
               
                   
                 AD-58116 
                 2.227 
                 0.604 
               
               
                   
                 AD-58644.1 
                 4.596 
                 0.3506 
               
               
                   
                 AD-58651.1 
                 59.76 
                 51.99 
               
               
                   
                 AD-58641.1 
                 0.82 
                 0.2618 
               
               
                   
                 AD-58648.1 
                 7.031 
                 1.256 
               
               
                   
                 AD-58642.1 
                 0.5414 
                 0.7334 
               
               
                   
                 AD-58649.1 
                 3.32 
                 4.922 
               
               
                   
                 AD-58647.1 
                 1.356 
                 0.5215 
               
               
                   
                 AD-58654.1 
                 2.09 
                 0.8338 
               
               
                   
                 AD-58645.1 
                 2.944 
                 0.3315 
               
               
                   
                 AD-58652.1 
                 5.316 
                 2.477 
               
               
                   
                 AD-58643.1 
                 2.179 
                 1.112 
               
               
                   
                 AD-58650.1 
                 8.223 
                 3.76 
               
               
                   
                 AD-58646.1 
                 2.581 
                 0.8186 
               
               
                   
                 AD-58653.1 
                 2.451 
                 1.249 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 13 
               
             
            
               
                   
               
               
                 C5 single dose screen in Hep3B cells 
               
               
                 with modified and unmodified iRNAs 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                 1 nM 
                 0.01 nM 
                 1 nM 
                 0.01 nM 
               
               
                   
                 Duplex 
                 AVG 
                 AVG 
                 STDEV 
                 STDEV 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 AD-58143.1 
                 12.13 
                 100.58 
                 3.47 
                 3.94 
               
               
                   
                 AD-58149.1 
                 10.46 
                 64.97 
                 0.98 
                 0.00 
               
               
                   
                 AD-58155.1 
                 44.88 
                 76.24 
                 1.56 
                 3.74 
               
               
                   
                 AD-58161.1 
                 8.51 
                 102.30 
                 1.06 
                 0.50 
               
               
                   
                 AD-58167.1 
                 6.54 
                 76.24 
                 1.15 
                 3.74 
               
               
                   
                 AD-58173.1 
                 6.85 
                 107.44 
                 0.85 
                 4.74 
               
               
                   
                 AD-58179.1 
                 10.19 
                 78.07 
                 0.59 
                 1.15 
               
               
                   
                 AD-58185.1 
                 29.46 
                 79.99 
                 3.64 
                 0.78 
               
               
                   
                 AD-58144.1 
                 16.82 
                 81.95 
                 1.09 
                 0.40 
               
               
                   
                 AD-58150.1 
                 11.05 
                 76.20 
                 2.55 
                 0.00 
               
               
                   
                 AD-58156.1 
                 25.92 
                 76.73 
                 2.72 
                 1.50 
               
               
                   
                 AD-58162.1 
                 13.25 
                 71.89 
                 0.43 
                 3.87 
               
               
                   
                 AD-58168.1 
                 9.74 
                 45.16 
                 0.52 
                 1.11 
               
               
                   
                 AD-58174.1 
                 4.84 
                 70.14 
                 0.25 
                 2.75 
               
               
                   
                 AD-58180.1 
                 9.41 
                 56.77 
                 1.91 
                 1.95 
               
               
                   
                 AD-58186.1 
                 9.97 
                 68.91 
                 1.03 
                 0.34 
               
               
                   
                 AD-58145.1 
                 14.29 
                 103.38 
                 1.94 
                 2.03 
               
               
                   
                 AD-58151.1 
                 10.16 
                 81.17 
                 1.71 
                 4.77 
               
               
                   
                 AD-58157.1 
                 4.72 
                 63.19 
                 1.05 
                 0.00 
               
               
                   
                 AD-58163.1 
                 4.95 
                 40.13 
                 1.65 
                 0.59 
               
               
                   
                 AD-58169.1 
                 17.02 
                 83.10 
                 1.88 
                 2.04 
               
               
                   
                 AD-58175.1 
                 8.30 
                 62.54 
                 0.28 
                 0.31 
               
               
                   
                 AD-58181.1 
                 21.89 
                 55.26 
                 4.22 
                 3.52 
               
               
                   
                 AD-58187.1 
                 61.96 
                 71.12 
                 2.61 
                 2.79 
               
               
                   
                 AD-58146.1 
                 14.25 
                 95.23 
                 2.64 
                 6.53 
               
               
                   
                 AD-58152.1 
                 11.22 
                 70.09 
                 0.80 
                 7.88 
               
               
                   
                 AD-58158.1 
                 7.96 
                 98.86 
                 0.76 
                 4.36 
               
               
                   
                 AD-58164.1 
                 11.60 
                 43.83 
                 2.06 
                 3.43 
               
               
                   
                 AD-58170.1 
                 12.28 
                 39.59 
                 0.96 
                 1.36 
               
               
                   
                 AD-58176.1 
                 6.89 
                 38.77 
                 1.04 
                 1.33 
               
               
                   
                 AD-58182.1 
                 18.65 
                 55.78 
                 0.96 
                 0.55 
               
               
                   
                 AD-58188.1 
                 5.40 
                 69.39 
                 1.07 
                 0.34 
               
               
                   
                 AD-58147.1 
                 8.22 
                 106.66 
                 0.77 
                 2.61 
               
               
                   
                 AD-58153.1 
                 68.10 
                 104.17 
                 4.44 
                 18.29 
               
               
                   
                 AD-58159.1 
                 8.76 
                 81.41 
                 1.54 
                 2.79 
               
               
                   
                 AD-58190.1 
                 21.94 
                 77.26 
                 2.23 
                 0.76 
               
               
                   
                 AD-58196.1 
                 15.97 
                 72.43 
                 1.07 
                 5.32 
               
               
                   
                 AD-58202.1 
                 11.99 
                 93.83 
                 5.34 
                 2.76 
               
               
                   
                 AD-58208.1 
                 18.63 
                 52.07 
                 12.88 
                 2.55 
               
               
                   
                 AD-58214.1 
                 6.85 
                 94.15 
                 0.51 
                 2.31 
               
               
                   
                 AD-58220.1 
                 11.50 
                 78.34 
                 3.85 
                 0.77 
               
               
                   
                 AD-58226.1 
                 5.77 
                 57.75 
                 1.71 
                 1.13 
               
               
                   
                 AD-58231.1 
                 7.23 
                 75.67 
                 1.07 
                 0.74 
               
               
                   
                 AD-58191.1 
                 35.40 
                 66.17 
                 5.50 
                 4.21 
               
               
                   
                 AD-58197.1 
                 12.05 
                 67.49 
                 1.70 
                 0.33 
               
               
                   
                 AD-58203.1 
                 15.16 
                 66.80 
                 1.46 
                 1.31 
               
               
                   
                 AD-58209.1 
                 7.58 
                 71.23 
                 3.58 
                 6.28 
               
               
                   
                 AD-58233.1 
                 27.01 
                 86.02 
                 0.86 
                 0.42 
               
               
                   
                 AD-58193.1 
                 15.37 
                 99.85 
                 1.44 
                 0.00 
               
               
                   
                 AD-58199.1 
                 21.52 
                 78.39 
                 6.02 
                 16.40 
               
               
                   
                 AD-58205.1 
                 24.13 
                 78.88 
                 5.46 
                 0.77 
               
               
                   
                 AD-58211.1 
                 16.38 
                 32.37 
                 2.61 
                 0.48 
               
               
                   
                 AD-58217.1 
                 12.23 
                 70.16 
                 0.29 
                 3.44 
               
               
                   
                 AD-58223.1 
                 8.51 
                 72.85 
                 3.01 
                 1.79 
               
               
                   
                 AD-58229.1 
                 5.50 
                 75.93 
                 1.96 
                 0.37 
               
               
                   
                 AD-58234.1 
                 46.86 
                 101.94 
                 15.59 
                 0.00 
               
               
                   
                 AD-58194.1 
                 14.49 
                 107.05 
                 2.47 
                 4.20 
               
               
                   
                 AD-58200.1 
                 16.21 
                 61.04 
                 0.96 
                 1.20 
               
               
                   
                 AD-58206.1 
                 13.25 
                 37.73 
                 2.82 
                 2.03 
               
               
                   
                 AD-58236.1 
                 8.29 
                 119.17 
                 1.16 
                 2.92 
               
               
                   
                 AD-58242.1 
                 12.05 
                 102.69 
                 0.44 
                 4.03 
               
               
                   
                 AD-58248.1 
                 62.78 
                 83.41 
                 15.22 
                 3.27 
               
               
                   
                 AD-58254.1 
                 11.18 
                 100.54 
                 1.59 
                 0.00 
               
               
                   
                 AD-58260.1 
                 8.42 
                 71.84 
                 1.10 
                 0.35 
               
               
                   
                 AD-58266.1 
                 14.05 
                 92.21 
                 1.91 
                 2.26 
               
               
                   
                 AD-58272.1 
                 22.63 
                 81.11 
                 1.62 
                 1.59 
               
               
                   
                 AD-58277.1 
                 70.51 
                 75.67 
                 4.80 
                 0.74 
               
               
                   
                 AD-58237.1 
                 28.10 
                 98.56 
                 1.96 
                 5.79 
               
               
                   
                 AD-58243.1 
                 14.16 
                 86.05 
                 1.11 
                 2.95 
               
               
                   
                 AD-58249.1 
                 77.08 
                 96.45 
                 15.14 
                 0.95 
               
               
                   
                 AD-58255.1 
                 12.27 
                 47.89 
                 2.58 
                 0.00 
               
               
                   
                 AD-58279.1 
                 25.78 
                 94.13 
                 5.52 
                 0.46 
               
               
                   
                 AD-58239.1 
                 22.98 
                 83.45 
                 0.28 
                 4.91 
               
               
                   
                 AD-58245.1 
                 89.60 
                 90.93 
                 15.24 
                 0.45 
               
               
                   
                 AD-58251.1 
                 28.39 
                 86.32 
                 7.29 
                 0.00 
               
               
                   
                 AD-58257.1 
                 48.97 
                 64.53 
                 9.10 
                 1.90 
               
               
                   
                 AD-58263.1 
                 9.14 
                 83.39 
                 1.27 
                 1.63 
               
               
                   
                 AD-58269.1 
                 83.84 
                 75.94 
                 15.90 
                 1.12 
               
               
                   
                 AD-58275.1 
                 10.29 
                 86.32 
                 0.73 
                 0.85 
               
               
                   
                 AD-58280.1 
                 72.77 
                 110.04 
                 7.44 
                 3.24 
               
               
                   
                 AD-58240.1 
                 65.42 
                 75.69 
                 3.82 
                 2.23 
               
               
                   
                 AD-58246.1 
                 59.19 
                 65.88 
                 28.95 
                 0.65 
               
               
                   
                 AD-58252.1 
                 15.35 
                 97.26 
                 1.14 
                 7.62 
               
               
                   
                 Mock 
                 76.53 
                 66.57 
                 14.26 
                 4.72 
               
               
                   
                 AD-1955 
                 72.30 
                 82.72 
                 19.54 
                 49.99 
               
               
                   
                 Untreated 
                 100.00 
                 100.00 
                 21.68 
                 26.78 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 14 
               
             
            
               
                   
               
               
                 C5 single dose screen in primary mouse hepatocytes 
               
               
                 with modified and unmodified iRNAs 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                 1 nM 
                 0.1 nM 
                 1 nM 
                 0.1 nM 
               
               
                   
                 Duplex ID 
                 AVG 
                 AVG 
                 STDEV 
                 STDEV 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 AD-58143.1 
                 4.51 
                 81.77 
                 3.13 
                 8.75 
               
               
                   
                 AD-58149.1 
                 4.65 
                 73.16 
                 3.14 
                 20.17 
               
               
                   
                 AD-58155.1 
                 65.56 
                 79.74 
                 4.66 
                 9.36 
               
               
                   
                 AD-58161.1 
                 16.82 
                 81.11 
                 6.22 
                 7.43 
               
               
                   
                 AD-58167.1 
                 4.72 
                 77.12 
                 1.17 
                 14.25 
               
               
                   
                 AD-58173.1 
                 5.57 
                 76.00 
                 3.14 
                 13.52 
               
               
                   
                 AD-58179.1 
                 14.55 
                 77.88 
                 1.44 
                 18.40 
               
               
                   
                 AD-58185.1 
                 15.69 
                 72.59 
                 8.67 
                 7.81 
               
               
                   
                 AD-58144.1 
                 8.70 
                 91.49 
                 0.90 
                 7.08 
               
               
                   
                 AD-58150.1 
                 12.51 
                 84.01 
                 1.64 
                 8.20 
               
               
                   
                 AD-58156.1 
                 18.23 
                 97.32 
                 1.47 
                 19.50 
               
               
                   
                 AD-58162.1 
                 7.72 
                 78.89 
                 5.19 
                 13.80 
               
               
                   
                 AD-58190.1 
                 11.86 
                 92.80 
                 2.82 
                 4.41 
               
               
                   
                 AD-58196.1 
                 7.27 
                 82.71 
                 1.39 
                 31.81 
               
               
                   
                 AD-58202.1 
                 10.67 
                 87.11 
                 1.04 
                 35.79 
               
               
                   
                 AD-58208.1 
                 32.21 
                 74.39 
                 8.60 
                 27.45 
               
               
                   
                 AD-58214.1 
                 4.24 
                 67.63 
                 0.45 
                 17.85 
               
               
                   
                 AD-58220.1 
                 13.64 
                 96.14 
                 4.56 
                 14.36 
               
               
                   
                 AD-58226.1 
                 3.83 
                 63.44 
                 1.30 
                 11.94 
               
               
                   
                 AD-58231.1 
                 5.95 
                 82.24 
                 2.80 
                 17.36 
               
               
                   
                 AD-58191.1 
                 14.50 
                 99.50 
                 5.48 
                 5.53 
               
               
                   
                 AD-58197.1 
                 16.12 
                 93.09 
                 0.81 
                 3.21 
               
               
                   
                 AD-58203.1 
                 12.52 
                 104.63 
                 5.98 
                 6.02 
               
               
                   
                 AD-58209.1 
                 8.79 
                 59.35 
                 3.05 
                 13.07 
               
               
                   
                 AD-58233.1 
                 9.50 
                 64.26 
                 5.69 
                 8.70 
               
               
                   
                 AD-58193.1 
                 8.88 
                 89.60 
                 3.36 
                 3.08 
               
               
                   
                 AD-58199.1 
                 13.56 
                 87.14 
                 2.18 
                 6.44 
               
               
                   
                 AD-58205.1 
                 46.84 
                 89.13 
                 4.48 
                 17.16 
               
               
                   
                 AD-58211.1 
                 13.10 
                 111.62 
                 1.10 
                 21.54 
               
               
                   
                 AD-58217.1 
                 29.79 
                 117.49 
                 11.85 
                 20.41 
               
               
                   
                 AD-58223.1 
                 20.53 
                 105.44 
                 1.94 
                 2.98 
               
               
                   
                 AD-58229.1 
                 13.76 
                 98.15 
                 1.05 
                 9.03 
               
               
                   
                 AD-58234.1 
                 12.33 
                 71.34 
                 0.72 
                 4.17 
               
               
                   
                 AD-58194.1 
                 14.02 
                 90.60 
                 1.39 
                 15.64 
               
               
                   
                 AD-58200.1 
                 5.25 
                 90.95 
                 1.37 
                 31.70 
               
               
                   
                 AD-58206.1 
                 8.19 
                 109.47 
                 3.99 
                 21.75 
               
               
                   
                 AD-58236.1 
                 2.07 
                 70.19 
                 0.80 
                 20.59 
               
               
                   
                 AD-58242.1 
                 4.76 
                 53.26 
                 1.59 
                 11.56 
               
               
                   
                 AD-58248.1 
                 62.42 
                 78.23 
                 5.47 
                 25.85 
               
               
                   
                 AD-58254.1 
                 16.47 
                 70.22 
                 2.92 
                 21.74 
               
               
                   
                 AD-58260.1 
                 2.84 
                 75.65 
                 0.38 
                 11.59 
               
               
                   
                 AD-58266.1 
                 40.70 
                 89.88 
                 16.05 
                 11.57 
               
               
                   
                 AD-58272.1 
                 21.42 
                 59.44 
                 13.29 
                 10.98 
               
               
                   
                 AD-58277.1 
                 71.72 
                 121.44 
                 16.35 
                 21.16 
               
               
                   
                 AD-58237.1 
                 11.85 
                 112.68 
                 9.22 
                 12.88 
               
               
                   
                 AD-58243.1 
                 10.46 
                 90.64 
                 3.42 
                 4.33 
               
               
                   
                 AD-58249.1 
                 71.47 
                 113.30 
                 4.30 
                 3.84 
               
               
                   
                 AD-58255.1 
                 6.86 
                 78.55 
                 2.22 
                 28.37 
               
               
                   
                 AD-58279.1 
                 7.15 
                 74.96 
                 2.84 
                 4.72 
               
               
                   
                 AD-58239.1 
                 13.64 
                 106.45 
                 1.87 
                 8.25 
               
               
                   
                 AD-58245.1 
                 68.67 
                 112.08 
                 21.89 
                 7.73 
               
               
                   
                 AD-58251.1 
                 47.01 
                 133.20 
                 4.69 
                 7.14 
               
               
                   
                 AD-58257.1 
                 30.68 
                 87.51 
                 2.87 
                 32.84 
               
               
                   
                 AD-58263.1 
                 7.22 
                 83.23 
                 2.55 
                 37.50 
               
               
                   
                 AD-58269.1 
                 78.90 
                 106.06 
                 5.07 
                 3.04 
               
               
                   
                 AD-58275.1 
                 8.92 
                 95.77 
                 1.91 
                 7.14 
               
               
                   
                 AD-58280.1 
                 16.67 
                 78.47 
                 4.15 
                 6.06 
               
               
                   
                 AD-58240.1 
                 71.03 
                 138.54 
                 5.32 
                 10.87 
               
               
                   
                 AD-58246.1 
                 71.87 
                 89.02 
                 4.95 
                 8.63 
               
               
                   
                 AD-58252.1 
                 4.04 
                 56.10 
                 1.23 
                 12.02 
               
               
                   
                 Mock 
                 66.84 
                 82.81 
                 2.75 
                 17.19 
               
               
                   
                 AD-1955 
                 87.44 
                 102.07 
                 3.64 
                 4.08 
               
               
                   
                 Untreated 
                 100.00 
                 100.00 
                 15.25 
                 18.37 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 15 
               
             
            
               
                   
               
               
                 IC 50  data in Hep3B cells with modified and unmodified iRNAs 
               
            
           
           
               
               
               
               
            
               
                   
                 Duplex ID 
                 IC 50  (pM) 
                 STDEV 
               
               
                   
                   
               
            
           
           
               
               
               
               
            
               
                   
                 AD-58143.1 
                 36.35 
                 12.26 
               
               
                   
                 AD-58149.1 
                 5.735 
                 6.196 
               
               
                   
                 AD-58161.1 
                 78.12 
                 26.64 
               
               
                   
                 AD-58167.1 
                 31.03 
                 18.14 
               
               
                   
                 AD-58173.1 
                 29.12 
                 16.53 
               
               
                   
                 AD-58236.1 
                 52.73 
                 32.02 
               
               
                   
                 AD-58242.1 
                 8.859 
                 4.321 
               
               
                   
                 AD-58260.1 
                 7.706 
                 5.094 
               
               
                   
                 AD-58263.1 
                 96.64 
                 47.61 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 16 
               
             
            
               
                   
               
               
                 IC 50  data in primary mouse hepatocytes 
               
               
                 with modified and unmodified iRNAs 
               
            
           
           
               
               
               
               
            
               
                   
                 Duplex ID 
                 IC 50  (pM) 
                 STDEV 
               
               
                   
                   
               
            
           
           
               
               
               
               
            
               
                   
                 AD-58260.1 
                 1.015 
                 0.9676 
               
               
                   
                 AD-58149.1 
                 1.309 
                 1.749 
               
               
                   
                 AD-58167.1 
                 1.991 
                 2.477 
               
               
                   
                 AD-58242.1 
                 0.5866 
                 1.8 
               
               
                   
                 AD-58236.1 
                 0.4517 
                 0.06392 
               
               
                   
                 AD-58143.1 
                 0.8876 
                 0.1613 
               
               
                   
                 AD-58279.1 
                 3.116 
                 0.7368 
               
               
                   
                 AD-58252.1 
                 7.153 
                 1.021 
               
               
                   
                 AD-58173.1 
                 7.144 
                 19.88 
               
               
                   
                 AD-58263.1 
                 3.224 
                 5.478 
               
               
                   
                   
               
            
           
         
       
     
     Example 3. In Vivo Screening 
     A subset of seven GalNAC conjugated iRNAs was selected for further in vivo evaluation. 
     C57BL/6 mice (N=3 per group) were injected subcutaneously with 10 mg/kg of GalNAc conjugated duplexes or an equal volume of 1× Dulbecco&#39;s Phosphate-Buffered Saline (DPBS) (Life Technologies, Cat #14040133). Forty-eight hours later, mice were euthanized and the livers were dissected and flash frozen in liquid nitrogen. Livers were ground in a 2000 Geno/Grinder (SPEX SamplePrep, Metuchen, N.J.). Approximately 10 mg of liver powder per sample was used for RNA isolation. Samples were first homogenized in a TissueLyserII (Qiagen Inc, Valencia, Calif.) and then RNA was extracted using a RNeasy 96 Universal Tissue Kit (Qiagen Inc, Cat #74881) following manufacturer&#39;s protocol using vacuum/spin technology. RNA concentration was measured by a NanoDrop 8000 (Thermo Scientific, Wilmington, Del.) and was adjusted to 100 ng/μ1. cDNA and RT-PCR were performed as described above. 
     The results of the single dose screen are depicted in  FIG. 2 . Table 17 shows the results of an in vivo single dose screen with the indicated GalNAC conjugated modified iRNAs. Data are expressed as percent of mRNA remaining relative to DPBS treated mice. The “Experiments” column lists the number of experiments from which the average was calculated. The standard deviation is calculated from all mice in a group across all experiments analyzed. 
     
       
         
           
               
             
               
                 TABLE 17 
               
             
            
               
                   
               
               
                 In vivo C5 single dose screen 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Duplex ID 
                 Experiments 
                 AVG 
                 STDEV 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 AD-58088.2 
                 2 
                 82.66 
                 13.54 
               
               
                   
                 AD-58644.1 
                 1 
                 37.79 
                 9.63 
               
               
                   
                 AD-58651.1 
                 1 
                 75.33 
                 5.21 
               
               
                   
                 AD-58099.2 
                 2 
                 71.94 
                 15.45 
               
               
                   
                 AD-58641.1 
                 1 
                 20.09 
                 4.09 
               
               
                   
                 AD-58648.1 
                 1 
                 48.43 
                 9.07 
               
               
                   
                 AD-58111.2 
                 3 
                 67.17 
                 13.60 
               
               
                   
                 AD-58642.1 
                 2 
                 21.78 
                 5.32 
               
               
                   
                 AD-58649.1 
                 1 
                 45.30 
                 14.02 
               
               
                   
                 AD-58116.2 
                 2 
                 70.16 
                 10.32 
               
               
                   
                 AD-58647.1 
                 1 
                 26.77 
                 4.14 
               
               
                   
                 AD-58654.1 
                 1 
                 50.06 
                 27.85 
               
               
                   
                 AD-58121.2 
                 2 
                 52.56 
                 13.00 
               
               
                   
                 AD-58645.1 
                 1 
                 24.60 
                 1.29 
               
               
                   
                 AD-58652.1 
                 1 
                 52.67 
                 3.87 
               
               
                   
                 AD-58123.2 
                 2 
                 65.70 
                 9.60 
               
               
                   
                 AD-58643.1 
                 1 
                 23.21 
                 2.41 
               
               
                   
                 AD-58650.1 
                 1 
                 46.75 
                 14.10 
               
               
                   
                 AD-58133.2 
                 3 
                 51.98 
                 13.45 
               
               
                   
                 AD-58646.1 
                 2 
                 28.67 
                 5.34 
               
               
                   
                 AD-58653.1 
                 1 
                 43.02 
                 10.61 
               
               
                   
                 PBS 
                 3 
                 100.00 
                 9.03 
               
               
                   
                   
               
            
           
         
       
     
     Two of the most efficacious GalNAC conjugated iRNAs were further modified to include additional phosphorothioate linkages (Table 18) and the efficacy of these duplexes was determined in vivo as described above. The results of the single dose screen are depicted in  FIG. 3  and demonstrate that the iRNA agents with additional phosphorothiate linkages are more efficacious than those iRNA agents without or with fewer phosphorothioate linkages. 
     
       
         
           
               
             
               
                 TABLE 18 
               
             
            
               
                   
               
               
                 Phosphorothioate Modifed GalNAC Conjugated C5 iRNAs 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                 SEQ 
                   
                   
                 SEQ 
                   
               
               
                   
                 Sense 
                   
                 ID 
                   
                   
                 ID 
                   
               
               
                 Duple ID 
                 strand 
                 Sense sequence 
                 NO: 
                 Antisense 
                 Antisense sequence 
                 NO: 
                 Cross Reactivity 
               
               
                   
               
               
                 AD-58642.1 
                 A-119324.1 
                 
                   GfsasCfaAfaAfuAfAfC 
                 
                 551 
                 A-119325.1 
                 
                   asUfsuAfuAfgUfgAfg 
                 
                 555 
                 HumRheMusRat 
               
               
                   
                   
                 
                   fuCfaCfuAfuAfaUfL96 
                 
                   
                   
                 
                   uuAfuUfuUfgUfcsasa 
                 
                   
                   
               
               
                   
               
               
                 AD-58111.2 
                 A-118316.1 
                 
                   GfaCfaAfaAfuAfAfCfu 
                 
                 552 
                 A-118317.1 
                 
                   aUfuAfuAfgUfgAfguu 
                 
                 556 
                 HumRheMusRat 
               
               
                   
                   
                 
                   CfaCfuAfuAfaUfL96 
                 
                   
                   
                 
                   AfuUfuUfgUfcsAfsa 
                 
                   
                   
               
               
                   
               
               
                 AD-58646.1 
                 A-119332.1 
                 
                   CfsasGfaUfcAfaAfCfA 
                 
                 553 
                 A-119333.1 
                 
                   asCfsuGfaAfaUfuGfu 
                 
                 557 
                 MusRat 
               
               
                   
                   
                 
                   fcAfaUfuUfcAfgUfL96 
                 
                   
                   
                 
                   guUfuGfaUfcUfgscsa 
                 
                   
                   
               
               
                   
               
               
                 AD-58133.2 
                 A-118386.1 
                 
                   CfaGfaUfcAfaAfCfAfc 
                 
                 554 
                 A-118387.1 
                 
                   aCfuGfaAfaUfuGfugu 
                 
                 558 
                 MusRat 
               
               
                   
                   
                 
                   AfaUfuUfcAfgUfL96 
                 
                   
                   
                 
                   UfuGfaUfcUfgsCfsa 
                 
                   
                   
               
               
                   
               
            
           
         
       
     
     Given the impact of the additional phosphorothioate linkages on the silencing ability of the iRNA agents described above, the efficacy of additional GalNAC conjugated iRNA duplexes including phosphorothioate linkages (Table 19) was determined in vivo as described above. The results of this single dose screen are depicted in  FIG. 4 . 
     The duration of silencing of AD-58642 in vivo was determined by administering a single 2.5 mg/kg, 10 mg/kg, or 25 mg/kg dose to rats and determining the amount of C5 protein ( FIG. 5B ) present on day 7 and the activity of C5 protein ( FIG. 5A ) present on days 4 and 7. As demonstrated in  FIG. 5 , there is a 50% reduction in the activity of C5 protein by Day 4 at a 25 mg/kg dose and at Day 7, a greater than 70% reduction in the activity of C5 protein. 
     The amount of C5 protein was determined by Western blot analysis of whole serum. The activity of C5 protein was determined by a hemolysis assay. Briefly, a fixed dilution of human C5 depleted human serum was mixed with mouse serum and incubated with antibody-coated sheep red blood cells for 1 hour. The hemoglobin absorbance was measured and the % hemolysis as compared to a reference curve (prepared using a dilution series of mouse serum) was calculated. 
     The efficacy of AD-58642 in vivo was also assayed in mice following a single subcutaneous injection of 1.25 mg/kg, 2.5 mg/kg, 5 mg/kg, 10 mg/kg, and 25 mg/kg of AD-58642. At day 5 C5 mRNA was assayed in liver samples using qPCR, C5 activity was assayed for hemolysis, and the amount of C5 protein was determined by Western blot analysis of whole serum. 
     As depicted in  FIGS. 6A and 6B , although there is only a minor improvement (i.e., about 5%) in efficacy of AD-58642 to inhibit C5 mRNA at a dose of 25 mg/kg as compared to a 10 mg/kg dose, there is an average of 85% silencing with a 25 mg/kg dose. In addition, there is a dose response effect with an IC 50  of about 2.5 mg/kg. 
       FIGS. 7A and 7B and 8  demonstrate that AD-58642 is efficacious for decreasing the amount of C5 protein ( FIG. 8 ) and C5 protein activity ( FIGS. 7A and 7B ). 
     The duration of silencing of AD-58641 in vivo was also determined by subcutaneously administering a single 0.625 mg/kg, 1.25 mg/kg, 2.5 mg/kg, 5.0 mg/kg, or 10 mg/kg dose of AD-58641 to C57Bl/6 (n=3) mice and determining the amount of C5 protein present in these animals on days 5 and 9 by ELISA. Briefly, serum was collected on day 0, pre-bleed, day 5, and day 9 and the levels of C5 proteins were quantified by ELISA. C5 protein levels were normalized to the day 0 pre-bleed level. As depicted in  FIG. 9 , the results demonstrate that there is a dose dependent potent and durable knock-down of C5 serum protein. (The single dose ED 50  was 0.6 mg/kg). 
     Compound AD-58641 was also tested for efficacy in C57Bl/6 mice using a multi-dosing administration protocol. Mice were subcutaneously administered compound AD-58641 at a 0.625 mg/kg, 1.25 mg/kg, or 2.5 mg/kg dose at days 0, 1, 2, and 3. Serum was collected at days 0 and 8 as illustrated in  FIG. 10  and analyzed for C5 protein levels by ELISA. C5 levels were normalized to the day 0 pre-bleed level.  FIG. 10  shows that multi-dosing of AD-58641 achieves silencing of C5 protein at all of the does tested, with a greater than 90% silencing of C5 protein at a dose of 2.5 mg/kg. 
     Compound AD-58641 was further tested for efficacy and to evaluate the cumulative effect of the compound in rats using a repeat administration protocol. Wild-type Sprague Dawley rats were subcutaneously injected with compound AD-58641 at a 2.5 mg/kg/dose or 5.0 mg/kg/dose twice a week for 3 weeks (q2w×3). Serum was collected on days 0, 4, 7, 11, 14, 18, 25, and 32. Serum hemolytic activity was quantified using a hemolysis assay in which a 1:150 dilution of rat serum was incubated with sensitized sheep rat blood cells in GVB++ buffer for 1 hour and hemoglobin release was quantified by measuring absorbance at 415 nm (see  FIG. 11A ). The amount of C5 protein present in the samples was also determined by ELISA ( FIG. 11B ). The results demonstrate a dose dependent potent and durable decrease in hemolytic activity, achieving about 90% hemolytic activity inhibition. 
     
       
         
           
               
             
               
                 TABLE 19 
               
             
            
               
                   
               
               
                 Additional Phosphorothioate Modifed GalNAC Conjugated CS iRNAs 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                 SEQ 
                   
                   
                 SEQ 
                   
                   
                   
               
               
                   
                 Sense 
                   
                 ID 
                   
                   
                 ID 
                 Start  
                 Cross 
                 PS 
               
               
                 Duplex ID 
                 strand 
                 Sense sequence 
                 NO: 
                 Antisense 
                 Antisense sequence 
                 NO: 
                 position 
                 Reactivity 
                 # 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                 AD-58088.2 
                 A-118324.1 
                 AfuUfuAfaAfcAfA 
                 559 
                 A-118325.1 
                 aAfaGfgUfaCfuUfguu 
                 580 
                  984 
                 HumRheMus 
                  2 
               
               
                   
                   
                 fCfaAfgUfaCfcUf 
                   
                   
                 GfuUfuAfaAfusCfsu 
                   
                   
                   
                   
               
               
                   
                   
                 uUfL96 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58644.1 
                 A-119328.1 
                 AfsusUfuAfaAfcA 
                 560 
                 A-119329.1 
                 asAfsaGfgUfaCfuUfg 
                 581 
                  984 
                 HumRheMus 
                  6 
               
               
                   
                   
                 fAfCfaAfgUfaCfc 
                   
                   
                 uuGfuUfuAfaAfuscsu 
                   
                   
                   
                   
               
               
                   
                   
                 UfuUfL96 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58651.1 
                 A-119328.2 
                 AfsusUfuAfaAfcA 
                 561 
                 A-119339.1 
                 asAfsaGfsgUfsaCfsu 
                 582 
                  984 
                 HumRheMus 
                 14 
               
               
                   
                   
                 fAfCfaAfgUfaCfc 
                   
                   
                 UfsguuGfsuUfsuAfsa 
                   
                   
                   
                   
               
               
                   
                   
                 UfuUfL96 
                   
                   
                 Afsuscsu 
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58099.2 
                 A-118312.1 
                 UfgAfcAfaAfaUfA 
                 562 
                 A-118313.1 
                 uUfaUfaGfuGfaGfuua 
                 583 
                 1513 
                 HumRheMusRat 
                  2 
               
               
                   
                   
                 fAfcUfcAfcUfaUf 
                   
                   
                 UfuUfuGfuCfasAfsu 
                   
                   
                   
                   
               
               
                   
                   
                 aAfL96 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58641.1 
                 A-119322.1 
                 UfsgsAfcAfaAfaU 
                 563 
                 A-119323.1 
                 usUfsaUfaGfuGfaGfu 
                 584 
                 1513 
                 HumRheMusRat 
                  6 
               
               
                   
                   
                 fAfAfcUfcAfcUfa 
                   
                   
                 uaUfuUfuGfuCfasasu 
                   
                   
                   
                   
               
               
                   
                   
                 UfaAfL96 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58648.1 
                 A-119322.2 
                 UfsgsAfcAfaAfaU 
                 564 
                 A-119336.1 
                 usUfsaUfsaGfsuGfsa 
                 585 
                 1513 
                 HumRheMusRat 
                 14 
               
               
                   
                   
                 fAfAfcUfcAfcUfa 
                   
                   
                 GfsuuaUfsuUfsuGfsu 
                   
                   
                   
                   
               
               
                   
                   
                 UfaAfL96 
                   
                   
                 Cfsasasu 
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58111.2 
                 A-118316.1 
                 GfaCfaAfqaAfuAf 
                 565 
                 A-118317.1 
                 aUfuAfuAfgUfgAfguu 
                 586 
                 1514 
                 HumRheMusRat 
                  2 
               
               
                   
                   
                 AfCfuCfaCfuAfuA 
                   
                   
                 AfuUfuUfgUfcsAfsa 
                   
                   
                   
                   
               
               
                   
                   
                 faUfL96 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58642.1 
                 A-119324.1 
                 GfsasCfaAfaAfuA 
                 566 
                 A-119325.1 
                 asUfsuAfuAfgUfgAfg 
                 587 
                 1514 
                 HumRheMusRat 
                  6 
               
               
                   
                   
                 fAfCfuCfaCfuAfu 
                   
                   
                 uuAfuUfuUfgUfcsasa 
                   
                   
                   
                   
               
               
                   
                   
                 AfaUfL96 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58649.1 
                 A-119324.2 
                 GfsasCfaAfaAfuA 
                 567 
                 A-119337.1 
                 asUfsuAfsuAfsgUfsg 
                 588 
                 1514 
                 HumRheMusRat 
                 14 
               
               
                   
                   
                 fAfCfuCfaCfuAfu 
                   
                   
                 AfsguuAfsuUfsuUfsg 
                   
                   
                   
                   
               
               
                   
                   
                 AfaUfL96 
                   
                   
                 Ufscsasa 
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58116.2 
                 A-118396.1 
                 GfuUfcCfgGfaUfA 
                 568 
                 A-118397.1 
                 aAfaAfgUfuCfaAfaua 
                 589 
                 4502 
                 MusRat 
                  2 
               
               
                   
                   
                 fUfuUfgAfaCfuUf 
                   
                   
                 UfcCfgGfaAfcsCfsg 
                   
                   
                   
                   
               
               
                   
                   
                 uUfL96 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58647.1 
                 A-119334.1 
                 GfsusUfcCfgGfaU 
                 569 
                 A-119335.1 
                 asAfsaAfgUfuCfaAfa 
                 590 
                 4502 
                 MusRat 
                  6 
               
               
                   
                   
                 fAfUfuUfgAfaCfu 
                   
                   
                 uaUfcCfgGfaAfcscsg 
                   
                   
                   
                   
               
               
                   
                   
                 UfuUfL96 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58654.1 
                 A-119334.2 
                 GfsusUfcCfgGfaU 
                 570 
                 A-119342.1 
                 asAfsaAfsgUfsuCfsa 
                 591 
                 4502 
                 MusRat 
                 14 
               
               
                   
                   
                 fAfUfuUfgAfaCfu 
                   
                   
                 AfsauaUfscCfsgGfsa 
                   
                   
                   
                   
               
               
                   
                   
                 UfuUfL96 
                   
                   
                 Afscscsg 
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58121.2 
                 A-118382.1 
                 UfgCfaGfaUfcAfA 
                 571 
                 A-118383.1 
                 uGfaAfaUfuGfuGfuuG 
                 592 
                 4945 
                 MusRat 
                  2 
               
               
                   
                   
                 fAfcAfcAfaUfuUf 
                   
                   
                 faUfcUfgCfasGfsa 
                   
                   
                   
                   
               
               
                   
                   
                 cAfL96 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58645.1 
                 A-119330.1 
                 UfsgsCfaGfaUfcA 
                 572 
                 A-119331.1 
                 usGfsaAfaUfuGfuGfu 
                 593 
                 4945 
                 MusRat 
                  6 
               
               
                   
                   
                 fAfAfcAfcAfaUfu 
                   
                   
                 uuGfaUfcUfgCfasgsa 
                   
                   
                   
                   
               
               
                   
                   
                 UfcAfL96 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58652.1 
                 A-119330.2 
                 UfsgsCfaGfaUfcA 
                 573 
                 A-119340.1 
                 usGfsaAfsaUfsuGfsu 
                 594 
                 4945 
                 MusRat 
                 14 
               
               
                   
                   
                 fAfAfcAfcAfaUfu 
                   
                   
                 GfsuuuGfsaUfscUfsg 
                   
                   
                   
                   
               
               
                   
                   
                 UfcAfL96 
                   
                   
                 Cfsasgsa 
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58123.2 
                 A-118320.1 
                 AfaGfcAfqaGfaUf 
                 574 
                 A-118321.1 
                 uAfuUfaUfaAfaAfaua 
                 595 
                  786 
                 HumRheMus 
                  2 
               
               
                   
                   
                 AfUfuUfuUfaUfaA 
                   
                   
                 UfcUfuGfcUfusUfsu 
                   
                   
                   
                   
               
               
                   
                   
                 fuAfL96 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58643.1 
                 A-119326.1 
                 AfsasGfcAfaGfaU 
                 575 
                 A-119327.1 
                 usAfsuUfaUfaAfaAfa 
                 596 
                  786 
                 HumRheMus 
                  6 
               
               
                   
                   
                 fAfUfuUfuUfaUfa 
                   
                   
                 uaUfcUfuGfcUfususu 
                   
                   
                   
                   
               
               
                   
                   
                 AfuAfL96 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58650.1 
                 A-119326.2 
                 AfsasGfcAfaGfaU 
                 576 
                 A-119338.1 
                 usAfsuUfsaUfsaAfsa 
                 597 
                  786 
                 HumRheMus 
                 14 
               
               
                   
                   
                 fAfUfuUfuUfaUfa 
                   
                   
                 AfsauaUfscUfsuGfsc 
                   
                   
                   
                   
               
               
                   
                   
                 AfuAfL96 
                   
                   
                 Ufsususu 
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58133.2 
                 A-118386.1 
                 CfaGfaUfcAfaAfC 
                 577 
                 A-118387.1 
                 aCfuGfaAfaUfuGfugu 
                 598 
                 4947 
                 MusRat 
                  2 
               
               
                   
                   
                 fAfcAfaUfuUfcAf 
                   
                   
                 UfuGfaUfcUgfsCfsa 
                   
                   
                   
                   
               
               
                   
                   
                 gUfL96 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58646.1 
                 A-119332.1 
                 CfsasGfaUfcAfaA 
                 578 
                 A-119333.1 
                 asCfsuGfaAfaUfuGfu 
                 599 
                 4947 
                 MusRat 
                  6 
               
               
                   
                   
                 fCfAfcAfaUfuUfc 
                   
                   
                 guUfuGfaUfcUfgscsa 
                   
                   
                   
                   
               
               
                   
                   
                 AfgUfL96 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD-58653.1 
                 A-119332.2 
                 CfsasGfaUfcAfaA 
                 579 
                 A-119341.1 
                 asCfsuGfsaAfsaUfsu 
                 600 
                 4947 
                 MusRat 
                 14 
               
               
                   
                   
                 FcFaFcAfaUfuUfc 
                   
                   
                 GfsuguUfsuGfsaUfsc 
                   
                   
                   
                   
               
               
                   
                   
                 AfgUfL96 
                   
                   
                 Ufsgscsa 
                   
                   
                   
                   
               
               
                   
               
            
           
         
       
     
     Example 4: Design, Synthesis, and In Vitro Screening of Additional siRNAs siRNA Design 
     C5 duplexes, 19 nucleotides long for both the sense and antisense strand, were designed using the human C5 mRNA sequence set forth in GenBank Accession No. NM_001735.2. Five-hundred and sixty-nine duplexes were initially identified that did not contain repeats longer than 7 nucleotides, spanning substantially the entire 5480 nucleotide transcript. All 569 duplexes are then scored for predicted efficacy according to a linear model that evaluates the nucleotide pair at each duplex position, and the dose and cell line to be used for screening. The duplexes are also matched against all transcripts in the human RefSeq collection using a custom brute force algorithm, and scored for lowest numbers of mismatches (per strand) to transcripts other than C5. Duplexes to be synthesized and screened are then selected from the 569, according to the following scheme: Beginning at the 5′ end of the transcript, a duplex is selected within a “window” of every 10±2 nucleotides that 
     1) had the highest predicted efficacy, 
     2) had at least one mismatch in both strands to all transcripts other than SERPINCL
         3) had not already been synthesized and screened as part of other duplex sets.       

     If no duplex is identified within a given window that satisfied all criteria, that window was skipped. 
     A detailed list of the 569 C5 sense and antisense strand sequences is shown in Table 20. 
     The in vitro efficacy of duplexes comprising the sense and antisense sequences listed in Table 20 is determined using the following methods. 
     Cell Culture and Transfections 
     HepG2 cells (ATCC, Manassas, Va.) are grown to near confluence at 37° C. in an atmosphere of 5% CO2 in Eagle&#39;s Minimum Essential Medium (ATCC) supplemented with 10% FBS, streptomycin, and glutamine (ATCC) before being released from the plate by trypsinization. Transfection is carried out by adding 14.8 μl of Opti-MEM plus 0.2 μl of Lipofectamine RNAiMax per well (Invitrogen, Carlsbad Calif. cat #13778-150) to 5 μl of each of the 164 siRNA duplexes to an individual well in a 96-well plate. The mixture is then incubated at room temperature for 15 minutes. 80 μl of complete growth media without antibiotic containing ˜2.5×10 4  HepG2 cells is then added to the siRNA mixture. Cells are incubated for 24 hours prior to RNA purification. Experiments are performed at 20 nM and included naïve cells and cells transfected with AD-1955, a luciferase targeting siRNA as negative controls. 
     Total RNA Isolation Using DYNABEADS mRNA Isolation Kit (Invitrogen, Part #: 610-12) 
     Cells are harvested and lysed in 150 μl of Lysis/Binding Buffer then mixed for 5 minute at 700 rpm on a platform shaker (the mixing speed was the same throughout the process). Ten microliters of magnetic beads and 80 μl Lysis/Binding Buffer mixture are added to a round bottom plate and mixed for 1 minute. Magnetic beads are captured using magnetic stand and the supernatant is removed without disturbing the beads. After removing supernatant, the lysed cells are added to the remaining beads and mixed for 5 minutes. After removing supernatant, magnetic beads are washed 2 times with 150 μl Wash Buffer A and mixed for 1 minute. Beads are captured again and supernatant removed. Beads are then washed with 150 μl Wash Buffer B, captured and supernatant is removed. Beads are next washed with 150 μl Elution Buffer, captured and supernatant removed. Beads are allowed to dry for 2 minutes. After drying, 50 μl of Elution Buffer is added and mixed for 5 minutes at 70° C. Beads are captured on magnet for 5 minutes. Forty μl of supernatant, containing the isolated RNA is removed and added to another 96 well plate. 
     cDNA Synthesis Using ABI High Capacity cDNA Reverse Transcription Kit (Applied Biosystems, Foster City, Calif., Cat #4368813) 
     A master mix of 2 μl 10× Buffer, 0.8 μl 25×dNTPs, 2 μl Random primers, 1 μl Reverse Transcriptase, 1 μl RNase inhibitor and 3.2 μl of H 2 O per reaction is added into 10 μl total RNA. cDNA is generated using a Bio-Rad C-1000 or S-1000 thermal cycler (Hercules, Calif.) through the following steps: 25° C. 10 min, 37° C. 120 min, 85° C. 5 sec, 4° C. hold. 
     Real Time PCR 
     Two μl of cDNA is added to a master mix containing 0.5 μl human GAPDH TaqMan Probe (Applied Biosystems Cat #4326317E), 0.5 μl human SERPINC1 TaqMan probe (Applied Biosystems cat #Hs00892758 ml) and 5 μl Lightcycler 480 probe master mix (Roche Cat #04887301001) per well in a 384-well plate (Roche cat #04887301001). Real time PCR is performed in an LC480 Real Time PCR machine (Roche). 
     To calculate relative fold change, real time data is analyzed using the ΔΔCt method and normalized to assays performed with cells transfected with 20 nM AD-1955. 
     
       
         
           
               
             
               
                 TABLE 20 
               
             
            
               
                   
               
               
                 Additional CS unmodified sense and antisense strand sequences 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 Position in 
                   
                 SEQ 
                   
                 SEQ 
               
               
                 Oligo Name 
                 NM_001735.2 
                 Sense Sequence 
                 ID NO: 
                 Antisense Sequence 
                 ID NO: 
               
               
                   
               
               
                 NM_001735.2_3-21_s 
                  3-21 
                 UAUCCGUGGUUUCCUGCUA 
                  601 
                 UAGCAGGAAACCACGGAUA 
                 1170 
               
               
                   
               
               
                 NM_001735.2_10-28_s 
                 10-28 
                 GGUUUCCUGCUACCUCCAA 
                  602 
                 UUGGAGGUAGCAGGAAACC 
                 1171 
               
               
                   
               
               
                 NM_001735.2_22-40_s 
                 22-40 
                 CCUCCAACCAUGGGCCUUU 
                  603 
                 AAAGGCCCAUGGUUGGAGG 
                 1172 
               
               
                   
               
               
                 NM_001735.2_33-51_s 
                 33-51 
                 GGGCCUUUUGGGAAUACUU 
                  604 
                 AAGUAUUCCCAAAAGGCCC 
                 1173 
               
               
                   
               
               
                 NM_001735.2_43-61_s 
                 43-61 
                 GGAAUACUUUGUUUUUUAA 
                  605 
                 UUAAAAAACAAAGUAUUCC 
                 1174 
               
               
                   
               
               
                 NM_001735.2_49-67_s 
                 49-67 
                 CUUUGUUUUUUAAUCUUCC 
                  606 
                 GGAAGAUUAAAAAACAAAG 
                 1175 
               
               
                   
               
               
                 NM_001735.2_63-81_s 
                 63-81 
                 CUUCCUGGGGAAAACCUGG 
                  607 
                 CCAGGUUUUCCCCAGGAAG 
                 1176 
               
               
                   
               
               
                 NM_001735.2_71-89_s 
                 71-89 
                 GGAAAACCUGGGGACAGGA 
                  608 
                 UCCUGUCCCCAGGUUUUCC 
                 1177 
               
               
                   
               
               
                 NM_001735.2_81-99_s 
                 81-99 
                 GGGACAGGAGCAAACAUAU 
                  609 
                 AUAUGUUUGCUCCUGUCCC 
                 1178 
               
               
                   
               
               
                 NM_001735.2_91-109_s 
                  91-109 
                 CAAACAUAUGUCAUUUCAG 
                  610 
                 CUGAAAUGACAUAUGUUUG 
                 1179 
               
               
                   
               
               
                 NM_001735.2_102-120_s 
                 102-120 
                 CAUUUCAGCACCAAAAAUA 
                  611 
                 UAUUUUUGGUGCUGAAAUG 
                 1180 
               
               
                   
               
               
                 NM_001735.2_109-127_s 
                 109-127 
                 GCACCAAAAAUAUUCCGUG 
                  612 
                 CACGGAAUAUUUUUGGUGC 
                 1181 
               
               
                   
               
               
                 NM_001735.2_123-141_s 
                 123-141 
                 CCGUGUUGGAGCAUCUGAA 
                  613 
                 UUCAGAUGCUCCAACACGG 
                 1182 
               
               
                   
               
               
                 NM_001735.2_130-148_s 
                 130-148 
                 GGAGCAUCUGAAAAUAUUG 
                  614 
                 CAAUAUUUUCAGAUGCUCC 
                 1183 
               
               
                   
               
               
                 NM_001735.2_139-157_s 
                 139157 
                 GAAAAUAUUGUGAUUCAAG 
                  615 
                 CUUGAAUCACAAUAUUUUC 
                 1184 
               
               
                   
               
               
                 NM_001735.2_150-168_s 
                 150-168 
                 GAUUCAAGUUUAUGGAUAC 
                  616 
                 GUAUCCAUAAACUUGAAUC 
                 1185 
               
               
                   
               
               
                 NM_001735.2_163-181_s 
                 163-181 
                 GGAUACACUGAAGCAUUUG 
                  617 
                 CAAAUGCUUCAGUGUAUCC 
                 1186 
               
               
                   
               
               
                 NM_001735.2_172-190_s 
                 172-190 
                 GAAGCAUUUGAUGCAACAA 
                  618 
                 UUGUUGCAUCAAAUGCUUC 
                 1187 
               
               
                   
               
               
                 NM_001735.2_183-201_s 
                 183-201 
                 UGCAACAAUCUCUAUUAAA 
                  619 
                 UUUAAUAGAGAUUGUUGCA 
                 1188 
               
               
                   
               
               
                 NM_001735.2_189-207_s 
                 189-207 
                 AAUCUCUAUUAAAAGUUAU 
                  620 
                 AUAACUUUUAAUAGAGAUU 
                 1189 
               
               
                   
               
               
                 NM_001735.2 201-219_s 
                 201-219 
                 AAGUUAUCCUGAUAAAAAA 
                  621 
                 UUUUUUAUCAGGAUAACUU 
                 1190 
               
               
                   
               
               
                 NM_001735.2_209-227_s 
                 209-227 
                 CUGAUAAAAAAUUUAGUUA 
                  622 
                 UAACUAAAUUUUUUAUCAG 
                 1191 
               
               
                   
               
               
                 NM_001735.2_221-239_s 
                 221-239 
                 UUAGUUACUCCUCAGGCCA 
                  623 
                 UGGCCUGAGGAGUAACUAA 
                 1192 
               
               
                   
               
               
                 NM_001735.2_230-248_s 
                 230-248 
                 CCUCAGGCCAUGUUCAUUU 
                  624 
                 AAAUGAACAUGGCCUGAGG 
                 1193 
               
               
                   
               
               
                 NM_001735.2_242-260_s 
                 242-260 
                 UUCAUUUAUCCUCAGAGAA 
                  625 
                 UUCUCUGAGGAUAAAUGAA 
                 1194 
               
               
                   
               
               
                 NM_001735.2_252-270_s 
                 252-270 
                 CUCAGAGAAUAAAUUCCAA 
                  626 
                 UUGGAAUUUAUUCUCUGAG 
                 1195 
               
               
                   
               
               
                 NM_001735.2_259-277_s 
                 259-277 
                 AAUAAAUUCCAAAACUCUG 
                  627 
                 CAGAGUUUUGGAAUUUAUU 
                 1196 
               
               
                   
               
               
                 NM_001735.2_273-291_s 
                 273-291 
                 CUCUGCAAUCUUAACAAUA 
                  628 
                 UAUUGUUAAGAUUGCAGAG 
                 1197 
               
               
                   
               
               
                 NM_001735.2_282-300_s 
                 282-300 
                 CUUAACAAUACAACCAAAA 
                  629 
                 UUUUGGUUGUAUUGUUAAG 
                 1198 
               
               
                   
               
               
                 NM_001735.2_292-310_s 
                 292-310 
                 CAACCAAAACAAUUGCCUG 
                  630 
                 CAGGCAAUUGUUUUGGUUG 
                 1199 
               
               
                   
               
               
                 NM_001735.2_301-319_s 
                 301-319 
                 CAAUUGCCUGGAGGACAAA 
                  631 
                 UUUGUCCUCCAGGCAAUUG 
                 1200 
               
               
                   
               
               
                 NM_001735.2_313-331_s 
                 313-331 
                 GGACAAAACCCAGUUUCUU 
                  632 
                 AAGAAACUGGGUUUUGUCC 
                 1201 
               
               
                   
               
               
                 NM_001735.2_322-340_s 
                 322-340 
                 CCAGUUUCUUAUGUGUAUU 
                  633 
                 AAUACACAUAAGAAACUGG 
                 1202 
               
               
                   
               
               
                 NM_001735.2_332-350_s 
                 332-350 
                 AUGUGUAUUUGGAAGUUGU 
                  634 
                 ACAACUUCCAAAUACACAU 
                 1203 
               
               
                   
               
               
                 NM_001735.2_342-360_s 
                 342-360 
                 GGAAGUUGUAUCAAAGCAU 
                  635 
                 AUGCUUUGAUACAACUUCC 
                 1204 
               
               
                   
               
               
                 NM_001735.2_349-367_s 
                 349-367 
                 GUAUCAAAGCAUUUUUCAA 
                  636 
                 UUGAAAAAUGCUUUGAUAC 
                 1205 
               
               
                   
               
               
                 NM_001735.2_361-379_s 
                 361-379 
                 UUUUCAAAAUCAAAAAGAA 
                  637 
                 UUCUUUUUGAUUUUGAAAA 
                 1206 
               
               
                   
               
               
                 NM_001735.2_371-389_s 
                 371-389 
                 CAAAAAGAAUGCCAAUAAC 
                  638 
                 GUUAUUGGCAUUCUUUUUG 
                 1207 
               
               
                   
               
               
                 NM_001735.2_381-399_s 
                 381-399 
                 GCCAAUAACCUAUGACAAU 
                  639 
                 AUUGUCAUAGGUUAUUGGC 
                 1208 
               
               
                   
               
               
                 NM_001735.2_389-407_s 
                 389-407 
                 CCUAUGACAAUGGAUUUCU 
                  640 
                 AGAAAUCCAUUGUCAUAGG 
                 1209 
               
               
                   
               
               
                 NM_001735.2_399-417_s 
                 399-417 
                 UGGAUUUCUCUUCAUUCAU 
                  641 
                 AUGAAUGAAGAGAAAUCCA 
                 1210 
               
               
                   
               
               
                 NM_001735.2_411-429_s 
                 411-429 
                 CAUUCAUACAGACAAACCU 
                  642 
                 AGGUUUGUCUGUAUGAAUG 
                 1211 
               
               
                   
               
               
                 NM_001735.2_419-437_s 
                 419-437 
                 CAGACAAACCUGUUUAUAC 
                  643 
                 GUAUAAACAGGUUUGUCUG 
                 1212 
               
               
                   
               
               
                 NM_001735.2_430-448_s 
                 430-448 
                 GUUUAUACUCCAGACCAGU 
                  644 
                 ACUGGUCUGGAGUAUAAAC 
                 1213 
               
               
                   
               
               
                 NM_001735.2_441-459_s 
                 441-459 
                 AGACCAGUCAGUAAAAGUU 
                  645 
                 AACUUUUACUGACUGGUCU 
                 1214 
               
               
                   
               
               
                 NM_001735.2_450-468_s 
                 450-468 
                 AGUAAAAGUUAGAGUUUAU 
                  646 
                 AUAAACUCUAACUUUUACU 
                 1215 
               
               
                   
               
               
                 NM_001735.2_460-478_s 
                 460-478 
                 AGAGUUUAUUCGUUGAAUG 
                  647 
                 CAUUCAACGAAUAAACUCU 
                 1216 
               
               
                   
               
               
                 NM_001735.2_470-488_s 
                 470-488 
                 CGUUGAAUGACGACUUGAA 
                  648 
                 UUCAAGUCGUCAUUCAACG 
                 1217 
               
               
                   
               
               
                 NM_001735.2_483-501_s 
                 483-501 
                 CUUGAAGCCAGCCAAAAGA 
                  649 
                 UCUUUUGGCUGGCUUCAAG 
                 1218 
               
               
                   
               
               
                 NM_001735.2_490-508_s 
                 490-508 
                 CCAGCCAAAAGAGAAACUG 
                  650 
                 CAGUUUCUCUUUUGGCUGG 
                 1219 
               
               
                   
               
               
                 NM_001735.2_503-521_s 
                 503-521 
                 AAACUGUCUUAACUUUCAU 
                  651 
                 AUGAAAGUUAAGACAGUUU 
                 1220 
               
               
                   
               
               
                 NM_001735.2_513-531_s 
                 513-531 
                 AACUUUCAUAGAUCCUGAA 
                  652 
                 UUCAGGAUCUAUGAAAGUU 
                 1221 
               
               
                   
               
               
                 NM_001735.2_519-537_s 
                 519-537 
                 CAUAGAUCCUGAAGGAUCA 
                  653 
                 UGAUCCUUCAGGAUCUAUG 
                 1222 
               
               
                   
               
               
                 NM_001735.2_529-547_s 
                 529-547 
                 GAAGGAUCAGAAGUUGACA 
                  654 
                 UGUCAACUUCUGAUCCUUC 
                 1223 
               
               
                   
               
               
                 NM_001735.2_543-561_s 
                 543-561 
                 UGACAUGGUAGAAGAAAUU 
                  655 
                 AAUUUCUUCUACCAUGUCA 
                 1224 
               
               
                   
               
               
                 NM_001735.2_553-571_s 
                 553-571 
                 GAAGAAAUUGAUCAUAUUG 
                  656 
                 CAAUAUGAUCAAUUUCUUC 
                 1225 
               
               
                   
               
               
                 NM_001735.2_562-580_s 
                 562-580 
                 GAUCAUAUUGGAAUUAUCU 
                  657 
                 AGAUAAUUCCAAUAUGAUC 
                 1226 
               
               
                   
               
               
                 NM_001735.2_571-589_s 
                 571-589 
                 GGAAUUAUCUCUUUUCCUG 
                  658 
                 CAGGAAAAGAGAUAAUUCC 
                 1227 
               
               
                   
               
               
                 NM_001735.2_579-597_s 
                 579-597 
                 CUCUUUUCCUGACUUCAAG 
                  659 
                 CUUGAAGUCAGGAAAAGAG 
                 1228 
               
               
                   
               
               
                 NM_001735.2_590-608_s 
                 590-608 
                 ACUUCAAGAUUCCGUCUAA 
                  660 
                 UUAGACGGAAUCUUGAAGU 
                 1229 
               
               
                   
               
               
                 NM_001735.2_601-619_s 
                 601-619 
                 CCGUCUAAUCCUAGAUAUG 
                  661 
                 CAUAUCUAGGAUUAGACGG 
                 1230 
               
               
                   
               
               
                 NM_001735.2_610-628_s 
                 610-628 
                 CCUAGAUAUGGUAUGUGGA 
                  662 
                 UCCACAUACCAUAUCUAGG 
                 1231 
               
               
                   
               
               
                 NM_001735.2_623-641_s 
                 623-641 
                 UGUGGACGAUCAAGGCUAA 
                  663 
                 UUAGCCUUGAUCGUCCACA 
                 1232 
               
               
                   
               
               
                 NM_001735.2_629-647_s 
                 629-647 
                 CGAUCAAGGCUAAAUAUAA 
                  664 
                 UUAUAUUUAGCCUUGAUCG 
                 1233 
               
               
                   
               
               
                 NM_001735.2_642-660_s 
                 642-660 
                 AUAUAAAGAGGACUUUUCA 
                  665 
                 UGAAAAGUCCUCUUUAUAU 
                 1234 
               
               
                   
               
               
                 NM_001735.2_649-667_s 
                 649-667 
                 GAGGACUUUUCAACAACUG 
                  666 
                 CAGUUGUUGAAAAGUCCUC 
                 1235 
               
               
                   
               
               
                 NM_001735.2_662-680_s 
                 662-680 
                 CAACUGGAACCGCAUAUUU 
                  667 
                 AAAUAUGCGGUUCCAGUUG 
                 1236 
               
               
                   
               
               
                 NM_001735.2_672-690_s 
                 672-690 
                 CGCAUAUUUUGAAGUUAAA 
                  668 
                 UUUAACUUCAAAAUAUGCG 
                 1237 
               
               
                   
               
               
                 NM_001735.2_683-701_s 
                 683-701 
                 AAGUUAAAGAAUAUGUCUU 
                  669 
                 AAGACAUAUUCUUUAACUU 
                 1238 
               
               
                   
               
               
                 NM_001735.2_691-709_s 
                 691-709 
                 GAAUAUGUCUUGCCACAUU 
                  670 
                 AAUGUGGCAAGACAUAUUC 
                 1239 
               
               
                   
               
               
                 NM_001735.2_703-721_s 
                 703-721 
                 CCACAUUUUUCUGUCUCAA 
                  671 
                 UUGAGACAGAAAAAUGUGG 
                 1240 
               
               
                   
               
               
                 NM_001735.2_713-731_s 
                 713-731 
                 CUGUCUCAAUCGAGCCAGA 
                  672 
                 UCUGGCUCGAUUGAGACAG 
                 1241 
               
               
                   
               
               
                 NM_001735.2_719-737_s 
                 719-737 
                 CAAUCGAGCCAGAAUAUAA 
                  673 
                 UUAUAUUCUGGCUCGAUUG 
                 1242 
               
               
                   
               
               
                 NM_001735.2_730-748_s 
                 730-748 
                 GAAUAUAAUUUCAUUGGUU 
                  674 
                 AACCAAUGAAAUUAUAUUC 
                 1243 
               
               
                   
               
               
                 NM_001735.2_742-760_s 
                 742-760 
                 AUUGGUUACAAGAACUUUA 
                  675 
                 UAAAGUUCUUGUAACCAAU 
                 1244 
               
               
                   
               
               
                 NM_001735.2_752-770_s 
                 752-770 
                 AGAACUUUAAGAAUUUUGA 
                  676 
                 UCAAAAUUCUUAAAGUUCU 
                 1245 
               
               
                   
               
               
                 NM_001735.2_762-780_s 
                 762-780 
                 GAAUUUUGAAAUUACUAUA 
                  677 
                 UAUAGUAAUUUCAAAAUUC 
                 1246 
               
               
                   
               
               
                 NM_001735.2_769-787_s 
                 769-787 
                 GAAAUUACUAUAAAAGCAA 
                  678 
                 UUGCUUUUAUAGUAAUUUC 
                 1247 
               
               
                   
               
               
                 NM_001735.2_781-799_s 
                 781-799 
                 AAAGCAAGAUAUUUUUAUA 
                  679 
                 UAUAAAAAUAUCUUGCUUU 
                 1248 
               
               
                   
               
               
                 NM_001735.2_789-807_s 
                 789-807 
                 AUAUUUUUAUAAUAAAGUA 
                  680 
                 UACUUUAUUAUAAAAAUAU 
                 1249 
               
               
                   
               
               
                 NM_001735.2_803-821_s 
                 803-821 
                 AAGUAGUCACUGAGGCUGA 
                  681 
                 UCAGCCUCAGUGACUACUU 
                 1250 
               
               
                   
               
               
                 NM_001735.2_810-828_s 
                 810-828 
                 CACUGAGGCUGACGUUUAU 
                  682 
                 AUAAACGUCAGCCUCAGUG 
                 1251 
               
               
                   
               
               
                 NM_001735.2_822-840_s 
                 822-840 
                 CGUUUAUAUCACAUUUGGA 
                  683 
                 UCCAAAUGUGAUAUAAACG 
                 1252 
               
               
                   
               
               
                 NM_001735.2_831-849_s 
                 831-849 
                 CACAUUUGGAAUAAGAGAA 
                  684 
                 UUCUCUUAUUCCAAAUGUG 
                 1253 
               
               
                   
               
               
                 NM_001735.2_840-858_s 
                 840-858 
                 AAUAAGAGAAGACUUAAAA 
                  685 
                 UUUUAAGUCUUCUCUUAUU 
                 1254 
               
               
                   
               
               
                 NM_001735.2_852-870_s 
                 852-870 
                 CUUAAAAGAUGAUCAAAAA 
                  686 
                 UUUUUGAUCAUCUUUUAAG 
                 1255 
               
               
                   
               
               
                 NM_001735.2_859-877_s 
                 859-877 
                 GAUGAUCAAAAAGAAAUGA 
                  687 
                 UCAUUUCUUUUUGAUCAUC 
                 1256 
               
               
                   
               
               
                 NM_001735.2_872-890_s 
                 872-890 
                 AAAUGAUGCAAACAGCAAU 
                  688 
                 AUUGCUGUUUGCAUCAUUU 
                 1257 
               
               
                   
               
               
                 NM_001735.2_883-901_s 
                 883-901 
                 ACAGCAAUGCAAAACACAA 
                  689 
                 UUGUGUUUUGCAUUGCUGU 
                 1258 
               
               
                   
               
               
                 NM_001735.2_893-911_s 
                 893-911 
                 AAAACACAAUGUUGAUAAA 
                  690 
                 UUUAUCAACAUUGUGUUUU 
                 1259 
               
               
                   
               
               
                 NM_001735.2_899-917_s 
                 899-917 
                 CAAUGUUGAUAAAUGGAAU 
                  691 
                 AUUCCAUUUAUCAACAUUG 
                 1260 
               
               
                   
               
               
                 NM_001735.2_913-931_s 
                 913-931 
                 GGAAUUGCUCAAGUCACAU 
                  692 
                 AUGUGACUUGAGCAAUUCC 
                 1261 
               
               
                   
               
               
                 NM_001735.2_919-937_s 
                 919-937 
                 GCUCAAGUCACAUUUGAUU 
                  693 
                 AAUCAAAUGUGACUUGAGC 
                 1262 
               
               
                   
               
               
                 NM_001735.2_930-948_s 
                 930-948 
                 AUUUGAUUCUGAAACAGCA 
                  694 
                 UGCUGUUUCAGAAUCAAAU 
                 1263 
               
               
                   
               
               
                 NM_001735.2_939-957_s 
                 939-957 
                 UGAAACAGCAGUCAAAGAA 
                  695 
                 UUCUUUGACUGCUGUUUCA 
                 1264 
               
               
                   
               
               
                 NM_001735.2_951-969_s 
                 951-969 
                 CAAAGAACUGUCAUACUAC 
                  696 
                 GUAGUAUGACAGUUCUUUG 
                 1265 
               
               
                   
               
               
                 NM_001735.2_962-980_s 
                 962-980 
                 CAUACUACAGUUUAGAAGA 
                  697 
                 UCUUCUAAACUGUAGUAUG 
                 1266 
               
               
                   
               
               
                 NM_001735.2_969-987_s 
                 969-987 
                 CAGUUUAGAAGAUUUAAAC 
                  698 
                 GUUUAAAUCUUCUAAACUG 
                 1267 
               
               
                   
               
               
                 NM_001735.2_983-1001_s 
                  983-1001 
                 UAAACAACAAGUACCUUUA 
                  699 
                 UAAAGGUACUUGUUGUUUA 
                 1268 
               
               
                   
               
               
                 NM_001735.2_990-1008_s 
                  990-1008 
                 CAAGUACCUUUAUAUUGCU 
                  700 
                 AGCAAUAUAAAGGUACUUG 
                 1269 
               
               
                   
               
               
                 NM_001735.2_1002-1020_s 
                 1002-1020 
                 UAUUGCUGUAACAGUCAUA 
                  701 
                 UAUGACUGUUACAGCAAUA 
                 1270 
               
               
                   
               
               
                 NM_001735.2_1011-1029_s 
                 1011-1029 
                 AACAGUCAUAGAGUCUACA 
                  702 
                 UGUAGACUCUAUGACUGUU 
                 1271 
               
               
                   
               
               
                 NM_001735.2_1020-1038_s 
                 1020-1038 
                 AGAGUCUACAGGUGGAUUU 
                  703 
                 AAAUCCACCUGUAGACUCU 
                 1272 
               
               
                   
               
               
                 NM_001735.2_1033-1051_s 
                 1033-1051 
                 GGAUUUUCUGAAGAGGCAG 
                  704 
                 CUGCCUCUUCAGAAAAUCC 
                 1273 
               
               
                   
               
               
                 NM_001735.2_1042-1060_s 
                 1042-1060 
                 GAAGAGGCAGAAAUACCUG 
                  705 
                 CAGGUAUUUCUGCCUCUUC 
                 1274 
               
               
                   
               
               
                 NM_001735.2_1050-1068_s 
                 1050-1068 
                 AGAAAUACCUGGCAUCAAA 
                  706 
                 UUUGAUGCCAGGUAUUUCU 
                 1275 
               
               
                   
               
               
                 NM_001735.2_1061-1079_s 
                 1061-1079 
                 GCAUCAAAUAUGUCCUCUC 
                  707 
                 GAGAGGACAUAUUUGAUGC 
                 1276 
               
               
                   
               
               
                 NM_001735.2_1071-1089_s 
                 1071-1089 
                 UGUCCUCUCUCCCUACAAA 
                  708 
                 UUUGUAGGGAGAGAGGACA 
                 1277 
               
               
                   
               
               
                 NM_001735.2_1092-1110_s 
                 1092-1110 
                 GAAUUUGGUUGCUACUCCU 
                  709 
                 AGGAGUAGCAACCAAAUUC 
                 1278 
               
               
                   
               
               
                 NM_001735.2_1102-1120_s 
                 1102-1120 
                 GCUACUCCUCUUUUCCUGA 
                  710 
                 UCAGGAAAAGAGGAGUAGC 
                 1279 
               
               
                   
               
               
                 NM_001735.2_1109-1127_s 
                 1109-1127 
                 CUCUUUUCCUGAAGCCUGG 
                  711 
                 CCAGGCUUCAGGAAAAGAG 
                 1280 
               
               
                   
               
               
                 NM_001735.2_1123-1141_s 
                 1123-1141 
                 CCUGGGAUUCCAUAUCCCA 
                  712 
                 UGGGAUAUGGAAUCCCAGG 
                 1281 
               
               
                   
               
               
                 NM_001735.2_1133-1151_s 
                 1133-1151 
                 CAUAUCCCAUCAAGGUGCA 
                  713 
                 UGCACCUUGAUGGGAUAUG 
                 1282 
               
               
                   
               
               
                 NM_001735.2_1139-1157_s 
                 1139-1157 
                 CCAUCAAGGUGCAGGUUAA 
                  714 
                 UUAACCUGCACCUUGAUGG 
                 1283 
               
               
                   
               
               
                 NM_001735.2_1150-1168_s 
                 1150-1168 
                 CAGGUUAAAGAUUCGCUUG 
                  715 
                 CAAGCGAAUCUUUAACCUG 
                 1284 
               
               
                   
               
               
                 NM_001735.2_1161-1179_s 
                 1161-1179 
                 UUCGCUUGACCAGUUGGUA 
                  716 
                 UACCAACUGGUCAAGCGAA 
                 1285 
               
               
                   
               
               
                 NM_001735.2_1170-1188_s 
                 1170-1188 
                 CCAGUUGGUAGGAGGAGUC 
                  717 
                 GACUCCUCCUACCAACUGG 
                 1286 
               
               
                   
               
               
                 NM_001735.2_1180-1198_s 
                 1180-1198 
                 GGAGGAGUCCCAGUAACAC 
                  718 
                 GUGUUACUGGGACUCCUCC 
                 1287 
               
               
                   
               
               
                 NM_001735.2_1190-1208_s 
                 1190-1208 
                 CAGUAACACUGAAUGCACA 
                  719 
                 UGUGCAUUCAGUGUUACUG 
                 1288 
               
               
                   
               
               
                 NM_001735.2_1200-1218_s 
                 1200-1218 
                 GAAUGCACAAACAAUUGAU 
                  720 
                 AUCAAUUGUUUGUGCAUUC 
                 1289 
               
               
                   
               
               
                 NM_001735.2_1209-1227_s 
                 1209-1227 
                 AACAAUUGAUGUAAACCAA 
                  721 
                 UUGGUUUACAUCAAUUGUU 
                 1290 
               
               
                   
               
               
                 NM_001735.2_1220-1238_s 
                 1220-1238 
                 UAAACCAAGAGACAUCUGA 
                  722 
                 UCAGAUGUCUCUUGGUUUA 
                 1291 
               
               
                   
               
               
                 NM_001735.2_1232-1250_s 
                 1232-1250 
                 CAUCUGACUUGGAUCCAAG 
                  723 
                 CUUGGAUCCAAGUCAGAUG 
                 1292 
               
               
                   
               
               
                 NM_001735.2_1243-1261_s 
                 1243-1261 
                 GAUCCAAGCAAAAGUGUAA 
                  724 
                 UUACACUUUUGCUUGGAUC 
                 1293 
               
               
                   
               
               
                 NM_001735.2_1251-1269_s 
                 1251-1269 
                 CAAAAGUGUAACACGUGUU 
                  725 
                 AACACGUGUUACACUUUUG 
                 1294 
               
               
                   
               
               
                 NM_001735.2_1260-1278_s 
                 1260-1278 
                 AACACGUGUUGAUGAUGGA 
                  726 
                 UCCAUCAUCAACACGUGUU 
                 1295 
               
               
                   
               
               
                 NM_001735.2_1272-1290_s 
                 1272-1290 
                 UGAUGGAGUAGCUUCCUUU 
                  727 
                 AAAGGAAGCUACUCCAUCA 
                 1296 
               
               
                   
               
               
                 NM_001735.2_1279-1297_s 
                 1279-1297 
                 GUAGCUUCCUUUGUGCUUA 
                  728 
                 UAAGCACAAAGGAAGCUAC 
                 1297 
               
               
                   
               
               
                 NM_001735.2_1293-131l_s 
                 1293-1311 
                 GCUUAAUCUCCCAUCUGGA 
                  729 
                 UCCAGAUGGGAGAUUAAGC 
                 1298 
               
               
                   
               
               
                 NM_001735.2_1303-1321_s 
                 1303-1321 
                 CCAUCUGGAGUGACGGUGC 
                  730 
                 GCACCGUCACUCCAGAUGG 
                 1299 
               
               
                   
               
               
                 NM_001735.2_1313-1331_s 
                 1313-1331 
                 UGACGGUGCUGGAGUUUAA 
                  731 
                 UUAAACUCCAGCACCGUCA 
                 1300 
               
               
                   
               
               
                 NM_001735.2_1320-1338_s 
                 1320-1338 
                 GCUGGAGUUUAAUGUCAAA 
                  732 
                 UUUGACAUUAAACUCCAGC 
                 1301 
               
               
                   
               
               
                 NM_001735.2_1332-1350_s 
                 1332-1350 
                 UGUCAAAACUGAUGCUCCA 
                  733 
                 UGGAGCAUCAGUUUUGACA 
                 1302 
               
               
                   
               
               
                 NM_001735.2_1342-1360_s 
                 1342-1360 
                 GAUGCUCCAGAUCUUCCAG 
                  734 
                 CUGGAAGAUCUGGAGCAUC 
                 1303 
               
               
                   
               
               
                 NM_001735.2_1349-1367_s 
                 1349-1367 
                 CAGAUCUUCCAGAAGAAAA 
                  735 
                 UUUUCUUCUGGAAGAUCUG 
                 1304 
               
               
                   
               
               
                 NM_001735.2_1362-1380_s 
                 1362-1380 
                 AGAAAAUCAGGCCAGGGAA 
                  736 
                 UUCCCUGGCCUGAUUUUCU 
                 1305 
               
               
                   
               
               
                 NM_001735.2_1371-1389_s 
                 1371-1389 
                 GGCCAGGGAAGGUUACCGA 
                  737 
                 UCGGUAACCUUCCCUGGCC 
                 1306 
               
               
                   
               
               
                 NM_001735.2_1382-1400_s 
                 1382-1400 
                 GUUACCGAGCAAUAGCAUA 
                  738 
                 UAUGCUAUUGCUCGGUAAC 
                 1307 
               
               
                   
               
               
                 NM_001735.2_1393-1411_s 
                 1393-1411 
                 AUAGCAUACUCAUCUCUCA 
                  739 
                 UGAGAGAUGAGUAUGCUAU 
                 1308 
               
               
                   
               
               
                 NM_001735.2_1399-1417_s 
                 1399-1471 
                 UACUCAUCUCUCAGCCAAA 
                  740 
                 UUUGGCUGAGAGAUGAGUA 
                 1309 
               
               
                   
               
               
                 NM_001735.2_1412-1430_s 
                 1412-1430 
                 GCCAAAGUUACCUUUAUAU 
                  741 
                 AUAUAAAGGUAACUUUGGC 
                 1310 
               
               
                   
               
               
                 NM_001735.2_1422-1440_s 
                 1422-1440 
                 CCUUUAUAUUGAUUGGACU 
                  742 
                 AGUCCAAUCAAUAUAAAGG 
                 1311 
               
               
                   
               
               
                 NM_001735.2_1432-1450_s 
                 1432-1450 
                 GAUUGGACUGAUAACCAUA 
                  743 
                 UAUGGUUAUCAGUCCAAUC 
                 1312 
               
               
                   
               
               
                 NM_001735.2_1439-1457_s 
                 1439-1457 
                 CUGAUAACCAUAAGGCUUU 
                  744 
                 AAAGCCUUAUGGUUAUCAG 
                 1313 
               
               
                   
               
               
                 NM_001735.2_1451-1469_s 
                 1451-1469 
                 AGGCUUUGCUAGUGGGAGA 
                  745 
                 UCUCCCACUAGCAAAGCCU 
                 1314 
               
               
                   
               
               
                 NM_001735.2_1462-1480_s 
                 1462-1480 
                 GUGGGAGAACAUCUGAAUA 
                  746 
                 UAUUCAGAUGUUCUCCCAC 
                 1315 
               
               
                   
               
               
                 NM_001735.2_1471-1489_s 
                 1471-1489 
                 CAUCUGAAUAUUAUUGUUA 
                  747 
                 UAACAAUAAUAUUCAGAUG 
                 1316 
               
               
                   
               
               
                 NM_001735.2_1479-1497_s 
                 1479-1497 
                 UAUUAUUGUUACCCCCAAA 
                  748 
                 UUUGGGGGUAACAAUAAUA 
                 1317 
               
               
                   
               
               
                 NM_001735.2_1492-1510_s 
                 1492-1510 
                 CCCAAAAGCCCAUAUAUUG 
                  749 
                 CAAUAUAUGGGCUUUUGGG 
                 1318 
               
               
                   
               
               
                 NM_001735.2_1493-1511_s 
                 1493-1511 
                 CCAAAAGCCCAUAUAUUGA 
                  750 
                 UCAAUAUAUGGGCUUUUGG 
                 1319 
               
               
                   
               
               
                 NM_001735.2_1494-1512_s 
                 1494-1512 
                 CAAAAGCCCAUAUAUUGAC 
                  751 
                 GUCAAUAUAUGGGCUUUUG 
                 1320 
               
               
                   
               
               
                 NM_001735.2_1495-1513_s 
                 1495-1513 
                 AAAAGCCCAUAUAUUGACA 
                  752 
                 UGUCAAUAUAUGGGCUUUU 
                 1321 
               
               
                   
               
               
                 NM_001735.2_1496-1514_s 
                 1496-1514 
                 AAAGCCCAUAUAUUGACAA 
                  753 
                 UUGUCAAUAUAUGGGCUUU 
                 1322 
               
               
                   
               
               
                 NM_001735.2_1497-1515_s 
                 1497-1515 
                 AAGCCCAUAUAUUGACAAA 
                  754 
                 UUUGUCAAUAUAUGGGCUU 
                 1323 
               
               
                   
               
               
                 NM_001735.2_1498-1516_s 
                 1498-1516 
                 AGCCCAUAUAUUGACAAAA 
                  755 
                 UUUUGUCAAUAUAUGGGCU 
                 1324 
               
               
                   
               
               
                 NM_001735.2_1499-1517_s 
                 1499-1517 
                 GCCCAUAUAUUGACAAAAU 
                  756 
                 AUUUUGUCAAUAUAUGGGC 
                 1325 
               
               
                   
               
               
                 NM_001735.2_1500-1518_s 
                 1500-1518 
                 CCCAUAUAUUGACAAAAUA 
                  757 
                 UAUUUUGUCAAUAUAUGGG 
                 1326 
               
               
                   
               
               
                 NM_001735.2_1501-1519_s 
                 1501-1519 
                 CCAUAUAUUGACAAAAUAA 
                  758 
                 UUAUUUUGUCAAUAUAUGG 
                 1327 
               
               
                   
               
               
                 NM_001735.2_1502-1520_s 
                 1502-1520 
                 CAUAUAUUGACAAAAUAAC 
                  759 
                 GUUAUUUUGUCAAUAUAUG 
                 1328 
               
               
                   
               
               
                 NM_001735.2_1503-1521_s 
                 1503-1521 
                 AUAUAUUGACAAAAUAACU 
                  760 
                 AGUUAUUUUGUCAAUAUAU 
                 1329 
               
               
                   
               
               
                 NM_001735.2_1504-1522_s 
                 1504-1522 
                 UAUAUUGACAAAAUAACUC 
                  761 
                 GAGUUAUUUUGUCAAUAUA 
                 1330 
               
               
                   
               
               
                 NM_001735.2_1505-1523_s 
                 1505-1523 
                 AUAUUGACAAAAUAACUCA 
                  762 
                 UGAGUUAUUUUGUCAAUAU 
                 1331 
               
               
                   
               
               
                 NM_001735.2_1506-1524_s 
                 1506-1524 
                 UAUUGACAAAAUAACUCAC 
                  763 
                 GUGAGUUAUUUUGUCAAUA 
                 1332 
               
               
                   
               
               
                 NM_001735.2_1507-1525_s 
                 1507-1525 
                 AUUGACAAAAUAACUCACU 
                  764 
                 AGUGAGUUAUUUUGUCAAU 
                 1333 
               
               
                   
               
               
                 NM_001735.2_1508-1526_s 
                 1508-1526 
                 UUGACAAAAUAACUCACUA 
                  765 
                 UAGUGAGUUAUUUUGUCAA 
                 1334 
               
               
                   
               
               
                 NM_001735.2_1509-1527_s 
                 1509-1527 
                 UGACAAAAUAACUCACUAU 
                  766 
                 AUAGUGAGUUAUUUUGUCA 
                 1335 
               
               
                   
               
               
                 NM_001735.2_1510-1528_s 
                 1510-1528 
                 GACAAAAUAACUCACUAUA 
                  767 
                 UAUAGUGAGUUAUUUUGUC 
                 1336 
               
               
                   
               
               
                 NM_001735.2_1513-1531_s 
                 1513-1531 
                 AAAAUAACUCACUAUAAUU 
                  768 
                 AAUUAUAGUGAGUUAUUUU 
                 1337 
               
               
                   
               
               
                 NM_001735.2_1514-1532_s 
                 1514-1532 
                 AAAUAACUCACUAUAAUUA 
                  769 
                 UAAUUAUAGUGAGUUAUUU 
                 1338 
               
               
                   
               
               
                 NM_001735.2_1515-1533_s 
                 1515-1533 
                 AAUAACUCACUAUAAUUAC 
                  770 
                 GUAAUUAUAGUGAGUUAUU 
                 1339 
               
               
                   
               
               
                 NM_001735.2_1516-1534_s 
                 1516-1534 
                 AUAACUCACUAUAAUUACU 
                  771 
                 AGUAAUUAUAGUGAGUUAU 
                 1340 
               
               
                   
               
               
                 NM_001735.2_1518-1536_s 
                 1518-1536 
                 AACUCACUAUAAUUACUUG 
                  772 
                 CAAGUAAUUAUAGUGAGUU 
                 1341 
               
               
                   
               
               
                 NM_001735.2_1519-1537_s 
                 1519-1537 
                 ACUCACUAUAAUUACUUGA 
                  773 
                 UCAAGUAAUUAUAGUGAGU 
                 1342 
               
               
                   
               
               
                 NM_001735.2_1520-1538_s 
                 1520-1538 
                 CUCACUAUAAUUACUUGAU 
                  774 
                 AUCAAGUAAUUAUAGUGAG 
                 1343 
               
               
                   
               
               
                 NM_001735.2_1521-1539_s 
                 1521-1539 
                 UCACUAUAAUUACUUGAUU 
                  775 
                 AAUCAAGUAAUUAUAGUGA 
                 1344 
               
               
                   
               
               
                 NM_001735.2_1523-1541_s 
                 1523-1541 
                 ACUAUAAUUACUUGAUUUU 
                  776 
                 AAAAUCAAGUAAUUAUAGU 
                 1345 
               
               
                   
               
               
                 NM_001735.2_1524-1542_s 
                 1524-1542 
                 CUAUAAUUACUUGAUUUUA 
                  777 
                 UAAAAUCAAGUAAUUAUAG 
                 1346 
               
               
                   
               
               
                 NM_001735.2_1525-1543_s 
                 1525-1543 
                 UAUAAUUACUUGAUUUUAU 
                  778 
                 AUAAAAUCAAGUAAUUAUA 
                 1347 
               
               
                   
               
               
                 NM_001735.2_1526-1544_s 
                 1526-1544 
                 AUAAUUACUUGAUUUUAUC 
                  779 
                 GAUAAAAUCAAGUAAUUAU 
                 1348 
               
               
                   
               
               
                 NM_001735.2_1527-1545_s 
                 1527-1545 
                 UAAUUACUUGAUUUUAUCC 
                  780 
                 GGAUAAAAUCAAGUAAUUA 
                 1349 
               
               
                   
               
               
                 NM_001735.2_1528-1546_s 
                 1528-1546 
                 AAUUACUUGAUUUUAUCCA 
                  781 
                 UGGAUAAAAUCAAGUAAUU 
                 1350 
               
               
                   
               
               
                 NM_001735.2_1529-1547_s 
                 1529-1547 
                 AUUACUUGAUUUUAUCCAA 
                  782 
                 UUGGAUAAAAUCAAGUAAU 
                 1351 
               
               
                   
               
               
                 NM_001735.2_1540-1558_s 
                 1540-1558 
                 UUAUCCAAGGGCAAAAUUA 
                  783 
                 UAAUUUUGCCCUUGGAUAA 
                 1352 
               
               
                   
               
               
                 NM_001735.2_1550-1568_s 
                 1550-1568 
                 GCAAAAUUAUCCACUUUGG 
                  784 
                 CCAAAGUGGAUAAUUUUGC 
                 1353 
               
               
                   
               
               
                 NM_001735.2_1561-1579_s 
                 1561-1579 
                 CACUUUGGCACGAGGGAGA 
                  785 
                 UCUCCCUCGUGCCAAAGUG 
                 1354 
               
               
                   
               
               
                 NM_001735.2_1571-1589_s 
                 1571-1589 
                 CGAGGGAGAAAUUUUCAGA 
                  786 
                 UCUGAAAAUUUCUCCCUCG 
                 1355 
               
               
                   
               
               
                 NM_001735.2_1581-1599_s 
                 1581-1599 
                 AUUUUCAGAUGCAUCUUAU 
                  787 
                 AUAAGAUGCAUCUGAAAAU 
                 1356 
               
               
                   
               
               
                 NM_001735.2_1591-1609_s 
                 1591-1609 
                 GCAUCUUAUCAAAGUAUAA 
                  788 
                 UUAUACUUUGAUAAGAUGC 
                 1357 
               
               
                   
               
               
                 NM_001735.2_1600-1618_s 
                 1600-1618 
                 CAAAGUAUAAACAUUCCAG 
                  789 
                 CUGGAAUGUUUAUACUUUG 
                 1358 
               
               
                   
               
               
                 NM_001735.2_1612-1630_s 
                 1612-1630 
                 AUUCCAGUAACACAGAACA 
                  790 
                 UGUUCUGUGUUACUGGAAU 
                 1359 
               
               
                   
               
               
                 NM_001735.2_1622-1640_s 
                 1622-1640 
                 CACAGAACAUGGUUCCUUC 
                  791 
                 GAAGGAACCAUGUUCUGUG 
                 1360 
               
               
                   
               
               
                 NM_001735.2_1632-1650_s 
                 1632-1560 
                 GGUUCCUUCAUCCCGACUU 
                  792 
                 AAGUCGGGAUGAAGGAACC 
                 1361 
               
               
                   
               
               
                 NM_001735.2_1643-1661_s 
                 1643-1661 
                 CCCGACUUCUGGUCUAUUA 
                  793 
                 UAAUAGACCAGAAGUCGGG 
                 1362 
               
               
                   
               
               
                 NM_001735.2_1653-1671_s 
                 1653-1671 
                 GGUCUAUUACAUCGUCACA 
                  794 
                 UGUGACGAUGUAAUAGACC 
                 1363 
               
               
                   
               
               
                 NM_001735.2_1663-1681_s 
                 1663-1681 
                 AUCGUCACAGGAGAACAGA 
                  795 
                 UCUGUUCUCCUGUGACGAU 
                 1364 
               
               
                   
               
               
                 NM_001735.2_1670-1688_s 
                 1670-1688 
                 CAGGAGAACAGACAGCAGA 
                  796 
                 UCUGCUGUCUGUUCUCCUG 
                 1365 
               
               
                   
               
               
                 NM_001735.2_1682-1700_s 
                 1682-1700 
                 CAGCAGAAUUAGUGUCUGA 
                  797 
                 UCAGACACUAAUUCUGCUG 
                 1366 
               
               
                   
               
               
                 NM_001735.2_1693-1711_s 
                 1693-1711 
                 GUGUCUGAUUCAGUCUGGU 
                  798 
                 ACCAGACUGAAUCAGACAC 
                 1367 
               
               
                   
               
               
                 NM_001735.2_1703-1721_s 
                 1703-1721 
                 CAGUCUGGUUAAAUAUUGA 
                  799 
                 UCAAUAUUUAACCAGACUG 
                 1368 
               
               
                   
               
               
                 NM_001735.2_1710-1728_s 
                 1710-1728 
                 GUUAAAUAUUGAAGAAAAA 
                  800 
                 UUUUUCUUCAAUAUUUAAC 
                 1369 
               
               
                   
               
               
                 NM_001735.2_1722-1740_s 
                 1722-1740 
                 AGAAAAAUGUGGCAACCAG 
                  801 
                 CUGGUUGCCACAUUUUUCU 
                 1370 
               
               
                   
               
               
                 NM_001735.2_1733-1751_s 
                 1733-1751 
                 GCAACCAGCUCCAGGUUCA 
                  802 
                 UGAACCUGGAGCUGGUUGC 
                 1371 
               
               
                   
               
               
                 NM_001735.2_1740-1758_s 
                 1740-1758 
                 GCUCCAGGUUCAUCUGUCU 
                  803 
                 AGACAGAUGAACCUGGAGC 
                 1372 
               
               
                   
               
               
                 NM_001735.2_1751-1769_s 
                 1751-1769 
                 AUCUGUCUCCUGAUGCAGA 
                  804 
                 UCUGCAUCAGGAGACAGAU 
                 1373 
               
               
                   
               
               
                 NM_001735.2_1762-1780_s 
                 1762-1780 
                 GAUGCAGAUGCAUAUUCUC 
                  805 
                 GAGAAUAUGCAUCUGCAUC 
                 1374 
               
               
                   
               
               
                 NM_001735.2_1771-1789_s 
                 1771-1789 
                 GCAUAUUCUCCAGGCCAAA 
                  806 
                 UUUGGCCUGGAGAAUAUGC 
                 1375 
               
               
                   
               
               
                 NM_001735.2_1782-1800_s 
                 1782-1800 
                 AGGCCAAACUGUGUCUCUU 
                  807 
                 AAGAGACACAGUUUGGCCU 
                 1376 
               
               
                   
               
               
                 NM_001735.2_1792-1810_s 
                 1792-1810 
                 GUGUCUCUUAAUAUGGCAA 
                  808 
                 UUGCCAUAUUAAGAGACAC 
                 1377 
               
               
                   
               
               
                 NM_001735.2_1799-1817_s 
                 1799-1817 
                 UUAAUAUGGCAACUGGAAU 
                  809 
                 AUUCCAGUUGCCAUAUUAA 
                 1378 
               
               
                   
               
               
                 NM_001735.2_1809-1827_s 
                 1809-1827 
                 AACUGGAAUGGAUUCCUGG 
                  810 
                 CCAGGAAUCCAUUCCAGUU 
                 1379 
               
               
                   
               
               
                 NM_001735.2_1821-1839_s 
                 1821-1839 
                 UUCCUGGGUGGCAUUAGCA 
                  811 
                 UGCUAAUGCCACCCAGGAA 
                 1380 
               
               
                   
               
               
                 NM_001735.2_1830-1848_s 
                 1830-1848 
                 GGCAUUAGCAGCAGUGGAC 
                  812 
                 GUCCACUGCUGCUAAUGCC 
                 1381 
               
               
                   
               
               
                 NM_001735.2_1842-1860_s 
                 1842-1860 
                 AGUGGACAGUGCUGUGUAU 
                  813 
                 AUACACAGCACUGUCCACU 
                 1382 
               
               
                   
               
               
                 NM_001735.2_1852-1870_s 
                 1852-1870 
                 GCUGUGUAUGGAGUCCAAA 
                  814 
                 UUUGGACUCCAUACACAGC 
                 1383 
               
               
                   
               
               
                 NM_001735.2_1863-1881_s 
                 1863-1881 
                 AGUCCAAAGAGGAGCCAAA 
                  815 
                 UUUGGCUCCUCUUUGGACU 
                 1384 
               
               
                   
               
               
                 NM_001735.2_1870-1888_s 
                 1870-1888 
                 AGAGGAGCCAAAAAGCCCU 
                  816 
                 AGGGCUUUUUGGCUCCUCU 
                 1385 
               
               
                   
               
               
                 NM_001735.2_1883-1901_s 
                 1883-1901 
                 AGCCCUUGGAAAGAGUAUU 
                  817 
                 AAUACUCUUUCCAAGGGCU 
                 1386 
               
               
                   
               
               
                 NM_001735.2_1893-1911_s 
                 1893-1911 
                 AAGAGUAUUUCAAUUCUUA 
                  818 
                 UAAGAAUUGAAAUACUCUU 
                 1387 
               
               
                   
               
               
                 NM_001735.2_1900-1918_s 
                 1900-1918 
                 UUUCAAUUCUUAGAGAAGA 
                  819 
                 UCUUCUCUAAGAAUUGAAA 
                 1388 
               
               
                   
               
               
                 NM_001735.2_1912-1930_s 
                 1912-1930 
                 GAGAAGAGUGAUCUGGGCU 
                  820 
                 AGCCCAGAUCACUCUUCUC 
                 1389 
               
               
                   
               
               
                 NM_001735.2_1920-1938_s 
                 1920-1938 
                 UGAUCUGGGCUGUGGGGCA 
                  821 
                 UGCCCCACAGCCCAGAUCA 
                 1390 
               
               
                   
               
               
                 NM_001735.2_1933-1951_s 
                 1933-1951 
                 GGGGCAGGUGGUGGCCUCA 
                  822 
                 UGAGGCCACCACCUGCCCC 
                 1391 
               
               
                   
               
               
                 NM_001735.2_1943-1961_s 
                 1943-1961 
                 GUGGCCUCAACAAUGCCAA 
                  823 
                 UUGGCAUUGUUGAGGCCAC 
                 1392 
               
               
                   
               
               
                 NM_001735.2_1950-1968_s 
                 1950-1968 
                 CAACAAUGCCAAUGUGUUC 
                  824 
                 GAACACAUUGGCAUUGUUG 
                 1393 
               
               
                   
               
               
                 NM_001735.2_1959-1977_s 
                 1959-1977 
                 CAAUGUGUUCCACCUAGCU 
                  825 
                 AGCUAGGUGGAACACAUUG 
                 1394 
               
               
                   
               
               
                 NM_001735.2_1969-1987_s 
                 1969-1987 
                 CACCUAGCUGGACUUACCU 
                  826 
                 AGGUAAGUCCAGCUAGGUG 
                 1395 
               
               
                   
               
               
                 NM_001735.2_1979-1997_s 
                 1979-1997 
                 GACUUACCUUCCUCACUAA 
                  827 
                 UUAGUGAGGAAGGUAAGUC 
                 1396 
               
               
                   
               
               
                 NM_001735.2_1991-2009_s 
                 1991-2009 
                 UCACUAAUGCAAAUGCAGA 
                  828 
                 UCUGCAUUUGCAUUAGUGA 
                 1397 
               
               
                   
               
               
                 NM_001735.2_2001-2019_s 
                 2001-2019 
                 AAAUGCAGAUGACUCCCAA 
                  829 
                 UUGGGAGUCAUCUGCAUUU 
                 1398 
               
               
                   
               
               
                 NM_001735.2_2013-2031_s 
                 2013-2013 
                 CUCCCAAGAAAAUGAUGAA 
                  830 
                 UUCAUCAUUUUCUUGGGAG 
                 1399 
               
               
                   
               
               
                 NM_001735.2_2032-2050_s 
                 2032-2050 
                 CCUUGUAAAGAAAUUCUCA 
                  831 
                 UGAGAAUUUCUUUACAAGG 
                 1400 
               
               
                   
               
               
                 NM_001735.2_2043-2061_s 
                 2043-2061 
                 AAUUCUCAGGCCAAGAAGA 
                  832 
                 UCUUCUUGGCCUGAGAAUU 
                 1401 
               
               
                   
               
               
                 NM_001735.2_2053-2071_s 
                 2053-2071 
                 CCAAGAAGAACGCUGCAAA 
                  833 
                 UUUGCAGCGUUCUUCUUGG 
                 1402 
               
               
                   
               
               
                 NM_001735.2_2063-2081_s 
                 2063-2081 
                 CGCUGCAAAAGAAGAUAGA 
                  834 
                 UCUAUCUUCUUUUGCAGCG 
                 1403 
               
               
                   
               
               
                 NM_001735.2 2070-2088_s 
                 2070-2088 
                 AAAGAAGAUAGAAGAAAUA 
                  835 
                 UAUUUCUUCUAUCUUCUUU 
                 1404 
               
               
                   
               
               
                 NM_001735.2_2082-2100_s 
                 2082-2100 
                 AGAAAUAGCUGCUAAAUAU 
                  836 
                 AUAUUUAGCAGCUAUUUCU 
                 1405 
               
               
                   
               
               
                 NM_001735.2_2089-2107_s 
                 2089-2107 
                 GCUGCUAAAUAUAAACAUU 
                  837 
                 AAUGUUUAUAUUUAGCAGC 
                 1406 
               
               
                   
               
               
                 NM_001735.2_2103-2121_s 
                 2103-2121 
                 ACAUUCAGUAGUGAAGAAA 
                  838 
                 UUUCUUCACUACUGAAUGU 
                 1407 
               
               
                   
               
               
                 NM_001735.2_2110-2128_s 
                 2110-2128 
                 GUAGUGAAGAAAUGUUGUU 
                  839 
                 AACAACAUUUCUUCACUAC 
                 1408 
               
               
                   
               
               
                 NM_001735.2_2119-2137_s 
                 2119-2137 
                 AAAUGUUGUUACGAUGGAG 
                  840 
                 CUCCAUCGUAACAACAUUU 
                 1409 
               
               
                   
               
               
                 NM_001735.2_2130-2148_s 
                 2130-2148 
                 CGAUGGAGCCUGCGUUAAU 
                  841 
                 AUUAACGCAGGCUCCAUCG 
                 1410 
               
               
                   
               
               
                 NM_001735.2_2142-2160_s 
                 2142-2160 
                 CGUUAAUAAUGAUGAAACC 
                  842 
                 GGUUUCAUCAUUAUUAACG 
                 1411 
               
               
                   
               
               
                 NM_001735.2_2150-2168_s 
                 2150-2168 
                 AUGAUGAAACCUGUGAGCA 
                  843 
                 UGCUCACAGGUUUCAUCAU 
                 1412 
               
               
                   
               
               
                 NM_001735.2_2160-2178_s 
                 2160-2178 
                 CUGUGAGCAGCGAGCUGCA 
                  844 
                 UGCAGCUCGCUGCUCACAG 
                 1413 
               
               
                   
               
               
                 NM_001735.2_2170-2188_s 
                 2170-2188 
                 CGAGCUGCACGGAUUAGUU 
                  845 
                 AACUAAUCCGUGCAGCUCG 
                 1414 
               
               
                   
               
               
                 NM_001735.2_2180-2198_s 
                 2180-2198 
                 GGAUUAGUUUAGGGCCAAG 
                  846 
                 CUUGGCCCUAAACUAAUCC 
                 1415 
               
               
                   
               
               
                 NM_001735.2_2191-2209_s 
                 2191-2209 
                 GGGCCAAGAUGCAUCAAAG 
                  847 
                 CUUUGAUGCAUCUUGGCCC 
                 1416 
               
               
                   
               
               
                 NM_001735.2_2202-2220_s 
                 2202-2220 
                 CAUCAAAGCUUUCACUGAA 
                  848 
                 UUCAGUGAAAGCUUUGAUG 
                 1417 
               
               
                   
               
               
                 NM_001735.2_2209-2227_s 
                 2209-2227 
                 GCUUUCACUGAAUGUUGUG 
                  849 
                 CACAACAUUCAGUGAAAGC 
                 1418 
               
               
                   
               
               
                 NM_001735.2_2219-2237_s 
                 2219-2237 
                 AAUGUUGUGUCGUCGCAAG 
                  850 
                 CUUGCGACGACACAACAUU 
                 1419 
               
               
                   
               
               
                 NM_001735.2_2229-2247_s 
                 2229-2247 
                 CGUCGCAAGCCAGCUCCGU 
                  851 
                 ACGGAGCUGGCUUGCGACG 
                 1420 
               
               
                   
               
               
                 NM_001735.2_2241-2259_s 
                 2241-2259 
                 GCUCCGUGCUAAUAUCUCU 
                  852 
                 AGAGAUAUUAGCACGGAGC 
                 1421 
               
               
                   
               
               
                 NM_001735.2_2249-2267_s 
                 2249-2267 
                 CUAAUAUCUCUCAUAAAGA 
                  853 
                 UCUUUAUGAGAGAUAUUAG 
                 1422 
               
               
                   
               
               
                 NM_001735.2_2263-2281_s 
                 2263-2281 
                 AAAGACAUGCAAUUGGGAA 
                  854 
                 UUCCCAAUUGCAUGUCUUU 
                 1423 
               
               
                   
               
               
                 NM_001735.2 2272-2290_s 
                 2272-2290 
                 CAAUUGGGAAGGCUACACA 
                  855 
                 UGUGUAGCCUUCCCAAUUG 
                 1424 
               
               
                   
               
               
                 NM_001735.2_2283-2301_s 
                 2283-2301 
                 GCUACACAUGAAGACCCUG 
                  856 
                 CAGGGUCUUCAUGUGUAGC 
                 1425 
               
               
                   
               
               
                 NM_001735.2_2289-2307_s 
                 2289-2307 
                 CAUGAAGACCCUGUUACCA 
                  857 
                 UGGUAACAGGGUCUUCAUG 
                 1426 
               
               
                   
               
               
                 NM_001735.2_2303-2321_s 
                 2303-2321 
                 UACCAGUAAGCAAGCCAGA 
                  858 
                 UCUGGCUUGCUUACUGGUA 
                 1427 
               
               
                   
               
               
                 NM_001735.2_2311-2329_s 
                 2311-2329 
                 AGCAAGCCAGAAAUUCGGA 
                  859 
                 UCCGAAUUUCUGGCUUGCU 
                 1428 
               
               
                   
               
               
                 NM_001735.2_2319-2337_s 
                 2319-2337 
                 AGAAAUUCGGAGUUAUUUU 
                  860 
                 AAAAUAACUCCGAAUUUCU 
                 1429 
               
               
                   
               
               
                 NM_001735.2 2329-2347_s 
                 2329-2347 
                 AGUUAUUUUCCAGAAAGCU 
                  861 
                 AGCUUUCUGGAAAAUAACU 
                 1430 
               
               
                   
               
               
                 NM_001735.2_2339-2357_s 
                 2339-2357 
                 CAGAAAGCUGGUUGUGGGA 
                  862 
                 UCCCACAACCAGCUUUCUG 
                 1431 
               
               
                   
               
               
                 NM_001735.2_2352-2370_s 
                 2352-2370 
                 GUGGGAAGUUCAUCUUGUU 
                  863 
                 AACAAGAUGAACUUCCCAC 
                 1432 
               
               
                   
               
               
                 NM_001735.2_2361-2379_s 
                 2361-2379 
                 UCAUCUUGUUCCCAGAAGA 
                  864 
                 UCUUCUGGGAACAAGAUGA 
                 1433 
               
               
                   
               
               
                 NM_001735.2_2372-2390_s 
                 2372-2390 
                 CCAGAAGAAAACAGUUGCA 
                  865 
                 UGCAACUGUUUUCUUCUGG 
                 1434 
               
               
                   
               
               
                 NM_001735.2_2383-2401_s 
                 2383-2401 
                 CAGUUGCAGUUUGCCCUAC 
                  866 
                 GUAGGGCAAACUGCAACUG 
                 1435 
               
               
                   
               
               
                 NM_001735.2_2389-2407_s 
                 2389-2407 
                 CAGUUUGCCCUACCUGAUU 
                  867 
                 AAUCAGGUAGGGCAAACUG 
                 1436 
               
               
                   
               
               
                 NM_001735.2_2401-2419_s 
                 2401-2419 
                 CCUGAUUCUCUAACCACCU 
                  868 
                 AGGUGGUUAGAGAAUCAGG 
                 1437 
               
               
                   
               
               
                 NM_001735.2_2413-2431_s 
                 2413-2431 
                 ACCACCUGGGAAAUUCAAG 
                  869 
                 CUUGAAUUUCCCAGGUGGU 
                 1438 
               
               
                   
               
               
                 NM_001735.2_2422-2440_s 
                 2422-2440 
                 GAAAUUCAAGGCGUUGGCA 
                  870 
                 UGCCAACGCCUUGAAUUUC 
                 1439 
               
               
                   
               
               
                 NM_001735.2_2433-2451_s 
                 2433-2451 
                 CGUUGGCAUUUCAAACACU 
                  871 
                 AGUGUUUGAAAUGCCAACG 
                 1440 
               
               
                   
               
               
                 NM_001735.2_2439-2457_s 
                 2439-2457 
                 CAUUUCAAACACUGGUAUA 
                  872 
                 UAUACCAGUGUUUGAAAUG 
                 1441 
               
               
                   
               
               
                 NM_001735.2_2453-2471_s 
                 2453-2471 
                 GUAUAUGUGUUGCUGAUAC 
                  873 
                 GUAUCAGCAACACAUAUAC 
                 1442 
               
               
                   
               
               
                 NM_001735.2_2463-2481_s 
                 2463-2481 
                 UGCUGAUACUGUCAAGGCA 
                  874 
                 UGCCUUGACAGUAUCAGCA 
                 1443 
               
               
                   
               
               
                 NM_001735.2_2471-2489_s 
                 2471-2489 
                 CUGUCAAGGCAAAGGUGUU 
                  875 
                 AACACCUUUGCCUUGACAG 
                 1444 
               
               
                   
               
               
                 NM_001735.2_2483-2501_s 
                 2483-2501 
                 AGGUGUUCAAAGAUGUCUU 
                  876 
                 AAGACAUCUUUGAACACCU 
                 1445 
               
               
                   
               
               
                 NM_001735.2_2490-2508_s 
                 2490-2508 
                 CAAAGAUGUCUUCCUGGAA 
                  877 
                 UUCCAGGAAGACAUCUUUG 
                 1446 
               
               
                   
               
               
                 NM_001735.2_2499-2517_s 
                 2499-2517 
                 CUUCCUGGAAAUGAAUAUA 
                  878 
                 UAUAUUCAUUUCCAGGAAG 
                 1447 
               
               
                   
               
               
                 NM_001735.2_2511-2529_s 
                 2511-2529 
                 GAAUAUACCAUAUUCUGUU 
                  879 
                 AACAGAAUAUGGUAUAUUC 
                 1448 
               
               
                   
               
               
                 NM_001735.2_2520-2538_s 
                 2520-2538 
                 AUAUUCUGUUGUACGAGGA 
                  880 
                 UCCUCGUACAACAGAAUAU 
                 1449 
               
               
                   
               
               
                 NM_001735.2_2533-2551_s 
                 2533-2551 
                 CGAGGAGAACAGAUCCAAU 
                  881 
                 AUUGGAUCUGUUCUCCUCG 
                 1450 
               
               
                   
               
               
                 NM_001735.2_2539-2557_s 
                 2539-2557 
                 GAACAGAUCCAAUUGAAAG 
                  882 
                 CUUUCAAUUGGAUCUGUUC 
                 1451 
               
               
                   
               
               
                 NM_001735.2_2553-2571_s 
                 2553-2571 
                 GAAAGGAACUGUUUACAAC 
                  883 
                 GUUGUAAACAGUUCCUUUC 
                 1452 
               
               
                   
               
               
                 NM_001735.2_2560-2578_s 
                 2560-2578 
                 ACUGUUUACAACUAUAGGA 
                  884 
                 UCCUAUAGUUGUAAACAGU 
                 1453 
               
               
                   
               
               
                 NM_001735.2_2569-2587_s 
                 2569-2587 
                 AACUAUAGGACUUCUGGGA 
                  885 
                 UCCCAGAAGUCCUAUAGUU 
                 1454 
               
               
                   
               
               
                 NM_001735.2_2583-2601_s 
                 2583-2601 
                 UGGGAUGCAGUUCUGUGUU 
                  886 
                 AACACAGAACUGCAUCCCA 
                 1455 
               
               
                   
               
               
                 NM_001735.2_2592-2610_s 
                 2592-2610 
                 GUUCUGUGUUAAAAUGUCU 
                  887 
                 AGACAUUUUAACACAGAAC 
                 1456 
               
               
                   
               
               
                 NM_001735.2_2600-2618_s 
                 2600-2618 
                 UUAAAAUGUCUGCUGUGGA 
                  888 
                 UCCACAGCAGACAUUUUAA 
                 1457 
               
               
                   
               
               
                 NM_001735.2_2612-2630_s 
                 2612-2630 
                 CUGUGGAGGGAAUCUGCAC 
                  889 
                 GUGCAGAUUCCCUCCACAG 
                 1458 
               
               
                   
               
               
                 NM_001735.2_2620-2638_s 
                 2620-2638 
                 GGAAUCUGCACUUCGGAAA 
                  890 
                 UUUCCGAAGUGCAGAUUCC 
                 1459 
               
               
                   
               
               
                 NM_001735.2_2633-2651_s 
                 2633-2651 
                 CGGAAAGCCCAGUCAUUGA 
                  891 
                 UCAAUGACUGGGCUUUCCG 
                 1460 
               
               
                   
               
               
                 NM_001735.2_2641-2659_s 
                 2641-2659 
                 CCAGUCAUUGAUCAUCAGG 
                  892 
                 CCUGAUGAUCAAUGACUGG 
                 1461 
               
               
                   
               
               
                 NM_001735.2_2653-2671_s 
                 2653-2671 
                 CAUCAGGGCACAAAGUCCU 
                  893 
                 AGGACUUUGUGCCCUGAUG 
                 1462 
               
               
                   
               
               
                 NM_001735.2_2659-2677_s 
                 2659-2677 
                 GGCACAAAGUCCUCCAAAU 
                  894 
                 AUUUGGAGGACUUUGUGCC 
                 1463 
               
               
                   
               
               
                 NM_001735.2 2673-2691_s 
                 2673-2691 
                 CAAAUGUGUGCGCCAGAAA 
                  895 
                 UUUCUGGCGCACACAUUUG 
                 1464 
               
               
                   
               
               
                 NM_001735.2_2682-2700_s 
                 2682-2700 
                 GCGCCAGAAAGUAGAGGGC 
                  896 
                 GCCCUCUACUUUCUGGCGC 
                 1465 
               
               
                   
               
               
                 NM_001735.2_2691-2709_s 
                 2691-2709 
                 AGUAGAGGGCUCCUCCAGU 
                  897 
                 ACUGGAGGAGCCCUCUACU 
                 1466 
               
               
                   
               
               
                 NM_001735.2_2702-2720_s 
                 2702-2720 
                 CCUCCAGUCACUUGGUGAC 
                  898 
                 GUCACCAAGUGACUGGAGG 
                 1467 
               
               
                   
               
               
                 NM_001735.2_2709-2727_s 
                 2709-2727 
                 UCACUUGGUGACAUUCACU 
                  899 
                 AGUGAAUGUCACCAAGUGA 
                 1468 
               
               
                   
               
               
                 NM_001735.2_2720-2738_s 
                 2720-2738 
                 CAUUCACUGUGCUUCCUCU 
                  900 
                 AGAGGAAGCACAGUGAAUG 
                 1469 
               
               
                   
               
               
                 NM_001735.2 2739-2757_s 
                 2739-2757 
                 GGAAAUUGGCCUUCACAAC 
                  901 
                 GUUGUGAAGGCCAAUUUCC 
                 1470 
               
               
                   
               
               
                 NM_001735.2_2749-2767_s 
                 2749-2767 
                 CUUCACAACAUCAAUUUUU 
                  902 
                 AAAAAUUGAUGUUGUGAAG 
                 1471 
               
               
                   
               
               
                 NM_001735.2_2761-2779_s 
                 2761-2779 
                 AAUUUUUCACUGGAGACUU 
                  903 
                 AAGUCUCCAGUGAAAAAUU 
                 1472 
               
               
                   
               
               
                 NM_001735.2_2770-2788_s 
                 2770-2788 
                 CUGGAGACUUGGUUUGGAA 
                  904 
                 UUCCAAACCAAGUCUCCAG 
                 1473 
               
               
                   
               
               
                 NM_001735.2_2780-2798_s 
                 2780-2798 
                 GGUUUGGAAAAGAAAUCUU 
                  905 
                 AAGAUUUCUUUUCCAAACC 
                 1474 
               
               
                   
               
               
                 NM_001735.2_2793-2811_s 
                 2793-2811 
                 AAUCUUAGUAAAAACAUUA 
                  906 
                 UAAUGUUUUUACUAAGAUU 
                 1475 
               
               
                   
               
               
                 NM_001735.2_2802-2820_s 
                 2802-2820 
                 AAAAACAUUACGAGUGGUG 
                  907 
                 CACCACUCGUAAUGUUUUU 
                 1476 
               
               
                   
               
               
                 NM_001735.2_2813-2831_s 
                 2813-2831 
                 GAGUGGUGCCAGAAGGUGU 
                  908 
                 ACACCUUCUGGCACCACUC 
                 1477 
               
               
                   
               
               
                 NM_001735.2_2823-2841_s 
                 2823-2841 
                 AGAAGGUGUCAAAAGGGAA 
                  909 
                 UUCCCUUUUGACACCUUCU 
                 1478 
               
               
                   
               
               
                 NM_001735.2_2829-2847_s 
                 2829-2847 
                 UGUCAAAAGGGAAAGCUAU 
                  910 
                 AUAGCUUUCCCUUUUGACA 
                 1479 
               
               
                   
               
               
                 NM_001735.2_2843-2861_s 
                 2843-2861 
                 GCUAUUCUGGUGUUACUUU 
                  911 
                 AAAGUAACACCAGAAUAGC 
                 1480 
               
               
                   
               
               
                 NM_001735.2_2852-2870_s 
                 2852-2870 
                 GUGUUACUUUGGAUCCUAG 
                  912 
                 CUAGGAUCCAAAGUAACAC 
                 1481 
               
               
                   
               
               
                 NM_001735.2_2862-2880_s 
                 2862-2880 
                 GGAUCCUAGGGGUAUUUAU 
                  913 
                 AUAAAUACCCCUAGGAUCC 
                 1482 
               
               
                   
               
               
                 NM_001735.2_2872-2890_s 
                 2872-2890 
                 GGUAUUUAUGGUACCAUUA 
                  914 
                 UAAUGGUACCAUAAAUACC 
                 1483 
               
               
                   
               
               
                 NM_001735.2 2882-2900_s 
                 2882-2900 
                 GUACCAUUAGCAGACGAAA 
                  915 
                 UUUCGUCUGCUAAUGGUAC 
                 1484 
               
               
                   
               
               
                 NM_001735.2_2892-2910_s 
                 2892-2910 
                 CAGACGAAAGGAGUUCCCA 
                  916 
                 UGGGAACUCCUUUCGUCUG 
                 1485 
               
               
                   
               
               
                 NM_001735.2_2900-2918_s 
                 2900-2918 
                 AGGAGUUCCCAUACAGGAU 
                  917 
                 AUCCUGUAUGGGAACUCCU 
                 1486 
               
               
                   
               
               
                 NM_001735.2_2909-2927_s 
                 2909-2927 
                 CAUACAGGAUACCCUUAGA 
                  918 
                 UCUAAGGGUAUCCUGUAUG 
                 1487 
               
               
                   
               
               
                 NM_001735.2_2922-2940_s 
                 2922-2940 
                 CUUAGAUUUGGUCCCCAAA 
                  919 
                 UUUGGGGACCAAAUCUAAG 
                 1488 
               
               
                   
               
               
                 NM_001735.2_2933-2951_s 
                 2933-2951 
                 UCCCCAAAACAGAAAUCAA 
                  920 
                 UUGAUUUCUGUUUUGGGGA 
                 1489 
               
               
                   
               
               
                 NM_001735.2_2941-2959_s 
                 2941-2959 
                 ACAGAAAUCAAAAGGAUUU 
                  921 
                 AAAUCCUUUUGAUUUCUGU 
                 1490 
               
               
                   
               
               
                 NM_001735.2_2951-2969_s 
                 2951-2969 
                 AAAGGAUUUUGAGUGUAAA 
                  922 
                 UUUACACUCAAAAUCCUUU 
                 1491 
               
               
                   
               
               
                 NM_001735.2_2962-2980_s 
                 2962-2980 
                 AGUGUAAAAGGACUGCUUG 
                  923 
                 CAAGCAGUCCUUUUACACU 
                 1492 
               
               
                   
               
               
                 NM_001735.2_2969-2987_s 
                 2969-2987 
                 AAGGACUGCUUGUAGGUGA 
                  924 
                 UCACCUACAAGCAGUCCUU 
                 1493 
               
               
                   
               
               
                 NM_001735.2_2980-2998_s 
                 2980-2998 
                 GUAGGUGAGAUCUUGUCUG 
                  925 
                 CAGACAAGAUCUCACCUAC 
                 1494 
               
               
                   
               
               
                 NM_001735.2_2989-3007_s 
                 2989-3007 
                 AUCUUGUCUGCAGUUCUAA 
                  926 
                 UUAGAACUGCAGACAAGAU 
                 1495 
               
               
                   
               
               
                 NM_001735.2_3001-3019_s 
                 3001-3019 
                 GUUCUAAGUCAGGAAGGCA 
                  927 
                 UGCCUUCCUGACUUAGAAC 
                 1496 
               
               
                   
               
               
                 NM_001735.2_3013-3031_s 
                 3013-3031 
                 GAAGGCAUCAAUAUCCUAA 
                  928 
                 UUAGGAUAUUGAUGCCUUC 
                 1497 
               
               
                   
               
               
                 NM_001735.2_3020-3038_s 
                 3020-3038 
                 UCAAUAUCCUAACCCACCU 
                  929 
                 AGGUGGGUUAGGAUAUUGA 
                 1498 
               
               
                   
               
               
                 NM_001735.2_3033-3051_s 
                 3033-3051 
                 CCACCUCCCCAAAGGGAGU 
                  930 
                 ACUCCCUUUGGGGAGGUGG 
                 1499 
               
               
                   
               
               
                 NM_001735.2_3039-3057_s 
                 3039-3057 
                 CCCCAAAGGGAGUGCAGAG 
                  931 
                 CUCUGCACUCCCUUUGGGG 
                 1500 
               
               
                   
               
               
                 NM_001735.2_3050-3068_s 
                 3050-3068 
                 GUGCAGAGGCGGAGCUGAU 
                  932 
                 AUCAGCUCCGCCUCUGCAC 
                 1501 
               
               
                   
               
               
                 NM_001735.2_3060-3078_s 
                 3060-3078 
                 GGAGCUGAUGAGCGUUGUC 
                  933 
                 GACAACGCUCAUCAGCUCC 
                 1502 
               
               
                   
               
               
                 NM_001735.2_3072-3090_s 
                 3072-3090 
                 CGUUGUCCCAGUAUUCUAU 
                  934 
                 AUAGAAUACUGGGACAACG 
                 1503 
               
               
                   
               
               
                 NM_001735.2_3079-3097_s 
                 3079-3097 
                 CCAGUAUUCUAUGUUUUUC 
                  935 
                 GAAAAACAUAGAAUACUGG 
                 1504 
               
               
                   
               
               
                 NM_001735.2_3091-3109_s 
                 3091-3109 
                 GUUUUUCACUACCUGGAAA 
                  936 
                 UUUCCAGGUAGUGAAAAAC 
                 1505 
               
               
                   
               
               
                 NM_001735.2_3102-3120_s 
                 3102-3120 
                 CCUGGAAACAGGAAAUCAU 
                  937 
                 AUGAUUUCCUGUUUCCAGG 
                 1506 
               
               
                   
               
               
                 NM_001735.2_3122-3140_s 
                 3122-3140 
                 GGAACAUUUUUCAUUCUGA 
                  938 
                 UCAGAAUGAAAAAUGUUCC 
                 1507 
               
               
                   
               
               
                 NM_001735.2_3133-3151_s 
                 3133-3151 
                 CAUUCUGACCCAUUAAUUG 
                  939 
                 CAAUUAAUGGGUCAGAAUG 
                 1508 
               
               
                   
               
               
                 NM_001735.2_3142-3160_s 
                 3142-3160 
                 CCAUUAAUUGAAAAGCAGA 
                  940 
                 UCUGCUUUUCAAUUAAUGG 
                 1509 
               
               
                   
               
               
                 NM_001735.2_3153-3171_s 
                 3153-3171 
                 AAAGCAGAAACUGAAGAAA 
                  941 
                 UUUCUUCAGUUUCUGCUUU 
                 1510 
               
               
                   
               
               
                 NM_001735.2_3161-3179_s 
                 3161-3179 
                 AACUGAAGAAAAAAUUAAA 
                  942 
                 UUUAAUUUUUUCUUCAGUU 
                 1511 
               
               
                   
               
               
                 NM_001735.2_3169-3187_s 
                 3169-3187 
                 AAAAAAUUAAAAGAAGGGA 
                  943 
                 UCCCUUCUUUUAAUUUUUU 
                 1512 
               
               
                   
               
               
                 NM_001735.2_3183-3201_s 
                 3183-3201 
                 AGGGAUGUUGAGCAUUAUG 
                  944 
                 CAUAAUGCUCAACAUCCCU 
                 1513 
               
               
                   
               
               
                 NM_001735.2_3192-3210_s 
                 3192-3210 
                 GAGCAUUAUGUCCUACAGA 
                  945 
                 UCUGUAGGACAUAAUGCUC 
                 1514 
               
               
                   
               
               
                 NM_001735.2_3200-3218_s 
                 3200-3218 
                 UGUCCUACAGAAAUGCUGA 
                  946 
                 UCAGCAUUUCUGUAGGACA 
                 1515 
               
               
                   
               
               
                 NM_001735.2_3211-3229_s 
                 3211-3229 
                 AAUGCUGACUACUCUUACA 
                  947 
                 UGUAAGAGUAGUCAGCAUU 
                 1516 
               
               
                   
               
               
                 NM_001735.2_3220-3238_s 
                 3220-3238 
                 UACUCUUACAGUGUGUGGA 
                  948 
                 UCCACACACUGUAAGAGUA 
                 1517 
               
               
                   
               
               
                 NM_001735.2_3229-3247_s 
                 3229-3247 
                 AGUGUGUGGAAGGGUGGAA 
                  949 
                 UUCCACCCUUCCACACACU 
                 1518 
               
               
                   
               
               
                 NM_001735.2_3240-3258_s 
                 3240-3258 
                 GGGUGGAAGUGCUAGCACU 
                  950 
                 AGUGCUAGCACUUCCACCC 
                 1519 
               
               
                   
               
               
                 NM_001735.2_3250-3268_s 
                 3250-3268 
                 GCUAGCACUUGGUUAACAG 
                  951 
                 CUGUUAACCAAGUGCUAGC 
                 1520 
               
               
                   
               
               
                 NM_001735.2_3260-3278_s 
                 3260-3278 
                 GGUUAACAGCUUUUGCUUU 
                  952 
                 AAAGCAAAAGCUGUUAACC 
                 1521 
               
               
                   
               
               
                 NM_001735.2_3273-3291_s 
                 3273-3291 
                 UGCUUUAAGAGUACUUGGA 
                  953 
                 UCCAAGUACUCUUAAAGCA 
                 1522 
               
               
                   
               
               
                 NM_001735.2_3283-3301_s 
                 3283-3301 
                 GUACUUGGACAAGUAAAUA 
                  954 
                 UAUUUACUUGUCCAAGUAC 
                 1523 
               
               
                   
               
               
                 NM_001735.2_3292-3310_s 
                 3292-3317 
                 CAAGUAAAUAAAUACGUAG 
                  955 
                 CUACGUAUUUAUUUACUUG 
                 1524 
               
               
                   
               
               
                 NM_001735.2_3299-3317_s 
                 3299-3317 
                 AUAAAUACGUAGAGCAGAA 
                  956 
                 UUCUGCUCUACGUAUUUAU 
                 1525 
               
               
                   
               
               
                 NM_001735.2_3310-3328_s 
                 3310-3328 
                 GAGCAGAACCAAAAUUCAA 
                  957 
                 UUGAAUUUUGGUUCUGCUC 
                 1526 
               
               
                   
               
               
                 NM_001735.2_3322-3340_s 
                 3322-3340 
                 AAUUCAAUUUGUAAUUCUU 
                  958 
                 AAGAAUUACAAAUUGAAUU 
                 1527 
               
               
                   
               
               
                 NM_001735.2_3332-3350_s 
                 3332-3350 
                 GUAAUUCUUUAUUGUGGCU 
                  959 
                 AGCCACAAUAAAGAAUUAC 
                 1528 
               
               
                   
               
               
                 NM_001735.2_3342-3360_s 
                 3342-3360 
                 AUUGUGGCUAGUUGAGAAU 
                  960 
                 AUUCUCAACUAGCCACAAU 
                 1529 
               
               
                   
               
               
                 NM_001735.2_3349-3367_s 
                 3349-3367 
                 CUAGUUGAGAAUUAUCAAU 
                  961 
                 AUUGAUAAUUCUCAACUAG 
                 1530 
               
               
                   
               
               
                 NM_001735.2_3360-3378_s 
                 3360-3378 
                 UUAUCAAUUAGAUAAUGGA 
                  962 
                 UCCAUUAUCUAAUUGAUAA 
                 1531 
               
               
                   
               
               
                 NM_001735.2_3373-3391_s 
                 3373-3391 
                 AAUGGAUCUUUCAAGGAAA 
                  963 
                 UUUCCUUGAAAGAUCCAUU 
                 1532 
               
               
                   
               
               
                 NM_001735.2_3380-3398_s 
                 3380-3398 
                 CUUUCAAGGAAAAUUCACA 
                  964 
                 UGUGAAUUUUCCUUGAAAG 
                 1533 
               
               
                   
               
               
                 NM_001735.2_3391-3409_s 
                 3391-3409 
                 AAUUCACAGUAUCAACCAA 
                  965 
                 UUGGUUGAUACUGUGAAUU 
                 1534 
               
               
                   
               
               
                 NM_001735.2_3399-3417_s 
                 3399-3417 
                 GUAUCAACCAAUAAAAUUA 
                  966 
                 UAAUUUUAUUGGUUGAUAC 
                 1535 
               
               
                   
               
               
                 NM_001735.2_3411-3429_s 
                 3411-3429 
                 AAAAUUACAGGGUACCUUG 
                  967 
                 CAAGGUACCCUGUAAUUUU 
                 1536 
               
               
                   
               
               
                 NM_001735.2_3419-3437_s 
                 3419-3437 
                 AGGGUACCUUGCCUGUUGA 
                  968 
                 UCAACAGGCAAGGUACCCU 
                 1537 
               
               
                   
               
               
                 NM_001735.2 j433-3451_s 
                 3433-3451 
                 GUUGAAGCCCGAGAGAACA 
                  969 
                 UGUUCUCUCGGGCUUCAAC 
                 1538 
               
               
                   
               
               
                 NM_001735.2_3441-3459_s 
                 3441-3559 
                 CCGAGAGAACAGCUUAUAU 
                  970 
                 AUAUAAGCUGUUCUCUCGG 
                 1539 
               
               
                   
               
               
                 NM_001735.2_3452-3470_s 
                 3452-3470 
                 GCUUAUAUCUUACAGCCUU 
                  971 
                 AAGGCUGUAAGAUAUAAGC 
                 1540 
               
               
                   
               
               
                 NM_001735.2_3460-3478_s 
                 3460-3478 
                 CUUACAGCCUUUACUGUGA 
                  972 
                 UCACAGUAAAGGCUGUAAG 
                 1541 
               
               
                   
               
               
                 NM_001735.2_3482-3500_s 
                 3482-3500 
                 GAAUUAGAAAGGCUUUCGA 
                  973 
                 UCGAAAGCCUUUCUAAUUC 
                 1542 
               
               
                   
               
               
                 NM_001735.2_3492-3510_s 
                 3492-3510 
                 GGCUUUCGAUAUAUGCCCC 
                  974 
                 GGGGCAUAUAUCGAAAGCC 
                 1543 
               
               
                   
               
               
                 NM_001735.2_3499-3517_s 
                 3499-3517 
                 GAUAUAUGCCCCCUGGUGA 
                  975 
                 UCACCAGGGGGCAUAUAUC 
                 1544 
               
               
                   
               
               
                 NM_001735.2_3513-3531_s 
                 3513-3531 
                 GGUGAAAAUCGACACAGCU 
                  976 
                 AGCUGUGUCGAUUUUCACC 
                 1545 
               
               
                   
               
               
                 NM_001735.2_3522-3540_s 
                 3522-3540 
                 CGACACAGCUCUAAUUAAA 
                  977 
                 UUUAAUUAGAGCUGUGUCG 
                 1546 
               
               
                   
               
               
                 NM_001735.2_3529-3547_s 
                 3529-3547 
                 GCUCUAAUUAAAGCUGACA 
                  978 
                 UGUCAGCUUUAAUUAGAGC 
                 1547 
               
               
                   
               
               
                 NM_001735.2_3542-3560_s 
                 3542-3560 
                 CUGACAACUUUCUGCUUGA 
                  979 
                 UCAAGCAGAAAGUUGUCAG 
                 1548 
               
               
                   
               
               
                 NM_001735.2_3549-3567_s 
                 3549-3567 
                 CUUUCUGCUUGAAAAUACA 
                  980 
                 UGUAUUUUCAAGCAGAAAG 
                 1549 
               
               
                   
               
               
                 NM_001735.2_3560-3578_s 
                 3560-3578 
                 AAAAUACACUGCCAGCCCA 
                  981 
                 UGGGCUGGCAGUGUAUUUU 
                 1550 
               
               
                   
               
               
                 NM_001735.2_3573-3591_s 
                 3573-3591 
                 AGCCCAGAGCACCUUUACA 
                  982 
                 UGUAAAGGUGCUCUGGGCU 
                 1551 
               
               
                   
               
               
                 NM_001735.2_3581-3599_s 
                 3581-3599 
                 GCACCUUUACAUUGGCCAU 
                  983 
                 AUGGCCAAUGUAAAGGUGC 
                 1552 
               
               
                   
               
               
                 NM_001735.2_3589-3607_s 
                 3589-3607 
                 ACAUUGGCCAUUUCUGCGU 
                  984 
                 ACGCAGAAAUGGCCAAUGU 
                 1553 
               
               
                   
               
               
                 NM_001735.2_3602-3620_s 
                 3602-3620 
                 CUGCGUAUGCUCUUUCCCU 
                  985 
                 AGGGAAAGAGCAUACGCAG 
                 1554 
               
               
                   
               
               
                 NM_001735.2_3613-3631_s 
                 3613-3631 
                 CUUUCCCUGGGAGAUAAAA 
                  986 
                 UUUUAUCUCCCAGGGAAAG 
                 1555 
               
               
                   
               
               
                 NM_001735.2_3623-3641_s 
                 3623-3641 
                 GAGAUAAAACUCACCCACA 
                  987 
                 UGUGGGUGAGUUUUAUCUC 
                 1556 
               
               
                   
               
               
                 NM_001735.2_3631-3649_s 
                 3631-3649 
                 ACUCACCCACAGUUUCGUU 
                  988 
                 AACGAAACUGUGGGUGAGU 
                 1557 
               
               
                   
               
               
                 NM_001735.2_3640-3658_s 
                 3640-3658 
                 CAGUUUCGUUCAAUUGUUU 
                  989 
                 AAACAAUUGAACGAAACUG 
                 1558 
               
               
                   
               
               
                 NM_001735.2_3650-3668_s 
                 3650-3668 
                 CAAUUGUUUCAGCUUUGAA 
                  990 
                 UUCAAAGCUGAAACAAUUG 
                 1559 
               
               
                   
               
               
                 NM_001735.2_3662-3680_s 
                 3662-3680 
                 CUUUGAAGAGAGAAGCUUU 
                  991 
                 AAAGCUUCUCUCUUCAAAG 
                 1560 
               
               
                   
               
               
                 NM_001735.2_3669-3687_s 
                 3669-3687 
                 GAGAGAAGCUUUGGUUAAA 
                  992 
                 UUUAACCAAAGCUUCUCUC 
                 1561 
               
               
                   
               
               
                 NM_001735.2_3682-3700_s 
                 3682-3700 
                 GUUAAAGGUAAUCCACCCA 
                  993 
                 UGGGUGGAUUACCUUUAAC 
                 1562 
               
               
                   
               
               
                 NM_001735.2_3691-3709_s 
                 3691-3709 
                 AAUCCACCCAUUUAUCGUU 
                  994 
                 AACGAUAAAUGGGUGGAUU 
                 1563 
               
               
                   
               
               
                 NM_001735.2_3699-3717_s 
                 3699-3717 
                 CAUUUAUCGUUUUUGGAAA 
                  995 
                 UUUCCAAAAACGAUAAAUG 
                 1564 
               
               
                   
               
               
                 NM_001735.2_3710-3728_s 
                 3710-3728 
                 UUUGGAAAGACAAUCUUCA 
                  996 
                 UGAAGAUUGUCUUUCCAAA 
                 1565 
               
               
                   
               
               
                 NM_001735.2_3721-3739_s 
                 3721-3739 
                 AAUCUUCAGCAUAAAGACA 
                  997 
                 UGUCUUUAUGCUGAAGAUU 
                 1566 
               
               
                   
               
               
                 NM_001735.2_3730-3748_s 
                 3730-3748 
                 CAUAAAGACAGCUCUGUAC 
                  998 
                 GUACAGAGCUGUCUUUAUG 
                 1567 
               
               
                   
               
               
                 NM_001735.2_3741-3759_s 
                 3741-3759 
                 CUCUGUACCUAACACUGGU 
                  999 
                 ACCAGUGUUAGGUACAGAG 
                 1568 
               
               
                   
               
               
                 NM_001735.2_3752-3770_s 
                 3752-3770 
                 ACACUGGUACGGCACGUAU 
                 1000 
                 AUACGUGCCGUACCAGUGU 
                 1569 
               
               
                   
               
               
                 NM_001735.2_3762-3780_s 
                 3762-3780 
                 GGCACGUAUGGUAGAAACA 
                 1001 
                 UGUUUCUACCAUACGUGCC 
                 1570 
               
               
                   
               
               
                 NM_001735.2_3771-3789_s 
                 3771-3789 
                 GGUAGAAACAACUGCCUAU 
                 1002 
                 AUAGGCAGUUGUUUCUACC 
                 1571 
               
               
                   
               
               
                 NM_001735.2_3779-3797_s 
                 3779-3797 
                 CAACUGCCUAUGCUUUACU 
                 1003 
                 AGUAAAGCAUAGGCAGUUG 
                 1572 
               
               
                   
               
               
                 NM_001735.2_3791-3809_s 
                 3791-3809 
                 CUUUACUCACCAGUCUGAA 
                 1004 
                 UUCAGACUGGUGAGUAAAG 
                 1573 
               
               
                   
               
               
                 NM_001735.2_3803-3821_s 
                 3803-3821 
                 GUCUGAACUUGAAAGAUAU 
                 1005 
                 AUAUCUUUCAAGUUCAGAC 
                 1574 
               
               
                   
               
               
                 NM_001735.2_3809-3827_s 
                 3809-3827 
                 ACUUGAAAGAUAUAAAUUA 
                 1006 
                 UAAUUUAUAUCUUUCAAGU 
                 1575 
               
               
                   
               
               
                 NM_001735.2_3819-3837_s 
                 3819-3837 
                 UAUAAAUUAUGUUAACCCA 
                 1007 
                 UGGGUUAACAUAAUUUAUA 
                 1576 
               
               
                   
               
               
                 NM_001735.2_3829-3847_s 
                 3829-3847 
                 GUUAACCCAGUCAUCAAAU 
                 1008 
                 AUUUGAUGACUGGGUUAAC 
                 1577 
               
               
                   
               
               
                 NM_001735.2_3839-3857_s 
                 3839-3857 
                 UCAUCAAAUGGCUAUCAGA 
                 1009 
                 UCUGAUAGCCAUUUGAUGA 
                 1578 
               
               
                   
               
               
                 NM_001735.2_3851-3869_s 
                 3851-3869 
                 UAUCAGAAGAGCAGAGGUA 
                 1010 
                 UACCUCUGCUCUUCUGAUA 
                 1579 
               
               
                   
               
               
                 NM_001735.2_3863-3881_s 
                 3863-3881 
                 AGAGGUAUGGAGGUGGCUU 
                 1011 
                 AAGCCACCUCCAUACCUCU 
                 1580 
               
               
                   
               
               
                 NM_001735.2_3872-3890_s 
                 3872-3890 
                 GAGGUGGCUUUUAUUCAAC 
                 1012 
                 GUUGAAUAAAAGCCACCUC 
                 1581 
               
               
                   
               
               
                 NM_001735.2_3883-3901_s 
                 3883-3901 
                 UAUUCAACCCAGGACACAA 
                 1013 
                 UUGUGUCCUGGGUUGAAUA 
                 1582 
               
               
                   
               
               
                 NM_001735.2_3893-3911_s 
                 3893-3911 
                 AGGACACAAUCAAUGCCAU 
                 1014 
                 AUGGCAUUGAUUGUGUCCU 
                 1583 
               
               
                   
               
               
                 NM_001735.2_3899-3917_s 
                 3899-3917 
                 CAAUCAAUGCCAUUGAGGG 
                 1015 
                 CCCUCAAUGGCAUUGAUUG 
                 1584 
               
               
                   
               
               
                 NM_001735.2_3909-3927_s 
                 3909-3927 
                 CAUUGAGGGCCUGACGGAA 
                 1016 
                 UUCCGUCAGGCCCUCAAUG 
                 1585 
               
               
                   
               
               
                 NM_001735.2_3922-3940_s 
                 3922-3940 
                 ACGGAAUAUUCACUCCUGG 
                 1017 
                 CCAGGAGUGAAUAUUCCGU 
                 1586 
               
               
                   
               
               
                 NM_001735.2_3930-3948_s 
                 3930-3948 
                 UUCACUCCUGGUUAAACAA 
                 1018 
                 UUGUUUAACCAGGAGUGAA 
                 1587 
               
               
                   
               
               
                 NM_001735.2_3939-3957_s 
                 3939-3957 
                 GGUUAAACAACUCCGCUUG 
                 1019 
                 CAAGCGGAGUUGUUUAACC 
                 1588 
               
               
                   
               
               
                 NM_001735.2_3951-3969_s 
                 3951-3969 
                 CCGCUUGAGUAUGGACAUC 
                 1020 
                 GAUGUCCAUACUCAAGCGG 
                 1589 
               
               
                   
               
               
                 NM_001735.2_3963-3981_s 
                 3963-3981 
                 GGACAUCGAUGUUUCUUAC 
                 1021 
                 GUAAGAAACAUCGAUGUCC 
                 1590 
               
               
                   
               
               
                 NM_001735.2_3969-3987_s 
                 3969-3987 
                 CGAUGUUUCUUACAAGCAU 
                 1022 
                 AUGCUUGUAAGAAACAUCG 
                 1591 
               
               
                   
               
               
                 NM_001735.2_3981-3999_s 
                 3981-3999 
                 CAAGCAUAAAGGUGCCUUA 
                 1023 
                 UAAGGCACCUUUAUGCUUG 
                 1592 
               
               
                   
               
               
                 NM_001735.2_3992-4010_s 
                 3992-4010 
                 GUGCCUUACAUAAUUAUAA 
                 1024 
                 UUAUAAUUAUGUAAGGCAC 
                 1593 
               
               
                   
               
               
                 NM_001735.2_3999-4017_s 
                 3999-4017 
                 ACAUAAUUAUAAAAUGACA 
                 1025 
                 UGUCAUUUUAUAAUUAUGU 
                 1594 
               
               
                   
               
               
                 NM_001735.2_4009-4027_s 
                 4009-4027 
                 AAAAUGACAGACAAGAAUU 
                 1026 
                 AAUUCUUGUCUGUCAUUUU 
                 1595 
               
               
                   
               
               
                 NM_001735.2_4020-4038_s 
                 4020-4038 
                 CAAGAAUUUCCUUGGGAGG 
                 1027 
                 CCUCCCAAGGAAAUUCUUG 
                 1596 
               
               
                   
               
               
                 NM_001735.2_4029-4047_s 
                 4029-4047 
                 CCUUGGGAGGCCAGUAGAG 
                 1028 
                 CUCUACUGGCCUCCCAAGG 
                 1597 
               
               
                   
               
               
                 NM_001735.2_4041-4059_s 
                 4041-4059 
                 AGUAGAGGUGCUUCUCAAU 
                 1029 
                 AUUGAGAAGCACCUCUACU 
                 1598 
               
               
                   
               
               
                 NM_001735.2_4051-4069_s 
                 4051-4069 
                 CUUCUCAAUGAUGACCUCA 
                 1030 
                 UGAGGUCAUCAUUGAGAAG 
                 1599 
               
               
                   
               
               
                 NM_001735.2_4062-4080_s 
                 4062-4080 
                 UGACCUCAUUGUCAGUACA 
                 1031 
                 UGUACUGACAAUGAGGUCA 
                 1600 
               
               
                   
               
               
                 NM_001735.2_4072-4090_s 
                 4072-4090 
                 GUCAGUACAGGAUUUGGCA 
                 1032 
                 UGCCAAAUCCUGUACUGAC 
                 1601 
               
               
                   
               
               
                 NM_001735.2_4080-4098_s 
                 4080-4098 
                 AGGAUUUGGCAGUGGCUUG 
                 1033 
                 CAAGCCACUGCCAAAUCCU 
                 1602 
               
               
                   
               
               
                 NM_001735.2_4092-4110_s 
                 4092-4110 
                 UGGCUUGGCUACAGUACAU 
                 1034 
                 AUGUACUGUAGCCAAGCCA 
                 1603 
               
               
                   
               
               
                 NM_001735.2_4099-4117_s 
                 4099-4117 
                 GCUACAGUACAUGUAACAA 
                 1035 
                 UUGUUACAUGUACUGUAGC 
                 1604 
               
               
                   
               
               
                 NM_001735.2_4113-4131_s 
                 4113-4131 
                 AACAACUGUAGUUCACAAA 
                 1036 
                 UUUGUGAACUACAGUUGUU 
                 1605 
               
               
                   
               
               
                 NM_001735.2_4120-4138_s 
                 4120-4138 
                 GUAGUUCACAAAACCAGUA 
                 1037 
                 UACUGGUUUUGUGAACUAC 
                 1606 
               
               
                   
               
               
                 NM_001735.2_4130-4148_s 
                 4130-4148 
                 AAACCAGUACCUCUGAGGA 
                 1038 
                 UCCUCAGAGGUACUGGUUU 
                 1607 
               
               
                   
               
               
                 NM_001735.2_4143-4161_s 
                 4143-4161 
                 UGAGGAAGUUUGCAGCUUU 
                 1039 
                 AAAGCUGCAAACUUCCUCA 
                 1608 
               
               
                   
               
               
                 NM_001735.2_4153-4171_s 
                 4153-4171 
                 UGCAGCUUUUAUUUGAAAA 
                 1040 
                 UUUUCAAAUAAAAGCUGCA 
                 1609 
               
               
                   
               
               
                 NM_001735.2_4163-4181_s 
                 4163-4181 
                 AUUUGAAAAUCGAUACUCA 
                 1041 
                 UGAGUAUCGAUUUUCAAAU 
                 1610 
               
               
                   
               
               
                 NM_001735.2_4173-4191_s 
                 4173-4191 
                 CGAUACUCAGGAUAUUGAA 
                 1042 
                 UUCAAUAUCCUGAGUAUCG 
                 1611 
               
               
                   
               
               
                 NM_001735.2_4182-4200_s 
                 4182-4200 
                 GGAUAUUGAAGCAUCCCAC 
                 1043 
                 GUGGGAUGCUUCAAUAUCC 
                 1612 
               
               
                   
               
               
                 NM_001735.2_4189-4207_s 
                 4189-4207 
                 GAAGCAUCCCACUACAGAG 
                 1044 
                 CUCUGUAGUGGGAUGCUUC 
                 1613 
               
               
                   
               
               
                 NM_001735.2_4199-4217_s 
                 4199-4217 
                 ACUACAGAGGCUACGGAAA 
                 1045 
                 UUUCCGUAGCCUCUGUAGU 
                 1614 
               
               
                   
               
               
                 NM_001735.2_4212-4230_s 
                 4212-4230 
                 CGGAAACUCUGAUUACAAA 
                 1046 
                 UUUGUAAUCAGAGUUUCCG 
                 1615 
               
               
                   
               
               
                 NM_001735.2_4221-4239_s 
                 4221-4239 
                 UGAUUACAAACGCAUAGUA 
                 1047 
                 UACUAUGCGUUUGUAAUCA 
                 1616 
               
               
                   
               
               
                 NM_001735.2_4232-4250_s 
                 4232-4250 
                 GCAUAGUAGCAUGUGCCAG 
                 1048 
                 CUGGCACAUGCUACUAUGC 
                 1617 
               
               
                   
               
               
                 NM_001735.2_4240-4258_s 
                 4240-4258 
                 GCAUGUGCCAGCUACAAGC 
                 1049 
                 GCUUGUAGCUGGCACAUGC 
                 1618 
               
               
                   
               
               
                 NM_001735.2_4251-4269_s 
                 4251-4269 
                 CUACAAGCCCAGCAGGGAA 
                 1050 
                 UUCCCUGCUGGGCUUGUAG 
                 1619 
               
               
                   
               
               
                 NM_001735.2_4260-4278_s 
                 4260-4278 
                 CAGCAGGGAAGAAUCAUCA 
                 1051 
                 UGAUGAUUCUUCCCUGCUG 
                 1620 
               
               
                   
               
               
                 NM_001735.2_4270-4288_s 
                 4270-4288 
                 GAAUCAUCAUCUGGAUCCU 
                 1052 
                 AGGAUCCAGAUGAUGAUUC 
                 1621 
               
               
                   
               
               
                 NM_001735.2_4283-4301_s 
                 4283-4301 
                 GAUCCUCUCAUGCGGUGAU 
                 1053 
                 AUCACCGCAUGAGAGGAUC 
                 1622 
               
               
                   
               
               
                 NM_001735.2_4289-4307_s 
                 4289-4307 
                 CUCAUGCGGUGAUGGACAU 
                 1054 
                 AUGUCCAUCACCGCAUGAG 
                 1623 
               
               
                   
               
               
                 NM_001735.2_4299-4317_s 
                 4299-4317 
                 GAUGGACAUCUCCUUGCCU 
                 1055 
                 AGGCAAGGAGAUGUCCAUC 
                 1624 
               
               
                   
               
               
                 NM_001735.2_4311-4329_s 
                 4311-4329 
                 CUUGCCUACUGGAAUCAGU 
                 1056 
                 ACUGAUUCCAGUAGGCAAG 
                 1625 
               
               
                   
               
               
                 NM_001735.2_4322-4340_s 
                 4322-4340 
                 GAAUCAGUGCAAAUGAAGA 
                 1057 
                 UCUUCAUUUGCACUGAUUC 
                 1626 
               
               
                   
               
               
                 NM_001735.2_4332-4350_s 
                 4332-4350 
                 AAAUGAAGAAGACUUAAAA 
                 1058 
                 UUUUAAGUCUUCUUCAUUU 
                 1627 
               
               
                   
               
               
                 NM_001735.2_4339-4357_s 
                 4339-4357 
                 GAAGACUUAAAAGCCCUUG 
                 1059 
                 CAAGGGCUUUUAAGUCUUC 
                 1628 
               
               
                   
               
               
                 NM_001735.2_4353-4371_s 
                 4353-4371 
                 CCUUGUGGAAGGGGUGGAU 
                 1060 
                 AUCCACCCCUUCCACAAGG 
                 1629 
               
               
                   
               
               
                 NM_001735.2_4360-4378_s 
                 4360-4378 
                 GAAGGGGUGGAUCAACUAU 
                 1061 
                 AUAGUUGAUCCACCCCUUC 
                 1630 
               
               
                   
               
               
                 NM_001735.2_4370-4388_s 
                 4370-4388 
                 AUCAACUAUUCACUGAUUA 
                 1062 
                 UAAUCAGUGAAUAGUUGAU 
                 1631 
               
               
                   
               
               
                 NM_001735.2_4380-4398_s 
                 4380-4398 
                 CACUGAUUACCAAAUCAAA 
                 1063 
                 UUUGAUUUGGUAAUCAGUG 
                 1632 
               
               
                   
               
               
                 NM_001735.2_4393-4411_s 
                 4393-4411 
                 AUCAAAGAUGGACAUGUUA 
                 1064 
                 UAACAUGUCCAUCUUUGAU 
                 1633 
               
               
                   
               
               
                 NM_001735.2_4402-4420_s 
                 4402-4420 
                 GGACAUGUUAUUCUGCAAC 
                 1065 
                 GUUGCAGAAUAACAUGUCC 
                 1634 
               
               
                   
               
               
                 NM_001735.2_4413-4431_s 
                 4413-4431 
                 UCUGCAACUGAAUUCGAUU 
                 1066 
                 AAUCGAAUUCAGUUGCAGA 
                 1635 
               
               
                   
               
               
                 NM_001735.2_4422-4440_s 
                 4422-4440 
                 GAAUUCGAUUCCCUCCAGU 
                 1067 
                 ACUGGAGGGAAUCGAAUUC 
                 1636 
               
               
                   
               
               
                 NM_001735.2_4432-4450_s 
                 4432-4450 
                 CCCUCCAGUGAUUUCCUUU 
                 1068 
                 AAAGGAAAUCACUGGAGGG 
                 1637 
               
               
                   
               
               
                 NM_001735.2_4441-4459_s 
                 4441-4459 
                 GAUUUCCUUUGUGUACGAU 
                 1069 
                 AUCGUACACAAAGGAAAUC 
                 1638 
               
               
                   
               
               
                 NM_001735.2_4453-4471_s 
                 4453-4471 
                 GUACGAUUCCGGAUAUUUG 
                 1070 
                 CAAAUAUCCGGAAUCGUAC 
                 1639 
               
               
                   
               
               
                 NM_001735.2_4462-4480_s 
                 4462-4480 
                 CGGAUAUUUGAACUCUUUG 
                 1071 
                 CAAAGAGUUCAAAUAUCCG 
                 1640 
               
               
                   
               
               
                 NM_001735.2_4473-4491_s 
                 4473-4491 
                 ACUCUUUGAAGUUGGGUUU 
                 1072 
                 AAACCCAACUUCAAAGAGU 
                 1641 
               
               
                   
               
               
                 NM_001735.2_4482-4500_s 
                 4482-4500 
                 AGUUGGGUUUCUCAGUCCU 
                 1073 
                 AGGACUGAGAAACCCAACU 
                 1642 
               
               
                   
               
               
                 NM_001735.2_4490-4508_s 
                 4490-4508 
                 UUCUCAGUCCUGCCACUUU 
                 1074 
                 AAAGUGGCAGGACUGAGAA 
                 1643 
               
               
                   
               
               
                 NM_001735.2_4503-4521_s 
                 4503-4521 
                 CACUUUCACAGUGUACGAA 
                 1075 
                 UUCGUACACUGUGAAAGUG 
                 1644 
               
               
                   
               
               
                 NM_001735.2_4509-4527_s 
                 4509-4527 
                 CACAGUGUACGAAUACCAC 
                 1076 
                 GUGGUAUUCGUACACUGUG 
                 1645 
               
               
                   
               
               
                 NM_001735.2_4523-4541_s 
                 4523-4541 
                 ACCACAGACCAGAUAAACA 
                 1077 
                 UGUUUAUCUGGUCUGUGGU 
                 1646 
               
               
                   
               
               
                 NM_001735.2_4531-4549_s 
                 4531-4549 
                 CCAGAUAAACAGUGUACCA 
                 1078 
                 UGGUACACUGUUUAUCUGG 
                 1647 
               
               
                   
               
               
                 NM_001735.2_4540-4558_s 
                 4540-4558 
                 CAGUGUACCAUGUUUUAUA 
                 1079 
                 UAUAAAACAUGGUACACUG 
                 1648 
               
               
                   
               
               
                 NM_001735.2_4551-4569_s 
                 4551-4569 
                 GUUUUAUAGCACUUCCAAU 
                 1080 
                 AUUGGAAGUGCUAUAAAAC 
                 1649 
               
               
                   
               
               
                 NM_001735.2_4562-4580_s 
                 4562-4580 
                 CUUCCAAUAUCAAAAUUCA 
                 1081 
                 UGAAUUUUGAUAUUGGAAG 
                 1650 
               
               
                   
               
               
                 NM_001735.2_4570-4588_s 
                 4570-4588 
                 AUCAAAAUUCAGAAAGUCU 
                 1082 
                 AGACUUUCUGAAUUUUGAU 
                 1651 
               
               
                   
               
               
                 NM_001735.2_4581-4599_s 
                 4581-4599 
                 GAAAGUCUGUGAAGGAGCC 
                 1083 
                 GGCUCCUUCACAGACUUUC 
                 1652 
               
               
                   
               
               
                 NM_001735.2_4591-4609_s 
                 4591-4609 
                 GAAGGAGCCGCGUGCAAGU 
                 1084 
                 ACUUGCACGCGGCUCCUUC 
                 1653 
               
               
                   
               
               
                 NM_001735.2_4601-4619_s 
                 4601-4619 
                 CGUGCAAGUGUGUAGAAGC 
                 1085 
                 GCUUCUACACACUUGCACG 
                 1654 
               
               
                   
               
               
                 NM_001735.2_4612-4630_s 
                 4612-4630 
                 GUAGAAGCUGAUUGUGGGC 
                 1086 
                 GCCCACAAUCAGCUUCUAC 
                 1655 
               
               
                   
               
               
                 NM_001735.2_4619-4637_s 
                 4619-4637 
                 CUGAUUGUGGGCAAAUGCA 
                 1087 
                 UGCAUUUGCCCACAAUCAG 
                 1656 
               
               
                   
               
               
                 NM_001735.2_4629-4647_s 
                 4629-4647 
                 GCAAAUGCAGGAAGAAUUG 
                 1088 
                 CAAUUCUUCCUGCAUUUGC 
                 1657 
               
               
                   
               
               
                 NM_001735.2_4639-4657_s 
                 4639-4657 
                 GAAGAAUUGGAUCUGACAA 
                 1089 
                 UUGUCAGAUCCAAUUCUUC 
                 1658 
               
               
                   
               
               
                 NM_001735.2_4651-4669_s 
                 4651-4669 
                 CUGACAAUCUCUGCAGAGA 
                 1090 
                 UCUCUGCAGAGAUUGUCAG 
                 1659 
               
               
                   
               
               
                 NM_001735.2_4663-4681_s 
                 4663-4681 
                 GCAGAGACAAGAAAACAAA 
                 1091 
                 UUUGUUUUCUUGUCUCUGC 
                 1660 
               
               
                   
               
               
                 NM_001735.2_4670-4688_s 
                 4670-4688 
                 CAAGAAAACAAACAGCAUG 
                 1092 
                 CAUGCUGUUUGUUUUCUUG 
                 1661 
               
               
                   
               
               
                 NM_001735.2_4681-4699_s 
                 4681-4699 
                 ACAGCAUGUAAACCAGAGA 
                 1093 
                 UCUCUGGUUUACAUGCUGU 
                 1662 
               
               
                   
               
               
                 NM_001735.2_4693-4711_s 
                 4693-4711 
                 CCAGAGAUUGCAUAUGCUU 
                 1094 
                 AAGCAUAUGCAAUCUCUGG 
                 1663 
               
               
                   
               
               
                 NM_001735.2_4702-4720_s 
                 4702-4720 
                 GCAUAUGCUUAUAAAGUUA 
                 1095 
                 UAACUUUAUAAGCAUAUGC 
                 1664 
               
               
                   
               
               
                 NM_001735.2_4710-4728_s 
                 4710-4728 
                 UUAUAAAGUUAGCAUCACA 
                 1096 
                 UGUGAUGCUAACUUUAUAA 
                 1665 
               
               
                   
               
               
                 NM_001735.2_4722-4740_s 
                 4722-4740 
                 CAUCACAUCCAUCACUGUA 
                 1097 
                 UACAGUGAUGGAUGUGAUG 
                 1666 
               
               
                   
               
               
                 NM_001735.2_4733-4751_s 
                 4733-4751 
                 UCACUGUAGAAAAUGUUUU 
                 1098 
                 AAAACAUUUUCUACAGUGA 
                 1667 
               
               
                   
               
               
                 NM_001735.2_4740-4758_s 
                 4740-4758 
                 AGAAAAUGUUUUUGUCAAG 
                 1099 
                 CUUGACAAAAACAUUUUCU 
                 1668 
               
               
                   
               
               
                 NM_001735.2_4750-4768_s 
                 4750-4768 
                 UUUGUCAAGUACAAGGCAA 
                 1100 
                 UUGCCUUGUACUUGACAAA 
                 1669 
               
               
                   
               
               
                 NM_001735.2_4763-4781_s 
                 4763-4781 
                 AGGCAACCCUUCUGGAUAU 
                 1101 
                 AUAUCCAGAAGGGUUGCCU 
                 1670 
               
               
                   
               
               
                 NM_001735.2_4770-4788_s 
                 4770-4788 
                 CCUUCUGGAUAUCUACAAA 
                 1102 
                 UUUGUAGAUAUCCAGAAGG 
                 1671 
               
               
                   
               
               
                 NM_001735.2_4779-4797_s 
                 4779-4797 
                 UAUCUACAAAACUGGGGAA 
                 1103 
                 UUCCCCAGUUUUGUAGAUA 
                 1672 
               
               
                   
               
               
                 NM_001735.2_4790-4808_s 
                 4790-4808 
                 CUGGGGAAGCUGUUGCUGA 
                 1104 
                 UCAGCAACAGCUUCCCCAG 
                 1673 
               
               
                   
               
               
                 NM_001735.2_4799-4817_s 
                 4799-4817 
                 CUGUUGCUGAGAAAGACUC 
                 1105 
                 GAGUCUUUCUCAGCAACAG 
                 1674 
               
               
                   
               
               
                 NM_001735.2_4813-4831_s 
                 4813-4831 
                 GACUCUGAGAUUACCUUCA 
                 1106 
                 UGAAGGUAAUCUCAGAGUC 
                 1675 
               
               
                   
               
               
                 NM_001735.2_4819-4837_s 
                 4819-4837 
                 GAGAUUACCUUCAUUAAAA 
                 1107 
                 UUUUAAUGAAGGUAAUCUC 
                 1676 
               
               
                   
               
               
                 NM_001735.2_4831-4849_s 
                 4831-4849 
                 AUUAAAAAGGUAACCUGUA 
                 1108 
                 UACAGGUUACCUUUUUAAU 
                 1677 
               
               
                   
               
               
                 NM_001735.2_4841-4859_s 
                 4841-4859 
                 UAACCUGUACUAACGCUGA 
                 1109 
                 UCAGCGUUAGUACAGGUUA 
                 1678 
               
               
                   
               
               
                 NM_001735.2_4850-4868_s 
                 4850-4868 
                 CUAACGCUGAGCUGGUAAA 
                 1110 
                 UUUACCAGCUCAGCGUUAG 
                 1679 
               
               
                   
               
               
                 NM_001735.2_4863-4881_s 
                 4863-4881 
                 GGUAAAAGGAAGACAGUAC 
                 1111 
                 GUACUGUCUUCCUUUUACC 
                 1680 
               
               
                   
               
               
                 NM_001735.2_4871-4889_s 
                 4871-4889 
                 GAAGACAGUACUUAAUUAU 
                 1112 
                 AUAAUUAAGUACUGUCUUC 
                 1681 
               
               
                   
               
               
                 NM_001735.2_4881-4899_s 
                 4881-4899 
                 CUUAAUUAUGGGUAAAGAA 
                 1113 
                 UUCUUUACCCAUAAUUAAG 
                 1682 
               
               
                   
               
               
                 NM_001735.2_4893-4911_s 
                 4893-4911 
                 UAAAGAAGCCCUCCAGAUA 
                 1114 
                 UAUCUGGAGGGCUUCUUUA 
                 1683 
               
               
                   
               
               
                 NM_001735.2_4902-4920_s 
                 4902-4920 
                 CCUCCAGAUAAAAUACAAU 
                 1115 
                 AUUGUAUUUUAUCUGGAGG 
                 1684 
               
               
                   
               
               
                 NM_001735.2_4912-4930_s 
                 4912-4930 
                 AAAUACAAUUUCAGUUUCA 
                 1116 
                 UGAAACUGAAAUUGUAUUU 
                 1685 
               
               
                   
               
               
                 NM_001735.2_4923-4941_s 
                 4923-4941 
                 CAGUUUCAGGUACAUCUAC 
                 1117 
                 GUAGAUGUACCUGAAACUG 
                 1686 
               
               
                   
               
               
                 NM_001735.2_4931-4949_s 
                 4931-4949 
                 GGUACAUCUACCCUUUAGA 
                 1118 
                 UCUAAAGGGUAGAUGUACC 
                 1687 
               
               
                   
               
               
                 NM_001735.2_4942-4960_s 
                 4942-4960 
                 CCUUUAGAUUCCUUGACCU 
                 1119 
                 AGGUCAAGGAAUCUAAAGG 
                 1688 
               
               
                   
               
               
                 NM_001735.2_4952-4970_s 
                 4952-4970 
                 CCUUGACCUGGAUUGAAUA 
                 1120 
                 UAUUCAAUCCAGGUCAAGG 
                 1689 
               
               
                   
               
               
                 NM_001735.2_4961-4979_s 
                 4961-4979 
                 GGAUUGAAUACUGGCCUAG 
                 1121 
                 CUAGGCCAGUAUUCAAUCC 
                 1690 
               
               
                   
               
               
                 NM_001735.2_4971-4989_s 
                 4971-4989 
                 CUGGCCUAGAGACACAACA 
                 1122 
                 UGUUGUGUCUCUAGGCCAG 
                 1691 
               
               
                   
               
               
                 NM_001735.2_4979-4997_s 
                 4979-4997 
                 GAGACACAACAUGUUCAUC 
                 1123 
                 GAUGAACAUGUUGUGUCUC 
                 1692 
               
               
                   
               
               
                 NM_001735.2_4991-5009_s 
                 4991-5009 
                 GUUCAUCGUGUCAAGCAUU 
                 1124 
                 AAUGCUUGACACGAUGAAC 
                 1693 
               
               
                   
               
               
                 NM_001735.2_5000-5018_s 
                 5000-5018 
                 GUCAAGCAUUUUUAGCUAA 
                 1125 
                 UUAGCUAAAAAUGCUUGAC 
                 1694 
               
               
                   
               
               
                 NM_001735.2_5013-5031_s 
                 5013-5031 
                 AGCUAAUUUAGAUGAAUUU 
                 1126 
                 AAAUUCAUCUAAAUUAGCU 
                 1695 
               
               
                   
               
               
                 NM_001735.2_5022-5040_s 
                 5022-5040 
                 AGAUGAAUUUGCCGAAGAU 
                 1127 
                 AUCUUCGGCAAAUUCAUCU 
                 1696 
               
               
                   
               
               
                 NM_001735.2_5033-5051_s 
                 5033-5051 
                 CCGAAGAUAUCUUUUUAAA 
                 1128 
                 UUUAAAAAGAUAUCUUCGG 
                 1697 
               
               
                   
               
               
                 NM_001735.2_5043-5061_s 
                 5043-5061 
                 CUUUUUAAAUGGAUGCUAA 
                 1129 
                 UUAGCAUCCAUUUAAAAAG 
                 1698 
               
               
                   
               
               
                 NM_001735.2_5053-5071_s 
                 5053-5071 
                 GGAUGCUAAAAUUCCUGAA 
                 1130 
                 UUCAGGAAUUUUAGCAUCC 
                 1699 
               
               
                   
               
               
                 NM_001735.2_5059-5077_s 
                 5059-5077 
                 UAAAAUUCCUGAAGUUCAG 
                 1131 
                 CUGAACUUCAGGAAUUUUA 
                 1700 
               
               
                   
               
               
                 NM_001735.2_5071-5089_s 
                 5071-5089 
                 AGUUCAGCUGCAUACAGUU 
                 1132 
                 AACUGUAUGCAGCUGAACU 
                 1701 
               
               
                   
               
               
                 NM_001735.2_5080-5098_s 
                 5080-5098 
                 GCAUACAGUUUGCACUUAU 
                 1133 
                 AUAAGUGCAAACUGUAUGC 
                 1702 
               
               
                   
               
               
                 NM_001735.2_5093-5111_s 
                 5093-5111 
                 ACUUAUGGACUCCUGUUGU 
                 1134 
                 ACAACAGGAGUCCAUAAGU 
                 1703 
               
               
                   
               
               
                 NM_001735.2_5099-5117_s 
                 5099-5117 
                 GGACUCCUGUUGUUGAAGU 
                 1135 
                 ACUUCAACAACAGGAGUCC 
                 1704 
               
               
                   
               
               
                 NM_001735.2_5109-5127_s 
                 5109-5127 
                 UGUUGAAGUUCGUUUUUUU 
                 1136 
                 AAAAAAACGAACUUCAACA 
                 1705 
               
               
                   
               
               
                 NM_001735.2_5122-5140_s 
                 5122-5140 
                 UUUUUUGUUUUCUUCUUUU 
                 1137 
                 AAAAGAAGAAAACAAAAAA 
                 1706 
               
               
                   
               
               
                 NM_001735.2_5132-5150_s 
                 5132-5150 
                 UCUUCUUUUUUUAAACAUU 
                 1138 
                 AAUGUUUAAAAAAAGAAGA 
                 1707 
               
               
                   
               
               
                 NM_001735.2_5139-5157_s 
                 5139-5157 
                 UUUUUAAACAUUCAUAGCU 
                 1139 
                 AGCUAUGAAUGUUUAAAAA 
                 1708 
               
               
                   
               
               
                 NM_001735.2_5152-5170_s 
                 5152-5170 
                 AUAGCUGGUCUUAUUUGUA 
                 1140 
                 UACAAAUAAGACCAGCUAU 
                 1709 
               
               
                   
               
               
                 NM_001735.2_5159-5177_s 
                 5159-5177 
                 GUCUUAUUUGUAAAGCUCA 
                 1141 
                 UGAGCUUUACAAAUAAGAC 
                 1710 
               
               
                   
               
               
                 NM_001735.2_5170-5188_s 
                 5170-5188 
                 AAAGCUCACUUUACUUAGA 
                 1142 
                 UCUAAGUAAAGUGAGCUUU 
                 1711 
               
               
                   
               
               
                 NM_001735.2_5182-5200_s 
                 5182-5200 
                 ACUUAGAAUUAGUGGCACU 
                 1143 
                 AGUGCCACUAAUUCUAAGU 
                 1712 
               
               
                   
               
               
                 NM_001735.2_5192-5210_s 
                 5192-5210 
                 AGUGGCACUUGCUUUUAUU 
                 1144 
                 AAUAAAAGCAAGUGCCACU 
                 1713 
               
               
                   
               
               
                 NM_001735.2_5202-5220_s 
                 5202-5220 
                 GCUUUUAUUAGAGAAUGAU 
                 1145 
                 AUCAUUCUCUAAUAAAAGC 
                 1714 
               
               
                   
               
               
                 NM_001735.2_5212-5230_s 
                 5212-5230 
                 GAGAAUGAUUUCAAAUGCU 
                 1146 
                 AGCAUUUGAAAUCAUUCUC 
                 1715 
               
               
                   
               
               
                 NM_001735.2_5220-5238_s 
                 5220-5238 
                 UUUCAAAUGCUGUAACUUU 
                 1147 
                 AAAGUUACAGCAUUUGAAA 
                 1716 
               
               
                   
               
               
                 NM_001735.2_5231-5249_s 
                 5231-5249 
                 GUAACUUUCUGAAAUAACA 
                 1148 
                 UGUUAUUUCAGAAAGUUAC 
                 1717 
               
               
                   
               
               
                 NM_001735.2_5241-5259_s 
                 5241-5259 
                 GAAAUAACAUGGCCUUGGA 
                 1149 
                 UCCAAGGCCAUGUUAUUUC 
                 1718 
               
               
                   
               
               
                 NM_001735.2_5253-5271_s 
                 5253-5271 
                 CCUUGGAGGGCAUGAAGAC 
                 1150 
                 GUCUUCAUGCCCUCCAAGG 
                 1719 
               
               
                   
               
               
                 NM_001735.2_5259-5277_s 
                 5259-5277 
                 AGGGCAUGAAGACAGAUAC 
                 1151 
                 GUAUCUGUCUUCAUGCCCU 
                 1720 
               
               
                   
               
               
                 NM_001735.2_5273-5291_s 
                 5273-5291 
                 GAUACUCCUCCAAGGUUAU 
                 1152 
                 AUAACCUUGGAGGAGUAUC 
                 1721 
               
               
                   
               
               
                 NM_001735.2_5279-5297_s 
                 5279-5297 
                 CCUCCAAGGUUAUUGGACA 
                 1153 
                 UGUCCAAUAACCUUGGAGG 
                 1722 
               
               
                   
               
               
                 NM_001735.2_5293-5311_s 
                 5293-5311 
                 GGACACCGGAAACAAUAAA 
                 1154 
                 UUUAUUGUUUCCGGUGUCC 
                 1723 
               
               
                   
               
               
                 NM_001735.2_5301-5319_s 
                 5301-5319 
                 GAAACAAUAAAUUGGAACA 
                 1155 
                 UGUUCCAAUUUAUUGUUUC 
                 1724 
               
               
                   
               
               
                 NM_001735.2_5311-5329_s 
                 5311-5329 
                 AUUGGAACACCUCCUCAAA 
                 1156 
                 UUUGAGGAGGUGUUCCAAU 
                 1725 
               
               
                   
               
               
                 NM_001735.2_5322-5340_s 
                 5322-5340 
                 UCCUCAAACCUACCACUCA 
                 1157 
                 UGAGUGGUAGGUUUGAGGA 
                 1726 
               
               
                   
               
               
                 NM_001735.2_5331-5349_s 
                 5331-5349 
                 CUACCACUCAGGAAUGUUU 
                 1158 
                 AAACAUUCCUGAGUGGUAG 
                 1727 
               
               
                   
               
               
                 NM_001735.2_5343-5361_s 
                 5343-5361 
                 AAUGUUUGCUGGGGCCGAA 
                 1159 
                 UUCGGCCCCAGCAAACAUU 
                 1728 
               
               
                   
               
               
                 NM_001735.2_5349-5367_s 
                 5349-5367 
                 UGCUGGGGCCGAAAGAACA 
                 1160 
                 UGUUCUUUCGGCCCCAGCA 
                 1729 
               
               
                   
               
               
                 NM_001735.2_5360-5378_s 
                 5360-5378 
                 AAAGAACAGUCCAUUGAAA 
                 1161 
                 UUUCAAUGGACUGUUCUUU 
                 1730 
               
               
                   
               
               
                 NM_001735.2_5371-5389_s 
                 5371-5389 
                 CAUUGAAAGGGAGUAUUAC 
                 1162 
                 GUAAUACUCCCUUUCAAUG 
                 1731 
               
               
                   
               
               
                 NM_001735.2_5380-5398_s 
                 5380-5398 
                 GGAGUAUUACAAAAACAUG 
                 1163 
                 CAUGUUUUUGUAAUACUCC 
                 1732 
               
               
                   
               
               
                 NM_001735.2_5391-5409_s 
                 5391-5409 
                 AAAACAUGGCCUUUGCUUG 
                 1164 
                 CAAGCAAAGGCCAUGUUUU 
                 1733 
               
               
                   
               
               
                 NM_001735.2_5399-5417_s 
                 5399-5417 
                 GCCUUUGCUUGAAAGAAAA 
                 1165 
                 UUUUCUUUCAAGCAAAGGC 
                 1734 
               
               
                   
               
               
                 NM_001735.2_5409-5427_s 
                 5409-5427 
                 GAAAGAAAAUACCAAGGAA 
                 1166 
                 UUCCUUGGUAUUUUCUUUC 
                 1735 
               
               
                   
               
               
                 NM_001735.2_5420-5438_s 
                 5420-5438 
                 CCAAGGAACAGGAAACUGA 
                 1167 
                 UCAGUUUCCUGUUCCUUGG 
                 1736 
               
               
                   
               
               
                 NM_001735.2_5433-5451_s 
                 5433-5451 
                 AACUGAUCAUUAAAGCCUG 
                 1168 
                 CAGGCUUUAAUGAUCAGUU 
                 1737 
               
               
                   
               
               
                 NM_001735.2_5441-5459_s 
                 5441-5459 
                 AUUAAAGCCUGAGUUUGCU 
                 1169 
                 AGCAAACUCAGGCUUUAAU 
                 1738 
               
               
                   
               
            
           
         
       
     
     Example 5: In Vivo C5 Silencing 
     Groups of three female cynomolgus macaques were treated with C5-siRNA AD-58641 subcutaneously in the scapular and mid-dorsal areas of the back at 2.5 mg/kg or 5 mg/kg doses or a vehicle control. Two rounds of dosing were administered with eight doses in each round given every third day. Serum C5 was collected and evaluated using an ELISA assay specific for C5 detection (Abcam) at the indicated time points ( FIG. 13 ). C5 levels were normalized to the average of three pre-dose samples. Samples collected prior to dosing, and on day 23 (24 hours after the last dose administered in the first round of treatment) were analyzed by complete serum chemistry, hematology and coagulation panels. 
     Analysis of serum C5 protein levels relative to pre-treatment serum C5 protein levels demonstrated that the 5 mg/kg AD-58641 dosing regimen reduced serum C5 protein levels up to 98% ( FIG. 12 ). The average serum C5 levels were reduced by 97% at the nadir, indicating that the majority of circulating C5 is hepatic in origin. There was potent, dose-dependent and durable knock-down of serum C5 protein levels with subcutaneous administration of AD-58641. No changes in hematology, serum chemistry or coagulation parameters were identified 24 hours after the first round of dosing. 
     Serum hemolytic activity was also analyzed using a sensitized sheep erythrocyte assay to measure classical pathway activity. The percent hemolysis was calculated relative to maximal hemolysis and to background hemolysis in control samples. Mean hemolysis values +/− the SEM for three animals were calculated and analyzed ( FIG. 13 ). Hemolysis was reduced up to 94% in the 5 mg/kg dosing regimen with an average inhibition of 92% at the nadir. The reduction in hemolysis was maintained for greater than two weeks following the last dose. 
     Example 6: In Vitro Screening of Additional siRNAs 
     The C5 sense and antisense strand sequences shown in Table 20 were modified at the 3′-terminus with a short sequence of deoxy-thymine nucleotides (dT) (Table 21). The in vitro efficacy of duplexes comprising the sense and antisense sequences listed in Table 21 was determined using the following methods. 
     Cell Culture and Transfections 
     Hep3B cells (ATCC, Manassas, Va.) were grown to near confluence at 37° C. in an atmosphere of 5% CO 2  in EMEM (ATCC) supplemented with 10% FBS, before being released from the plate by trypsinization. Transfection was carried out by adding 5 μl of Opti-MEM plus 0.1 μl of Lipofectamine RNAiMax per well (Invitrogen, Carlsbad Calif. cat #13778-150) to Sul of siRNA duplexes per well into a 384-well plate and incubated at room temperature for 15 minutes. 40 μl of complete growth media containing ˜5×10 3  Hep3B cells were then added to the siRNA mixture. Cells were incubated for 24 hours prior to RNA purification. Experiments were performed at 10 nM final duplex concentration. 
     Total RNA Isolation Using DYNABEADS mRNA Isolation Kit (Invitrogen, Part #: 610-12) 
     RNA isolation was performed using a semi-automated process of a Biotek EL 405 washer. Briefly, cells were lysed in 75 μl of Lysis/Binding Buffer containing 2 μl of Dynabeads, then mixed for 10 minutes on setting 7 of an electromagnetic shaker (Union Scientific). Magnetic beads were captured using magnetic stand and the supernatant was removed. After removing supernatant, magnetic beads were washed with 90 μl Wash Buffer A, followed by 90 μl of Wash buffer B. Beads were then washed twice with 100 μl of Elution buffer which was then aspirated and cDNA generated directly on bead bound RNA in the 384 well plate. 
     cDNA Synthesis Using ABI High Capacity cDNA Reverse Transcription Kit (Applied Biosystems, Foster City, Calif., Cat #4368813) 
     A master mix of 2 μl 10× Buffer, 0.8 μl 25× dNTPs, 2 μl Random primers, 1 μl Reverse Transcriptase, 1 μl RNase inhibitor and 3.2 μl of H 2 O per reaction were added directly to the bead bound RNA in the 384 well plates used for RNA isolation. Plates were then shaken on an electromagnetic shaker for 10 minutes and then placed in a 37° C. incubator for 2 hours. Following this incubation, plates were place on a shake in an 80° C. incubator for 7 minutes to inactivate the enzyme and elute the RNA/cDNA from the beads. 
     Real Time PCR 
     2 μl of cDNA were added to a master mix containing 0.5 μl GAPDH TaqMan Probe (Applied Biosystems Cat #4326317E), 0.5 μl C5 TaqMan probe (Applied Biosystems cat #Hs00156197_M1) and 5 μl Lightcycler 480 probe master mix (Roche Cat #04887301001) per well in a 384 well plates (Roche cat #04887301001). Real time PCR was done in a Roche LC480 Real Time PCR system (Roche). Each duplex was tested in in at least two independent transfections and each transfection was assayed in duplicate. 
     To calculate relative fold change, real time data were analyzed using the ΔΔCt method and normalized to assays performed with cells transfected with 10 nM AD-1955, or mock transfected cells. 
     Table 22 shows the results of a single dose screen in Hep3B cells transfected with the indicated dT modified iRNAs. Data are expressed as percent of message remaining relative to untreated cells. 
     
       
         
           
               
             
               
                 TABLE 21 
               
             
            
               
                   
               
               
                 dT Modified C5 iRNAs 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                 SEQ ID 
                 Position in 
                   
                 SEQ ID 
               
               
                 Duplex ID 
                 Sense Sequence 
                 NO: 
                 NM_001735.2 
                 Antisense Sequence 
                 NO: 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 AD-61779.2 
                 UAUCCGUGGUUUCCUGCUAdTdT 
                 1739 
                  3-21 
                 UAGCAGGAAACCACGGAUAdTdT 
                 2306 
               
               
                   
               
               
                 AD-61785.2 
                 GGUUUCCUGCUACCUCCAAdTdT 
                 1740 
                 10-28 
                 UUGGAGGUAGCAGGAAACCdTdT 
                 2307 
               
               
                   
               
               
                 AD-61791.2 
                 CCUCCAACCAUGGGCCUUUdTdT 
                 1741 
                 22-40 
                 AAAGGCCCAUGGUUGGAGGdTdT 
                 2308 
               
               
                   
               
               
                 AD-61797.2 
                 GGGCCUUUUGGGAAUACUUdTdT 
                 1742 
                 33-51 
                 AAGUAUUCCCAAAAGGCCCdTdT 
                 2309 
               
               
                   
               
               
                 AD-61803.2 
                 GGAAUACUUUGUUUUUUAAdTdT 
                 1743 
                 43-61 
                 UUAAAAAACAAAGUAUUCCdTdT 
                 2310 
               
               
                   
               
               
                 AD-61809.2 
                 CUUUGUUUUUUAAUCUUCCdTdT 
                 1744 
                 49-67 
                 GGAAGAUUAAAAAACAAAGdTdT 
                 2311 
               
               
                   
               
               
                 AD-61815.2 
                 CUUCCUGGGGAAAACCUGGdTdT 
                 1745 
                 63-81 
                 CCAGGUUUUCCCCAGGAAGdTdT 
                 2312 
               
               
                   
               
               
                 AD-61821.2 
                 GGAAAACCUGGGGACAGGAdTdT 
                 1746 
                 71-89 
                 UCCUGUCCCCAGGUUUUCCdTdT 
                 2313 
               
               
                   
               
               
                 AD-61780.2 
                 GGGACAGGAGCAAACAUAUdTdT 
                 1747 
                 81-99 
                 AUAUGUUUGCUCCUGUCCCdTdT 
                 2314 
               
               
                   
               
               
                 AD-61786.2 
                 CAAACAUAUGUCAUUUCAGdTdT 
                 1748 
                  91-109 
                 CUGAAAUGACAUAUGUUUGdTdT 
                 2315 
               
               
                   
               
               
                 AD-61792.2 
                 CAUUUCAGCACCAAAAAUAdTdT 
                 1749 
                 102-120 
                 UAUUUUUGGUGCUGAAAUGdTdT 
                 2316 
               
               
                   
               
               
                 AD-61798.2 
                 GCACCAAAAAUAUUCCGUGdTdT 
                 1750 
                 109-127 
                 CACGGAAUAUUUUUGGUGCdTdT 
                 2317 
               
               
                   
               
               
                 AD-61804.2 
                 CCGUGUUGGAGCAUCUGAAdTdT 
                 1751 
                 123-141 
                 UUCAGAUGCUCCAACACGGdTdT 
                 2318 
               
               
                   
               
               
                 AD-61810.2 
                 GGAGCAUCUGAAAAUAUUGdTdT 
                 1752 
                 130-148 
                 CAAUAUUUUCAGAUGCUCCdTdT 
                 2319 
               
               
                   
               
               
                 AD-61816.2 
                 GAAAAUAUUGUGAUUCAAGdTdT 
                 1753 
                 139-157 
                 CUUGAAUCACAAUAUUUUCdTdT 
                 2320 
               
               
                   
               
               
                 AD-61822.2 
                 GAUUCAAGUUUAUGGAUACdTdT 
                 1754 
                 150-168 
                 GUAUCCAUAAACUUGAAUCdTdT 
                 2321 
               
               
                   
               
               
                 AD-61781.2 
                 GGAUACACUGAAGCAUUUGdTdT 
                 1755 
                 163-181 
                 CAAAUGCUUCAGUGUAUCCdTdT 
                 2322 
               
               
                   
               
               
                 AD-61787.2 
                 GAAGCAUUUGAUGCAACAAdTdT 
                 1756 
                 172-190 
                 UUGUUGCAUCAAAUGCUUCdTdT 
                 2323 
               
               
                   
               
               
                 AD-61793.2 
                 UGCAACAAUCUCUAUUAAAdTdT 
                 1757 
                 183-201 
                 UUUAAUAGAGAUUGUUGCAdTdT 
                 2324 
               
               
                   
               
               
                 AD-61799.2 
                 AAUCUCUAUUAAAAGUUAUdTdT 
                 1758 
                 189-207 
                 AUAACUUUUAAUAGAGAUUdTdT 
                 2325 
               
               
                   
               
               
                 AD-61805.2 
                 AAGUUAUCCUGAUAAAAAAdTdT 
                 1759 
                 201-219 
                 UUUUUUAUCAGGAUAACUUdTdT 
                 2326 
               
               
                   
               
               
                 AD-61811.2 
                 CUGAUAAAAAAUUUAGUUAdTdT 
                 1760 
                 209-227 
                 UAACUAAAUUUUUUAUCAGdTdT 
                 2327 
               
               
                   
               
               
                 AD-61817.2 
                 UUAGUUACUCCUCAGGCCAdTdT 
                 1761 
                 221-239 
                 UGGCCUGAGGAGUAACUAAdTdT 
                 2328 
               
               
                   
               
               
                 AD-61823.2 
                 CCUCAGGCCAUGUUCAUUUdTdT 
                 1762 
                 230-248 
                 AAAUGAACAUGGCCUGAGGdTdT 
                 2329 
               
               
                   
               
               
                 AD-61782.2 
                 UUCAUUUAUCCUCAGAGAAdTdT 
                 1763 
                 242-260 
                 UUCUCUGAGGAUAAAUGAAdTdT 
                 2330 
               
               
                   
               
               
                 AD-61788.2 
                 CUCAGAGAAUAAAUUCCAAdTdT 
                 1764 
                 252-270 
                 UUGGAAUUUAUUCUCUGAGdTdT 
                 2331 
               
               
                   
               
               
                 AD-61794.2 
                 AAUAAAUUCCAAAACUCUGdTdT 
                 1765 
                 259-277 
                 CAGAGUUUUGGAAUUUAUUdTdT 
                 2332 
               
               
                   
               
               
                 AD-61800.2 
                 CUCUGCAAUCUUAACAAUAdTdT 
                 1766 
                 273-291 
                 UAUUGUUAAGAUUGCAGAGdTdT 
                 2333 
               
               
                   
               
               
                 AD-61806.2 
                 CUUAACAAUACAACCAAAAdTdT 
                 1767 
                 282-300 
                 UUUUGGUUGUAUUGUUAAGdTdT 
                 2334 
               
               
                   
               
               
                 AD-61812.2 
                 CAACCAAAACAAUUGCCUGdTdT 
                 1768 
                 292-310 
                 CAGGCAAUUGUUUUGGUUGdTdT 
                 2335 
               
               
                   
               
               
                 AD-61818.2 
                 CAAUUGCCUGGAGGACAAAdTdT 
                 1769 
                 301-319 
                 UUUGUCCUCCAGGCAAUUGdTdT 
                 2336 
               
               
                   
               
               
                 AD-61824.2 
                 GGACAAAACCCAGUUUCUUdTdT 
                 1770 
                 313-331 
                 AAGAAACUGGGUUUUGUCCdTdT 
                 2337 
               
               
                   
               
               
                 AD-61783.2 
                 CCAGUUUCUUAUGUGUAUUdTdT 
                 1771 
                 322-340 
                 AAUACACAUAAGAAACUGGdTdT 
                 2338 
               
               
                   
               
               
                 AD-61789.2 
                 AUGUGUAUUUGGAAGUUGUdTdT 
                 1772 
                 332-350 
                 ACAACUUCCAAAUACACAUdTdT 
                 2339 
               
               
                   
               
               
                 AD-61795.2 
                 GGAAGUUGUAUCAAAGCAUdTdT 
                 1773 
                 342-360 
                 AUGCUUUGAUACAACUUCCdTdT 
                 2340 
               
               
                   
               
               
                 AD-61801.2 
                 GUAUCAAAGCAUUUUUCAAdTdT 
                 1774 
                 349-367 
                 UUGAAAAAUGCUUUGAUACdTdT 
                 2341 
               
               
                   
               
               
                 AD-61807.2 
                 UUUUCAAAAUCAAAAAGAAdTdT 
                 1775 
                 361-379 
                 UUCUUUUUGAUUUUGAAAAdTdT 
                 2342 
               
               
                   
               
               
                 AD-61813.2 
                 CAAAAAGAAUGCCAAUAACdTdT 
                 1776 
                 371-389 
                 GUUAUUGGCAUUCUUUUUGdTdT 
                 2343 
               
               
                   
               
               
                 AD-61819.2 
                 GCCAAUAACCUAUGACAAUdTdT 
                 1777 
                 381-399 
                 AUUGUCAUAGGUUAUUGGCdTdT 
                 2344 
               
               
                   
               
               
                 AD-61825.2 
                 CCUAUGACAAUGGAUUUCUdTdT 
                 1778 
                 389-407 
                 AGAAAUCCAUUGUCAUAGGdTdT 
                 2345 
               
               
                   
               
               
                 AD-61784.2 
                 UGGAUUUCUCUUCAUUCAUdTdT 
                 1779 
                 399-417 
                 AUGAAUGAAGAGAAAUCCAdTdT 
                 2346 
               
               
                   
               
               
                 AD-61790.2 
                 CAUUCAUACAGACAAACCUdTdT 
                 1780 
                 411-429 
                 AGGUUUGUCUGUAUGAAUGdTdT 
                 2347 
               
               
                   
               
               
                 AD-61796.2 
                 CAGACAAACCUGUUUAUACdTdT 
                 1781 
                 419-437 
                 GUAUAAACAGGUUUGUCUGdTdT 
                 2348 
               
               
                   
               
               
                 AD-61802.2 
                 GUUUAUACUCCAGACCAGUdTdT 
                 1782 
                 430-448 
                 ACUGGUCUGGAGUAUAAACdTdT 
                 2349 
               
               
                   
               
               
                 AD-61808.2 
                 AGACCAGUCAGUAAAAGUUdTdT 
                 1783 
                 441-459 
                 AACUUUUACUGACUGGUCUdTdT 
                 2350 
               
               
                   
               
               
                 AD-61814.2 
                 AGUAAAAGUUAGAGUUUAUdTdT 
                 1784 
                 450-468 
                 AUAAACUCUAACUUUUACUdTdT 
                 2351 
               
               
                   
               
               
                 AD-61820.2 
                 AGAGUUUAUUCGUUGAAUGdTdT 
                 1785 
                 460-478 
                 CAUUCAACGAAUAAACUCUdTdT 
                 2352 
               
               
                   
               
               
                 AD-61826.2 
                 CGUUGAAUGACGACUUGAAdTdT 
                 1786 
                 470-488 
                 UUCAAGUCGUCAUUCAACGdTdT 
                 2353 
               
               
                   
               
               
                 AD-61832.2 
                 CUUGAAGCCAGCCAAAAGAdTdT 
                 1787 
                 483-501 
                 UCUUUUGGCUGGCUUCAAGdTdT 
                 2354 
               
               
                   
               
               
                 AD-61838.2 
                 CCAGCCAAAAGAGAAACUGdTdT 
                 1788 
                 490-508 
                 CAGUUUCUCUUUUGGCUGGdTdT 
                 2355 
               
               
                   
               
               
                 AD-61844.2 
                 AAACUGUCUUAACUUUCAUdTdT 
                 1789 
                 503-521 
                 AUGAAAGUUAAGACAGUUUdTdT 
                 2356 
               
               
                   
               
               
                 AD-61850.2 
                 AACUUUCAUAGAUCCUGAAdTdT 
                 1790 
                 513-531 
                 UUCAGGAUCUAUGAAAGUUdTdT 
                 2357 
               
               
                   
               
               
                 AD-61856.2 
                 CAUAGAUCCUGAAGGAUCAdTdT 
                 1791 
                 519-537 
                 UGAUCCUUCAGGAUCUAUGdTdT 
                 2358 
               
               
                   
               
               
                 AD-61862.2 
                 GAAGGAUCAGAAGUUGACAdTdT 
                 1792 
                 529-547 
                 UGUCAACUUCUGAUCCUUCdTdT 
                 2359 
               
               
                   
               
               
                 AD-61868.2 
                 UGACAUGGUAGAAGAAAUUdTdT 
                 1793 
                 543-561 
                 AAUUUCUUCUACCAUGUCAdTdT 
                 2360 
               
               
                   
               
               
                 AD-61827.2 
                 GAAGAAAUUGAUCAUAUUGdTdT 
                 1794 
                 553-571 
                 CAAUAUGAUCAAUUUCUUCdTdT 
                 2361 
               
               
                   
               
               
                 AD-61833.2 
                 GAUCAUAUUGGAAUUAUCUdTdT 
                 1795 
                 562-580 
                 AGAUAAUUCCAAUAUGAUCdTdT 
                 2362 
               
               
                   
               
               
                 AD-61839.2 
                 GGAAUUAUCUCUUUUCCUGdTdT 
                 1796 
                 571-589 
                 CAGGAAAAGAGAUAAUUCCdTdT 
                 2363 
               
               
                   
               
               
                 AD-61845.2 
                 CUCUUUUCCUGACUUCAAGdTdT 
                 1797 
                 579-597 
                 CUUGAAGUCAGGAAAAGAGdTdT 
                 2364 
               
               
                   
               
               
                 AD-61851.2 
                 ACUUCAAGAUUCCGUCUAAdTdT 
                 1798 
                 590-608 
                 UUAGACGGAAUCUUGAAGUdTdT 
                 2365 
               
               
                   
               
               
                 AD-61857.2 
                 CCGUCUAAUCCUAGAUAUGdTdT 
                 1799 
                 601-619 
                 CAUAUCUAGGAUUAGACGGdTdT 
                 2366 
               
               
                   
               
               
                 AD-61863.2 
                 CCUAGAUAUGGUAUGUGGAdTdT 
                 1800 
                 610-628 
                 UCCACAUACCAUAUCUAGGdTdT 
                 2367 
               
               
                   
               
               
                 AD-61869.2 
                 UGUGGACGAUCAAGGCUAAdTdT 
                 1801 
                 623-641 
                 UUAGCCUUGAUCGUCCACAdTdT 
                 2368 
               
               
                   
               
               
                 AD-61828.2 
                 CGAUCAAGGCUAAAUAUAAdTdT 
                 1802 
                 629-647 
                 UUAUAUUUAGCCUUGAUCGdTdT 
                 2369 
               
               
                   
               
               
                 AD-61834.2 
                 AUAUAAAGAGGACUUUUCAdTdT 
                 1803 
                 642-660 
                 UGAAAAGUCCUCUUUAUAUdTdT 
                 2370 
               
               
                   
               
               
                 AD-61840.2 
                 GAGGACUUUUCAACAACUGdTdT 
                 1804 
                 649-667 
                 CAGUUGUUGAAAAGUCCUCdTdT 
                 2371 
               
               
                   
               
               
                 AD-61846.2 
                 CAACUGGAACCGCAUAUUUdTdT 
                 1805 
                 662-680 
                 AAAUAUGCGGUUCCAGUUGdTdT 
                 2372 
               
               
                   
               
               
                 AD-61852.2 
                 CGCAUAUUUUGAAGUUAAAdTdT 
                 1806 
                 672-690 
                 UUUAACUUCAAAAUAUGCGdTdT 
                 2373 
               
               
                   
               
               
                 AD-61858.2 
                 AAGUUAAAGAAUAUGUCUUdTdT 
                 1807 
                 683-701 
                 AAGACAUAUUCUUUAACUUdTdT 
                 2374 
               
               
                   
               
               
                 AD-61864.2 
                 GAAUAUGUCUUGCCACAUUdTdT 
                 1808 
                 691-709 
                 AAUGUGGCAAGACAUAUUCdTdT 
                 2375 
               
               
                   
               
               
                 AD-61870.2 
                 CCACAUUUUUCUGUCUCAAdTdT 
                 1809 
                 703-721 
                 UUGAGACAGAAAAAUGUGGdTdT 
                 2376 
               
               
                   
               
               
                 AD-61829.2 
                 CUGUCUCAAUCGAGCCAGAdTdT 
                 1810 
                 713-731 
                 UCUGGCUCGAUUGAGACAGdTdT 
                 2377 
               
               
                   
               
               
                 AD-61835.2 
                 CAAUCGAGCCAGAAUAUAAdTdT 
                 1811 
                 719-737 
                 UUAUAUUCUGGCUCGAUUGdTdT 
                 2378 
               
               
                   
               
               
                 AD-61841.2 
                 GAAUAUAAUUUCAUUGGUUdTdT 
                 1812 
                 730-748 
                 AACCAAUGAAAUUAUAUUCdTdT 
                 2379 
               
               
                   
               
               
                 AD-61847.2 
                 AUUGGUUACAAGAACUUUAdTdT 
                 1813 
                 742-760 
                 UAAAGUUCUUGUAACCAAUdTdT 
                 2380 
               
               
                   
               
               
                 AD-61853.2 
                 AGAACUUUAAGAAUUUUGAdTdT 
                 1814 
                 752-770 
                 UCAAAAUUCUUAAAGUUCUdTdT 
                 2381 
               
               
                   
               
               
                 AD-61859.2 
                 GAAUUUUGAAAUUACUAUAdTdT 
                 1815 
                 762-780 
                 UAUAGUAAUUUCAAAAUUCdTdT 
                 2382 
               
               
                   
               
               
                 AD-61865.2 
                 GAAAUUACUAUAAAAGCAAdTdT 
                 1816 
                 769-787 
                 UUGCUUUUAUAGUAAUUUCdTdT 
                 2383 
               
               
                   
               
               
                 AD-61871.2 
                 AAAGCAAGAUAUUUUUAUAdTdT 
                 1817 
                 781-799 
                 UAUAAAAAUAUCUUGCUUUdTdT 
                 2384 
               
               
                   
               
               
                 AD-61830.2 
                 AUAUUUUUAUAAUAAAGUAdTdT 
                 1818 
                 789-807 
                 UACUUUAUUAUAAAAAUAUdTdT 
                 2385 
               
               
                   
               
               
                 AD-61836.2 
                 AAGUAGUCACUGAGGCUGAdTdT 
                 1819 
                 803-821 
                 UCAGCCUCAGUGACUACUUdTdT 
                 2386 
               
               
                   
               
               
                 AD-61842.2 
                 CACUGAGGCUGACGUUUAUdTdT 
                 1820 
                 810-828 
                 AUAAACGUCAGCCUCAGUGdTdT 
                 2387 
               
               
                   
               
               
                 AD-61848.2 
                 CGUUUAUAUCACAUUUGGAdTdT 
                 1821 
                 822-840 
                 UCCAAAUGUGAUAUAAACGdTdT 
                 2388 
               
               
                   
               
               
                 AD-61854.2 
                 CACAUUUGGAAUAAGAGAAdTdT 
                 1822 
                 831-849 
                 UUCUCUUAUUCCAAAUGUGdTdT 
                 2389 
               
               
                   
               
               
                 AD-61860.2 
                 AAUAAGAGAAGACUUAAAAdTdT 
                 1823 
                 840-858 
                 UUUUAAGUCUUCUCUUAUUdTdT 
                 2390 
               
               
                   
               
               
                 AD-61866.2 
                 CUUAAAAGAUGAUCAAAAAdTdT 
                 1824 
                 852-870 
                 UUUUUGAUCAUCUUUUAAGdTdT 
                 2391 
               
               
                   
               
               
                 AD-61872.2 
                 GAUGAUCAAAAAGAAAUGAdTdT 
                 1825 
                 859-877 
                 UCAUUUCUUUUUGAUCAUCdTdT 
                 2392 
               
               
                   
               
               
                 AD-61831.2 
                 AAAUGAUGCAAACAGCAAUdTdT 
                 1826 
                 872-890 
                 AUUGCUGUUUGCAUCAUUUdTdT 
                 2393 
               
               
                   
               
               
                 AD-61837.2 
                 ACAGCAAUGCAAAACACAAdTdT 
                 1827 
                 883-901 
                 UUGUGUUUUGCAUUGCUGUdTdT 
                 2394 
               
               
                   
               
               
                 AD-61843.2 
                 AAAACACAAUGUUGAUAAAdTdT 
                 1828 
                 893-911 
                 UUUAUCAACAUUGUGUUUUdTdT 
                 2395 
               
               
                   
               
               
                 AD-61849.2 
                 CAAUGUUGAUAAAUGGAAUdTdT 
                 1829 
                 899-917 
                 AUUCCAUUUAUCAACAUUGdTdT 
                 2396 
               
               
                   
               
               
                 AD-61855.2 
                 GGAAUUGCUCAAGUCACAUdTdT 
                 1830 
                 913-931 
                 AUGUGACUUGAGCAAUUCCdTdT 
                 2397 
               
               
                   
               
               
                 AD-61861.2 
                 GCUCAAGUCACAUUUGAUUdTdT 
                 1831 
                 919-937 
                 AAUCAAAUGUGACUUGAGCdTdT 
                 2398 
               
               
                   
               
               
                 AD-61867.2 
                 AUUUGAUUCUGAAACAGCAdTdT 
                 1832 
                 930-948 
                 UGCUGUUUCAGAAUCAAAUdTdT 
                 2399 
               
               
                   
               
               
                 AD-62062.1 
                 UGAAACAGCAGUCAAAGAAdTdT 
                 1833 
                 939-957 
                 UUCUUUGACUGCUGUUUCAdTdT 
                 2400 
               
               
                   
               
               
                 AD-62068.1 
                 CAAAGAACUGUCAUACUACdTdT 
                 1834 
                 951-969 
                 GUAGUAUGACAGUUCUUUGdTdT 
                 2401 
               
               
                   
               
               
                 AD-62074.1 
                 CAUACUACAGUUUAGAAGAdTdT 
                 1835 
                 962-980 
                 UCUUCUAAACUGUAGUAUGdTdT 
                 2402 
               
               
                   
               
               
                 AD-62080.1 
                 CAGUUUAGAAGAUUUAAACdTdT 
                 1836 
                 969-987 
                 GUUUAAAUCUUCUAAACUGdTdT 
                 2403 
               
               
                   
               
               
                 AD-62086.1 
                 UAAACAACAAGUACCUUUAdTdT 
                 1837 
                  983-1001 
                 UAAAGGUACUUGUUGUUUAdTdT 
                 2404 
               
               
                   
               
               
                 AD-62092.1 
                 CAAGUACCUUUAUAUUGCUdTdT 
                 1838 
                  990-1008 
                 AGCAAUAUAAAGGUACUUGdTdT 
                 2405 
               
               
                   
               
               
                 AD-62098.1 
                 UAUUGCUGUAACAGUCAUAdTdT 
                 1839 
                 1002-1020 
                 UAUGACUGUUACAGCAAUAdTdT 
                 2406 
               
               
                   
               
               
                 AD-62104.1 
                 AACAGUCAUAGAGUCUACAdTdT 
                 1840 
                 1011-1029 
                 UGUAGACUCUAUGACUGUUdTdT 
                 2407 
               
               
                   
               
               
                 AD-62063.1 
                 AGAGUCUACAGGUGGAUUUdTdT 
                 1841 
                 1020-1038 
                 AAAUCCACCUGUAGACUCUdTdT 
                 2408 
               
               
                   
               
               
                 AD-62069.1 
                 GGAUUUUCUGAAGAGGCAGdTdT 
                 1842 
                 1033-1051 
                 CUGCCUCUUCAGAAAAUCCdTdT 
                 2409 
               
               
                   
               
               
                 AD-62075.1 
                 GAAGAGGCAGAAAUACCUGdTdT 
                 1843 
                 1042-1060 
                 CAGGUAUUUCUGCCUCUUCdTdT 
                 2410 
               
               
                   
               
               
                 AD-62081.1 
                 AGAAAUACCUGGCAUCAAAdTdT 
                 1844 
                 1050-1068 
                 UUUGAUGCCAGGUAUUUCUdTdT 
                 2411 
               
               
                   
               
               
                 AD-62087.1 
                 GCAUCAAAUAUGUCCUCUCdTdT 
                 1845 
                 1061-1079 
                 GAGAGGACAUAUUUGAUGCdTdT 
                 2412 
               
               
                   
               
               
                 AD-62093.1 
                 UGUCCUCUCUCCCUACAAAdTdT 
                 1846 
                 1071-1089 
                 UUUGUAGGGAGAGAGGACAdTdT 
                 2413 
               
               
                   
               
               
                 AD-62099.1 
                 GAAUUUGGUUGCUACUCCUdTdT 
                 1847 
                 1092-1110 
                 AGGAGUAGCAACCAAAUUCdTdT 
                 2414 
               
               
                   
               
               
                 AD-62105.1 
                 GCUACUCCUCUUUUCCUGAdTdT 
                 1848 
                 1102-1120 
                 UCAGGAAAAGAGGAGUAGCdTdT 
                 2415 
               
               
                   
               
               
                 AD-62064.1 
                 CUCUUUUCCUGAAGCCUGGdTdT 
                 1849 
                 1109-1127 
                 CCAGGCUUCAGGAAAAGAGdTdT 
                 2416 
               
               
                   
               
               
                 AD-62070.1 
                 CCUGGGAUUCCAUAUCCCAdTdT 
                 1850 
                 1123-1141 
                 UGGGAUAUGGAAUCCCAGGdTdT 
                 2417 
               
               
                   
               
               
                 AD-62076.1 
                 CAUAUCCCAUCAAGGUGCAdTdT 
                 1851 
                 1133-1151 
                 UGCACCUUGAUGGGAUAUGdTdT 
                 2418 
               
               
                   
               
               
                 AD-62082.1 
                 CCAUCAAGGUGCAGGUUAAdTdT 
                 1852 
                 1139-1157 
                 UUAACCUGCACCUUGAUGGdTdT 
                 2419 
               
               
                   
               
               
                 AD-62088.1 
                 CAGGUUAAAGAUUCGCUUGdTdT 
                 1853 
                 1150-1168 
                 CAAGCGAAUCUUUAACCUGdTdT 
                 2420 
               
               
                   
               
               
                 AD-62094.1 
                 UUCGCUUGACCAGUUGGUAdTdT 
                 1854 
                 1161-1179 
                 UACCAACUGGUCAAGCGAAdTdT 
                 2421 
               
               
                   
               
               
                 AD-62100.1 
                 CCAGUUGGUAGGAGGAGUCdTdT 
                 1855 
                 1170-1188 
                 GACUCCUCCUACCAACUGGdTdT 
                 2422 
               
               
                   
               
               
                 AD-62106.1 
                 GGAGGAGUCCCAGUAACACdTdT 
                 1856 
                 1180-1198 
                 GUGUUACUGGGACUCCUCCdTdT 
                 2423 
               
               
                   
               
               
                 AD-62065.1 
                 CAGUAACACUGAAUGCACAdTdT 
                 1857 
                 1190-1208 
                 UGUGCAUUCAGUGUUACUGdTdT 
                 2424 
               
               
                   
               
               
                 AD-62071.1 
                 GAAUGCACAAACAAUUGAUdTdT 
                 1858 
                 1200-1218 
                 AUCAAUUGUUUGUGCAUUCdTdT 
                 2425 
               
               
                   
               
               
                 AD-62077.1 
                 AACAAUUGAUGUAAACCAAdTdT 
                 1859 
                 1209-1227 
                 UUGGUUUACAUCAAUUGUUdTdT 
                 2426 
               
               
                   
               
               
                 AD-62083.1 
                 UAAACCAAGAGACAUCUGAdTdT 
                 1860 
                 1220-1238 
                 UCAGAUGUCUCUUGGUUUAdTdT 
                 2427 
               
               
                   
               
               
                 AD-62089.1 
                 CAUCUGACUUGGAUCCAAGdTdT 
                 1861 
                 1232-1250 
                 CUUGGAUCCAAGUCAGAUGdTdT 
                 2428 
               
               
                   
               
               
                 AD-62095.1 
                 GAUCCAAGCAAAAGUGUAAdTdT 
                 1862 
                 1243-1261 
                 UUACACUUUUGCUUGGAUCdTdT 
                 2429 
               
               
                   
               
               
                 AD-62101.1 
                 CAAAAGUGUAACACGUGUUdTdT 
                 1863 
                 1251-1269 
                 AACACGUGUUACACUUUUGdTdT 
                 2430 
               
               
                   
               
               
                 AD-62107.1 
                 AACACGUGUUGAUGAUGGAdTdT 
                 1864 
                 1260-1278 
                 UCCAUCAUCAACACGUGUUdTdT 
                 2431 
               
               
                   
               
               
                 AD-62066.1 
                 UGAUGGAGUAGCUUCCUUUdTdT 
                 1865 
                 1272-1290 
                 AAAGGAAGCUACUCCAUCAdTdT 
                 2432 
               
               
                   
               
               
                 AD-62072.1 
                 GUAGCUUCCUUUGUGCUUAdTdT 
                 1866 
                 1279-1297 
                 UAAGCACAAAGGAAGCUACdTdT 
                 2433 
               
               
                   
               
               
                 AD-62078.1 
                 GCUUAAUCUCCCAUCUGGAdTdT 
                 1867 
                 1293-1311 
                 UCCAGAUGGGAGAUUAAGCdTdT 
                 2434 
               
               
                   
               
               
                 AD-62084.1 
                 CCAUCUGGAGUGACGGUGCdTdT 
                 1868 
                 1303-1321 
                 GCACCGUCACUCCAGAUGGdTdT 
                 2435 
               
               
                   
               
               
                 AD-62090.1 
                 UGACGGUGCUGGAGUUUAAdTdT 
                 1869 
                 1313-1331 
                 UUAAACUCCAGCACCGUCAdTdT 
                 2436 
               
               
                   
               
               
                 AD-62096.1 
                 GCUGGAGUUUAAUGUCAAAdTdT 
                 1870 
                 1320-1338 
                 UUUGACAUUAAACUCCAGCdTdT 
                 2437 
               
               
                   
               
               
                 AD-62102.1 
                 UGUCAAAACUGAUGCUCCAdTdT 
                 1871 
                 1332-1350 
                 UGGAGCAUCAGUUUUGACAdTdT 
                 2438 
               
               
                   
               
               
                 AD-62108.1 
                 GAUGCUCCAGAUCUUCCAGdTdT 
                 1872 
                 1342-1360 
                 CUGGAAGAUCUGGAGCAUCdTdT 
                 2439 
               
               
                   
               
               
                 AD-62067.1 
                 CAGAUCUUCCAGAAGAAAAdTdT 
                 1873 
                 1349-1367 
                 UUUUCUUCUGGAAGAUCUGdTdT 
                 2440 
               
               
                   
               
               
                 AD-62073.1 
                 AGAAAAUCAGGCCAGGGAAdTdT 
                 1874 
                 1362-1380 
                 UUCCCUGGCCUGAUUUUCUdTdT 
                 2441 
               
               
                   
               
               
                 AD-62079.1 
                 GGCCAGGGAAGGUUACCGAdTdT 
                 1875 
                 1371-1389 
                 UCGGUAACCUUCCCUGGCCdTdT 
                 2442 
               
               
                   
               
               
                 AD-62085.1 
                 GUUACCGAGCAAUAGCAUAdTdT 
                 1876 
                 1382-1400 
                 UAUGCUAUUGCUCGGUAACdTdT 
                 2443 
               
               
                   
               
               
                 AD-62091.1 
                 AUAGCAUACUCAUCUCUCAdTdT 
                 1877 
                 1393-1411 
                 UGAGAGAUGAGUAUGCUAUdTdT 
                 2444 
               
               
                   
               
               
                 AD-62097.1 
                 UACUCAUCUCUCAGCCAAAdTdT 
                 1878 
                 1399-1417 
                 UUUGGCUGAGAGAUGAGUAdTdT 
                 2445 
               
               
                   
               
               
                 AD-62103.1 
                 GCCAAAGUUACCUUUAUAUdTdT 
                 1879 
                 1412-1430 
                 AUAUAAAGGUAACUUUGGCdTdT 
                 2446 
               
               
                   
               
               
                 AD-62109.1 
                 CCUUUAUAUUGAUUGGACUdTdT 
                 1880 
                 1422-1440 
                 AGUCCAAUCAAUAUAAAGGdTdT 
                 2447 
               
               
                   
               
               
                 AD-62115.1 
                 GAUUGGACUGAUAACCAUAdTdT 
                 1881 
                 1432-1450 
                 UAUGGUUAUCAGUCCAAUCdTdT 
                 2448 
               
               
                   
               
               
                 AD-62121.1 
                 CUGAUAACCAUAAGGCUUUdTdT 
                 1882 
                 1439-1457 
                 AAAGCCUUAUGGUUAUCAGdTdT 
                 2449 
               
               
                   
               
               
                 AD-62127.1 
                 AGGCUUUGCUAGUGGGAGAdTdT 
                 1883 
                 1451-1469 
                 UCUCCCACUAGCAAAGCCUdTdT 
                 2450 
               
               
                   
               
               
                 AD-62133.1 
                 GUGGGAGAACAUCUGAAUAdTdT 
                 1884 
                 1462-1480 
                 UAUUCAGAUGUUCUCCCACdTdT 
                 2451 
               
               
                   
               
               
                 AD-62139.1 
                 CAUCUGAAUAUUAUUGUUAdTdT 
                 1885 
                 1471-1489 
                 UAACAAUAAUAUUCAGAUGdTdT 
                 2452 
               
               
                   
               
               
                 AD-62145.1 
                 UAUUAUUGUUACCCCCAAAdTdT 
                 1886 
                 1479-1497 
                 UUUGGGGGUAACAAUAAUAdTdT 
                 2453 
               
               
                   
               
               
                 AD-62151.1 
                 CCCAAAAGCCCAUAUAUUGdTdT 
                 1887 
                 1492-1510 
                 CAAUAUAUGGGCUUUUGGGdTdT 
                 2454 
               
               
                   
               
               
                 AD-62110.1 
                 CCAAAAGCCCAUAUAUUGAdTdT 
                 1888 
                 1493-1511 
                 UCAAUAUAUGGGCUUUUGGdTdT 
                 2455 
               
               
                   
               
               
                 AD-62116.1 
                 CAAAAGCCCAUAUAUUGACdTdT 
                 1889 
                 1494-1512 
                 GUCAAUAUAUGGGCUUUUGdTdT 
                 2456 
               
               
                   
               
               
                 AD-62122.1 
                 AAAAGCCCAUAUAUUGACAdTdT 
                 1890 
                 1495-1513 
                 UGUCAAUAUAUGGGCUUUUdTdT 
                 2457 
               
               
                   
               
               
                 AD-62128.1 
                 AAAGCCCAUAUAUUGACAAdTdT 
                 1891 
                 1496-1514 
                 UUGUCAAUAUAUGGGCUUUdTdT 
                 2458 
               
               
                   
               
               
                 AD-62134.1 
                 AAGCCCAUAUAUUGACAAAdTdT 
                 1892 
                 1497-1515 
                 UUUGUCAAUAUAUGGGCUUdTdT 
                 2459 
               
               
                   
               
               
                 AD-62140.1 
                 AGCCCAUAUAUUGACAAAAdTdT 
                 1893 
                 1498-1516 
                 UUUUGUCAAUAUAUGGGCUdTdT 
                 2460 
               
               
                   
               
               
                 AD-62146.1 
                 GCCCAUAUAUUGACAAAAUdTdT 
                 1894 
                 1499-1517 
                 AUUUUGUCAAUAUAUGGGCdTdT 
                 2461 
               
               
                   
               
               
                 AD-62152.1 
                 CCCAUAUAUUGACAAAAUAdTdT 
                 1895 
                 1500-1518 
                 UAUUUUGUCAAUAUAUGGGdTdT 
                 2462 
               
               
                   
               
               
                 AD-62111.1 
                 CCAUAUAUUGACAAAAUAAdTdT 
                 1896 
                 1501-1519 
                 UUAUUUUGUCAAUAUAUGGdTdT 
                 2463 
               
               
                   
               
               
                 AD-62117.1 
                 CAUAUAUUGACAAAAUAACdTdT 
                 1897 
                 1502-1520 
                 GUUAUUUUGUCAAUAUAUGdTdT 
                 2464 
               
               
                   
               
               
                 AD-62123.1 
                 AUAUAUUGACAAAAUAACUdTdT 
                 1898 
                 1503-1521 
                 AGUUAUUUUGUCAAUAUAUdTdT 
                 2465 
               
               
                   
               
               
                 AD-62129.1 
                 UAUAUUGACAAAAUAACUCdTdT 
                 1899 
                 1504-1522 
                 GAGUUAUUUUGUCAAUAUAdTdT 
                 2466 
               
               
                   
               
               
                 AD-62135.1 
                 AUAUUGACAAAAUAACUCAdTdT 
                 1900 
                 1505-1523 
                 UGAGUUAUUUUGUCAAUAUdTdT 
                 2467 
               
               
                   
               
               
                 AD-62141.1 
                 UAUUGACAAAAUAACUCACdTdT 
                 1901 
                 1506-1524 
                 GUGAGUUAUUUUGUCAAUAdTdT 
                 2468 
               
               
                   
               
               
                 AD-62147.1 
                 AUUGACAAAAUAACUCACUdTdT 
                 1902 
                 1507-1525 
                 AGUGAGUUAUUUUGUCAAUdTdT 
                 2469 
               
               
                   
               
               
                 AD-62153.1 
                 UUGACAAAAUAACUCACUAdTdT 
                 1903 
                 1508-1526 
                 UAGUGAGUUAUUUUGUCAAdTdT 
                 2470 
               
               
                   
               
               
                 AD-62112.1 
                 UGACAAAAUAACUCACUAUdTdT 
                 1904 
                 1509-1527 
                 AUAGUGAGUUAUUUUGUCAdTdT 
                 2471 
               
               
                   
               
               
                 AD-62118.1 
                 GACAAAAUAACUCACUAUAdTdT 
                 1905 
                 1510-1528 
                 UAUAGUGAGUUAUUUUGUCdTdT 
                 2472 
               
               
                   
               
               
                 AD-62124.1 
                 AAAAUAACUCACUAUAAUUdTdT 
                 1906 
                 1513-1531 
                 AAUUAUAGUGAGUUAUUUUdTdT 
                 2473 
               
               
                   
               
               
                 AD-62130.1 
                 AAAUAACUCACUAUAAUUAdTdT 
                 1907 
                 1514-1532 
                 UAAUUAUAGUGAGUUAUUUdTdT 
                 2474 
               
               
                   
               
               
                 AD-62136.1 
                 AAUAACUCACUAUAAUUACdTdT 
                 1908 
                 1515-1533 
                 GUAAUUAUAGUGAGUUAUUdTdT 
                 2475 
               
               
                   
               
               
                 AD-62142.1 
                 AUAACUCACUAUAAUUACUdTdT 
                 1909 
                 1516-1534 
                 AGUAAUUAUAGUGAGUUAUdTdT 
                 2476 
               
               
                   
               
               
                 AD-62148.1 
                 AACUCACUAUAAUUACUUGdTdT 
                 1910 
                 1518-1536 
                 CAAGUAAUUAUAGUGAGUUdTdT 
                 2477 
               
               
                   
               
               
                 AD-62154.1 
                 ACUCACUAUAAUUACUUGAdTdT 
                 1911 
                 1519-1537 
                 UCAAGUAAUUAUAGUGAGUdTdT 
                 2478 
               
               
                   
               
               
                 AD-62113.1 
                 CUCACUAUAAUUACUUGAUdTdT 
                 1912 
                 1520-1538 
                 AUCAAGUAAUUAUAGUGAGdTdT 
                 2479 
               
               
                   
               
               
                 AD-62119.1 
                 UCACUAUAAUUACUUGAUUdTdT 
                 1913 
                 1521-1539 
                 AAUCAAGUAAUUAUAGUGAdTdT 
                 2480 
               
               
                   
               
               
                 AD-62125.1 
                 ACUAUAAUUACUUGAUUUUdTdT 
                 1914 
                 1523-1541 
                 AAAAUCAAGUAAUUAUAGUdTdT 
                 2481 
               
               
                   
               
               
                 AD-62131.1 
                 CUAUAAUUACUUGAUUUUAdTdT 
                 1915 
                 1524-1542 
                 UAAAAUCAAGUAAUUAUAGdTdT 
                 2482 
               
               
                   
               
               
                 AD-62137.1 
                 UAUAAUUACUUGAUUUUAUdTdT 
                 1916 
                 1525-1543 
                 AUAAAAUCAAGUAAUUAUAdTdT 
                 2483 
               
               
                   
               
               
                 AD-62143.1 
                 AUAAUUACUUGAUUUUAUCdTdT 
                 1917 
                 1526-1544 
                 GAUAAAAUCAAGUAAUUAUdTdT 
                 2484 
               
               
                   
               
               
                 AD-62149.1 
                 UAAUUACUUGAUUUUAUCCdTdT 
                 1918 
                 1527-1545 
                 GGAUAAAAUCAAGUAAUUAdTdT 
                 2485 
               
               
                   
               
               
                 AD-62155.1 
                 AAUUACUUGAUUUUAUCCAdTdT 
                 1919 
                 1528-1546 
                 UGGAUAAAAUCAAGUAAUUdTdT 
                 2486 
               
               
                   
               
               
                 AD-62114.1 
                 AUUACUUGAUUUUAUCCAAdTdT 
                 1920 
                 1529-1547 
                 UUGGAUAAAAUCAAGUAAUdTdT 
                 2487 
               
               
                   
               
               
                 AD-62120.1 
                 UUAUCCAAGGGCAAAAUUAdTdT 
                 1921 
                 1540-1558 
                 UAAUUUUGCCCUUGGAUAAdTdT 
                 2488 
               
               
                   
               
               
                 AD-62126.1 
                 GCAAAAUUAUCCACUUUGGdTdT 
                 1922 
                 1550-1568 
                 CCAAAGUGGAUAAUUUUGCdTdT 
                 2489 
               
               
                   
               
               
                 AD-62132.1 
                 CACUUUGGCACGAGGGAGAdTdT 
                 1923 
                 1561-1579 
                 UCUCCCUCGUGCCAAAGUGdTdT 
                 2490 
               
               
                   
               
               
                 AD-62138.1 
                 CGAGGGAGAAAUUUUCAGAdTdT 
                 1924 
                 1571-1589 
                 UCUGAAAAUUUCUCCCUCGdTdT 
                 2491 
               
               
                   
               
               
                 AD-62144.1 
                 AUUUUCAGAUGCAUCUUAUdTdT 
                 1925 
                 1581-1599 
                 AUAAGAUGCAUCUGAAAAUdTdT 
                 2492 
               
               
                   
               
               
                 AD-62150.1 
                 GCAUCUUAUCAAAGUAUAAdTdT 
                 1926 
                 1591-1609 
                 UUAUACUUUGAUAAGAUGCdTdT 
                 2493 
               
               
                   
               
               
                 AD-62156.1 
                 CAAAGUAUAAACAUUCCAGdTdT 
                 1927 
                 1600-1618 
                 CUGGAAUGUUUAUACUUUGdTdT 
                 2494 
               
               
                   
               
               
                 AD-62162.1 
                 AUUCCAGUAACACAGAACAdTdT 
                 1928 
                 1612-1630 
                 UGUUCUGUGUUACUGGAAUdTdT 
                 2495 
               
               
                   
               
               
                 AD-62168.1 
                 CACAGAACAUGGUUCCUUCdTdT 
                 1929 
                 1622-1640 
                 GAAGGAACCAUGUUCUGUGdTdT 
                 2496 
               
               
                   
               
               
                 AD-62174.1 
                 GGUUCCUUCAUCCCGACUUdTdT 
                 1930 
                 1632-1650 
                 AAGUCGGGAUGAAGGAACCdTdT 
                 2497 
               
               
                   
               
               
                 AD-62180.1 
                 CCCGACUUCUGGUCUAUUAdTdT 
                 1931 
                 1643-1661 
                 UAAUAGACCAGAAGUCGGGdTdT 
                 2498 
               
               
                   
               
               
                 AD-62186.1 
                 GGUCUAUUACAUCGUCACAdTdT 
                 1932 
                 1653-1671 
                 UGUGACGAUGUAAUAGACCdTdT 
                 2499 
               
               
                   
               
               
                 AD-62192.1 
                 AUCGUCACAGGAGAACAGAdTdT 
                 1933 
                 1663-1681 
                 UCUGUUCUCCUGUGACGAUdTdT 
                 2500 
               
               
                   
               
               
                 AD-62198.1 
                 CAGGAGAACAGACAGCAGAdTdT 
                 1934 
                 1670-1688 
                 UCUGCUGUCUGUUCUCCUGdTdT 
                 2501 
               
               
                   
               
               
                 AD-62157.1 
                 CAGCAGAAUUAGUGUCUGAdTdT 
                 1935 
                 1682-1700 
                 UCAGACACUAAUUCUGCUGdTdT 
                 2502 
               
               
                   
               
               
                 AD-62163.1 
                 GUGUCUGAUUCAGUCUGGUdTdT 
                 1936 
                 1693-1711 
                 ACCAGACUGAAUCAGACACdTdT 
                 2503 
               
               
                   
               
               
                 AD-62169.1 
                 CAGUCUGGUUAAAUAUUGAdTdT 
                 1937 
                 1703-1721 
                 UCAAUAUUUAACCAGACUGdTdT 
                 2504 
               
               
                   
               
               
                 AD-62175.1 
                 GUUAAAUAUUGAAGAAAAAdTdT 
                 1938 
                 1710-1728 
                 UUUUUCUUCAAUAUUUAACdTdT 
                 2505 
               
               
                   
               
               
                 AD-62181.1 
                 AGAAAAAUGUGGCAACCAGdTdT 
                 1939 
                 1722-1740 
                 CUGGUUGCCACAUUUUUCUdTdT 
                 2506 
               
               
                   
               
               
                 AD-62187.1 
                 GCAACCAGCUCCAGGUUCAdTdT 
                 1940 
                 1733-1751 
                 UGAACCUGGAGCUGGUUGCdTdT 
                 2507 
               
               
                   
               
               
                 AD-62193.1 
                 GCUCCAGGUUCAUCUGUCUdTdT 
                 1941 
                 1740-1758 
                 AGACAGAUGAACCUGGAGCdTdT 
                 2508 
               
               
                   
               
               
                 AD-62199.1 
                 AUCUGUCUCCUGAUGCAGAdTdT 
                 1942 
                 1751-1769 
                 UCUGCAUCAGGAGACAGAUdTdT 
                 2509 
               
               
                   
               
               
                 AD-62158.1 
                 GAUGCAGAUGCAUAUUCUCdTdT 
                 1943 
                 1762-1780 
                 GAGAAUAUGCAUCUGCAUCdTdT 
                 2510 
               
               
                   
               
               
                 AD-62164.1 
                 GCAUAUUCUCCAGGCCAAAdTdT 
                 1944 
                 1771-1789 
                 UUUGGCCUGGAGAAUAUGCdTdT 
                 2511 
               
               
                   
               
               
                 AD-62170.1 
                 AGGCCAAACUGUGUCUCUUdTdT 
                 1945 
                 1782-1800 
                 AAGAGACACAGUUUGGCCUdTdT 
                 2512 
               
               
                   
               
               
                 AD-62176.1 
                 GUGUCUCUUAAUAUGGCAAdTdT 
                 1946 
                 1792-1810 
                 UUGCCAUAUUAAGAGACACdTdT 
                 2513 
               
               
                   
               
               
                 AD-62182.1 
                 UUAAUAUGGCAACUGGAAUdTdT 
                 1947 
                 1799-1817 
                 AUUCCAGUUGCCAUAUUAAdTdT 
                 2514 
               
               
                   
               
               
                 AD-62188.1 
                 AACUGGAAUGGAUUCCUGGdTdT 
                 1948 
                 1809-1827 
                 CCAGGAAUCCAUUCCAGUUdTdT 
                 2515 
               
               
                   
               
               
                 AD-62194.1 
                 UUCCUGGGUGGCAUUAGCAdTdT 
                 1949 
                 1821-1839 
                 UGCUAAUGCCACCCAGGAAdTdT 
                 2516 
               
               
                   
               
               
                 AD-62200.1 
                 GGCAUUAGCAGCAGUGGACdTdT 
                 1950 
                 1830-1848 
                 GUCCACUGCUGCUAAUGCCdTdT 
                 2517 
               
               
                   
               
               
                 AD-62159.1 
                 AGUGGACAGUGCUGUGUAUdTdT 
                 1951 
                 1842-1860 
                 AUACACAGCACUGUCCACUdTdT 
                 2518 
               
               
                   
               
               
                 AD-62165.1 
                 GCUGUGUAUGGAGUCCAAAdTdT 
                 1952 
                 1852-1870 
                 UUUGGACUCCAUACACAGCdTdT 
                 2519 
               
               
                   
               
               
                 AD-62171.1 
                 AGUCCAAAGAGGAGCCAAAdTdT 
                 1953 
                 1863-1881 
                 UUUGGCUCCUCUUUGGACUdTdT 
                 2520 
               
               
                   
               
               
                 AD-62177.1 
                 AGAGGAGCCAAAAAGCCCUdTdT 
                 1954 
                 1870-1888 
                 AGGGCUUUUUGGCUCCUCUdTdT 
                 2521 
               
               
                   
               
               
                 AD-62183.1 
                 AGCCCUUGGAAAGAGUAUUdTdT 
                 1955 
                 1883-1901 
                 AAUACUCUUUCCAAGGGCUdTdT 
                 2522 
               
               
                   
               
               
                 AD-62189.1 
                 AAGAGUAUUUCAAUUCUUAdTdT 
                 1956 
                 1893-1911 
                 UAAGAAUUGAAAUACUCUUdTdT 
                 2523 
               
               
                   
               
               
                 AD-62195.1 
                 UUUCAAUUCUUAGAGAAGAdTdT 
                 1957 
                 1900-1918 
                 UCUUCUCUAAGAAUUGAAAdTdT 
                 2524 
               
               
                   
               
               
                 AD-62201.1 
                 GAGAAGAGUGAUCUGGGCUdTdT 
                 1958 
                 1912-1930 
                 AGCCCAGAUCACUCUUCUCdTdT 
                 2525 
               
               
                   
               
               
                 AD-62160.1 
                 UGAUCUGGGCUGUGGGGCAdTdT 
                 1959 
                 1920-1938 
                 UGCCCCACAGCCCAGAUCAdTdT 
                 2526 
               
               
                   
               
               
                 AD-62166.1 
                 GGGGCAGGUGGUGGCCUCAdTdT 
                 1960 
                 1933-1951 
                 UGAGGCCACCACCUGCCCCdTdT 
                 2527 
               
               
                   
               
               
                 AD-62172.1 
                 GUGGCCUCAACAAUGCCAAdTdT 
                 1961 
                 1943-1961 
                 UUGGCAUUGUUGAGGCCACdTdT 
                 2528 
               
               
                   
               
               
                 AD-62178.1 
                 CAACAAUGCCAAUGUGUUCdTdT 
                 1962 
                 1950-1968 
                 GAACACAUUGGCAUUGUUGdTdT 
                 2529 
               
               
                   
               
               
                 AD-62184.1 
                 CAAUGUGUUCCACCUAGCUdTdT 
                 1963 
                 1959-1977 
                 AGCUAGGUGGAACACAUUGdTdT 
                 2530 
               
               
                   
               
               
                 AD-62190.1 
                 CACCUAGCUGGACUUACCUdTdT 
                 1964 
                 1969-1987 
                 AGGUAAGUCCAGCUAGGUGdTdT 
                 2531 
               
               
                   
               
               
                 AD-62196.1 
                 GACUUACCUUCCUCACUAAdTdT 
                 1965 
                 1979-1997 
                 UUAGUGAGGAAGGUAAGUCdTdT 
                 2532 
               
               
                   
               
               
                 AD-62202.1 
                 UCACUAAUGCAAAUGCAGAdTdT 
                 1966 
                 1991-2009 
                 UCUGCAUUUGCAUUAGUGAdTdT 
                 2533 
               
               
                   
               
               
                 AD-62161.1 
                 AAAUGCAGAUGACUCCCAAdTdT 
                 1967 
                 2001-2019 
                 UUGGGAGUCAUCUGCAUUUdTdT 
                 2534 
               
               
                   
               
               
                 AD-62167.1 
                 CUCCCAAGAAAAUGAUGAAdTdT 
                 1968 
                 2013-2031 
                 UUCAUCAUUUUCUUGGGAGdTdT 
                 2535 
               
               
                   
               
               
                 AD-62173.1 
                 CCUUGUAAAGAAAUUCUCAdTdT 
                 1969 
                 2032-2050 
                 UGAGAAUUUCUUUACAAGGdTdT 
                 2536 
               
               
                   
               
               
                 AD-62179.1 
                 AAUUCUCAGGCCAAGAAGAdTdT 
                 1970 
                 2043-2061 
                 UCUUCUUGGCCUGAGAAUUdTdT 
                 2537 
               
               
                   
               
               
                 AD-62185.1 
                 CCAAGAAGAACGCUGCAAAdTdT 
                 1971 
                 2053-2071 
                 UUUGCAGCGUUCUUCUUGGdTdT 
                 2538 
               
               
                   
               
               
                 AD-62191.1 
                 CGCUGCAAAAGAAGAUAGAdTdT 
                 1972 
                 2063-2081 
                 UCUAUCUUCUUUUGCAGCGdTdT 
                 2539 
               
               
                   
               
               
                 AD-62197.1 
                 AAAGAAGAUAGAAGAAAUAdTdT 
                 1973 
                 2070-2088 
                 UAUUUCUUCUAUCUUCUUUdTdT 
                 2540 
               
               
                   
               
               
                 AD-62203.1 
                 AGAAAUAGCUGCUAAAUAUdTdT 
                 1974 
                 2082-2100 
                 AUAUUUAGCAGCUAUUUCUdTdT 
                 2541 
               
               
                   
               
               
                 AD-62209.1 
                 GCUGCUAAAUAUAAACAUUdTdT 
                 1975 
                 2089-2107 
                 AAUGUUUAUAUUUAGCAGCdTdT 
                 2542 
               
               
                   
               
               
                 AD-62215.1 
                 ACAUUCAGUAGUGAAGAAAdTdT 
                 1976 
                 2103-2121 
                 UUUCUUCACUACUGAAUGUdTdT 
                 2543 
               
               
                   
               
               
                 AD-62221.1 
                 GUAGUGAAGAAAUGUUGUUdTdT 
                 1977 
                 2110-2128 
                 AACAACAUUUCUUCACUACdTdT 
                 2544 
               
               
                   
               
               
                 AD-62227.1 
                 AAAUGUUGUUACGAUGGAGdTdT 
                 1978 
                 2119-2137 
                 CUCCAUCGUAACAACAUUUdTdT 
                 2545 
               
               
                   
               
               
                 AD-62233.1 
                 CGAUGGAGCCUGCGUUAAUdTdT 
                 1979 
                 2130-2148 
                 AUUAACGCAGGCUCCAUCGdTdT 
                 2546 
               
               
                   
               
               
                 AD-62239.1 
                 CGUUAAUAAUGAUGAAACCdTdT 
                 1980 
                 2142-2160 
                 GGUUUCAUCAUUAUUAACGdTdT 
                 2547 
               
               
                   
               
               
                 AD-62245.1 
                 AUGAUGAAACCUGUGAGCAdTdT 
                 1981 
                 2150-2168 
                 UGCUCACAGGUUUCAUCAUdTdT 
                 2548 
               
               
                   
               
               
                 AD-62204.1 
                 CUGUGAGCAGCGAGCUGCAdTdT 
                 1982 
                 2160-2178 
                 UGCAGCUCGCUGCUCACAGdTdT 
                 2549 
               
               
                   
               
               
                 AD-62210.1 
                 CGAGCUGCACGGAUUAGUUdTdT 
                 1983 
                 2170-2188 
                 AACUAAUCCGUGCAGCUCGdTdT 
                 2550 
               
               
                   
               
               
                 AD-62216.1 
                 GGAUUAGUUUAGGGCCAAGdTdT 
                 1984 
                 2180-2198 
                 CUUGGCCCUAAACUAAUCCdTdT 
                 2551 
               
               
                   
               
               
                 AD-62222.1 
                 GGGCCAAGAUGCAUCAAAGdTdT 
                 1985 
                 2191-2209 
                 CUUUGAUGCAUCUUGGCCCdTdT 
                 2552 
               
               
                   
               
               
                 AD-62228.1 
                 CAUCAAAGCUUUCACUGAAdTdT 
                 1986 
                 2202-2220 
                 UUCAGUGAAAGCUUUGAUGdTdT 
                 2553 
               
               
                   
               
               
                 AD-62234.1 
                 GCUUUCACUGAAUGUUGUGdTdT 
                 1987 
                 2209-2227 
                 CACAACAUUCAGUGAAAGCdTdT 
                 2554 
               
               
                   
               
               
                 AD-62240.1 
                 AAUGUUGUGUCGUCGCAAGdTdT 
                 1988 
                 2219-2237 
                 CUUGCGACGACACAACAUUdTdT 
                 2555 
               
               
                   
               
               
                 AD-62246.1 
                 CGUCGCAAGCCAGCUCCGUdTdT 
                 1989 
                 2229-2247 
                 ACGGAGCUGGCUUGCGACGdTdT 
                 2556 
               
               
                   
               
               
                 AD-62205.1 
                 GCUCCGUGCUAAUAUCUCUdTdT 
                 1990 
                 2241-2259 
                 AGAGAUAUUAGCACGGAGCdTdT 
                 2557 
               
               
                   
               
               
                 AD-62211.1 
                 CUAAUAUCUCUCAUAAAGAdTdT 
                 1991 
                 2249-2267 
                 UCUUUAUGAGAGAUAUUAGdTdT 
                 2558 
               
               
                   
               
               
                 AD-62217.1 
                 AAAGACAUGCAAUUGGGAAdTdT 
                 1992 
                 2263-2281 
                 UUCCCAAUUGCAUGUCUUUdTdT 
                 2559 
               
               
                   
               
               
                 AD-62223.1 
                 CAAUUGGGAAGGCUACACAdTdT 
                 1993 
                 2272-2290 
                 UGUGUAGCCUUCCCAAUUGdTdT 
                 2560 
               
               
                   
               
               
                 AD-62229.1 
                 GCUACACAUGAAGACCCUGdTdT 
                 1994 
                 2283-2301 
                 CAGGGUCUUCAUGUGUAGCdTdT 
                 2561 
               
               
                   
               
               
                 AD-62235.1 
                 CAUGAAGACCCUGUUACCAdTdT 
                 1995 
                 2289-2307 
                 UGGUAACAGGGUCUUCAUGdTdT 
                 2562 
               
               
                   
               
               
                 AD-62241.1 
                 UACCAGUAAGCAAGCCAGAdTdT 
                 1996 
                 2303-2321 
                 UCUGGCUUGCUUACUGGUAdTdT 
                 2563 
               
               
                   
               
               
                 AD-62247.1 
                 AGCAAGCCAGAAAUUCGGAdTdT 
                 1997 
                 2311-2329 
                 UCCGAAUUUCUGGCUUGCUdTdT 
                 2564 
               
               
                   
               
               
                 AD-62206.1 
                 AGAAAUUCGGAGUUAUUUUdTdT 
                 1998 
                 2319-2337 
                 AAAAUAACUCCGAAUUUCUdTdT 
                 2565 
               
               
                   
               
               
                 AD-62212.1 
                 AGUUAUUUUCCAGAAAGCUdTdT 
                 1999 
                 2329-2347 
                 AGCUUUCUGGAAAAUAACUdTdT 
                 2566 
               
               
                   
               
               
                 AD-62218.1 
                 CAGAAAGCUGGUUGUGGGAdTdT 
                 2000 
                 2339-2357 
                 UCCCACAACCAGCUUUCUGdTdT 
                 2567 
               
               
                   
               
               
                 AD-62224.1 
                 GUGGGAAGUUCAUCUUGUUdTdT 
                 2001 
                 2352-2370 
                 AACAAGAUGAACUUCCCACdTdT 
                 2568 
               
               
                   
               
               
                 AD-62230.1 
                 UCAUCUUGUUCCCAGAAGAdTdT 
                 2002 
                 2361-2379 
                 UCUUCUGGGAACAAGAUGAdTdT 
                 2569 
               
               
                   
               
               
                 AD-62236.1 
                 CCAGAAGAAAACAGUUGCAdTdT 
                 2003 
                 2372-2390 
                 UGCAACUGUUUUCUUCUGGdTdT 
                 2570 
               
               
                   
               
               
                 AD-62242.1 
                 CAGUUGCAGUUUGCCCUACdTdT 
                 2004 
                 2383-2401 
                 GUAGGGCAAACUGCAACUGdTdT 
                 2571 
               
               
                   
               
               
                 AD-62248.1 
                 CAGUUUGCCCUACCUGAUUdTdT 
                 2005 
                 2389-2407 
                 AAUCAGGUAGGGCAAACUGdTdT 
                 2572 
               
               
                   
               
               
                 AD-62207.1 
                 CCUGAUUCUCUAACCACCUdTdT 
                 2006 
                 2401-2419 
                 AGGUGGUUAGAGAAUCAGGdTdT 
                 2573 
               
               
                   
               
               
                 AD-62213.1 
                 ACCACCUGGGAAAUUCAAGdTdT 
                 2007 
                 2413-2431 
                 CUUGAAUUUCCCAGGUGGUdTdT 
                 2574 
               
               
                   
               
               
                 AD-62219.1 
                 GAAAUUCAAGGCGUUGGCAdTdT 
                 2008 
                 2422-2440 
                 UGCCAACGCCUUGAAUUUCdTdT 
                 2575 
               
               
                   
               
               
                 AD-62225.1 
                 CGUUGGCAUUUCAAACACUdTdT 
                 2009 
                 2433-2451 
                 AGUGUUUGAAAUGCCAACGdTdT 
                 2576 
               
               
                   
               
               
                 AD-62231.1 
                 CAUUUCAAACACUGGUAUAdTdT 
                 2010 
                 2439-2457 
                 UAUACCAGUGUUUGAAAUGdTdT 
                 2577 
               
               
                   
               
               
                 AD-62237.1 
                 GUAUAUGUGUUGCUGAUACdTdT 
                 2011 
                 2453-2471 
                 GUAUCAGCAACACAUAUACdTdT 
                 2578 
               
               
                   
               
               
                 AD-62243.1 
                 UGCUGAUACUGUCAAGGCAdTdT 
                 2012 
                 2463-2481 
                 UGCCUUGACAGUAUCAGCAdTdT 
                 2579 
               
               
                   
               
               
                 AD-62249.1 
                 CUGUCAAGGCAAAGGUGUUdTdT 
                 2013 
                 2471-2489 
                 AACACCUUUGCCUUGACAGdTdT 
                 2580 
               
               
                   
               
               
                 AD-62208.1 
                 AGGUGUUCAAAGAUGUCUUdTdT 
                 2014 
                 2483-2501 
                 AAGACAUCUUUGAACACCUdTdT 
                 2581 
               
               
                   
               
               
                 AD-62214.1 
                 CAAAGAUGUCUUCCUGGAAdTdT 
                 2015 
                 2490-2508 
                 UUCCAGGAAGACAUCUUUGdTdT 
                 2582 
               
               
                   
               
               
                 AD-62220.1 
                 CUUCCUGGAAAUGAAUAUAdTdT 
                 2016 
                 2499-2517 
                 UAUAUUCAUUUCCAGGAAGdTdT 
                 2583 
               
               
                   
               
               
                 AD-62226.1 
                 GAAUAUACCAUAUUCUGUUdTdT 
                 2017 
                 2511-2529 
                 AACAGAAUAUGGUAUAUUCdTdT 
                 2584 
               
               
                   
               
               
                 AD-62232.1 
                 AUAUUCUGUUGUACGAGGAdTdT 
                 2018 
                 2520-2538 
                 UCCUCGUACAACAGAAUAUdTdT 
                 2585 
               
               
                   
               
               
                 AD-62238.1 
                 CGAGGAGAACAGAUCCAAUdTdT 
                 2019 
                 2533-2551 
                 AUUGGAUCUGUUCUCCUCGdTdT 
                 2586 
               
               
                   
               
               
                 AD-62244.1 
                 GAACAGAUCCAAUUGAAAGdTdT 
                 2020 
                 2539-2557 
                 CUUUCAAUUGGAUCUGUUCdTdT 
                 2587 
               
               
                   
               
               
                 AD-61874.1 
                 GAAAGGAACUGUUUACAACdTdT 
                 2021 
                 2553-2571 
                 GUUGUAAACAGUUCCUUUCdTdT 
                 2588 
               
               
                   
               
               
                 AD-61880.1 
                 ACUGUUUACAACUAUAGGAdTdT 
                 2022 
                 2560-2578 
                 UCCUAUAGUUGUAAACAGUdTdT 
                 2589 
               
               
                   
               
               
                 AD-61886.1 
                 AACUAUAGGACUUCUGGGAdTdT 
                 2023 
                 2569-2587 
                 UCCCAGAAGUCCUAUAGUUdTdT 
                 2590 
               
               
                   
               
               
                 AD-61892.1 
                 UGGGAUGCAGUUCUGUGUUdTdT 
                 2024 
                 2583-2601 
                 AACACAGAACUGCAUCCCAdTdT 
                 2591 
               
               
                   
               
               
                 AD-61898.1 
                 GUUCUGUGUUAAAAUGUCUdTdT 
                 2025 
                 2592-2610 
                 AGACAUUUUAACACAGAACdTdT 
                 2592 
               
               
                   
               
               
                 AD-61904.1 
                 UUAAAAUGUCUGCUGUGGAdTdT 
                 2026 
                 2600-2618 
                 UCCACAGCAGACAUUUUAAdTdT 
                 2593 
               
               
                   
               
               
                 AD-61910.1 
                 CUGUGGAGGGAAUCUGCACdTdT 
                 2027 
                 2612-2630 
                 GUGCAGAUUCCCUCCACAGdTdT 
                 2594 
               
               
                   
               
               
                 AD-61916.1 
                 GGAAUCUGCACUUCGGAAAdTdT 
                 2028 
                 2620-2638 
                 UUUCCGAAGUGCAGAUUCCdTdT 
                 2595 
               
               
                   
               
               
                 AD-61875.1 
                 CGGAAAGCCCAGUCAUUGAdTdT 
                 2029 
                 2633-2651 
                 UCAAUGACUGGGCUUUCCGdTdT 
                 2596 
               
               
                   
               
               
                 AD-61881.1 
                 CCAGUCAUUGAUCAUCAGGdTdT 
                 2030 
                 2641-2659 
                 CCUGAUGAUCAAUGACUGGdTdT 
                 2597 
               
               
                   
               
               
                 AD-61887.1 
                 CAUCAGGGCACAAAGUCCUdTdT 
                 2031 
                 2653-2671 
                 AGGACUUUGUGCCCUGAUGdTdT 
                 2598 
               
               
                   
               
               
                 AD-61893.1 
                 GGCACAAAGUCCUCCAAAUdTdT 
                 2032 
                 2659-2677 
                 AUUUGGAGGACUUUGUGCCdTdT 
                 2599 
               
               
                   
               
               
                 AD-61899.1 
                 CAAAUGUGUGCGCCAGAAAdTdT 
                 2033 
                 2673-2691 
                 UUUCUGGCGCACACAUUUGdTdT 
                 2600 
               
               
                   
               
               
                 AD-61905.1 
                 GCGCCAGAAAGUAGAGGGCdTdT 
                 2034 
                 2682-2700 
                 GCCCUCUACUUUCUGGCGCdTdT 
                 2601 
               
               
                   
               
               
                 AD-61911.1 
                 AGUAGAGGGCUCCUCCAGUdTdT 
                 2035 
                 2691-2709 
                 ACUGGAGGAGCCCUCUACUdTdT 
                 2602 
               
               
                   
               
               
                 AD-61917.1 
                 CCUCCAGUCACUUGGUGACdTdT 
                 2036 
                 2702-2720 
                 GUCACCAAGUGACUGGAGGdTdT 
                 2603 
               
               
                   
               
               
                 AD-61876.1 
                 UCACUUGGUGACAUUCACUdTdT 
                 2037 
                 2709-2727 
                 AGUGAAUGUCACCAAGUGAdTdT 
                 2604 
               
               
                   
               
               
                 AD-61882.1 
                 CAUUCACUGUGCUUCCUCUdTdT 
                 2038 
                 2720-2738 
                 AGAGGAAGCACAGUGAAUGdTdT 
                 2605 
               
               
                   
               
               
                 AD-61888.1 
                 GGAAAUUGGCCUUCACAACdTdT 
                 2039 
                 2739-2757 
                 GUUGUGAAGGCCAAUUUCCdTdT 
                 2606 
               
               
                   
               
               
                 AD-61894.1 
                 CUUCACAACAUCAAUUUUUdTdT 
                 2040 
                 2749-2767 
                 AAAAAUUGAUGUUGUGAAGdTdT 
                 2607 
               
               
                   
               
               
                 AD-61900.1 
                 AAUUUUUCACUGGAGACUUdTdT 
                 2041 
                 2761-2779 
                 AAGUCUCCAGUGAAAAAUUdTdT 
                 2608 
               
               
                   
               
               
                 AD-61906.1 
                 CUGGAGACUUGGUUUGGAAdTdT 
                 2042 
                 2770-2788 
                 UUCCAAACCAAGUCUCCAGdTdT 
                 2609 
               
               
                   
               
               
                 AD-61912.1 
                 GGUUUGGAAAAGAAAUCUUdTdT 
                 2043 
                 2780-2798 
                 AAGAUUUCUUUUCCAAACCdTdT 
                 2610 
               
               
                   
               
               
                 AD-61918.1 
                 AAUCUUAGUAAAAACAUUAdTdT 
                 2044 
                 2793-2811 
                 UAAUGUUUUUACUAAGAUUdTdT 
                 2611 
               
               
                   
               
               
                 AD-61877.1 
                 AAAAACAUUACGAGUGGUGdTdT 
                 2045 
                 2802-2820 
                 CACCACUCGUAAUGUUUUUdTdT 
                 2612 
               
               
                   
               
               
                 AD-61883.1 
                 GAGUGGUGCCAGAAGGUGUdTdT 
                 2046 
                 2813-2831 
                 ACACCUUCUGGCACCACUCdTdT 
                 2613 
               
               
                   
               
               
                 AD-61889.1 
                 AGAAGGUGUCAAAAGGGAAdTdT 
                 2047 
                 2823-2841 
                 UUCCCUUUUGACACCUUCUdTdT 
                 2614 
               
               
                   
               
               
                 AD-61895.1 
                 UGUCAAAAGGGAAAGCUAUdTdT 
                 2048 
                 2829-2847 
                 AUAGCUUUCCCUUUUGACAdTdT 
                 2615 
               
               
                   
               
               
                 AD-61901.1 
                 GCUAUUCUGGUGUUACUUUdTdT 
                 2049 
                 2843-2861 
                 AAAGUAACACCAGAAUAGCdTdT 
                 2616 
               
               
                   
               
               
                 AD-61907.1 
                 GUGUUACUUUGGAUCCUAGdTdT 
                 2050 
                 2852-2870 
                 CUAGGAUCCAAAGUAACACdTdT 
                 2617 
               
               
                   
               
               
                 AD-61913.1 
                 GGAUCCUAGGGGUAUUUAUdTdT 
                 2051 
                 2862-2880 
                 AUAAAUACCCCUAGGAUCCdTdT 
                 2618 
               
               
                   
               
               
                 AD-61919.1 
                 GGUAUUUAUGGUACCAUUAdTdT 
                 2052 
                 2872-2890 
                 UAAUGGUACCAUAAAUACCdTdT 
                 2619 
               
               
                   
               
               
                 AD-61878.1 
                 GUACCAUUAGCAGACGAAAdTdT 
                 2053 
                 2882-2900 
                 UUUCGUCUGCUAAUGGUACdTdT 
                 2620 
               
               
                   
               
               
                 AD-61884.1 
                 CAGACGAAAGGAGUUCCCAdTdT 
                 2054 
                 2892-2910 
                 UGGGAACUCCUUUCGUCUGdTdT 
                 2621 
               
               
                   
               
               
                 AD-61890.1 
                 AGGAGUUCCCAUACAGGAUdTdT 
                 2055 
                 2900-2918 
                 AUCCUGUAUGGGAACUCCUdTdT 
                 2622 
               
               
                   
               
               
                 AD-61896.1 
                 CAUACAGGAUACCCUUAGAdTdT 
                 2056 
                 2909-2927 
                 UCUAAGGGUAUCCUGUAUGdTdT 
                 2623 
               
               
                   
               
               
                 AD-61902.1 
                 CUUAGAUUUGGUCCCCAAAdTdT 
                 2057 
                 2922-2940 
                 UUUGGGGACCAAAUCUAAGdTdT 
                 2624 
               
               
                   
               
               
                 AD-61908.1 
                 UCCCCAAAACAGAAAUCAAdTdT 
                 2058 
                 2933-2951 
                 UUGAUUUCUGUUUUGGGGAdTdT 
                 2625 
               
               
                   
               
               
                 AD-61914.1 
                 ACAGAAAUCAAAAGGAUUUdTdT 
                 2059 
                 2941-2959 
                 AAAUCCUUUUGAUUUCUGUdTdT 
                 2626 
               
               
                   
               
               
                 AD-61920.1 
                 AAAGGAUUUUGAGUGUAAAdTdT 
                 2060 
                 2951-2969 
                 UUUACACUCAAAAUCCUUUdTdT 
                 2627 
               
               
                   
               
               
                 AD-61879.1 
                 AGUGUAAAAGGACUGCUUGdTdT 
                 2061 
                 2962-2980 
                 CAAGCAGUCCUUUUACACUdTdT 
                 2628 
               
               
                   
               
               
                 AD-61885.1 
                 AAGGACUGCUUGUAGGUGAdTdT 
                 2062 
                 2969-2987 
                 UCACCUACAAGCAGUCCUUdTdT 
                 2629 
               
               
                   
               
               
                 AD-61891.1 
                 GUAGGUGAGAUCUUGUCUGdTdT 
                 2063 
                 2980-2998 
                 CAGACAAGAUCUCACCUACdTdT 
                 2630 
               
               
                   
               
               
                 AD-61897.1 
                 AUCUUGUCUGCAGUUCUAAdTdT 
                 2064 
                 2989-3007 
                 UUAGAACUGCAGACAAGAUdTdT 
                 2631 
               
               
                   
               
               
                 AD-61903.1 
                 GUUCUAAGUCAGGAAGGCAdTdT 
                 2065 
                 3001-3019 
                 UGCCUUCCUGACUUAGAACdTdT 
                 2632 
               
               
                   
               
               
                 AD-61909.1 
                 GAAGGCAUCAAUAUCCUAAdTdT 
                 2066 
                 3013-3031 
                 UUAGGAUAUUGAUGCCUUCdTdT 
                 2633 
               
               
                   
               
               
                 AD-61915.1 
                 UCAAUAUCCUAACCCACCUdTdT 
                 2067 
                 3020-3038 
                 AGGUGGGUUAGGAUAUUGAdTdT 
                 2634 
               
               
                   
               
               
                 AD-61921.1 
                 CCACCUCCCCAAAGGGAGUdTdT 
                 2068 
                 3033-3051 
                 ACUCCCUUUGGGGAGGUGGdTdT 
                 2635 
               
               
                   
               
               
                 AD-61927.1 
                 CCCCAAAGGGAGUGCAGAGdTdT 
                 2069 
                 3039-3057 
                 CUCUGCACUCCCUUUGGGGdTdT 
                 2636 
               
               
                   
               
               
                 AD-61933.1 
                 GUGCAGAGGCGGAGCUGAUdTdT 
                 2070 
                 3050-3068 
                 AUCAGCUCCGCCUCUGCACdTdT 
                 2637 
               
               
                   
               
               
                 AD-61939.1 
                 GGAGCUGAUGAGCGUUGUCdTdT 
                 2071 
                 3060-3078 
                 GACAACGCUCAUCAGCUCCdTdT 
                 2638 
               
               
                   
               
               
                 AD-61945.1 
                 CGUUGUCCCAGUAUUCUAUdTdT 
                 2072 
                 3072-3090 
                 AUAGAAUACUGGGACAACGdTdT 
                 2639 
               
               
                   
               
               
                 AD-61951.1 
                 CCAGUAUUCUAUGUUUUUCdTdT 
                 2073 
                 3079-3097 
                 GAAAAACAUAGAAUACUGGdTdT 
                 2640 
               
               
                   
               
               
                 AD-61957.1 
                 GUUUUUCACUACCUGGAAAdTdT 
                 2074 
                 3091-3109 
                 UUUCCAGGUAGUGAAAAACdTdT 
                 2641 
               
               
                   
               
               
                 AD-61963.1 
                 CCUGGAAACAGGAAAUCAUdTdT 
                 2075 
                 3102-3120 
                 AUGAUUUCCUGUUUCCAGGdTdT 
                 2642 
               
               
                   
               
               
                 AD-61922.1 
                 GGAACAUUUUUCAUUCUGAdTdT 
                 2076 
                 3122-3140 
                 UCAGAAUGAAAAAUGUUCCdTdT 
                 2643 
               
               
                   
               
               
                 AD-61928.1 
                 CAUUCUGACCCAUUAAUUGdTdT 
                 2077 
                 3133-3151 
                 CAAUUAAUGGGUCAGAAUGdTdT 
                 2644 
               
               
                   
               
               
                 AD-61934.1 
                 CCAUUAAUUGAAAAGCAGAdTdT 
                 2078 
                 3142-3160 
                 UCUGCUUUUCAAUUAAUGGdTdT 
                 2645 
               
               
                   
               
               
                 AD-61940.1 
                 AAAGCAGAAACUGAAGAAAdTdT 
                 2079 
                 3153-3171 
                 UUUCUUCAGUUUCUGCUUUdTdT 
                 2646 
               
               
                   
               
               
                 AD-61946.1 
                 AACUGAAGAAAAAAUUAAAdTdT 
                 2080 
                 3161-3179 
                 UUUAAUUUUUUCUUCAGUUdTdT 
                 2647 
               
               
                   
               
               
                 AD-61952.1 
                 AAAAAAUUAAAAGAAGGGAdTdT 
                 2081 
                 3169-3187 
                 UCCCUUCUUUUAAUUUUUUdTdT 
                 2648 
               
               
                   
               
               
                 AD-61958.1 
                 AGGGAUGUUGAGCAUUAUGdTdT 
                 2082 
                 3183-3201 
                 CAUAAUGCUCAACAUCCCUdTdT 
                 2649 
               
               
                   
               
               
                 AD-61964.1 
                 GAGCAUUAUGUCCUACAGAdTdT 
                 2083 
                 3192-3210 
                 UCUGUAGGACAUAAUGCUCdTdT 
                 2650 
               
               
                   
               
               
                 AD-61923.1 
                 UGUCCUACAGAAAUGCUGAdTdT 
                 2084 
                 3200-3218 
                 UCAGCAUUUCUGUAGGACAdTdT 
                 2651 
               
               
                   
               
               
                 AD-61929.1 
                 AAUGCUGACUACUCUUACAdTdT 
                 2085 
                 3211-3229 
                 UGUAAGAGUAGUCAGCAUUdTdT 
                 2652 
               
               
                   
               
               
                 AD-61935.1 
                 UACUCUUACAGUGUGUGGAdTdT 
                 2086 
                 3220-3238 
                 UCCACACACUGUAAGAGUAdTdT 
                 2653 
               
               
                   
               
               
                 AD-61941.1 
                 AGUGUGUGGAAGGGUGGAAdTdT 
                 2087 
                 3229-3247 
                 UUCCACCCUUCCACACACUdTdT 
                 2654 
               
               
                   
               
               
                 AD-61947.1 
                 GGGUGGAAGUGCUAGCACUdTdT 
                 2088 
                 3240-3258 
                 AGUGCUAGCACUUCCACCCdTdT 
                 2655 
               
               
                   
               
               
                 AD-61953.1 
                 GCUAGCACUUGGUUAACAGdTdT 
                 2089 
                 3250-3268 
                 CUGUUAACCAAGUGCUAGCdTdT 
                 2656 
               
               
                   
               
               
                 AD-61959.1 
                 GGUUAACAGCUUUUGCUUUdTdT 
                 2090 
                 3260-3278 
                 AAAGCAAAAGCUGUUAACCdTdT 
                 2657 
               
               
                   
               
               
                 AD-61965.1 
                 UGCUUUAAGAGUACUUGGAdTdT 
                 2091 
                 3273-3291 
                 UCCAAGUACUCUUAAAGCAdTdT 
                 2658 
               
               
                   
               
               
                 AD-61924.1 
                 GUACUUGGACAAGUAAAUAdTdT 
                 2092 
                 3283-3301 
                 UAUUUACUUGUCCAAGUACdTdT 
                 2659 
               
               
                   
               
               
                 AD-61930.1 
                 CAAGUAAAUAAAUACGUAGdTdT 
                 2093 
                 3292-3310 
                 CUACGUAUUUAUUUACUUGdTdT 
                 2660 
               
               
                   
               
               
                 AD-61936.1 
                 AUAAAUACGUAGAGCAGAAdTdT 
                 2094 
                 3299-3317 
                 UUCUGCUCUACGUAUUUAUdTdT 
                 2661 
               
               
                   
               
               
                 AD-61942.1 
                 GAGCAGAACCAAAAUUCAAdTdT 
                 2095 
                 3310-3328 
                 UUGAAUUUUGGUUCUGCUCdTdT 
                 2662 
               
               
                   
               
               
                 AD-61948.1 
                 AAUUCAAUUUGUAAUUCUUdTdT 
                 2096 
                 3322-3340 
                 AAGAAUUACAAAUUGAAUUdTdT 
                 2663 
               
               
                   
               
               
                 AD-61954.1 
                 GUAAUUCUUUAUUGUGGCUdTdT 
                 2097 
                 3332-3350 
                 AGCCACAAUAAAGAAUUACdTdT 
                 2664 
               
               
                   
               
               
                 AD-61960.1 
                 AUUGUGGCUAGUUGAGAAUdTdT 
                 2098 
                 3342-3360 
                 AUUCUCAACUAGCCACAAUdTdT 
                 2665 
               
               
                   
               
               
                 AD-61966.1 
                 CUAGUUGAGAAUUAUCAAUdTdT 
                 2099 
                 3349-3367 
                 AUUGAUAAUUCUCAACUAGdTdT 
                 2666 
               
               
                   
               
               
                 AD-61925.1 
                 UUAUCAAUUAGAUAAUGGAdTdT 
                 2100 
                 3360-3378 
                 UCCAUUAUCUAAUUGAUAAdTdT 
                 2667 
               
               
                   
               
               
                 AD-61931.1 
                 AAUGGAUCUUUCAAGGAAAdTdT 
                 2101 
                 3373-3391 
                 UUUCCUUGAAAGAUCCAUUdTdT 
                 2668 
               
               
                   
               
               
                 AD-61937.1 
                 CUUUCAAGGAAAAUUCACAdTdT 
                 2102 
                 3380-3398 
                 UGUGAAUUUUCCUUGAAAGdTdT 
                 2669 
               
               
                   
               
               
                 AD-61943.1 
                 AAUUCACAGUAUCAACCAAdTdT 
                 2103 
                 3391-3409 
                 UUGGUUGAUACUGUGAAUUdTdT 
                 2670 
               
               
                   
               
               
                 AD-61949.1 
                 GUAUCAACCAAUAAAAUUAdTdT 
                 2104 
                 3399-3417 
                 UAAUUUUAUUGGUUGAUACdTdT 
                 2671 
               
               
                   
               
               
                 AD-61955.1 
                 AAAAUUACAGGGUACCUUGdTdT 
                 2105 
                 3411-3429 
                 CAAGGUACCCUGUAAUUUUdTdT 
                 2672 
               
               
                   
               
               
                 AD-61961.1 
                 AGGGUACCUUGCCUGUUGAdTdT 
                 2106 
                 3419-3437 
                 UCAACAGGCAAGGUACCCUdTdT 
                 2673 
               
               
                   
               
               
                 AD-61967.1 
                 GUUGAAGCCCGAGAGAACAdTdT 
                 2107 
                 3433-3451 
                 UGUUCUCUCGGGCUUCAACdTdT 
                 2674 
               
               
                   
               
               
                 AD-61926.1 
                 CCGAGAGAACAGCUUAUAUdTdT 
                 2108 
                 3441-3459 
                 AUAUAAGCUGUUCUCUCGGdTdT 
                 2675 
               
               
                   
               
               
                 AD-61932.1 
                 GCUUAUAUCUUACAGCCUUdTdT 
                 2109 
                 3452-3470 
                 AAGGCUGUAAGAUAUAAGCdTdT 
                 2676 
               
               
                   
               
               
                 AD-61938.1 
                 CUUACAGCCUUUACUGUGAdTdT 
                 2110 
                 3460-3478 
                 UCACAGUAAAGGCUGUAAGdTdT 
                 2677 
               
               
                   
               
               
                 AD-61944.1 
                 GAAUUAGAAAGGCUUUCGAdTdT 
                 2111 
                 3482-3500 
                 UCGAAAGCCUUUCUAAUUCdTdT 
                 2678 
               
               
                   
               
               
                 AD-61950.1 
                 GGCUUUCGAUAUAUGCCCCdTdT 
                 2112 
                 3492-3510 
                 GGGGCAUAUAUCGAAAGCCdTdT 
                 2679 
               
               
                   
               
               
                 AD-61956.1 
                 GAUAUAUGCCCCCUGGUGAdTdT 
                 2113 
                 3499-3517 
                 UCACCAGGGGGCAUAUAUCdTdT 
                 2680 
               
               
                   
               
               
                 AD-61962.1 
                 GGUGAAAAUCGACACAGCUdTdT 
                 2114 
                 3513-3531 
                 AGCUGUGUCGAUUUUCACCdTdT 
                 2681 
               
               
                   
               
               
                 AD-61968.1 
                 CGACACAGCUCUAAUUAAAdTdT 
                 2115 
                 3522-3540 
                 UUUAAUUAGAGCUGUGUCGdTdT 
                 2682 
               
               
                   
               
               
                 AD-61974.1 
                 GCUCUAAUUAAAGCUGACAdTdT 
                 2116 
                 3529-3547 
                 UGUCAGCUUUAAUUAGAGCdTdT 
                 2683 
               
               
                   
               
               
                 AD-61980.1 
                 CUGACAACUUUCUGCUUGAdTdT 
                 2117 
                 3542-3560 
                 UCAAGCAGAAAGUUGUCAGdTdT 
                 2684 
               
               
                   
               
               
                 AD-61986.1 
                 CUUUCUGCUUGAAAAUACAdTdT 
                 2118 
                 3549-3567 
                 UGUAUUUUCAAGCAGAAAGdTdT 
                 2685 
               
               
                   
               
               
                 AD-61992.1 
                 AAAAUACACUGCCAGCCCAdTdT 
                 2119 
                 3560-3578 
                 UGGGCUGGCAGUGUAUUUUdTdT 
                 2686 
               
               
                   
               
               
                 AD-61998.1 
                 AGCCCAGAGCACCUUUACAdTdT 
                 2120 
                 3573-3591 
                 UGUAAAGGUGCUCUGGGCUdTdT 
                 2687 
               
               
                   
               
               
                 AD-62004.1 
                 GCACCUUUACAUUGGCCAUdTdT 
                 2121 
                 3581-3599 
                 AUGGCCAAUGUAAAGGUGCdTdT 
                 2688 
               
               
                   
               
               
                 AD-62010.1 
                 ACAUUGGCCAUUUCUGCGUdTdT 
                 2122 
                 3589-3607 
                 ACGCAGAAAUGGCCAAUGUdTdT 
                 2689 
               
               
                   
               
               
                 AD-61969.1 
                 CUGCGUAUGCUCUUUCCCUdTdT 
                 2123 
                 3602-3620 
                 AGGGAAAGAGCAUACGCAGdTdT 
                 2690 
               
               
                   
               
               
                 AD-61975.1 
                 CUUUCCCUGGGAGAUAAAAdTdT 
                 2124 
                 3613-3631 
                 UUUUAUCUCCCAGGGAAAGdTdT 
                 2691 
               
               
                   
               
               
                 AD-61981.1 
                 GAGAUAAAACUCACCCACAdTdT 
                 2125 
                 3623-3641 
                 UGUGGGUGAGUUUUAUCUCdTdT 
                 2692 
               
               
                   
               
               
                 AD-61987.1 
                 ACUCACCCACAGUUUCGUUdTdT 
                 2126 
                 3631-3649 
                 AACGAAACUGUGGGUGAGUdTdT 
                 2693 
               
               
                   
               
               
                 AD-61993.1 
                 CAGUUUCGUUCAAUUGUUUdTdT 
                 2127 
                 3640-3658 
                 AAACAAUUGAACGAAACUGdTdT 
                 2694 
               
               
                   
               
               
                 AD-61999.1 
                 CAAUUGUUUCAGCUUUGAAdTdT 
                 2128 
                 3650-3668 
                 UUCAAAGCUGAAACAAUUGdTdT 
                 2695 
               
               
                   
               
               
                 AD-62005.1 
                 CUUUGAAGAGAGAAGCUUUdTdT 
                 2129 
                 3662-3680 
                 AAAGCUUCUCUCUUCAAAGdTdT 
                 2696 
               
               
                   
               
               
                 AD-62011.1 
                 GAGAGAAGCUUUGGUUAAAdTdT 
                 2130 
                 3669-3687 
                 UUUAACCAAAGCUUCUCUCdTdT 
                 2697 
               
               
                   
               
               
                 AD-61970.1 
                 GUUAAAGGUAAUCCACCCAdTdT 
                 2131 
                 3682-3700 
                 UGGGUGGAUUACCUUUAACdTdT 
                 2698 
               
               
                   
               
               
                 AD-61976.1 
                 AAUCCACCCAUUUAUCGUUdTdT 
                 2132 
                 3691-3709 
                 AACGAUAAAUGGGUGGAUUdTdT 
                 2699 
               
               
                   
               
               
                 AD-61982.1 
                 CAUUUAUCGUUUUUGGAAAdTdT 
                 2133 
                 3699-3717 
                 UUUCCAAAAACGAUAAAUGdTdT 
                 2700 
               
               
                   
               
               
                 AD-61988.1 
                 UUUGGAAAGACAAUCUUCAdTdT 
                 2134 
                 3710-3728 
                 UGAAGAUUGUCUUUCCAAAdTdT 
                 2701 
               
               
                   
               
               
                 AD-61994.1 
                 AAUCUUCAGCAUAAAGACAdTdT 
                 2135 
                 3721-3739 
                 UGUCUUUAUGCUGAAGAUUdTdT 
                 2702 
               
               
                   
               
               
                 AD-62006.1 
                 CUCUGUACCUAACACUGGUdTdT 
                 2136 
                 3741-3759 
                 ACCAGUGUUAGGUACAGAGdTdT 
                 2703 
               
               
                   
               
               
                 AD-62012.1 
                 ACACUGGUACGGCACGUAUdTdT 
                 2137 
                 3752-3770 
                 AUACGUGCCGUACCAGUGUdTdT 
                 2704 
               
               
                   
               
               
                 AD-61971.1 
                 GGCACGUAUGGUAGAAACAdTdT 
                 2138 
                 3762-3780 
                 UGUUUCUACCAUACGUGCCdTdT 
                 2705 
               
               
                   
               
               
                 AD-61977.1 
                 GGUAGAAACAACUGCCUAUdTdT 
                 2139 
                 3771-3789 
                 AUAGGCAGUUGUUUCUACCdTdT 
                 2706 
               
               
                   
               
               
                 AD-61983.1 
                 CAACUGCCUAUGCUUUACUdTdT 
                 2140 
                 3779-3797 
                 AGUAAAGCAUAGGCAGUUGdTdT 
                 2707 
               
               
                   
               
               
                 AD-61989.1 
                 CUUUACUCACCAGUCUGAAdTdT 
                 2141 
                 3791-3809 
                 UUCAGACUGGUGAGUAAAGdTdT 
                 2708 
               
               
                   
               
               
                 AD-61995.1 
                 GUCUGAACUUGAAAGAUAUdTdT 
                 2142 
                 3803-3821 
                 AUAUCUUUCAAGUUCAGACdTdT 
                 2709 
               
               
                   
               
               
                 AD-62001.1 
                 ACUUGAAAGAUAUAAAUUAdTdT 
                 2143 
                 3809-3827 
                 UAAUUUAUAUCUUUCAAGUdTdT 
                 2710 
               
               
                   
               
               
                 AD-62007.1 
                 UAUAAAUUAUGUUAACCCAdTdT 
                 2144 
                 3819-3837 
                 UGGGUUAACAUAAUUUAUAdTdT 
                 2711 
               
               
                   
               
               
                 AD-62013.1 
                 GUUAACCCAGUCAUCAAAUdTdT 
                 2145 
                 3829-3847 
                 AUUUGAUGACUGGGUUAACdTdT 
                 2712 
               
               
                   
               
               
                 AD-61972.1 
                 UCAUCAAAUGGCUAUCAGAdTdT 
                 2146 
                 3839-3857 
                 UCUGAUAGCCAUUUGAUGAdTdT 
                 2713 
               
               
                   
               
               
                 AD-61978.1 
                 UAUCAGAAGAGCAGAGGUAdTdT 
                 2147 
                 3851-3869 
                 UACCUCUGCUCUUCUGAUAdTdT 
                 2714 
               
               
                   
               
               
                 AD-61984.1 
                 AGAGGUAUGGAGGUGGCUUdTdT 
                 2148 
                 3863-3881 
                 AAGCCACCUCCAUACCUCUdTdT 
                 2715 
               
               
                   
               
               
                 AD-61990.1 
                 GAGGUGGCUUUUAUUCAACdTdT 
                 2149 
                 3872-3890 
                 GUUGAAUAAAAGCCACCUCdTdT 
                 2716 
               
               
                   
               
               
                 AD-61996.1 
                 UAUUCAACCCAGGACACAAdTdT 
                 2150 
                 3883-3901 
                 UUGUGUCCUGGGUUGAAUAdTdT 
                 2717 
               
               
                   
               
               
                 AD-62002.1 
                 AGGACACAAUCAAUGCCAUdTdT 
                 2151 
                 3893-3911 
                 AUGGCAUUGAUUGUGUCCUdTdT 
                 2718 
               
               
                   
               
               
                 AD-62008.1 
                 CAAUCAAUGCCAUUGAGGGdTdT 
                 2152 
                 3899-3917 
                 CCCUCAAUGGCAUUGAUUGdTdT 
                 2719 
               
               
                   
               
               
                 AD-62014.1 
                 CAUUGAGGGCCUGACGGAAdTdT 
                 2153 
                 3909-3927 
                 UUCCGUCAGGCCCUCAAUGdTdT 
                 2720 
               
               
                   
               
               
                 AD-61973.1 
                 ACGGAAUAUUCACUCCUGGdTdT 
                 2154 
                 3922-3940 
                 CCAGGAGUGAAUAUUCCGUdTdT 
                 2721 
               
               
                   
               
               
                 AD-61979.1 
                 UUCACUCCUGGUUAAACAAdTdT 
                 2155 
                 3930-3948 
                 UUGUUUAACCAGGAGUGAAdTdT 
                 2722 
               
               
                   
               
               
                 AD-61985.1 
                 GGUUAAACAACUCCGCUUGdTdT 
                 2156 
                 3939-3957 
                 CAAGCGGAGUUGUUUAACCdTdT 
                 2723 
               
               
                   
               
               
                 AD-61991.1 
                 CCGCUUGAGUAUGGACAUCdTdT 
                 2157 
                 3951-3969 
                 GAUGUCCAUACUCAAGCGGdTdT 
                 2724 
               
               
                   
               
               
                 AD-61997.1 
                 GGACAUCGAUGUUUCUUACdTdT 
                 2158 
                 3963-3981 
                 GUAAGAAACAUCGAUGUCCdTdT 
                 2725 
               
               
                   
               
               
                 AD-62003.1 
                 CGAUGUUUCUUACAAGCAUdTdT 
                 2159 
                 3969-3987 
                 AUGCUUGUAAGAAACAUCGdTdT 
                 2726 
               
               
                   
               
               
                 AD-62009.1 
                 CAAGCAUAAAGGUGCCUUAdTdT 
                 2160 
                 3981-3999 
                 UAAGGCACCUUUAUGCUUGdTdT 
                 2727 
               
               
                   
               
               
                 AD-62056.1 
                 GUGCCUUACAUAAUUAUAAdTdT 
                 2161 
                 3992-4010 
                 UUAUAAUUAUGUAAGGCACdTdT 
                 2728 
               
               
                   
               
               
                 AD-62015.1 
                 ACAUAAUUAUAAAAUGACAdTdT 
                 2162 
                 3999-4017 
                 UGUCAUUUUAUAAUUAUGUdTdT 
                 2729 
               
               
                   
               
               
                 AD-62021.1 
                 AAAAUGACAGACAAGAAUUdTdT 
                 2163 
                 4009-4027 
                 AAUUCUUGUCUGUCAUUUUdTdT 
                 2730 
               
               
                   
               
               
                 AD-62027.1 
                 CAAGAAUUUCCUUGGGAGGdTdT 
                 2164 
                 4020-4038 
                 CCUCCCAAGGAAAUUCUUGdTdT 
                 2731 
               
               
                   
               
               
                 AD-62033.1 
                 CCUUGGGAGGCCAGUAGAGdTdT 
                 2165 
                 4029-4047 
                 CUCUACUGGCCUCCCAAGGdTdT 
                 2732 
               
               
                   
               
               
                 AD-62039.1 
                 AGUAGAGGUGCUUCUCAAUdTdT 
                 2166 
                 4041-4059 
                 AUUGAGAAGCACCUCUACUdTdT 
                 2733 
               
               
                   
               
               
                 AD-62045.1 
                 CUUCUCAAUGAUGACCUCAdTdT 
                 2167 
                 4051-4069 
                 UGAGGUCAUCAUUGAGAAGdTdT 
                 2734 
               
               
                   
               
               
                 AD-62051.1 
                 UGACCUCAUUGUCAGUACAdTdT 
                 2168 
                 4062-4080 
                 UGUACUGACAAUGAGGUCAdTdT 
                 2735 
               
               
                   
               
               
                 AD-62057.1 
                 GUCAGUACAGGAUUUGGCAdTdT 
                 2169 
                 4072-4090 
                 UGCCAAAUCCUGUACUGACdTdT 
                 2736 
               
               
                   
               
               
                 AD-62016.1 
                 AGGAUUUGGCAGUGGCUUGdTdT 
                 2170 
                 4080-4098 
                 CAAGCCACUGCCAAAUCCUdTdT 
                 2737 
               
               
                   
               
               
                 AD-62022.1 
                 UGGCUUGGCUACAGUACAUdTdT 
                 2171 
                 4092-4110 
                 AUGUACUGUAGCCAAGCCAdTdT 
                 2738 
               
               
                   
               
               
                 AD-62028.1 
                 GCUACAGUACAUGUAACAAdTdT 
                 2172 
                 4099-4117 
                 UUGUUACAUGUACUGUAGCdTdT 
                 2739 
               
               
                   
               
               
                 AD-62034.1 
                 AACAACUGUAGUUCACAAAdTdT 
                 2173 
                 4113-4131 
                 UUUGUGAACUACAGUUGUUdTdT 
                 2740 
               
               
                   
               
               
                 AD-62040.1 
                 GUAGUUCACAAAACCAGUAdTdT 
                 2174 
                 4120-4138 
                 UACUGGUUUUGUGAACUACdTdT 
                 2741 
               
               
                   
               
               
                 AD-62046.1 
                 AAACCAGUACCUCUGAGGAdTdT 
                 2175 
                 4130-4148 
                 UCCUCAGAGGUACUGGUUUdTdT 
                 2742 
               
               
                   
               
               
                 AD-62052.1 
                 UGAGGAAGUUUGCAGCUUUdTdT 
                 2176 
                 4143-4161 
                 AAAGCUGCAAACUUCCUCAdTdT 
                 2743 
               
               
                   
               
               
                 AD-62058.1 
                 UGCAGCUUUUAUUUGAAAAdTdT 
                 2177 
                 4153-4171 
                 UUUUCAAAUAAAAGCUGCAdTdT 
                 2744 
               
               
                   
               
               
                 AD-62017.1 
                 AUUUGAAAAUCGAUACUCAdTdT 
                 2178 
                 4163-4181 
                 UGAGUAUCGAUUUUCAAAUdTdT 
                 2745 
               
               
                   
               
               
                 AD-62023.1 
                 CGAUACUCAGGAUAUUGAAdTdT 
                 2179 
                 4173-4191 
                 UUCAAUAUCCUGAGUAUCGdTdT 
                 2746 
               
               
                   
               
               
                 AD-62029.1 
                 GGAUAUUGAAGCAUCCCACdTdT 
                 2180 
                 4182-4200 
                 GUGGGAUGCUUCAAUAUCCdTdT 
                 2747 
               
               
                   
               
               
                 AD-62035.1 
                 GAAGCAUCCCACUACAGAGdTdT 
                 2181 
                 4189-4207 
                 CUCUGUAGUGGGAUGCUUCdTdT 
                 2748 
               
               
                   
               
               
                 AD-62041.1 
                 ACUACAGAGGCUACGGAAAdTdT 
                 2182 
                 4199-4217 
                 UUUCCGUAGCCUCUGUAGUdTdT 
                 2749 
               
               
                   
               
               
                 AD-62047.1 
                 CGGAAACUCUGAUUACAAAdTdT 
                 2183 
                 4212-4230 
                 UUUGUAAUCAGAGUUUCCGdTdT 
                 2750 
               
               
                   
               
               
                 AD-62053.1 
                 UGAUUACAAACGCAUAGUAdTdT 
                 2184 
                 4221-4239 
                 UACUAUGCGUUUGUAAUCAdTdT 
                 2751 
               
               
                   
               
               
                 AD-62059.1 
                 GCAUAGUAGCAUGUGCCAGdTdT 
                 2185 
                 4232-4250 
                 CUGGCACAUGCUACUAUGCdTdT 
                 2752 
               
               
                   
               
               
                 AD-62018.1 
                 GCAUGUGCCAGCUACAAGCdTdT 
                 2186 
                 4240-4258 
                 GCUUGUAGCUGGCACAUGCdTdT 
                 2753 
               
               
                   
               
               
                 AD-62024.1 
                 CUACAAGCCCAGCAGGGAAdTdT 
                 2187 
                 4251-4269 
                 UUCCCUGCUGGGCUUGUAGdTdT 
                 2754 
               
               
                   
               
               
                 AD-62030.1 
                 CAGCAGGGAAGAAUCAUCAdTdT 
                 2188 
                 4260-4278 
                 UGAUGAUUCUUCCCUGCUGdTdT 
                 2755 
               
               
                   
               
               
                 AD-62036.1 
                 GAAUCAUCAUCUGGAUCCUdTdT 
                 2189 
                 4270-4288 
                 AGGAUCCAGAUGAUGAUUCdTdT 
                 2756 
               
               
                   
               
               
                 AD-62042.1 
                 GAUCCUCUCAUGCGGUGAUdTdT 
                 2190 
                 4283-4301 
                 AUCACCGCAUGAGAGGAUCdTdT 
                 2757 
               
               
                   
               
               
                 AD-62048.1 
                 CUCAUGCGGUGAUGGACAUdTdT 
                 2191 
                 4289-4307 
                 AUGUCCAUCACCGCAUGAGdTdT 
                 2758 
               
               
                   
               
               
                 AD-62054.1 
                 GAUGGACAUCUCCUUGCCUdTdT 
                 2192 
                 4299-4317 
                 AGGCAAGGAGAUGUCCAUCdTdT 
                 2759 
               
               
                   
               
               
                 AD-62060.1 
                 CUUGCCUACUGGAAUCAGUdTdT 
                 2193 
                 4311-4329 
                 ACUGAUUCCAGUAGGCAAGdTdT 
                 2760 
               
               
                   
               
               
                 AD-62019.1 
                 GAAUCAGUGCAAAUGAAGAdTdT 
                 2194 
                 4322-4340 
                 UCUUCAUUUGCACUGAUUCdTdT 
                 2761 
               
               
                   
               
               
                 AD-62025.1 
                 AAAUGAAGAAGACUUAAAAdTdT 
                 2195 
                 4332-4350 
                 UUUUAAGUCUUCUUCAUUUdTdT 
                 2762 
               
               
                   
               
               
                 AD-62031.1 
                 GAAGACUUAAAAGCCCUUGdTdT 
                 2196 
                 4339-4357 
                 CAAGGGCUUUUAAGUCUUCdTdT 
                 2763 
               
               
                   
               
               
                 AD-62037.1 
                 CCUUGUGGAAGGGGUGGAUdTdT 
                 2197 
                 4353-4371 
                 AUCCACCCCUUCCACAAGGdTdT 
                 2764 
               
               
                   
               
               
                 AD-62043.1 
                 GAAGGGGUGGAUCAACUAUdTdT 
                 2198 
                 4360-4378 
                 AUAGUUGAUCCACCCCUUCdTdT 
                 2765 
               
               
                   
               
               
                 AD-62049.1 
                 AUCAACUAUUCACUGAUUAdTdT 
                 2199 
                 4370-4388 
                 UAAUCAGUGAAUAGUUGAUdTdT 
                 2766 
               
               
                   
               
               
                 AD-62055.1 
                 CACUGAUUACCAAAUCAAAdTdT 
                 2200 
                 4380-4398 
                 UUUGAUUUGGUAAUCAGUGdTdT 
                 2767 
               
               
                   
               
               
                 AD-62061.1 
                 AUCAAAGAUGGACAUGUUAdTdT 
                 2201 
                 4393-4411 
                 UAACAUGUCCAUCUUUGAUdTdT 
                 2768 
               
               
                   
               
               
                 AD-62020.1 
                 GGACAUGUUAUUCUGCAACdTdT 
                 2202 
                 4402-4420 
                 GUUGCAGAAUAACAUGUCCdTdT 
                 2769 
               
               
                   
               
               
                 AD-62026.1 
                 UCUGCAACUGAAUUCGAUUdTdT 
                 2203 
                 4413-4431 
                 AAUCGAAUUCAGUUGCAGAdTdT 
                 2770 
               
               
                   
               
               
                 AD-62032.1 
                 GAAUUCGAUUCCCUCCAGUdTdT 
                 2204 
                 4422-4440 
                 ACUGGAGGGAAUCGAAUUCdTdT 
                 2771 
               
               
                   
               
               
                 AD-62038.1 
                 CCCUCCAGUGAUUUCCUUUdTdT 
                 2205 
                 4432-4450 
                 AAAGGAAAUCACUGGAGGGdTdT 
                 2772 
               
               
                   
               
               
                 AD-62044.1 
                 GAUUUCCUUUGUGUACGAUdTdT 
                 2206 
                 4441-4459 
                 AUCGUACACAAAGGAAAUCdTdT 
                 2773 
               
               
                   
               
               
                 AD-62050.1 
                 GUACGAUUCCGGAUAUUUGdTdT 
                 2207 
                 4453-4471 
                 CAAAUAUCCGGAAUCGUACdTdT 
                 2774 
               
               
                   
               
               
                 AD-62320.1 
                 CGGAUAUUUGAACUCUUUGdTdT 
                 2208 
                 4462-4480 
                 CAAAGAGUUCAAAUAUCCGdTdT 
                 2775 
               
               
                   
               
               
                 AD-62326.1 
                 ACUCUUUGAAGUUGGGUUUdTdT 
                 2209 
                 4473-4491 
                 AAACCCAACUUCAAAGAGUdTdT 
                 2776 
               
               
                   
               
               
                 AD-62332.1 
                 AGUUGGGUUUCUCAGUCCUdTdT 
                 2210 
                 4482-4500 
                 AGGACUGAGAAACCCAACUdTdT 
                 2777 
               
               
                   
               
               
                 AD-62338.1 
                 UUCUCAGUCCUGCCACUUUdTdT 
                 2211 
                 4490-4508 
                 AAAGUGGCAGGACUGAGAAdTdT 
                 2778 
               
               
                   
               
               
                 AD-62344.1 
                 CACUUUCACAGUGUACGAAdTdT 
                 2212 
                 4503-4521 
                 UUCGUACACUGUGAAAGUGdTdT 
                 2779 
               
               
                   
               
               
                 AD-62350.1 
                 CACAGUGUACGAAUACCACdTdT 
                 2213 
                 4509-4527 
                 GUGGUAUUCGUACACUGUGdTdT 
                 2780 
               
               
                   
               
               
                 AD-62356.1 
                 ACCACAGACCAGAUAAACAdTdT 
                 2214 
                 4523-4541 
                 UGUUUAUCUGGUCUGUGGUdTdT 
                 2781 
               
               
                   
               
               
                 AD-62362.1 
                 CCAGAUAAACAGUGUACCAdTdT 
                 2215 
                 4531-4549 
                 UGGUACACUGUUUAUCUGGdTdT 
                 2782 
               
               
                   
               
               
                 AD-62321.1 
                 CAGUGUACCAUGUUUUAUAdTdT 
                 2216 
                 4540-4558 
                 UAUAAAACAUGGUACACUGdTdT 
                 2783 
               
               
                   
               
               
                 AD-62327.1 
                 GUUUUAUAGCACUUCCAAUdTdT 
                 2217 
                 4551-4569 
                 AUUGGAAGUGCUAUAAAACdTdT 
                 2784 
               
               
                   
               
               
                 AD-62333.1 
                 CUUCCAAUAUCAAAAUUCAdTdT 
                 2218 
                 4562-4580 
                 UGAAUUUUGAUAUUGGAAGdTdT 
                 2785 
               
               
                   
               
               
                 AD-62339.1 
                 AUCAAAAUUCAGAAAGUCUdTdT 
                 2219 
                 4570-4588 
                 AGACUUUCUGAAUUUUGAUdTdT 
                 2786 
               
               
                   
               
               
                 AD-62345.1 
                 GAAAGUCUGUGAAGGAGCCdTdT 
                 2220 
                 4581-4599 
                 GGCUCCUUCACAGACUUUCdTdT 
                 2787 
               
               
                   
               
               
                 AD-62351.1 
                 GAAGGAGCCGCGUGCAAGUdTdT 
                 2221 
                 4591-4609 
                 ACUUGCACGCGGCUCCUUCdTdT 
                 2788 
               
               
                   
               
               
                 AD-62357.1 
                 CGUGCAAGUGUGUAGAAGCdTdT 
                 2222 
                 4601-4619 
                 GCUUCUACACACUUGCACGdTdT 
                 2789 
               
               
                   
               
               
                 AD-62363.1 
                 GUAGAAGCUGAUUGUGGGCdTdT 
                 2223 
                 4612-4630 
                 GCCCACAAUCAGCUUCUACdTdT 
                 2790 
               
               
                   
               
               
                 AD-62322.1 
                 CUGAUUGUGGGCAAAUGCAdTdT 
                 2224 
                 4619-4637 
                 UGCAUUUGCCCACAAUCAGdTdT 
                 2791 
               
               
                   
               
               
                 AD-62328.1 
                 GCAAAUGCAGGAAGAAUUGdTdT 
                 2225 
                 4629-4647 
                 CAAUUCUUCCUGCAUUUGCdTdT 
                 2792 
               
               
                   
               
               
                 AD-62334.1 
                 GAAGAAUUGGAUCUGACAAdTdT 
                 2226 
                 4639-4657 
                 UUGUCAGAUCCAAUUCUUCdTdT 
                 2793 
               
               
                   
               
               
                 AD-62340.1 
                 CUGACAAUCUCUGCAGAGAdTdT 
                 2227 
                 4651-4669 
                 UCUCUGCAGAGAUUGUCAGdTdT 
                 2794 
               
               
                   
               
               
                 AD-62346.1 
                 GCAGAGACAAGAAAACAAAdTdT 
                 2228 
                 4663-4681 
                 UUUGUUUUCUUGUCUCUGCdTdT 
                 2795 
               
               
                   
               
               
                 AD-62352.1 
                 CAAGAAAACAAACAGCAUGdTdT 
                 2229 
                 4670-4688 
                 CAUGCUGUUUGUUUUCUUGdTdT 
                 2796 
               
               
                   
               
               
                 AD-62358.1 
                 ACAGCAUGUAAACCAGAGAdTdT 
                 2230 
                 4681-4699 
                 UCUCUGGUUUACAUGCUGUdTdT 
                 2797 
               
               
                   
               
               
                 AD-62364.1 
                 CCAGAGAUUGCAUAUGCUUdTdT 
                 2231 
                 4693-4711 
                 AAGCAUAUGCAAUCUCUGGdTdT 
                 2798 
               
               
                   
               
               
                 AD-62323.1 
                 GCAUAUGCUUAUAAAGUUAdTdT 
                 2232 
                 4702-4720 
                 UAACUUUAUAAGCAUAUGCdTdT 
                 2799 
               
               
                   
               
               
                 AD-62329.1 
                 UUAUAAAGUUAGCAUCACAdTdT 
                 2233 
                 4710-4728 
                 UGUGAUGCUAACUUUAUAAdTdT 
                 2800 
               
               
                   
               
               
                 AD-62335.1 
                 CAUCACAUCCAUCACUGUAdTdT 
                 2234 
                 4722-4740 
                 UACAGUGAUGGAUGUGAUGdTdT 
                 2801 
               
               
                   
               
               
                 AD-62341.1 
                 UCACUGUAGAAAAUGUUUUdTdT 
                 2235 
                 4733-4751 
                 AAAACAUUUUCUACAGUGAdTdT 
                 2802 
               
               
                   
               
               
                 AD-62347.1 
                 AGAAAAUGUUUUUGUCAAGdTdT 
                 2236 
                 4740-4758 
                 CUUGACAAAAACAUUUUCUdTdT 
                 2803 
               
               
                   
               
               
                 AD-62353.1 
                 UUUGUCAAGUACAAGGCAAdTdT 
                 2237 
                 4750-4768 
                 UUGCCUUGUACUUGACAAAdTdT 
                 2804 
               
               
                   
               
               
                 AD-62359.1 
                 AGGCAACCCUUCUGGAUAUdTdT 
                 2238 
                 4763-4781 
                 AUAUCCAGAAGGGUUGCCUdTdT 
                 2805 
               
               
                   
               
               
                 AD-62365.1 
                 CCUUCUGGAUAUCUACAAAdTdT 
                 2239 
                 4770-4788 
                 UUUGUAGAUAUCCAGAAGGdTdT 
                 2806 
               
               
                   
               
               
                 AD-62324.1 
                 UAUCUACAAAACUGGGGAAdTdT 
                 2240 
                 4779-4797 
                 UUCCCCAGUUUUGUAGAUAdTdT 
                 2807 
               
               
                   
               
               
                 AD-62330.1 
                 CUGGGGAAGCUGUUGCUGAdTdT 
                 2241 
                 4790-4808 
                 UCAGCAACAGCUUCCCCAGdTdT 
                 2808 
               
               
                   
               
               
                 AD-62336.1 
                 CUGUUGCUGAGAAAGACUCdTdT 
                 2242 
                 4799-4817 
                 GAGUCUUUCUCAGCAACAGdTdT 
                 2809 
               
               
                   
               
               
                 AD-62342.1 
                 GACUCUGAGAUUACCUUCAdTdT 
                 2243 
                 4813-4831 
                 UGAAGGUAAUCUCAGAGUCdTdT 
                 2810 
               
               
                   
               
               
                 AD-62348.1 
                 GAGAUUACCUUCAUUAAAAdTdT 
                 2244 
                 4819-4837 
                 UUUUAAUGAAGGUAAUCUCdTdT 
                 2811 
               
               
                   
               
               
                 AD-62354.1 
                 AUUAAAAAGGUAACCUGUAdTdT 
                 2245 
                 4831-4849 
                 UACAGGUUACCUUUUUAAUdTdT 
                 2812 
               
               
                   
               
               
                 AD-62360.1 
                 UAACCUGUACUAACGCUGAdTdT 
                 2246 
                 4841-4859 
                 UCAGCGUUAGUACAGGUUAdTdT 
                 2813 
               
               
                   
               
               
                 AD-62366.1 
                 CUAACGCUGAGCUGGUAAAdTdT 
                 2247 
                 4850-4868 
                 UUUACCAGCUCAGCGUUAGdTdT 
                 2814 
               
               
                   
               
               
                 AD-62325.1 
                 GGUAAAAGGAAGACAGUACdTdT 
                 2248 
                 4863-4881 
                 GUACUGUCUUCCUUUUACCdTdT 
                 2815 
               
               
                   
               
               
                 AD-62331.1 
                 GAAGACAGUACUUAAUUAUdTdT 
                 2249 
                 4871-4889 
                 AUAAUUAAGUACUGUCUUCdTdT 
                 2816 
               
               
                   
               
               
                 AD-62337.1 
                 CUUAAUUAUGGGUAAAGAAdTdT 
                 2250 
                 4881-4899 
                 UUCUUUACCCAUAAUUAAGdTdT 
                 2817 
               
               
                   
               
               
                 AD-62343.1 
                 UAAAGAAGCCCUCCAGAUAdTdT 
                 2251 
                 4893-4911 
                 UAUCUGGAGGGCUUCUUUAdTdT 
                 2818 
               
               
                   
               
               
                 AD-62349.1 
                 CCUCCAGAUAAAAUACAAUdTdT 
                 2252 
                 4902-4920 
                 AUUGUAUUUUAUCUGGAGGdTdT 
                 2819 
               
               
                   
               
               
                 AD-62355.1 
                 AAAUACAAUUUCAGUUUCAdTdT 
                 2253 
                 4912-4930 
                 UGAAACUGAAAUUGUAUUUdTdT 
                 2820 
               
               
                   
               
               
                 AD-62361.1 
                 CAGUUUCAGGUACAUCUACdTdT 
                 2254 
                 4923-4941 
                 GUAGAUGUACCUGAAACUGdTdT 
                 2821 
               
               
                   
               
               
                 AD-62367.1 
                 GGUACAUCUACCCUUUAGAdTdT 
                 2255 
                 4931-4949 
                 UCUAAAGGGUAGAUGUACCdTdT 
                 2822 
               
               
                   
               
               
                 AD-62373.1 
                 CCUUUAGAUUCCUUGACCUdTdT 
                 2256 
                 4942-4960 
                 AGGUCAAGGAAUCUAAAGGdTdT 
                 2823 
               
               
                   
               
               
                 AD-62379.1 
                 CCUUGACCUGGAUUGAAUAdTdT 
                 2257 
                 4952-4970 
                 UAUUCAAUCCAGGUCAAGGdTdT 
                 2824 
               
               
                   
               
               
                 AD-62385.1 
                 GGAUUGAAUACUGGCCUAGdTdT 
                 2258 
                 4961-4979 
                 CUAGGCCAGUAUUCAAUCCdTdT 
                 2825 
               
               
                   
               
               
                 AD-62391.1 
                 CUGGCCUAGAGACACAACAdTdT 
                 2259 
                 4971-4989 
                 UGUUGUGUCUCUAGGCCAGdTdT 
                 2826 
               
               
                   
               
               
                 AD-62397.1 
                 GAGACACAACAUGUUCAUCdTdT 
                 2260 
                 4979-4997 
                 GAUGAACAUGUUGUGUCUCdTdT 
                 2827 
               
               
                   
               
               
                 AD-62403.1 
                 GUUCAUCGUGUCAAGCAUUdTdT 
                 2261 
                 4991-5009 
                 AAUGCUUGACACGAUGAACdTdT 
                 2828 
               
               
                   
               
               
                 AD-62409.1 
                 GUCAAGCAUUUUUAGCUAAdTdT 
                 2262 
                 5000-5018 
                 UUAGCUAAAAAUGCUUGACdTdT 
                 2829 
               
               
                   
               
               
                 AD-62368.1 
                 AGCUAAUUUAGAUGAAUUUdTdT 
                 2263 
                 5013-5031 
                 AAAUUCAUCUAAAUUAGCUdTdT 
                 2830 
               
               
                   
               
               
                 AD-62374.1 
                 AGAUGAAUUUGCCGAAGAUdTdT 
                 2264 
                 5022-5040 
                 AUCUUCGGCAAAUUCAUCUdTdT 
                 2831 
               
               
                   
               
               
                 AD-62380.1 
                 CCGAAGAUAUCUUUUUAAAdTdT 
                 2265 
                 5033-5051 
                 UUUAAAAAGAUAUCUUCGGdTdT 
                 2832 
               
               
                   
               
               
                 AD-62386.1 
                 CUUUUUAAAUGGAUGCUAAdTdT 
                 2266 
                 5043-5061 
                 UUAGCAUCCAUUUAAAAAGdTdT 
                 2833 
               
               
                   
               
               
                 AD-62392.1 
                 GGAUGCUAAAAUUCCUGAAdTdT 
                 2267 
                 5053-5071 
                 UUCAGGAAUUUUAGCAUCCdTdT 
                 2834 
               
               
                   
               
               
                 AD-62398.1 
                 UAAAAUUCCUGAAGUUCAGdTdT 
                 2268 
                 5059-5077 
                 CUGAACUUCAGGAAUUUUAdTdT 
                 2835 
               
               
                   
               
               
                 AD-62404.1 
                 AGUUCAGCUGCAUACAGUUdTdT 
                 2269 
                 5071-5089 
                 AACUGUAUGCAGCUGAACUdTdT 
                 2836 
               
               
                   
               
               
                 AD-62410.1 
                 GCAUACAGUUUGCACUUAUdTdT 
                 2270 
                 5080-5098 
                 AUAAGUGCAAACUGUAUGCdTdT 
                 2837 
               
               
                   
               
               
                 AD-62369.1 
                 ACUUAUGGACUCCUGUUGUdTdT 
                 2271 
                 5093-5111 
                 ACAACAGGAGUCCAUAAGUdTdT 
                 2838 
               
               
                   
               
               
                 AD-62375.1 
                 GGACUCCUGUUGUUGAAGUdTdT 
                 2272 
                 5099-5117 
                 ACUUCAACAACAGGAGUCCdTdT 
                 2839 
               
               
                   
               
               
                 AD-62381.1 
                 UGUUGAAGUUCGUUUUUUUdTdT 
                 2273 
                 5109-5127 
                 AAAAAAACGAACUUCAACAdTdT 
                 2840 
               
               
                   
               
               
                 AD-62387.1 
                 UUUUUUGUUUUCUUCUUUUdTdT 
                 2274 
                 5122-5140 
                 AAAAGAAGAAAACAAAAAAdTdT 
                 2841 
               
               
                   
               
               
                 AD-62393.1 
                 UCUUCUUUUUUUAAACAUUdTdT 
                 2275 
                 5132-5150 
                 AAUGUUUAAAAAAAGAAGAdTdT 
                 2842 
               
               
                   
               
               
                 AD-62399.1 
                 UUUUUAAACAUUCAUAGCUdTdT 
                 2276 
                 5139-5157 
                 AGCUAUGAAUGUUUAAAAAdTdT 
                 2843 
               
               
                   
               
               
                 AD-62405.1 
                 AUAGCUGGUCUUAUUUGUAdTdT 
                 2277 
                 5152-5170 
                 UACAAAUAAGACCAGCUAUdTdT 
                 2844 
               
               
                   
               
               
                 AD-62411.1 
                 GUCUUAUUUGUAAAGCUCAdTdT 
                 2278 
                 5159-5177 
                 UGAGCUUUACAAAUAAGACdTdT 
                 2845 
               
               
                   
               
               
                 AD-62370.1 
                 AAAGCUCACUUUACUUAGAdTdT 
                 2279 
                 5170-5188 
                 UCUAAGUAAAGUGAGCUUUdTdT 
                 2846 
               
               
                   
               
               
                 AD-62376.1 
                 ACUUAGAAUUAGUGGCACUdTdT 
                 2280 
                 5182-5200 
                 AGUGCCACUAAUUCUAAGUdTdT 
                 2847 
               
               
                   
               
               
                 AD-62382.1 
                 AGUGGCACUUGCUUUUAUUdTdT 
                 2281 
                 5192-5210 
                 AAUAAAAGCAAGUGCCACUdTdT 
                 2848 
               
               
                   
               
               
                 AD-62388.1 
                 GCUUUUAUUAGAGAAUGAUdTdT 
                 2282 
                 5202-5220 
                 AUCAUUCUCUAAUAAAAGCdTdT 
                 2849 
               
               
                   
               
               
                 AD-62394.1 
                 GAGAAUGAUUUCAAAUGCUdTdT 
                 2283 
                 5212-5230 
                 AGCAUUUGAAAUCAUUCUCdTdT 
                 2850 
               
               
                   
               
               
                 AD-62400.1 
                 UUUCAAAUGCUGUAACUUUdTdT 
                 2284 
                 5220-5238 
                 AAAGUUACAGCAUUUGAAAdTdT 
                 2851 
               
               
                   
               
               
                 AD-62406.1 
                 GUAACUUUCUGAAAUAACAdTdT 
                 2285 
                 5231-5249 
                 UGUUAUUUCAGAAAGUUACdTdT 
                 2852 
               
               
                   
               
               
                 AD-62412.1 
                 GAAAUAACAUGGCCUUGGAdTdT 
                 2286 
                 5241-5259 
                 UCCAAGGCCAUGUUAUUUCdTdT 
                 2853 
               
               
                   
               
               
                 AD-62371.1 
                 CCUUGGAGGGCAUGAAGACdTdT 
                 2287 
                 5253-5271 
                 GUCUUCAUGCCCUCCAAGGdTdT 
                 2854 
               
               
                   
               
               
                 AD-62377.1 
                 AGGGCAUGAAGACAGAUACdTdT 
                 2288 
                 5259-5277 
                 GUAUCUGUCUUCAUGCCCUdTdT 
                 2855 
               
               
                   
               
               
                 AD-62383.1 
                 GAUACUCCUCCAAGGUUAUdTdT 
                 2289 
                 5273-5291 
                 AUAACCUUGGAGGAGUAUCdTdT 
                 2856 
               
               
                   
               
               
                 AD-62389.1 
                 CCUCCAAGGUUAUUGGACAdTdT 
                 2290 
                 5279-5297 
                 UGUCCAAUAACCUUGGAGGdTdT 
                 2857 
               
               
                   
               
               
                 AD-62395.1 
                 GGACACCGGAAACAAUAAAdTdT 
                 2291 
                 5293-5311 
                 UUUAUUGUUUCCGGUGUCCdTdT 
                 2858 
               
               
                   
               
               
                 AD-62401.1 
                 GAAACAAUAAAUUGGAACAdTdT 
                 2292 
                 5301-5319 
                 UGUUCCAAUUUAUUGUUUCdTdT 
                 2859 
               
               
                   
               
               
                 AD-62407.1 
                 AUUGGAACACCUCCUCAAAdTdT 
                 2293 
                 5311-5329 
                 UUUGAGGAGGUGUUCCAAUdTdT 
                 2860 
               
               
                   
               
               
                 AD-62413.1 
                 UCCUCAAACCUACCACUCAdTdT 
                 2294 
                 5322-5340 
                 UGAGUGGUAGGUUUGAGGAdTdT 
                 2861 
               
               
                   
               
               
                 AD-62372.1 
                 CUACCACUCAGGAAUGUUUdTdT 
                 2295 
                 5331-5349 
                 AAACAUUCCUGAGUGGUAGdTdT 
                 2862 
               
               
                   
               
               
                 AD-62378.1 
                 AAUGUUUGCUGGGGCCGAAdTdT 
                 2296 
                 5343-5361 
                 UUCGGCCCCAGCAAACAUUdTdT 
                 2863 
               
               
                   
               
               
                 AD-62384.1 
                 UGCUGGGGCCGAAAGAACAdTdT 
                 2297 
                 5349-5367 
                 UGUUCUUUCGGCCCCAGCAdTdT 
                 2864 
               
               
                   
               
               
                 AD-62390.1 
                 AAAGAACAGUCCAUUGAAAdTdT 
                 2298 
                 5360-5378 
                 UUUCAAUGGACUGUUCUUUdTdT 
                 2865 
               
               
                   
               
               
                 AD-62396.1 
                 CAUUGAAAGGGAGUAUUACdTdT 
                 2299 
                 5371-5389 
                 GUAAUACUCCCUUUCAAUGdTdT 
                 2866 
               
               
                   
               
               
                 AD-62402.1 
                 GGAGUAUUACAAAAACAUGdTdT 
                 2300 
                 5380-5398 
                 CAUGUUUUUGUAAUACUCCdTdT 
                 2867 
               
               
                   
               
               
                 AD-62408.1 
                 AAAACAUGGCCUUUGCUUGdTdT 
                 2301 
                 5391-5409 
                 CAAGCAAAGGCCAUGUUUUdTdT 
                 2868 
               
               
                   
               
               
                 AD-62414.1 
                 GCCUUUGCUUGAAAGAAAAdTdT 
                 2302 
                 5399-5417 
                 UUUUCUUUCAAGCAAAGGCdTdT 
                 2869 
               
               
                   
               
               
                 AD-62415.1 
                 GAAAGAAAAUACCAAGGAAdTdT 
                 2303 
                 5409-5427 
                 UUCCUUGGUAUUUUCUUUCdTdT 
                 2870 
               
               
                   
               
               
                 AD-62416.1 
                 CCAAGGAACAGGAAACUGAdTdT 
                 2304 
                 5420-5438 
                 UCAGUUUCCUGUUCCUUGGdTdT 
                 2871 
               
               
                   
               
               
                 AD-62417.1 
                 AACUGAUCAUUAAAGCCUGdTdT 
                 2305 
                 5433-5451 
                 CAGGCUUUAAUGAUCAGUUdTdT 
                 2872 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 22 
               
             
            
               
                   
               
               
                 C5 single dose screen (10 mM) in Hep3B 
               
               
                 cells with dT modified iRNAs 
               
            
           
           
               
               
               
            
               
                   
                 Duplex ID 
                 Avg. % message remaining 
               
               
                   
                   
               
            
           
           
               
               
               
            
               
                   
                 AD-61779.2 
                 43.2 
               
               
                   
                 AD-61785.2 
                 22.5 
               
               
                   
                 AD-61791.2 
                 27.3 
               
               
                   
                 AD-61797.2 
                 30.5 
               
               
                   
                 AD-61803.2 
                 30.9 
               
               
                   
                 AD-61809.2 
                 75.1 
               
               
                   
                 AD-61815.2 
                 90.7 
               
               
                   
                 AD-61821.2 
                 33.7 
               
               
                   
                 AD-61780.2 
                 53.5 
               
               
                   
                 AD-61786.2 
                 34.4 
               
               
                   
                 AD-61792.2 
                 27.5 
               
               
                   
                 AD-61798.2 
                 23.3 
               
               
                   
                 AD-61804.2 
                 23.6 
               
               
                   
                 AD-61810.2 
                 33.4 
               
               
                   
                 AD-61816.2 
                 39.7 
               
               
                   
                 AD-61822.2 
                 24.9 
               
               
                   
                 AD-61781.2 
                 31.2 
               
               
                   
                 AD-61787.2 
                 22.8 
               
               
                   
                 AD-61793.2 
                 28.4 
               
               
                   
                 AD-61799.2 
                 91 
               
               
                   
                 AD-61805.2 
                 22.1 
               
               
                   
                 AD-61811.2 
                 90.9 
               
               
                   
                 AD-61817.2 
                 26.1 
               
               
                   
                 AD-61823.2 
                 41.3 
               
               
                   
                 AD-61782.2 
                 42.5 
               
               
                   
                 AD-61788.2 
                 28.9 
               
               
                   
                 AD-61794.2 
                 133.5 
               
               
                   
                 AD-61800.2 
                 27.9 
               
               
                   
                 AD-61806.2 
                 42.8 
               
               
                   
                 AD-61812.2 
                 26.9 
               
               
                   
                 AD-61818.2 
                 30.6 
               
               
                   
                 AD-61824.2 
                 29.3 
               
               
                   
                 AD-61783.2 
                 61.3 
               
               
                   
                 AD-61789.2 
                 25.5 
               
               
                   
                 AD-61795.2 
                 34.2 
               
               
                   
                 AD-61801.2 
                 24.2 
               
               
                   
                 AD-61807.2 
                 42.8 
               
               
                   
                 AD-61813.2 
                 31 
               
               
                   
                 AD-61819.2 
                 42.2 
               
               
                   
                 AD-61825.2 
                 31 
               
               
                   
                 AD-61784.2 
                 34.1 
               
               
                   
                 AD-61790.2 
                 26.8 
               
               
                   
                 AD-61796.2 
                 34.6 
               
               
                   
                 AD-61802.2 
                 30 
               
               
                   
                 AD-61808.2 
                 23.5 
               
               
                   
                 AD-61814.2 
                 45.3 
               
               
                   
                 AD-61820.2 
                 56 
               
               
                   
                 AD-61826.2 
                 31.6 
               
               
                   
                 AD-61832.2 
                 36.2 
               
               
                   
                 AD-61838.2 
                 39.7 
               
               
                   
                 AD-61844.2 
                 37 
               
               
                   
                 AD-61850.2 
                 66.3 
               
               
                   
                 AD-61856.2 
                 172.6 
               
               
                   
                 AD-61862.2 
                 41.3 
               
               
                   
                 AD-61868.2 
                 32.2 
               
               
                   
                 AD-61827.2 
                 52.7 
               
               
                   
                 AD-61833.2 
                 29.6 
               
               
                   
                 AD-61839.2 
                 41.5 
               
               
                   
                 AD-61845.2 
                 29.7 
               
               
                   
                 AD-61851.2 
                 37 
               
               
                   
                 AD-61857.2 
                 34.9 
               
               
                   
                 AD-61863.2 
                 33.3 
               
               
                   
                 AD-61869.2 
                 38.2 
               
               
                   
                 AD-61828.2 
                 30.3 
               
               
                   
                 AD-61834.2 
                 27.1 
               
               
                   
                 AD-61840.2 
                 64.3 
               
               
                   
                 AD-61846.2 
                 42 
               
               
                   
                 AD-61852.2 
                 25.2 
               
               
                   
                 AD-61858.2 
                 96.7 
               
               
                   
                 AD-61864.2 
                 29.6 
               
               
                   
                 AD-61870.2 
                 30.5 
               
               
                   
                 AD-61829.2 
                 92.7 
               
               
                   
                 AD-61835.2 
                 24.8 
               
               
                   
                 AD-61841.2 
                 59.2 
               
               
                   
                 AD-61847.2 
                 30.9 
               
               
                   
                 AD-61853.2 
                 35.2 
               
               
                   
                 AD-61859.2 
                 40.1 
               
               
                   
                 AD-61865.2 
                 42.3 
               
               
                   
                 AD-61871.2 
                 55.8 
               
               
                   
                 AD-61830.2 
                 162.9 
               
               
                   
                 AD-61836.2 
                 28.8 
               
               
                   
                 AD-61842.2 
                 18.2 
               
               
                   
                 AD-61848.2 
                 25 
               
               
                   
                 AD-61854.2 
                 42.3 
               
               
                   
                 AD-61860.2 
                 41.7 
               
               
                   
                 AD-61866.2 
                 28.9 
               
               
                   
                 AD-61872.2 
                 64.7 
               
               
                   
                 AD-61831.2 
                 16.9 
               
               
                   
                 AD-61837.2 
                 24.9 
               
               
                   
                 AD-61843.2 
                 27.5 
               
               
                   
                 AD-61849.2 
                 25.8 
               
               
                   
                 AD-61855.2 
                 20 
               
               
                   
                 AD-61861.2 
                 28.6 
               
               
                   
                 AD-61867.2 
                 18 
               
               
                   
                 AD-62062.1 
                 22 
               
               
                   
                 AD-62068.1 
                 29.9 
               
               
                   
                 AD-62074.1 
                 40.2 
               
               
                   
                 AD-62080.1 
                 30.4 
               
               
                   
                 AD-62086.1 
                 21 
               
               
                   
                 AD-62092.1 
                 20 
               
               
                   
                 AD-62098.1 
                 38.4 
               
               
                   
                 AD-62104.1 
                 42.7 
               
               
                   
                 AD-62063.1 
                 26.6 
               
               
                   
                 AD-62069.1 
                 55.6 
               
               
                   
                 AD-62075.1 
                 114.4 
               
               
                   
                 AD-62081.1 
                 21.2 
               
               
                   
                 AD-62087.1 
                 33.8 
               
               
                   
                 AD-62093.1 
                 26.3 
               
               
                   
                 AD-62099.1 
                 23.9 
               
               
                   
                 AD-62105.1 
                 30.1 
               
               
                   
                 AD-62064.1 
                 32 
               
               
                   
                 AD-62070.1 
                 135.7 
               
               
                   
                 AD-62076.1 
                 84.3 
               
               
                   
                 AD-62082.1 
                 42.3 
               
               
                   
                 AD-62088.1 
                 36.5 
               
               
                   
                 AD-62094.1 
                 66 
               
               
                   
                 AD-62100.1 
                 66.4 
               
               
                   
                 AD-62106.1 
                 33.9 
               
               
                   
                 AD-62065.1 
                 33 
               
               
                   
                 AD-62071.1 
                 38.4 
               
               
                   
                 AD-62077.1 
                 27.8 
               
               
                   
                 AD-62083.1 
                 44.7 
               
               
                   
                 AD-62089.1 
                 42.7 
               
               
                   
                 AD-62095.1 
                 46.6 
               
               
                   
                 AD-62101.1 
                 35.3 
               
               
                   
                 AD-62107.1 
                 29.9 
               
               
                   
                 AD-62066.1 
                 33.5 
               
               
                   
                 AD-62072.1 
                 27.5 
               
               
                   
                 AD-62078.1 
                 49.9 
               
               
                   
                 AD-62084.1 
                 117.6 
               
               
                   
                 AD-62090.1 
                 44 
               
               
                   
                 AD-62096.1 
                 33.5 
               
               
                   
                 AD-62102.1 
                 39.2 
               
               
                   
                 AD-62108.1 
                 69.5 
               
               
                   
                 AD-62067.1 
                 32.3 
               
               
                   
                 AD-62073.1 
                 81.1 
               
               
                   
                 AD-62079.1 
                 46.8 
               
               
                   
                 AD-62085.1 
                 31.6 
               
               
                   
                 AD-62091.1 
                 32 
               
               
                   
                 AD-62097.1 
                 35.3 
               
               
                   
                 AD-62103.1 
                 35.6 
               
               
                   
                 AD-62109.1 
                 24.7 
               
               
                   
                 AD-62115.1 
                 25.7 
               
               
                   
                 AD-62121.1 
                 23.1 
               
               
                   
                 AD-62127.1 
                 36.3 
               
               
                   
                 AD-62133.1 
                 50.9 
               
               
                   
                 AD-62139.1 
                 84.1 
               
               
                   
                 AD-62145.1 
                 90.8 
               
               
                   
                 AD-62151.1 
                 56.9 
               
               
                   
                 AD-62110.1 
                 26 
               
               
                   
                 AD-62116.1 
                 145.5 
               
               
                   
                 AD-62122.1 
                 198.7 
               
               
                   
                 AD-62128.1 
                 178.4 
               
               
                   
                 AD-62134.1 
                 52.4 
               
               
                   
                 AD-62140.1 
                 55.6 
               
               
                   
                 AD-62146.1 
                 47.2 
               
               
                   
                 AD-62152.1 
                 16.4 
               
               
                   
                 AD-62111.1 
                 49.3 
               
               
                   
                 AD-62117.1 
                 46.2 
               
               
                   
                 AD-62123.1 
                 95.1 
               
               
                   
                 AD-62129.1 
                 156.2 
               
               
                   
                 AD-62135.1 
                 62 
               
               
                   
                 AD-62141.1 
                 128.1 
               
               
                   
                 AD-62147.1 
                 146.2 
               
               
                   
                 AD-62153.1 
                 35.5 
               
               
                   
                 AD-62112.1 
                 43 
               
               
                   
                 AD-62118.1 
                 32 
               
               
                   
                 AD-62124.1 
                 48.4 
               
               
                   
                 AD-62130.1 
                 49.4 
               
               
                   
                 AD-62136.1 
                 141.9 
               
               
                   
                 AD-62142.1 
                 38.7 
               
               
                   
                 AD-62148.1 
                 165.2 
               
               
                   
                 AD-62154.1 
                 94.7 
               
               
                   
                 AD-62113.1 
                 52.5 
               
               
                   
                 AD-62119.1 
                 44 
               
               
                   
                 AD-62125.1 
                 129.9 
               
               
                   
                 AD-62131.1 
                 68.9 
               
               
                   
                 AD-62137.1 
                 106 
               
               
                   
                 AD-62143.1 
                 176.1 
               
               
                   
                 AD-62149.1 
                 201.3 
               
               
                   
                 AD-62155.1 
                 143.3 
               
               
                   
                 AD-62114.1 
                 22.8 
               
               
                   
                 AD-62120.1 
                 34.6 
               
               
                   
                 AD-62126.1 
                 44.6 
               
               
                   
                 AD-62132.1 
                 39.5 
               
               
                   
                 AD-62138.1 
                 34.5 
               
               
                   
                 AD-62144.1 
                 28 
               
               
                   
                 AD-62150.1 
                 22.1 
               
               
                   
                 AD-62156.1 
                 44.1 
               
               
                   
                 AD-62162.1 
                 19.8 
               
               
                   
                 AD-62168.1 
                 17.3 
               
               
                   
                 AD-62174.1 
                 27 
               
               
                   
                 AD-62180.1 
                 15.8 
               
               
                   
                 AD-62186.1 
                 20.5 
               
               
                   
                 AD-62192.1 
                 33.9 
               
               
                   
                 AD-62198.1 
                 14 
               
               
                   
                 AD-62157.1 
                 19.3 
               
               
                   
                 AD-62163.1 
                 15.4 
               
               
                   
                 AD-62169.1 
                 23.6 
               
               
                   
                 AD-62175.1 
                 29.6 
               
               
                   
                 AD-62181.1 
                 26.4 
               
               
                   
                 AD-62187.1 
                 28.8 
               
               
                   
                 AD-62193.1 
                 22.9 
               
               
                   
                 AD-62199.1 
                 16.4 
               
               
                   
                 AD-62158.1 
                 18.5 
               
               
                   
                 AD-62164.1 
                 19.1 
               
               
                   
                 AD-62170.1 
                 15 
               
               
                   
                 AD-62176.1 
                 62.7 
               
               
                   
                 AD-62182.1 
                 70.8 
               
               
                   
                 AD-62188.1 
                 81.1 
               
               
                   
                 AD-62194.1 
                 63.6 
               
               
                   
                 AD-62200.1 
                 21.6 
               
               
                   
                 AD-62159.1 
                 42.8 
               
               
                   
                 AD-62165.1 
                 27.7 
               
               
                   
                 AD-62171.1 
                 31.9 
               
               
                   
                 AD-62177.1 
                 29.6 
               
               
                   
                 AD-62183.1 
                 25.2 
               
               
                   
                 AD-62189.1 
                 32.7 
               
               
                   
                 AD-62195.1 
                 73.1 
               
               
                   
                 AD-62201.1 
                 35.6 
               
               
                   
                 AD-62160.1 
                 56.5 
               
               
                   
                 AD-62166.1 
                 115.1 
               
               
                   
                 AD-62172.1 
                 107.4 
               
               
                   
                 AD-62178.1 
                 71.3 
               
               
                   
                 AD-62184.1 
                 27.2 
               
               
                   
                 AD-62190.1 
                 37.2 
               
               
                   
                 AD-62196.1 
                 19.5 
               
               
                   
                 AD-62202.1 
                 19.4 
               
               
                   
                 AD-62161.1 
                 23.7 
               
               
                   
                 AD-62167.1 
                 24.4 
               
               
                   
                 AD-62173.1 
                 36 
               
               
                   
                 AD-62179.1 
                 50.5 
               
               
                   
                 AD-62185.1 
                 40.5 
               
               
                   
                 AD-62191.1 
                 39.3 
               
               
                   
                 AD-62197.1 
                 39.4 
               
               
                   
                 AD-62203.1 
                 34.1 
               
               
                   
                 AD-62209.1 
                 34.6 
               
               
                   
                 AD-62215.1 
                 31 
               
               
                   
                 AD-62221.1 
                 16.3 
               
               
                   
                 AD-62227.1 
                 68.5 
               
               
                   
                 AD-62233.1 
                 34.3 
               
               
                   
                 AD-62239.1 
                 37.2 
               
               
                   
                 AD-62245.1 
                 31.2 
               
               
                   
                 AD-62204.1 
                 33 
               
               
                   
                 AD-62210.1 
                 29 
               
               
                   
                 AD-62216.1 
                 38.7 
               
               
                   
                 AD-62222.1 
                 34.5 
               
               
                   
                 AD-62228.1 
                 30.3 
               
               
                   
                 AD-62234.1 
                 15.2 
               
               
                   
                 AD-62240.1 
                 26.2 
               
               
                   
                 AD-62246.1 
                 40.4 
               
               
                   
                 AD-62205.1 
                 17.1 
               
               
                   
                 AD-62211.1 
                 20.9 
               
               
                   
                 AD-62217.1 
                 49.8 
               
               
                   
                 AD-62223.1 
                 40 
               
               
                   
                 AD-62229.1 
                 26.7 
               
               
                   
                 AD-62235.1 
                 21.5 
               
               
                   
                 AD-62241.1 
                 46.2 
               
               
                   
                 AD-62247.1 
                 40.4 
               
               
                   
                 AD-62206.1 
                 42.2 
               
               
                   
                 AD-62212.1 
                 51.7 
               
               
                   
                 AD-62218.1 
                 26 
               
               
                   
                 AD-62224.1 
                 40.3 
               
               
                   
                 AD-62230.1 
                 32.8 
               
               
                   
                 AD-62236.1 
                 52.4 
               
               
                   
                 AD-62242.1 
                 33.1 
               
               
                   
                 AD-62248.1 
                 18 
               
               
                   
                 AD-62207.1 
                 19.7 
               
               
                   
                 AD-62213.1 
                 43.4 
               
               
                   
                 AD-62219.1 
                 39.8 
               
               
                   
                 AD-62225.1 
                 34.3 
               
               
                   
                 AD-62231.1 
                 37.2 
               
               
                   
                 AD-62237.1 
                 25.9 
               
               
                   
                 AD-62243.1 
                 19.8 
               
               
                   
                 AD-62249.1 
                 13.8 
               
               
                   
                 AD-62208.1 
                 13.7 
               
               
                   
                 AD-62214.1 
                 16.6 
               
               
                   
                 AD-62220.1 
                 25.2 
               
               
                   
                 AD-62226.1 
                 27 
               
               
                   
                 AD-62232.1 
                 36.5 
               
               
                   
                 AD-62238.1 
                 51.5 
               
               
                   
                 AD-62244.1 
                 31.5 
               
               
                   
                 AD-61874.1 
                 27.1 
               
               
                   
                 AD-61880.1 
                 30.8 
               
               
                   
                 AD-61886.1 
                 30.4 
               
               
                   
                 AD-61892.1 
                 48.9 
               
               
                   
                 AD-61898.1 
                 24.7 
               
               
                   
                 AD-61904.1 
                 125.9 
               
               
                   
                 AD-61910.1 
                 45.7 
               
               
                   
                 AD-61916.1 
                 25.7 
               
               
                   
                 AD-61875.1 
                 33.4 
               
               
                   
                 AD-61881.1 
                 64 
               
               
                   
                 AD-61887.1 
                 36.7 
               
               
                   
                 AD-61893.1 
                 22.9 
               
               
                   
                 AD-61899.1 
                 84.5 
               
               
                   
                 AD-61905.1 
                 32.1 
               
               
                   
                 AD-61911.1 
                 23.7 
               
               
                   
                 AD-61917.1 
                 22.1 
               
               
                   
                 AD-61876.1 
                 47.3 
               
               
                   
                 AD-61882.1 
                 26.5 
               
               
                   
                 AD-61888.1 
                 27.7 
               
               
                   
                 AD-61894.1 
                 64.8 
               
               
                   
                 AD-61900.1 
                 89.8 
               
               
                   
                 AD-61906.1 
                 22.4 
               
               
                   
                 AD-61912.1 
                 19.8 
               
               
                   
                 AD-61918.1 
                 37.1 
               
               
                   
                 AD-61877.1 
                 145 
               
               
                   
                 AD-61883.1 
                 31.5 
               
               
                   
                 AD-61889.1 
                 33.9 
               
               
                   
                 AD-61895.1 
                 37.5 
               
               
                   
                 AD-61901.1 
                 26.1 
               
               
                   
                 AD-61907.1 
                 33 
               
               
                   
                 AD-61913.1 
                 33.1 
               
               
                   
                 AD-61919.1 
                 36.6 
               
               
                   
                 AD-61878.1 
                 26.9 
               
               
                   
                 AD-61884.1 
                 33.9 
               
               
                   
                 AD-61890.1 
                 37.2 
               
               
                   
                 AD-61896.1 
                 41.7 
               
               
                   
                 AD-61902.1 
                 58.6 
               
               
                   
                 AD-61908.1 
                 28 
               
               
                   
                 AD-61914.1 
                 31.4 
               
               
                   
                 AD-61920.1 
                 27.1 
               
               
                   
                 AD-61879.1 
                 33.1 
               
               
                   
                 AD-61885.1 
                 33.7 
               
               
                   
                 AD-61891.1 
                 41.3 
               
               
                   
                 AD-61897.1 
                 39.4 
               
               
                   
                 AD-61903.1 
                 51.5 
               
               
                   
                 AD-61909.1 
                 48.6 
               
               
                   
                 AD-61915.1 
                 122.4 
               
               
                   
                 AD-61921.1 
                 66.4 
               
               
                   
                 AD-61927.1 
                 40.5 
               
               
                   
                 AD-61933.1 
                 27.7 
               
               
                   
                 AD-61939.1 
                 28.1 
               
               
                   
                 AD-61945.1 
                 30 
               
               
                   
                 AD-61951.1 
                 33.7 
               
               
                   
                 AD-61957.1 
                 32.6 
               
               
                   
                 AD-61963.1 
                 17 
               
               
                   
                 AD-61922.1 
                 32.9 
               
               
                   
                 AD-61928.1 
                 28.3 
               
               
                   
                 AD-61934.1 
                 24 
               
               
                   
                 AD-61940.1 
                 28.2 
               
               
                   
                 AD-61946.1 
                 33.2 
               
               
                   
                 AD-61952.1 
                 167.9 
               
               
                   
                 AD-61958.1 
                 37 
               
               
                   
                 AD-61964.1 
                 30.6 
               
               
                   
                 AD-61923.1 
                 51.2 
               
               
                   
                 AD-61929.1 
                 29.4 
               
               
                   
                 AD-61935.1 
                 61 
               
               
                   
                 AD-61941.1 
                 29.5 
               
               
                   
                 AD-61947.1 
                 28.9 
               
               
                   
                 AD-61953.1 
                 23.7 
               
               
                   
                 AD-61959.1 
                 18.9 
               
               
                   
                 AD-61965.1 
                 17 
               
               
                   
                 AD-61924.1 
                 24.1 
               
               
                   
                 AD-61930.1 
                 31.9 
               
               
                   
                 AD-61936.1 
                 36.9 
               
               
                   
                 AD-61942.1 
                 13.8 
               
               
                   
                 AD-61948.1 
                 40.2 
               
               
                   
                 AD-61954.1 
                 41.8 
               
               
                   
                 AD-61960.1 
                 24.1 
               
               
                   
                 AD-61966.1 
                 18.9 
               
               
                   
                 AD-61925.1 
                 52.4 
               
               
                   
                 AD-61931.1 
                 25.8 
               
               
                   
                 AD-61937.1 
                 19.1 
               
               
                   
                 AD-61943.1 
                 27.8 
               
               
                   
                 AD-61949.1 
                 26.5 
               
               
                   
                 AD-61955.1 
                 83.8 
               
               
                   
                 AD-61961.1 
                 26 
               
               
                   
                 AD-61967.1 
                 16.3 
               
               
                   
                 AD-61926.1 
                 17.8 
               
               
                   
                 AD-61932.1 
                 18.6 
               
               
                   
                 AD-61938.1 
                 31.9 
               
               
                   
                 AD-61944.1 
                 29.5 
               
               
                   
                 AD-61950.1 
                 57.8 
               
               
                   
                 AD-61956.1 
                 42.1 
               
               
                   
                 AD-61962.1 
                 30 
               
               
                   
                 AD-61968.1 
                 29.1 
               
               
                   
                 AD-61974.1 
                 50.8 
               
               
                   
                 AD-61980.1 
                 19.7 
               
               
                   
                 AD-61986.1 
                 36.4 
               
               
                   
                 AD-61992.1 
                 36.3 
               
               
                   
                 AD-61998.1 
                 18.3 
               
               
                   
                 AD-62004.1 
                 14 
               
               
                   
                 AD-62010.1 
                 56.8 
               
               
                   
                 AD-61969.1 
                 30 
               
               
                   
                 AD-61975.1 
                 51.1 
               
               
                   
                 AD-61981.1 
                 37.6 
               
               
                   
                 AD-61987.1 
                 32.5 
               
               
                   
                 AD-61993.1 
                 23.4 
               
               
                   
                 AD-61999.1 
                 43.8 
               
               
                   
                 AD-62005.1 
                 23.8 
               
               
                   
                 AD-62011.1 
                 32.7 
               
               
                   
                 AD-61970.1 
                 39.6 
               
               
                   
                 AD-61976.1 
                 27.5 
               
               
                   
                 AD-61982.1 
                 64.9 
               
               
                   
                 AD-61988.1 
                 29.5 
               
               
                   
                 AD-61994.1 
                 40.5 
               
               
                   
                 AD-62006.1 
                 42.1 
               
               
                   
                 AD-62012.1 
                 21 
               
               
                   
                 AD-61971.1 
                 27.1 
               
               
                   
                 AD-61977.1 
                 23.4 
               
               
                   
                 AD-61983.1 
                 57.5 
               
               
                   
                 AD-61989.1 
                 25.8 
               
               
                   
                 AD-61995.1 
                 18.2 
               
               
                   
                 AD-62001.1 
                 29.7 
               
               
                   
                 AD-62007.1 
                 106.4 
               
               
                   
                 AD-62013.1 
                 36.1 
               
               
                   
                 AD-61972.1 
                 40.5 
               
               
                   
                 AD-61978.1 
                 49.1 
               
               
                   
                 AD-61984.1 
                 24.3 
               
               
                   
                 AD-61990.1 
                 38.8 
               
               
                   
                 AD-61996.1 
                 40.5 
               
               
                   
                 AD-62002.1 
                 32.5 
               
               
                   
                 AD-62008.1 
                 35.3 
               
               
                   
                 AD-62014.1 
                 23.6 
               
               
                   
                 AD-61973.1 
                 39.3 
               
               
                   
                 AD-61979.1 
                 27.4 
               
               
                   
                 AD-61985.1 
                 31.3 
               
               
                   
                 AD-61991.1 
                 34.9 
               
               
                   
                 AD-61997.1 
                 29.2 
               
               
                   
                 AD-62003.1 
                 25.9 
               
               
                   
                 AD-62009.1 
                 21.1 
               
               
                   
                 AD-62056.1 
                 16.3 
               
               
                   
                 AD-62015.1 
                 139.3 
               
               
                   
                 AD-62021.1 
                 36.4 
               
               
                   
                 AD-62027.1 
                 42.4 
               
               
                   
                 AD-62033.1 
                 62 
               
               
                   
                 AD-62039.1 
                 35.2 
               
               
                   
                 AD-62045.1 
                 30.8 
               
               
                   
                 AD-62051.1 
                 22.9 
               
               
                   
                 AD-62057.1 
                 31.8 
               
               
                   
                 AD-62016.1 
                 29.2 
               
               
                   
                 AD-62022.1 
                 36.9 
               
               
                   
                 AD-62028.1 
                 52.6 
               
               
                   
                 AD-62034.1 
                 31 
               
               
                   
                 AD-62040.1 
                 30.7 
               
               
                   
                 AD-62046.1 
                 28.2 
               
               
                   
                 AD-62052.1 
                 23.7 
               
               
                   
                 AD-62058.1 
                 77.9 
               
               
                   
                 AD-62017.1 
                 41 
               
               
                   
                 AD-62023.1 
                 27 
               
               
                   
                 AD-62029.1 
                 31.8 
               
               
                   
                 AD-62035.1 
                 46.4 
               
               
                   
                 AD-62041.1 
                 25.3 
               
               
                   
                 AD-62047.1 
                 20 
               
               
                   
                 AD-62053.1 
                 37.1 
               
               
                   
                 AD-62059.1 
                 31 
               
               
                   
                 AD-62018.1 
                 37.8 
               
               
                   
                 AD-62024.1 
                 34.7 
               
               
                   
                 AD-62030.1 
                 50.4 
               
               
                   
                 AD-62036.1 
                 25.5 
               
               
                   
                 AD-62042.1 
                 32.5 
               
               
                   
                 AD-62048.1 
                 28.3 
               
               
                   
                 AD-62054.1 
                 55.6 
               
               
                   
                 AD-62060.1 
                 26.9 
               
               
                   
                 AD-62019.1 
                 29 
               
               
                   
                 AD-62025.1 
                 78.5 
               
               
                   
                 AD-62031.1 
                 152.8 
               
               
                   
                 AD-62037.1 
                 27.3 
               
               
                   
                 AD-62043.1 
                 33.8 
               
               
                   
                 AD-62049.1 
                 46 
               
               
                   
                 AD-62055.1 
                 24.5 
               
               
                   
                 AD-62061.1 
                 30.5 
               
               
                   
                 AD-62020.1 
                 25.1 
               
               
                   
                 AD-62026.1 
                 24.9 
               
               
                   
                 AD-62032.1 
                 23 
               
               
                   
                 AD-62038.1 
                 21.2 
               
               
                   
                 AD-62044.1 
                 34.1 
               
               
                   
                 AD-62050.1 
                 22.4 
               
               
                   
                 AD-62320.1 
                 16.6 
               
               
                   
                 AD-62326.1 
                 16.6 
               
               
                   
                 AD-62332.1 
                 15.4 
               
               
                   
                 AD-62338.1 
                 41.9 
               
               
                   
                 AD-62344.1 
                 19.6 
               
               
                   
                 AD-62350.1 
                 32.3 
               
               
                   
                 AD-62356.1 
                 20.4 
               
               
                   
                 AD-62362.1 
                 27.8 
               
               
                   
                 AD-62321.1 
                 18.7 
               
               
                   
                 AD-62327.1 
                 14.8 
               
               
                   
                 AD-62333.1 
                 22.2 
               
               
                   
                 AD-62339.1 
                 134.5 
               
               
                   
                 AD-62345.1 
                 32.1 
               
               
                   
                 AD-62351.1 
                 35.6 
               
               
                   
                 AD-62357.1 
                 31 
               
               
                   
                 AD-62363.1 
                 28.2 
               
               
                   
                 AD-62322.1 
                 45.1 
               
               
                   
                 AD-62328.1 
                 30.1 
               
               
                   
                 AD-62334.1 
                 39.1 
               
               
                   
                 AD-62340.1 
                 24.3 
               
               
                   
                 AD-62346.1 
                 35.4 
               
               
                   
                 AD-62352.1 
                 33.8 
               
               
                   
                 AD-62358.1 
                 45.7 
               
               
                   
                 AD-62364.1 
                 19.7 
               
               
                   
                 AD-62323.1 
                 40.5 
               
               
                   
                 AD-62329.1 
                 57.5 
               
               
                   
                 AD-62335.1 
                 27.6 
               
               
                   
                 AD-62341.1 
                 69.2 
               
               
                   
                 AD-62347.1 
                 125.9 
               
               
                   
                 AD-62353.1 
                 53.1 
               
               
                   
                 AD-62359.1 
                 38.1 
               
               
                   
                 AD-62365.1 
                 23.6 
               
               
                   
                 AD-62324.1 
                 27.1 
               
               
                   
                 AD-62330.1 
                 25.1 
               
               
                   
                 AD-62336.1 
                 25.3 
               
               
                   
                 AD-62342.1 
                 45.4 
               
               
                   
                 AD-62348.1 
                 91.6 
               
               
                   
                 AD-62354.1 
                 132.1 
               
               
                   
                 AD-62360.1 
                 31.6 
               
               
                   
                 AD-62366.1 
                 14.2 
               
               
                   
                 AD-62325.1 
                 27.9 
               
               
                   
                 AD-62331.1 
                 31.5 
               
               
                   
                 AD-62337.1 
                 33.9 
               
               
                   
                 AD-62343.1 
                 36.1 
               
               
                   
                 AD-62349.1 
                 37.6 
               
               
                   
                 AD-62355.1 
                 38.8 
               
               
                   
                 AD-62361.1 
                 46.1 
               
               
                   
                 AD-62367.1 
                 23.6 
               
               
                   
                 AD-62373.1 
                 32.1 
               
               
                   
                 AD-62379.1 
                 29.6 
               
               
                   
                 AD-62385.1 
                 35.7 
               
               
                   
                 AD-62391.1 
                 33.7 
               
               
                   
                 AD-62397.1 
                 54.1 
               
               
                   
                 AD-62403.1 
                 34.8 
               
               
                   
                 AD-62409.1 
                 28.2 
               
               
                   
                 AD-62368.1 
                 29.7 
               
               
                   
                 AD-62374.1 
                 29.6 
               
               
                   
                 AD-62380.1 
                 30.6 
               
               
                   
                 AD-62386.1 
                 23.4 
               
               
                   
                 AD-62392.1 
                 30.5 
               
               
                   
                 AD-62398.1 
                 48.7 
               
               
                   
                 AD-62404.1 
                 24.8 
               
               
                   
                 AD-62410.1 
                 21.9 
               
               
                   
                 AD-62369.1 
                 27.4 
               
               
                   
                 AD-62375.1 
                 31.9 
               
               
                   
                 AD-62381.1 
                 27.3 
               
               
                   
                 AD-62387.1 
                 77 
               
               
                   
                 AD-62393.1 
                 93.3 
               
               
                   
                 AD-62399.1 
                 150.2 
               
               
                   
                 AD-62405.1 
                 28.5 
               
               
                   
                 AD-62411.1 
                 19.4 
               
               
                   
                 AD-62370.1 
                 16.3 
               
               
                   
                 AD-62376.1 
                 48.2 
               
               
                   
                 AD-62382.1 
                 28.5 
               
               
                   
                 AD-62388.1 
                 49.9 
               
               
                   
                 AD-62394.1 
                 29.9 
               
               
                   
                 AD-62400.1 
                 45.2 
               
               
                   
                 AD-62406.1 
                 23 
               
               
                   
                 AD-62412.1 
                 45.5 
               
               
                   
                 AD-62371.1 
                 66.5 
               
               
                   
                 AD-62377.1 
                 49.5 
               
               
                   
                 AD-62383.1 
                 73.8 
               
               
                   
                 AD-62389.1 
                 82.4 
               
               
                   
                 AD-62395.1 
                 31.8 
               
               
                   
                 AD-62401.1 
                 31.2 
               
               
                   
                 AD-62407.1 
                 30.2 
               
               
                   
                 AD-62413.1 
                 28.1 
               
               
                   
                 AD-62372.1 
                 43 
               
               
                   
                 AD-62378.1 
                 17.9 
               
               
                   
                 AD-62384.1 
                 29.6 
               
               
                   
                 AD-62390.1 
                 37.7 
               
               
                   
                 AD-62396.1 
                 26 
               
               
                   
                 AD-62402.1 
                 31.6 
               
               
                   
                 AD-62408.1 
                 46.6 
               
               
                   
                 AD-62414.1 
                 27.2 
               
               
                   
                 AD-62415.1 
                 17.6 
               
               
                   
                 AD-62416.1 
                 25.3 
               
               
                   
                 AD-62417.1 
                 36.3 
               
               
                   
                 AD-61779.2 
                 43.2 
               
               
                   
                 AD-61785.2 
                 22.5 
               
               
                   
                 AD-61791.2 
                 27.3 
               
               
                   
                 AD-61797.2 
                 30.5 
               
               
                   
                 AD-61803.2 
                 30.9 
               
               
                   
                 AD-61809.2 
                 75.1 
               
               
                   
                 AD-61815.2 
                 90.7 
               
               
                   
                 AD-61821.2 
                 33.7 
               
               
                   
                 AD-61780.2 
                 53.5 
               
               
                   
                 AD-61786.2 
                 34.4 
               
               
                   
                 AD-61792.2 
                 27.5 
               
               
                   
                 AD-61798.2 
                 23.3 
               
               
                   
                 AD-61804.2 
                 23.6 
               
               
                   
                   
               
            
           
         
       
     
     Example 7: In Vivo Screening of Additional siRNAs 
     Based on the sequence of AD-58643, an additional four sense and three antisense sequences were synthesized and used to prepare twelve, 21/25 mer compounds (Table 23). In general, the antisense strands of these compounds were extended with a dTdT and the duplexes had fewer fluoro-modified nucleotides. 
     C57BL/6 mice (N=3 per group) were injected subcutaneously with 1 mg/kg of these GalNAc conjugated duplexes, serum was collected on day 0 pre-bleed, and day 5, and the levels of C5 proteins were quantified by ELISA. C5 protein levels were normalized to the day 0 pre-bleed level. 
       FIG. 14  shows the results of an in vivo single dose screen with the indicated iRNAs. Data are expressed as percent of C5 protein remaining relative to pre-bleed levels. Those iRNAs having improved efficacy as compared to the parent compound included AD-62510, AD-62643, AD-62645, AD-62646, AD-62650, and AD-62651. These iRNAs also demonstrated similar potencies (IC 50  of about 23-59 pM). 
     The efficacy of these iRNAs was also tested in C57Bl/6 mice using a single-dosing administration protocol. Mice were subcutaneously administered AD-62510, AD-62643, AD-62645, AD-62646, AD-62650, and AD-62651 at a 0.25 mg/kg, 0.5 mg/kg, 1.0 mg/kg, or 2.5 mg/kg dose. Serum was collected at days 0 and 5 and analyzed for C5 protein levels by ELISA. C5 levels were normalized to the day 0 pre-bleed level. 
       FIG. 15  shows that there is a dose response with all of the tested iRNAs and that single-dosing of all of these iRNAs achieved silencing of C5 protein similar to or better than AD-58641. 
     The duration of silencing of AD-62510, AD-62643, AD-62645, AD-62646, AD-62650, and AD-62651 in vivo was determined by administering a single 1.0 mg/kg dose to C57Bl/6 mice and determining the amount of C5 protein present on days 6, 13, 20, 27, and 34 by ELISA. C5 levels were normalized to the day 0 pre-bleed level. 
     As demonstrated in  FIG. 16 , each of the iRNAs tested has the same recovery kinetics as AD-62643 trending toward the best silencing, but within the error of the assay. 
     AD-62510, AD-62643, AD-62645, AD-62646, AD-62650, and AD-62651 were further tested for efficacy and to evaluate the cumulative effect of the iRNAs in rats using a repeat administration protocol. Wild-type Sprague Dawley rats were subcutaneously injected with each of the iRNAs at a 5.0 mg/kg/dose on days 0, 4, and 7. Serum was collected on days 0, 4, 7, 11, 14, 18, 25, 28, and 32. Serum hemolytic activity was quantified as described above. 
     The results depicted in  FIG. 17  demonstrate that all of the tested iRNAs have a potent and durable decrease in hemolytic activity and a similar recovery of hemolysis to that observed with AD-58641 treatment. 
     
       
         
           
               
             
               
                 TABLE 23 
               
             
            
               
                   
               
               
                 Modified Sense and Antisense Strand 
               
               
                 Sequences of GalNAc-Conjugated C5 dsRNAs. 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Duplex 
                   
                 Sense 
                 SEQ ID 
                   
                 Antisense 
                 SEQ ID 
               
               
                 ID 
                 sense ID 
                 (5′ to 3′) 
                 NO: 
                 AS ID 
                 (5′ to 3′) 
                 NO: 
               
               
                   
               
               
                 AD-58643 
                 A-119326.1 
                 AfsasGfcAfaGf 
                 2873 
                 A-119327.1 
                 usAfsuUfaUfaA 
                 2886 
               
               
                   
                   
                 aUfAfUfuUfuUf 
                   
                   
                 faAfauaUfcUfu 
                   
               
               
                   
                   
                 aUfaAfuAfL96 
                   
                   
                 GfcUfususu 
                   
               
               
                   
               
               
                 AD-62642 
                 A-125167.7 
                 asasGfcAfaGfa 
                 2874 
                 A-125139.1 
                 usAfsuuaUfaAf 
                 2887 
               
               
                   
                   
                 UfAfUfuUfuuAf 
                   
                   
                 aAfauaUfcUfuG 
                   
               
               
                   
                   
                 uAfauaL96 
                   
                   
                 fcuususudTdT 
                   
               
               
                   
               
               
                 AD-62510 
                 A-125167.7 
                 asasGfcAfaGfa 
                 2875 
                 A-125173.2 
                 usAfsUfuAfuAf 
                 2888 
               
               
                   
                   
                 UfAfUfuUfuuAf 
                   
                   
                 AfaAfauaUfcUf 
                   
               
               
                   
                   
                 uAfauaL96 
                   
                   
                 uGfcuususudTdT 
                   
               
               
                   
               
               
                 AD-62643 
                 A-125167.7 
                 asasGfcAfaGfa 
                 2876 
                 A-125647.1 
                 usAfsUfuAfuaA 
                 2889 
               
               
                   
                   
                 UfAfUfuUfuuAf 
                   
                   
                 faAfauaUfcUfu 
                   
               
               
                   
                   
                 nAfauaL96 
                   
                   
                 GfcuususudTdT 
                   
               
               
                   
               
               
                 AD-62644 
                 A-125157.17 
                 asasGfcAfaGfa 
                 2877 
                 A-125139.1 
                 usAfsuuaUfaAf 
                 2890 
               
               
                   
                   
                 UfAfUfuUfuuAf 
                   
                   
                 aAfauaUfcUfuG 
                   
               
               
                   
                   
                 uaAfuaL96 
                   
                   
                 fcuususudTdT 
                   
               
               
                   
               
               
                 AD-62645 
                 A-125157.17 
                 asasGfcAfaGfa 
                 2878 
                 A-125173.2 
                 usAfsUfuAfuAf 
                 2891 
               
               
                   
                   
                 UfAfUfuUfuuAf 
                   
                   
                 AfaAfauaUfcUf 
                   
               
               
                   
                   
                 uaAfuaL96 
                   
                   
                 uGfcuususudTdT 
                   
               
               
                   
               
               
                 AD-62646 
                 A-125157.17 
                 asasGfcAfaGfa 
                 2879 
                 A-125647.1 
                 usAfsUfuAfuaA 
                 2892 
               
               
                   
                   
                 UfAfUfuUfuuAf 
                   
                   
                 faAfauaUfcUfu 
                   
               
               
                   
                   
                 uaAfuaL96 
                   
                   
                 GfcuususudTdT 
                   
               
               
                   
               
               
                 AD-62647 
                 A-125134.1 
                 asasgcaagauaU 
                 2880 
                 A-125139.1 
                 usAfsuuaUfaAf 
                 2893 
               
               
                   
                   
                 fuuuua(Tgn)aa 
                   
                   
                 aAfauaUfcUfuG 
                   
               
               
                   
                   
                 uaL96 
                   
                   
                 fcuususudTdT 
                   
               
               
                   
               
               
                 AD-62648 
                 A-125134.1 
                 asasgcaagauaU 
                 2881 
                 A-125173.2 
                 usAfsUfuAfuAf 
                 2894 
               
               
                   
                   
                 fuuuua(Tgn)aa 
                   
                   
                 AfaAfauaUfcUf 
                   
               
               
                   
                   
                 uaL96 
                   
                   
                 uGfcuususudTdT 
                   
               
               
                   
               
               
                 AD-62649 
                 A-125134.1 
                 asasgcaagauaU 
                 2882 
                 A-125647.1 
                 usAfsUfuAfuaA 
                 2895 
               
               
                   
                   
                 fuuuua(Tgn)aa 
                   
                   
                 faAfauaUfcUfu 
                   
               
               
                   
                   
                 uaL96 
                   
                   
                 GfcuususudTdT 
                   
               
               
                   
               
               
                 AD-62428 
                 A-125127.2 
                 asasgcaagaUfa 
                 2883 
                 A-125139.1 
                 usAfsuuaUfaAf 
                 2896 
               
               
                   
                   
                 UfuuuuauaauaL 
                   
                   
                 aAfauaUfcUfuG 
                   
               
               
                   
                   
                 96 
                   
                   
                 fcuususudTdT 
                   
               
               
                   
               
               
                 AD-62650 
                 A-125127.2 
                 asasgcaagaUfa 
                 2884 
                 A-125173.2 
                 usAfsUfuAfuAf 
                 2897 
               
               
                   
                   
                 UfuuuuauaauaL 
                   
                   
                 AfaAfauaUfcUf 
                   
               
               
                   
                   
                 96 
                   
                   
                 uGfcuususudTdT 
                   
               
               
                   
               
               
                 AD-62651 
                 A-125127.2 
                 asasgcaagaUfa 
                 2885 
                 A-125647.1 
                 usAfsUfuAfuaA 
                 2898 
               
               
                   
                   
                 UfuuuuauaauaL 
                   
                   
                 faAfauaUfcUfu 
                   
               
               
                   
                   
                 96 
                   
                   
                 GfcuususudTdT 
               
               
                   
               
            
           
         
       
     
     Example 8: Sustained C5 Protein Knockdown in Non-Human Primates 
     AD-62643 was tested for its ability to decrease the serum levels of C5 protein after long-term treatment. Cynomolgus macaques (N=3 per group) were administered AD-62643 via subcutaneous injection using two dosing regimens. In the first dosing regimen (Q2W), AD-62643 was administered every week for 8 weeks at a dose of 5 mg/kg, followed by administration every 2 weeks at a dose of 5 mg/kg thereafter (5 mg/kg, qw×8, q2w thereafter). In the second dosing regimen (QM), AD-62643 was administered every day at a dose of 5 mg/kg for 5 days, followed by administration every week for 8 weeks at a dose of 5 mg/kg, followed by a monthly administration of a dose of 10 mg/kg thereafter (5 mg/kg, qd×5, qw×8/10 mg/kg qm thereafter). The levels of C5 protein were quantified by ELISA, and C5 protein levels were normalized to the day 0 pre-bleed level. Serum hemolytic activity was analyzed using a sensitized sheep erythrocyte assay to measure classical pathway activity. The percent hemolysis was calculated relative to maximal hemolysis and to background hemolysis in control samples. The alternative complement pathway (CAP) activity was also measured. 
       FIG. 19A  shows the average % serum C5 levels relative to the pre-bleed levels for the two tested dosing regimens.  FIG. 19B  shows the % serum C5 levels relative to the pre-bleed levels for each individual animal tested. The data demonstrates that both dosing regimens are able to achieve and maintain, on average, up to −99% (98.2±0.8%) knockdown of serum C5, with low inter-animal variation. 
       FIG. 20A  shows % hemolysis and % CAP activity relative to control with the QM regimen and  FIG. 20B  showns % hemolysis and % CAP activity relative to control with the Q2W regimen.  FIG. 20C  shows the correlation of the hemolysis and CAP activity with the levels of C5 knockdown. The data demonstrate robust inhibition of both classical and alternative pathway of complement activity; specifically, C5 knockdown is associated with &gt;80% (up to 96.2%) lowering of complement serum hemolytic activity and &gt;90% (up to 96.9%) lowering of CAP activity. 
     Example 9: C5 Silencing and Clinical Disease Activity in Mouse Model of Arthritis 
     AD-61679 was tested in a mouse model of anti-collagen antibody-induced arthritis (CAIA) for its ability to decrease serum C5 levels and to inhibit clinical disease activity, and compared to an anti-C5 antibody. CAIA mice were administered AD-61679 (5 mg/kg, N=7), control siRNA (10 mg/kg, N=6), anti-C5 antibody (50 mg/kg, N=7) and PBS (N=7). AD-61679 and siRNA control were administered three times (every 5 days-days −5, 0, 5); while the anti-C5 antibody was administered once at day 0. Serum levels of C5 protein were measured using ELISA and are shown in  FIG. 21 . Clinical disease activity (CDA) was scored each day of the 10-day interval starting at day 0 and the results are shown in  FIG. 22 . Joint inflammation, pannus, and cartilage and bone damage were measured by scoring of hematoxylin and eosin (H&amp;E) and Toluidine Blue histological stains ( FIG. 23A ). C3 deposition was also measured by immunohistochemistry using anti-C3 antibody ( FIG. 23B ). 
     As shown in  FIG. 21 , upregulation of the C5 levels over the 10-day treatment period is observed in mice treated with PBS, and control siRNA and anti-C5 antibody, while robust knockdown of plasma C5 protein is observed in AD-61679 treated animals. No modulation of C5 knockdown by LPS, injected on day 3, is observed. Circulating liver-derived C5 appears to be a key driver of pathology in CAIA mice, with the locally produced C5 playing little or no role. The data in  FIGS. 22A and 22B  demonstrate that treatment with AD-61679, similar to the treatment with the anti-C5 antibody, preserves joint histology, e.g., prevents inflammation, cartilage damage, bone damage and pannus, and prevents C3 deposition in the synovium and cartilage. 
     Example 10: Effect of C5 Protein Knockdown in Rat Model of Membranous Nephropathy 
     AD-61679 was tested in a rat model of Passive Neymann Nephritis for its ability to reduce proteinurea. Nephritis was induced by injection of sheep anti-rat kidney fraction antiserum (anti-Fx1A) at day 0 and day 1. Control rats received no AD-61679 or anti-Fx1A treatment. Prior to the injection of anti-Fx1A, rats were administered AD-61679 at day−10, day−7 and day−3. AD-61679 was also administered on days 0, 1 and 4. Serum hemolytic activity in control rats, as well as rats treated with anti-Fx1a alone or with anti-Fx1a and AD-61679 was measured and is shown in  FIG. 23A . Urine was collected on days 2 and 5, and levels of urinary protein at day were measured and are shown in  FIG. 23B . The data indicate that AD-61679 is efficient in reducing serum hemolytic activity and proteinurea in the rat model of Passive Neymann Nephritis. 
     Example 11: Phase I/II—Part A Clinical Trial of AD-62643 
     A Phase I/II, randomized, double-blind, placebo-controlled, single-dose, dose escalation study was conducted in normal healthy volunteers (n=20) to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of subcutaneously administered AD-62643 as described below. 
     Five cohorts, each including 4 subjects, participated in this study. One cohort was subcutaneously administered a single 50 mg dose of AD-62643; a second cohort was subcutaneously administered a single 200 mg dose of AD-62643; a third cohort was subcutaneously administered a single 400 mg dose of AD-62643; a fourth cohort was subcutaneously administered a single 600 mg dose of AD-62643; and a fifth cohort was subcutaneously administered a single 900 mg dose of AD-62643. A 200 mg/ml solution of AD-62643 was used for administration. The demographics and baseline characteristics of the subjects participating in the study are provided in Table 24. 
     
       
         
           
               
             
               
                 TABLE 24 
               
             
            
               
                   
               
               
                 Demographics and baseline characteristics of healthy volunteers 
               
            
           
           
               
               
            
               
                   
                 Part A: Single Ascending Dose (SAD) 
               
               
                   
                 Single subcutaneous injection 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 50 mg 
                 200 mg 
                 400 mg 
                 600 mg 
                 900 mg 
               
               
                   
                 N = 4 
                 N = 4 
                 N = 4 
                 N = 4 
                 N = 4 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Age (years), 
                 23.8 
                 22.5 
                 22.0 
                 28.5 
                 26.8 
               
               
                 Mean (Min, Max) 
                 (20, 26) 
                 (21, 24) 
                 (20, 27) 
                 (23, 38) 
                 (22, 33) 
               
               
                 Gender: Male(%) 
                 100%  
                 100%  
                 75% 
                 0% 
                 50% 
               
               
                 BMI (kg/m 2 ), Mean 
                  24.08 
                  22.35 
                  21.38 
                  24.80 
                  23.53 
               
               
                 Race (%) 
               
               
                 Asian 
                  0% 
                  0% 
                 25% 
                 50%  
                  0% 
               
               
                 Black/African 
                 25% 
                 50% 
                  0% 
                 0% 
                 25% 
               
               
                 Caucasian 
                 50% 
                 25% 
                 50% 
                 50%  
                 75% 
               
               
                 Other 
                 25% 
                 25% 
                 25% 
                 0% 
                  0% 
               
               
                 Time on study, 
                 115   
                 286   
                 211   
                 293   
                 258   
               
               
                 Mean (days) 
               
               
                   
               
            
           
         
       
     
     There were no injection site reactions, serious adverse events, or study discontinuations and no clinically significant changes in vital signs, physical exams, clinical laboratories (hematology, biochemistry, coagulation, and urinalysis), or ECGs. 
     The knockdown of C5 levels in the single fixed dose 50 mg, 200 mg, 400 mg, 600, and 900 mg cohorts, shown as a mean C5 knockdown relative to baseline, is depicted in  FIG. 24 . The maximum C5 knockdown relative to baseline was 99% and the mean maximum C5 knockdown was 98±0.9% (mean±SEM). The mean C5 knockdown of 96±1.0% (mean±SEM) was observed at Day 98 in the 900 mg cohort; the mean C5 knockdown of 97±1.1% (mean±SEM) was observed at Day 98 in the 600 mg cohort; and the mean C5 knockdown of 94±1.1% (mean±SEM) was observed at Day 182 in the 600 mg cohort. 
     The effect of administration of a single 50 mg, 200 mg, 400 mg, 600, and 900 mg dose of AD-62643 to inhibit complement activity, measured as alternative complement pathway (CAP) activity and as classical complement pathway (CCP) activity were assessed by determining the amount of active C5 b-9 formation. CCP and CAP activation are ELISA based assays where complement in a serum sample is activated by a pathway specific activator present in the plate and the formation of Membrane Attack Complex (MAC) (C5 b-9) is detected using antibody-based detection. 
     As shown in  FIG. 25 , the maximum CAP inhibition, relative to baseline, was up to 95%, with a mean maximum of inhibition of 93±1.3% (mean±SEM).  FIG. 26  shows that the maximum CCP inhibition, relative to baseline, was up to 97%, with a mean maximum of inhibition of 96±0.7% (mean±SEM). 
     The effect of administration of a single 50 mg, 200 mg, 400 mg, 600, and 900 mg dose of AD-62643 to inhibit complement activity as measured by serum hemolytic activity was assessed using a sensitized sheep erythrocyte assays to measure CCP activation. As shown in  FIG. 27 , the maximum serum hemolysis inhibition, relative to baseline, was up to 79%, with a mean maximum hemolysis inhibition of 74±4.2% (mean±SEM). 
     A correlation analysis of the C5 knockdown in human and non-human primates was also performed. The correlation analysis assumed that a 50 mg dose in humans was equivalent to a 1 mg/kg dose in NHP and that a 400 mg dose in humans was equivalent to a 5 mg/kg dose in NHP. The knockdown of C5 levels in humans administered a single 50 mg or 400 mg subcutaneous dose of AD-62643 and NHP administered a single 1 mg/kg or 5 mg/kg subcutaneous dose of AD-62643 is shown in  FIG. 28B  and a graph showing the correlation of C5 knockdown in humans versus NHP is shown in  FIG. 28A . This analysis demonstrated that there is a statistically significant correlation between C5 knockdown in humans and NHP with r=0.83 and p&lt;0.0001 and that there is a 3 to 5 time increased potency of the dsRNAi agent for C5 knockdown in humans as compared to NHP. 
       FIG. 29  and Table 25 show that, in addition to knocking down C5 levels, AD-62643 also inhibits complement activity, measured as classical complement pathway (CCP) activity assessed by the amount of active C5 b-9 formation, described above. 
     
       
         
           
               
             
               
                 TABLE 25 
               
             
            
               
                   
               
               
                 Serum C5 knockdown and inhibition of complement activity 
               
            
           
           
               
               
               
               
            
               
                   
                 50 mg 
                 200 mg 
                 400 mg 
               
               
                   
                 N = 3 
                 N = 3 
                 N = 3 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 Mean max C5 
                 79 ± 2.2 
                 94 ± 0.2 
                 94 ± 2.0 
               
               
                   
                 KD (% ± 
               
               
                   
                 SEM) 
               
               
                   
                 Max C5 KD 
                 84 
                 94 
                 96 
               
               
                   
                 (%) 
               
               
                   
                 Mean max 
                 59 ± 6.5 
                 84 ± 1.7 
                 82 ± 6.1 
               
               
                   
                 CCP 
               
               
                   
                 inhibition 
               
               
                   
                 (% ± SEM) 
               
               
                   
                 Max CCP 
                 72 
                 86 
                 92 
               
               
                   
                 inhibition 
               
               
                   
                 (%) 
               
               
                   
                 Mean max 
                 59 ± 7.3 
                 79 ± 1.2 
                 75 ± 7.2 
               
               
                   
                 CAP 
               
               
                   
                 inhibition 
               
               
                   
                 (% ± SEM) 
               
               
                   
                 Max CAP 
                 73 
                 81 
                 87 
               
               
                   
                 inhibition 
               
               
                   
                 (%) 
               
               
                   
                   
               
            
           
         
       
     
     Complement activity measured by serum hemolytic activity was analyzed using a the sensitized sheep erythrocyte assay to measure classical pathway activity, described above. The percent hemolysis was calculated relative to maximal hemolysis and to background hemolysis in control samples. 
       FIG. 30A  shows % hemolysis relative to control in subjects administered a single subcutaneous dose of AD-62643 and  FIG. 30B  showns % hemolysis in NHP administered a single subcutaneous dose of AD-62643. These data demonstrate that there is up to a 61% inhibition of serum hemolytic activity in humans with a single subcutaneous dose of AD-62643 and a mean maximum inhibition of 43±9.1%. Furthermore, comparison of the data in  FIGS. 30A and 30B  demonstrates that there is comparable hemolysis inhibition in humans and NHP administered a single dose of AD-62643. 
     A summary of the results of this Phase I/II clinical trail are provided in Table 26. 
     
       
         
           
               
             
               
                 TABLE 26 
               
             
            
               
                   
               
               
                 Summary of Phase I/II Part A Study 
               
            
           
           
               
               
            
               
                   
                 Part A: Single Ascending Dose (SAD) 
               
               
                   
                 Single subcutaneous injection 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 50 mg 
                 200 mg 
                 400 mg 
                 600 mg 
                 900 mg 
                 Placebo 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Residual C5 
                   
                   
                   
                   
                   
                   
               
               
                 Mean nadir; μg/mL ± SEM 
                 15.3 ± 2.5     
                 5.2 ± 0.5  
                 3.8 ± 1.0  
                 2.2 ± 0.8  
                 1.8 ± 0.2  
                 59.6 ± 2.6     
               
               
                 Nadir; μg/mL 
                   10.8 
                   4.3 
                   1.8 
                   1.1 
                   1.4 
                   53.5 
               
               
                 C5 knockdown 
               
               
                 Mean max; % ± SEM 
                 78 ± 3.2 
                 93 ± 0.9 
                 95 ± 1.4 
                 98 ± 0.9 
                 98 ± 0.3 
                 14 ± 2.7 
               
               
                 Max; % 
                 84 
                 95 
                 97 
                 99 
                 98 
                 20 
               
               
                 CCP inhibition 
               
               
                 Mean max; % ± SEM 
                 59 ± 6.5 
                 84 ± 1.6 
                 86 ± 3.2 
                 96 ± 0.7 
                 92 ± 1.1 
                 20 ± 5.1 
               
               
                 Max; % 
                 72 
                 86 
                 93 
                 97 
                 94 
                 37 
               
               
                 CAP inhibition 
               
               
                 Mean max; % ± SEM 
                 59 ± 7.3 
                 79 ± 1.2 
                 80 ± 5.7 
                 93 ± 1.3 
                 93 ± 0.7 
                 26 ± 7.6 
               
               
                 Max; % 
                 73 
                 81 
                 91 
                 95 
                 94 
                 44 
               
               
                 Hemolysis inhibition 
               
               
                 Mean max; % ± SEM 
                 35 ± 7.9 
                 41 ± 4.4 
                  48 ± 11.9 
                 74 ± 4.2 
                 71 ± 4.7 
                  9 ± 1.4 
               
               
                 Max; % 
                 51 
                 47 
                 71 
                 79 
                 78 
                 13 
               
               
                   
               
            
           
         
       
     
     In summary, these data demonstrate that there is a robust, dose-dependent, statistically significant, and durable knockdown of serum C5 with a single dose of AD-62643. There was up 99% C5 knockdown with mean maximum knockdown of 98±9% (mean±SEM) after a single fixed dose which was durable and lasted for months. In addition, a single dose of AD-62643 resulted in a clinically meaningful reduction in complement activity as complement activity. Furthermore, these data demonstrate that there was an excellent translation from NHP studies suggesting a 3-5× increased potency in humans. 
     Example 12: Phase I/II—Part B Clinical Trial of AD-62643 
     A Phase I/II, randomized, double-blind, placebo-controlled, multiple-dose, dose escalation study was conducted in normal healthy volunteers (n=24) to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of subcutaneously administered AD-62643 as described below. 
     Six cohorts, each including 4 subjects, participated in this study. One cohort was subcutaneously administered a weekly 100 mg dose of AD-62643 for five weeks (q1W×5); a second cohort was subcutaneously administered a weekly 200 mg dose of AD-62643 for five weeks (q1W×5); a third cohort was subcutaneously administered a weekly 400 mg dose of AD-62643 for five weeks (q1W×5); a fourth cohort was administered a 600 mg dose of AD-62643 once every two weeks for seven weeks (q2W×7); a fifth cohort was administered a weekly 200 mg dose of AD-62643 for five weeks, followed by a 200 mg dose of AD-62643 once every two weeks for four weeks (qW×5, q2w×4); and a sixth cohort was administered a weekly 200 mg dose of AD-62643 for five weeks, followed by a 200 mg dose of AD-62643 once every month for two months (qW×5, qM×2). A 200 mg/ml solution of AD-62643 was used for administration. The demographics and baseline characteristics of the subjects participating in the study are provided in Table 27. 
     
       
         
           
               
             
               
                 TABLE 27 
               
             
            
               
                   
               
               
                 Demographics and baseline characteristics of healthy volunteers 
               
            
           
           
               
               
            
               
                   
                 Part B: Multiple Ascending Dose (MAD) 
               
               
                   
                 N = 4/cohort 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                 200 mg 
                 200 mg 
               
               
                   
                 100 mg 
                 200 mg 
                 400 mg 
                 600 mg 
                 qW x 5, 
                 qW x 5, 
               
               
                   
                 qW x 5 
                 qW x 5 
                 qW x 5 
                 q2W x 7 
                 q2W x 4 
                 qM x 2 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Age (years), Mean 
                 33.8  
                 28.0  
                 25.0  
                 28.0  
                 25.0  
                 24.5  
               
               
                 (Min, Max) 
                 (24, 39) 
                 (24, 32) 
                 (20, 30) 
                 (24, 32) 
                 (23, 30) 
                 (19, 30) 
               
               
                 Gender: Male (%) 
                 75%  
                 25%  
                 50%  
                 50%  
                 75% 
                 50%  
               
               
                 BMI (kg/m 2 ), Mean 
                 24.55 
                 23.68 
                 25.48 
                 22.68 
                 23.50 
                 26.65 
               
               
                 Race (%) 
               
               
                 Asian 
                 0% 
                 0% 
                 0% 
                 0% 
                  0% 
                 0% 
               
               
                 Black/African 
                 0% 
                 0% 
                 0% 
                 0% 
                  0% 
                 0% 
               
               
                 Caucasian 
                 100%  
                 100%  
                 100%  
                 100%  
                 75% 
                 100%  
               
               
                 Other 
                 0% 
                 0% 
                 0% 
                 0% 
                 25% 
                 0% 
               
               
                 Time on study, Mean 
                 316    
                 267    
                 219    
                 156    
                 125    
                 112    
               
               
                 (days) 
               
               
                   
               
            
           
         
       
     
     There were no injection site reactions, serious adverse events, or study discontinuations and no clinically significant changes in vital signs, physical exams, clinical laboratories (hematology, biochemistry, coagulation, and urinalysis), or ECGs. 
     The knockdown of C5 levels in the six cohorts, shown as a mean C5 knockdown relative to baseline, is depicted in  FIG. 31 . The maximum C5 knockdown, relative to baseline was 99% and the mean maximum C5 knockdown was 99±0.2% (mean±SEM). The mean C5 knockdown of 99±0.2% (mean±SEM) was observed at Day 112 in the 600 mg q2w×7 cohort. 
     The effect of multiple dose administration of AD-62643 to inhibit complement activity, measured as alternative complement pathway (CAP) activity and as classical complement pathway (CCP) activity was also assessed by determining the amount of active C5 b-9 formation, as described above. 
     As shown in  FIG. 32 , the maximum CAP inhibition, relative to baseline, was up to 99.5%, with a mean maximum of inhibition of 97±1.5% (mean±SEM).  FIG. 33  shows that the maximum CCP inhibition, relative to baseline, was up to 99.4%, with a mean maximum of inhibition of 97.3±1.0% (mean±SEM). The observed levels of inhibition of CAP and CAP activity in the second through the sixth cohorts (200 mg qW×5 and higher) were comparable to the levels of inhibition of CAP and CCP activity observed in subjects having a homozygous deletion of C5 (Seelen, et al. (2005)  J Immunol Methods  296:187-198). 
     The effect of administration of multiple weekly doses of AD-62643 to inhibit complement activity as measured by serum hemolytic activity using a sensitized sheep erythrocyte assay to measure CCP activation (described above) was also assessed. As shown in  FIG. 34 , the maximum serum hemolysis inhibition, relative to baseline, was up to 98%, with a mean maximum hemolysis inhibition of 86±1.5% (mean±SEM). 
     A summary of the results of this Phase 1/II clinical trial are provided in Table 28. 
     
       
         
           
               
             
               
                 TABLE 28 
               
             
            
               
                   
               
               
                 Summary of Phase I/II Part B Study 
               
            
           
           
               
               
            
               
                   
                 Part B: Multiple Ascending Dose (MAD) 
               
               
                   
                 Multiple Subcutaneous Injections 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                 200 mg 
                 200 mg 
                   
               
               
                   
                 100 mg 
                 200 mg 
                 400 mg 
                 600 mg 
                 qW x 5, 
                 qW x 5, 
                 Placebo 
               
               
                   
                 qW x 5 
                 qW x 5 
                 qW x 5 
                 q2W x 7 
                 q2W x 4 
                 qM x 2 
                 N = 6 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 Residual C5 levels 
                   
                   
                   
                   
                   
                   
                   
               
               
                 Mean nadir; mcg/mL ± SEM 
                 4.2 ± 0.5  
                 1.3 ± 0.3  
                 1.3 ± 0.2  
                 0.8 ± 0.1  
                 1.4 ± 0.3  
                 2.7 ± 1.7  
                 60.2 ± 5.4     
               
               
                 Nadir; mcg/mL 
                   3.5 
                   0.6 
                   1.0 
                   0.7 
                   1.0 
                   1.0 
                   37.3 
               
               
                 C5 knockdown 
               
               
                 Mean max; % ± SEM 
                 95 ± 0.4 
                 98 ± 0.5 
                 98 ± 0.2 
                 99 ± 0.2 
                 98 ± 0.4 
                 97 ± 2.1 
                 24 ± 5.3 
               
               
                 Max; % 
                 96 
                 99 
                 99 
                 99 
                 99 
                 99 
                 43 
               
               
                 CAP inhibition 
               
               
                 Mean max; % ± SEM 
                 84 ± 2.1 
                 95 ± 1.0 
                 97 ± 1.5 
                 97 ± 0.8 
                 95 ± 0.8 
                 89 ± 6.5 
                 25 ± 5.8 
               
               
                 Max; % 
                 88 
                 97 
                 100  
                 98 
                 96 
                 96 
                   50.4 
               
               
                 CCP inhibition 
               
               
                 Mean max; % ± SEM 
                 85 ± 2.6 
                 96 ± 0.9 
                 97 ± 1.0 
                 97 ± 0.7 
                 96 ± 1.0 
                 89 ± 6.0 
                 28 ± 7.0 
               
               
                 Max; % 
                 91 
                 97 
                 99 
                 98 
                 98 
                 95 
                 50 
               
               
                 Hemolysis inhibition 
               
               
                 Mean max; % ± SEM 
                 52 ± 4.9 
                 75 ± 8.0 
                 84 ± 7.6 
                 86 ± 1.5 
                 — 
                 — 
                  5 ± 2.0 
               
               
                 Max; % 
                 58 
                 91 
                 98 
                 89 
                 — 
                 — 
                 10 
               
               
                   
               
            
           
         
       
     
     An indirect comparison of residual C5 levels in the serum of healthy human volunteers administered multiple doses of AD-62643 and the levels of free C5 in aHUS subjects administered eculizumab was performed. Free C5 was measured using a validated electrochemiluminescence immunoassay and residual C5 was measured using a validated liquid chromatography-mass spectrometry (LCMS) assay The results of this analysis demonstrate that the residual C5 levels achieved with AD-62643 multi-administration are comparable to the levels of free C5 in patients administered eculizumab; the maximum percent inhibition of free C5 following administration of Eculizumab was 93.5% ( FIG. 35A ) and the maximum percent inhibition of residual C5, relative to baseline, following administration of AD-62643 was 100% ( FIG. 35B ), with a mean maximum inhibition of 100%±0.2% (mean±SEM). 
     In summary, these data demonstrate that there is a robust, dose-dependent, statistically significant, and durable knockdown of serum C5 with multi-dose subcutaneous administration of AD-62643. After 5 weekly doses of AD-62643 there was up to 99% C5 knockdown, with a mean maximum knockdown of 99±0.2%, which was durable and lasted for months. In addition, very low inter-subject variability was observed. 
     Furthermore, a multiple dose of AD-62643 resulted in a clinically meaningful reduction in complement activity. The observed nadir of residual C5 was as low as 0.6 microgram (mcg)/mL and after five weekly doses of AD-62643, complement activity (CAP and CCP activity) were reduced by up to 99.5% with mean maximum inhibition of 97±1.5% for CAP and 99±0.2% for CCP. A reduction of serum hemolytic activity up to 98% with mean maximum inhibition of 86±1.5% was also observed following administration of five weekly doses of AD-62643. 
     Example 13: Phase I/II—Part C Clinical Trial of AD-62643 
     Part C of the Phase I/II Clinical Trial of AD-62643 was an exploratory evaluation of subcutaneously administered AD-62643 and hepatic C5 knockdown for the treatment of PNH. AD-62643 was administered as a monotherapy to eculizuman naïve PNH patients (n=3) or as a combination therapy to PNH patients being treated with eculizumab (n=3), including a patient with inadequate response to eculizumab. 
     The demographics and baseline characteristics of the subjects participating in the study are provided in Table 29. 
     
       
         
           
               
             
               
                 TABLE 29 
               
               
                   
               
               
                 Demographics and baseline characteristics of 
               
               
                 six PNH patients administered AD-62643 
               
               
                 Part C: PNH Patients 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 Age (years), 
                 43.7 
               
               
                   
                 Mean (Min, Max) 
                 (25, 58) 
               
               
                   
                 Gender: Male (%) 
                 50%  
               
               
                   
                 BMI (kg/m 2 ), Mean 
                 24.6 
               
               
                   
                 Race (%) 
               
               
                   
                 Asian 
                 0% 
               
               
                   
                 Black/African 
                 0% 
               
               
                   
                 Caucasian 
                 100%  
               
               
                   
                 Other 
                 0% 
               
               
                   
                 Time on study, Mean (days) 
                 256   
               
               
                   
                 Time in exploratory Eculizumab sparing 
                 108   
               
               
                   
                 study, days; mean 
               
               
                   
                   
               
            
           
         
       
     
     Two cohorts, each including 3 subjects, participated in this study. The first cohort included eculizumab naïve subjects. Two subjects in the first cohort were subcutaneously administered a weekly 200 mg dose of AD-62643 for twelve weeks (q1W×12), followed by a weekly 400 mg dose for 3 weeks (q1W×3). The third subject in the first cohort was subcutaneously administered a weekly 400 mg dose for 7 weeks (qW×7). After AD-62643 dosing was completed, all subjects in the first cohort received a single 600 mg dose of eculizumab for residual hemolysis. 
     The second cohort included two subjects receiving 900 mg of eculizumab every other week (background eculizumab subjects) and one subject receiving 1200 mg of eculizumab every other week (an inadequate responder to eculizumab). The first subject on 900 mg of eculizumab was subcutaneously administered a weekly 400 mg dose of AD-62643 for 3 weeks (q1W×3); the second subject on 900 mg of eculizumab was subcutaneously administered a weekly 400 mg dose of AD-62643 for 2 weeks (q1W×2); and the third subject on 1200 mg of eculizumab was subcutaneously administered a weekly 200 mg dose of AD-62643 for 11 weeks (q1W×11). The dosing schedules for each patient are summarized in Table 30 below. 
     
       
         
           
               
             
               
                 TABLE 30 
               
             
            
               
                   
               
               
                 Dosing schedule of PNH patients administered AD-62643 
               
            
           
           
               
               
               
            
               
                 Patient 
                   
                   
               
               
                 No. 
                 Eculizumab Status 
                 AD-62643 Dosing Schedule 
               
               
                   
               
               
                 0081 
                 Naïve 
                 200 mg once weekly for 12 weeks, then 
               
               
                   
                   
                 400 mg once weekly for 3 weeks 
               
               
                 0082 
                 Naïve 
                 200 mg once weekly for 12 weeks, then 
               
               
                   
                   
                 400 mg once weekly for 3 weeks 
               
               
                 0061 
                 Naïve 
                 400 mg once weekly for 7 weeks 
               
               
                 0063 
                 Receiving 900 mg 
                 400 mg once weekly for 3 weeks 
               
               
                   
                 every other week 
               
               
                 0064 
                 Receiving 900 mg 
                 400 mg once weekly for 2 weeks 
               
               
                   
                 every other week 
               
               
                 0083 
                 Receiving 1200 mg 
                 200 mg once weekly for 11 weeks 
               
               
                   
                 every other week 
               
               
                   
                 inadequate responder 
               
               
                   
               
            
           
         
       
     
     There were no serious adverse events or study discontinuations due to adverse events. All six patients reported at least one adverse event, and the majority of reported adverse events were mild to moderate in severity. No other clinically significant changes in vital signs, EKG, physical exams or clinical laboratories (hematology, biochemistry, coagulation, and urinalysis) were observed. 
     The knockdown of C5 levels were measured in the eculizumab naïve subjects, and the data is depicted in  FIG. 36A  as a mean C5 knockdown relative to baseline. In these subjects, maximum C5 knockdown, relative to baseline was up to 98.7%, the mean maximum C5 knockdown was 98.2±0.3% (mean±SEM), and the minimum residual C5 levels were 0.9 mcg/mL. 
     The knockdown of C5 levels was also measured in subjects receiving eculizumab, and the data is depicted in  FIG. 36B  as a mean C5 knockdown relative to baseline. In these subjects, the maximum C5 knockdown, relative to baseline was up to 97.8%, the mean maximum C5 knockdown was 86.7±S.6% (mean±SEM), and the minimum residual C5 levels were 7.9 mcg/mL. Interestingly, starting levels of total C5 in subjects receiving eculizumab were markedly higher than the levels in eculizumab naïve patients, suggesting that treatment with eculizumab may lead to increased total C5 levels. 
     The effect of AD-62643 administration on complement activity, measured as classical complement pathway (CCP) activity and alternative complement pathway (CAP) activity, was also assessed by determining the amount of active C5 b-9 formation, as described above. The results for eculizumab naïve subjects are depicted in  FIG. 37A . In these subjects, the maximum CCP inhibition, relative to baseline, was up to 96.7%, and the mean maximum of inhibition of 94.2±1.7% (mean±SEM). Similar results were observed with alternative pathway assay (CAP C5 b-9 ELISA). The results for subjects receiving eculizumab are depicted in  FIG. 37B . In these subjects, residual complement activity was measured as being &lt;2% from day 21 onward. 
     The effect of AD-62643 administration on complement activity as measured by serum hemolytic activity using a sensitized sheep erythrocyte assays (described above) was also assessed. The results for eculizumab naïve subjects are shown in  FIG. 38A . In these subjects, the maximum serum hemolysis inhibition, relative to baseline, was up to 81.5%, with a mean maximum hemolysis inhibition of 75.6±4.5% (mean±SEM). The results for background eculizumab subjects are depicted in  FIG. 38B . In these subjects, residual sheep red blood cell (sRBC) hemolysis was &lt;3% from day 21 onward. 
     During treatment of subjects with AD-62643, LDH levels were also monitored in all patients.  FIG. 39  depicts levels of LDH measured in eculizumab naïve patients. In these patients, maximum LDH reduction relative to baseline of 37% and 50% was observed in patients 0082 and 0081, respectively, however, LDH levels remained &gt;1.5×ULN. In patient 0061, who had lower LDH at baseline and received only 8 doses of AD-62643, LDH lowering was not observed. LDH levels were also monitored in eculizumab naïve subjects after administration of a single 600 mg dose of eculizumab. In all three subjects, lowering of LDH &lt;1.5ULN was observed and was sustained out to 4 weeks. The data on LDH levels after administration of a single dose of eculimumab is presented in Table 31 below. 
     
       
         
           
               
             
               
                 TABLE 31 
               
             
            
               
                   
               
               
                 LDH levels after administration of a single 600 mg dose 
               
               
                 of eculizumab in eculizumab naïve patients. 
               
            
           
           
               
               
            
               
                   
                 LDH (Ul/L) 
               
               
                   
                 Days post Ecu single dose (600 mg) 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Patient 
                 Day 0 
                 Day 14 
                 Day 28 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 0061 
                 426 
                 217 
                 222 
               
               
                   
                 0081 
                 874 
                 ND 
                 224 
               
               
                   
                 0082 
                 1089 
                 ND 
                 280 
               
               
                   
                   
               
               
                   
                 LDH ULN: 214-225 (1.5 × ULN values: 321-338) 
               
               
                   
                 ND—not determined; samples were not collected. 
               
            
           
         
       
     
     LDH levels were also measured in subjects receiving eculizumab. In the two background eculizumab subjects (patients 0063 and 0064), normal LDH at baseline was maintained during the treatment with AD-62643. In the eculizumab inadequate responder (patient 0083), LDH at day 0 was 966 IU/L while this patient received eculizumab at above labeled dose of 1200 mg every other week. Treatment of this subject with AD-62643 resulted in lowering of LDH levels by day 35 to within reference range. On day 56, eculizumab dose was reduced to labeled dose of 900 mg, every other week. As evidenced by the data presented in  FIG. 40 , LDH control was maintained out to day 11 in the eculizumab inadequate responder. 
     Shown in  FIG. 41  is plasma concentration of eculizumab in one subject receiving eculizumab during treatment with AD-62643. The results in  FIG. 41  demonstrate that, in one subject, serum knockdown of C5 levels with AD-62643 results in &gt;3× increase in pre-dose eculizumab through levels. 
     The results of the Part C of Phase I/II clinical trial indicate that AD-62643 is well tolerated, with most adverse events being mild or moderate in severity. In eculizumab naïve subjects, AD-62643 achieved robust knockdown of the C5 levels, inhibition of complement activity and modest lowering of LDH, but at levels &gt;1.5 ULN. In these patients, normalization of LDH levels was achieved for 4 weeks with a single 600 mg dose of eculizumab following treatment with AD-62643, which represents 25% of eculizumab induction label dose. Therefore, the experimental data supports a reduced eculizumab dose and frequency of administration when this treatment is combined with AD-62643 administration. 
     In subjects receiving eculizumab, treatment with AD-62643 also achieved robust knockdown of the C5 levels and inhibition of complement activity. In the eculizumab inadequate responder, AD-62643 demonstrated preliminary evidence of clinical activity by normalizing LDH levels to &lt;1.5×ULN and improving hemoglobin levels and achieving higher eculizumab plasma concentration through levels. This allowed for the lowering of the initial eculizumab dose of 1200 mg to 900 mg administered every other week. 
     Example 14: Phase I/II—Extension of Part C Clinical Trial of AD-62643 
     Upon completion of dosing with AD-62643 in the study described in Example 13, the investigators initiated eculizumab treatment in eculizumab naïve PNH patients in the setting of ongoing AD-62643 pharmacology (i.e., in the absence of additional dosing of AD-62643) (referred to herein as the “Ecu sparing study”) in order to explore the potential for reducing the dose and frequency of eculizumab administration. Additionally, the investigators initiated a reduction in the frequency of dosing in patients that had previously received eculizumab. 
     The patients participating in this part of the study were those described above in Example 13, and included 3 eculizumab naïve patients, 2 background eculizumab patients, and 1 inadequate responder to eculizumab subject (also referred to as a background eculizumab subject). The demographics and background characteristics for these patients at the beginning of the multiple dosing study of AD-62643 described in Example 13 are summarized in Table 29, above, and the dosing schedules for the multiple dosing study of AD-62643 described in Example 13 for each subject are summarized, above, in Table 30. The time between the last dose of AD-62643 and the initiation of the Ecu sparing study varied from subject to subject and ranged from weeks to months. Specifically, for the three eculizumab naïve subjects, there were 28, 28, or 7 days between the last AD-62643 dose and start of ecu sparing study. For the three background eculizumab subjects, there were 63, 70 or 70 days between the last eculizumab dose and the start of the ecu sparing study. During the gap, the background eculizumab patients received 900 mg of eculizumab q2W until the start of the ecu sparing study where monthly dosing of eculizumab began. 
     As shown in  FIG. 42 , in the Ecu sparing study, the Ecu naïve patients were administered a single 600 mg dose of eculizumab once every four weeks (Ecu 600 mg q4W), and the background eculizumab patients were transitioned to a spared eculizumab regimen of a single 900 mg dose of eculizumab once every four weeks (Ecu 900 mg q4W). These doses of eculizumab, 600 mg or 900 mg once every four weeks, represent 33% or 50% of the label maintenance dose of eculizumab, respectively. Patients were followed every 2 weeks until study Day 280 and monitored for safety and laboratory parameters including LDH, PD and Ecu PK.  FIG. 42  also summarizes the patients, the number of AD-62643 doses received prior to initiation of the Ecu sparing study, and the % of C5 knockdown at the start of the Ecu sparing study. 
     There were no serious adverse events or study discontinuations due to adverse events. All six patients reported at least one adverse event, and the majority of reported adverse events were mild to moderate in severity. No other clinically significant changes in vital signs, EKG, physical exams or clinical laboratories (hematology, biochemistry, coagulation, and urinalysis) were observed. 
     LDH levels were measured in the subjects and, as shown in  FIG. 43 , Ecu naïve patients receiving a single 600 mg dose of eculizumab q4W achieved and maintained LDH levels of less than or about 1.5×ULN.  FIG. 43  also demonstrates that background eculizumab patients receiving a single 900 mg dose of eculizumab q4W maintained LDH levels less than or about 1.5×ULN. Furthermore, in the background eculizumab patient with prior inadequate eculizumab response, LDH normalization was generally maintained with a 900 mg dose of eculizumab q4W. 
     The effect of Ecu sparing on complement activity, measured as classical complement pathway (CCP) activity, was also assessed by determining the amount of active C5 b-9 formation, as described above. As demonstrated in  FIG. 44A , the CCP level at Day 84 since the start of the Ecu sparing study was 0.3±0.3% for 600 mg q4W patients, and, for the 900 mg q4W patients, the CCP level was 0.4±0.2%. Similar results were observed with an alternative pathway assay (CAP C5 b-9 ELISA). 
     The effect of Ecu sparing on complement activity as measured by serum hemolytic activity using a sensitized sheep erythrocyte assay (described above) was also assessed. As shown in  FIG. 44B , residual sheep red blood cell (sRBC) hemolysis at day 84 since start of Ecu sparing was 0% for the 600 mg q4W patients and 0.4±0.4% for the 900 mg q4W patients. 
     Shown in  FIG. 45  is plasma concentration of eculizumab in the patients participating in the Ecu sparing study which demonstrate that eculizumab trough levels are sustained with monthly dosing of 600 mg or 900 mg of eculizumab. 
     In summary, the study demonstrates that, in eculizumab Ecu naïve patients, normalization of LDH levels was achieved and maintained for up to 6 months with a dose of 600 mg of eculizumab q4W. This dose of eculizumab represents a 67% reduction in the eculizumab label maintenance dose. In background eculizumab patients, maintenance of LDH levels was achieved for 5 months with a dose of 900 mg of eculizumab q4W. This dose of eculizumab represents a 50% reduction in the eculizumab label maintenance dose. In the background eculizumab patient with prior inadequate response at 1200 mg of eculizumab q2W, LDH normalization was maintained with 900 mg q4W. Accordingly, this study demonstrates the efficacy of AD-62643 treatment for patients having PNH as part of a treatment paradigm for reducing the dose and frequency of eculizumab in naïve and background eculizumab patients and for improving disease control in inadequate eculizumab responders.