Patent Publication Number: US-2022213473-A1

Title: Compositions and methods for inhibiting expression of the lect2 gene

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is a divisional of U.S. application Ser. No. 16/052,719, filed Aug. 2, 2018, which is a divisional of U.S. application Ser. No. 15/026,897, filed Apr. 1, 2016, now U.S. Pat. No. 10,077,444, which is the U.S. National Phase application under 35 U.S.C. § 371 of International Application No. PCT/US2014/058624, filed Oct. 1, 2014, which claims the benefit of U.S. Provisional Application No. 61/885,693, filed Oct. 2, 2013 and U.S. Provisional Application No. 62/035,819, filed Aug. 11, 2014. The contents of the aforesaid applications are hereby incorporated by reference in their entirety. 
    
    
     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 Sep. 29, 2014, is named A2038-7200WO_SL.txt and is 294,414 bytes in size. 
     FIELD OF THE INVENTION 
     The invention relates to the specific inhibition of the expression of the LECT2 gene. 
     BACKGROUND OF THE INVENTION 
     Amyloidosis is a group of diseases characterized by deposition of insoluble fibrous protein aggregates, called amyloids, in organs or tissues. Amyloids can form from mutant or wild type proteins. One system of nomenclature for amyloid diseases uses an abbreviation for the protein that forms amyloid deposits, preceded by the letter “A.” Thus, for example, ALECT2 is the abbreviation for an amyloidosis involving deposit of amyloids formed from leukocyte cell derived chemotactic factor-2 (ALECT2). 
     LECT2 amyloidosis (ALECT2) is one of the most recently discovered types of amyloidosis. LECT2 amyloidosis has been observed in individuals with renal or hepatic amyloidosis. This form of amyloidosis can present with nephrotic syndrome or with liver involvement (e.g., hepatitis, e.g., chronic hepatitis). It may be particularly prevalent in Mexican Americans and/or individuals who are homozygous for the G allele encoding valine at position 40 in the mature LECT2 protein (or at position 58 in the unprocessed protein). Treatments for LECT2 amyloidosis are limited, and new treatments are needed. 
     SUMMARY OF THE INVENTION 
     The present invention describes methods and iRNA compositions for modulating the expression of a LECT2 gene. In certain embodiments, expression of a LECT2 gene is reduced or inhibited using a LECT2-specific iRNA. Such inhibition can be useful in treating disorders related to LECT2 expression, such as amyloidosis, e.g. a LECT2 amyloidosis (ALECT2). 
     Accordingly, described herein are compositions and methods that effect the RNA-induced silencing complex (RISC)-mediated cleavage of RNA transcripts of the LECT2 gene, such as in a cell or in a subject (e.g., in a mammal, such as a human subject). Also described are compositions and methods for treating a disorder related to expression of a LECT2 gene, such as a LECT2 amyloidosis. 
     In some embodiments, the LECT2 amyloidosis is a renal amyloidosis. 
     In some embodiments, the LECT2 amyloidosis involves amyloid deposition in the kidney. 
     In some embodiments, LECT2 amyloidosis is associated with renal disease (e.g., nephrotic syndrome). In some embodiments, the amyloidosis is associated with proteinuria. In some embodiments, proteinuria is absent. 
     In some embodiments, the LECT2 amyloidosis is a hepatic amyloidosis. In some embodiments, the LECT2 amyloidosis involves amyloid deposition in the liver. 
     In some embodiments, the LECT2 amyloidosis is associated with inflammation in the liver (e.g., hepatitis, e.g., chronic hepatitis). 
     In some embodiments, the subject is of Mexican descent (e.g., a Mexican American). 
     In embodiments, the subject carries the G allele of the LECT2 gene that encodes valine at position 40 in the mature protein (or amino acid 58 in the unprocessed protein). In embodiments, the subject is homozygous for the G allele (G/G genotype). In embodiments, a LECT2 protein expressed in the subject has valine at position 40 in the mature protein (or at amino acid 58 in the unprocessed protein). 
     In some embodiments, the methods described herein are effective to inhibit amyloid deposition (e.g., by preventing amyloid deposition or reducing amyloid deposition, e.g., by reducing size, number, or extent of amyloid deposits) or symptoms associated with amyloid deposition. 
     As used herein, the term “iRNA,” “RNAi”, “iRNA agent,” “RNAi agent,” or “iRNA molecule,” refers to an agent that contains RNA as that term is defined herein, and which mediates the targeted cleavage of an RNA transcript, e.g., via an RNA-induced silencing complex (RISC) pathway. In one embodiment, an iRNA as described herein inhibits LECT2 expression in a cell or mammal. 
     The iRNAs (e.g., dsRNAs) included in the compositions featured herein include an RNA strand (the antisense strand) having a region, e.g., a region that is 30 nucleotides or less, generally 19-24 nucleotides in length, that is substantially complementary to at least part of an mRNA transcript of a LECT2 gene (e.g., a mouse or human LECT2 gene) (also referred to herein as a “LECT2-specific iRNA”). In embodiments, the LECT2 mRNA transcript is a human LECT2 mRNA transcript, e.g., SEQ ID NO: 1. In embodiments, the LECT2 mRNA transcript has an A to G substitution at nucleotide position 373 of SEQ ID NO: 1. In embodiments, the mRNA transcript encodes valine at position 40 in the mature LECT2 protein (or amino acid 58 in the unprocessed protein). In embodiments, the mRNA transcript encodes isoleucine at position 40 in the mature LECT2 protein (or amino acid 58 in the unprocessed protein). 
     In embodiments, the iRNA (e.g, dsRNA) described herein comprises an antisense strand having a region that is substantially complementary to a region of a human LECT2 mRNA. In embodiments, the human LECT2 mRNA has the sequence of NM_002302.2 (SEQ ID NO: 1). In embodiments, the human LECT2 mRNA has an A to G substitution at nucleotide position 373 of SEQ ID NO: 1. 
     In other embodiments, an iRNA encompasses a dsRNA having an RNA strand (the antisense strand) having a region that is substantially complementary to a portion of a LECT2 mRNA. In one embodiment, the iRNA encompasses a dsRNA having an RNA strand (the antisense strand) having a region that is substantially complementary to a portion of a LECT2 mRNA, e.g., a human LECT2 mRNA (e.g., a human LECT2 mRNA as provided in NM_002302.2 (SEQ ID NO: 1) or having an A to G substitution at nucleotide position 373 of SEQ ID NO: 1). 
     In one embodiment, an iRNA for inhibiting expression of a LECT2 gene includes at least two sequences that are complementary to each other. The iRNA includes a sense strand having a first sequence and an antisense strand having a second sequence. The antisense strand includes a nucleotide sequence that is substantially complementary to at least part of an mRNA encoding a LECT2 transcript, and the region of complementarity is 30 nucleotides or less, and at least 15 nucleotides in length. Generally, the iRNA is 19 to 24 nucleotides in length. 
     In some embodiments, the iRNA is 19-21 nucleotides in length. In some embodiments, the iRNA is 19-21 nucleotides in length and is in a lipid formulation, e.g. a lipid nanoparticle (LNP) formulation (e.g., an LNP11 formulation). In one embodiment, the iRNA targeting LECT2 is formulated in a stable nucleic acid lipid particle (SNALP). 
     In some embodiments, the iRNA is 21-23 nucleotides in length. In some embodiments, the iRNA is 21-23 nucleotides in length and is in the form of a conjugate, e.g., conjugated to one or more GalNAc derivatives as described herein. 
     In some embodiments the iRNA is from about 15 to about 25 nucleotides in length, and in other embodiments the iRNA is from about 25 to about 30 nucleotides in length. An iRNA targeting LECT2, upon contact with a cell expressing LECT2, inhibits the expression of a LECT2 gene (e.g., by at least 10%, at least 20%, at least 25%, at least 30%, at least 35% or at least 40%, at least 50%, at least 60%, at least 70%, or at least 80%) when assayed by a method known in the art or as described herein. 
     In one embodiment, an iRNA (e.g., a dsRNA) featured herein comprises or consists of a first sequence of a dsRNA that is selected from the group consisting of the sense sequences of Tables 2-3, 5-6 and 9-10 and a second sequence that is selected from the group consisting of the corresponding antisense sequences of Tables 2-3, 5-6 and 9-10. 
     In embodiments, an iRNA (e.g., dsRNA) featured herein comprises or consists of a sense and/or antisense sequence selected from those provided in Table 2-3, 5-6 and 9-10. 
     The iRNA molecules featured herein can include naturally occurring nucleotides or can include at least one modified nucleotide, including, but not limited to a 2′-O-methyl modified nucleotide, a nucleotide having a 5′-phosphorothioate group, and a terminal nucleotide linked to a cholesteryl derivative. Alternatively, the modified nucleotide may be chosen from the group of: a 2′-deoxy-2′-fluoro modified nucleotide, a 2′-deoxy-modified nucleotide, a locked nucleotide, an acyclic nucleotide, an abasic nucleotide, 2′-amino-modified nucleotide, 2′-alkyl-modified nucleotide, morpholino nucleotide, a phosphoramidate, and a non-natural base comprising nucleotide. Such a modified sequence can be based, e.g., on a first sequence of said iRNA selected from the group consisting of the sense sequences of Tables 2-3, 5-6 and 9-10, and a second sequence selected from the group consisting of the corresponding antisense sequences of Tables 2-3, 5-6 and 9-10. 
     In one embodiment, an iRNA as described herein targets a wildtype LECT2 RNA transcript variant, and in another embodiment, the iRNA targets a mutant transcript (e.g., a LECT2 RNA carrying an allelic variant). For example, an iRNA featured in the invention can target a polymorphic variant, such as a single nucleotide polymorphism (SNP), of LECT2. 
     In some embodiments, the iRNA (e.g., dsRNA) targets (e.g., reduces) mRNA that encodes valine at position 40 in the mature LECT2 protein (or amino acid 58 in the unprocessed protein). In some embodiments, the iRNA (e.g., dsRNA) targets (e.g., reduces) mRNA that encodes isoleucine at position 40 in the mature LECT2 protein (or amino acid 58 in the unprocessed protein). In another embodiment, the iRNA (e.g., dsRNA) targets (e.g., reduces) both mRNA that encodes valine and mRNA that encodes isoleucine at position 40 in the mature LECT2 protein (or amino acid 58 in the unprocessed protein). 
     In another embodiment, the iRNA targets both a wildtype and a mutant LECT2 transcript. In yet another embodiment, the iRNA targets a particular transcript variant of LECT2. In yet another embodiment, the iRNA agent targets multiple transcript variants. 
     In one embodiment, an iRNA featured in the invention targets a non-coding region of a LECT2 RNA transcript, such as the 5′ or 3′ untranslated region of a transcript. 
     In some embodiments, an iRNA as described herein is in the form of a conjugate, e.g., a carbohydrate conjugate, which may serve as a targeting moiety and/or ligand, as described herein. In one embodiment, the conjugate is attached to the 3′ end of the sense strand of the dsRNA. In some embodiments, the conjugate is attached via a linker, e.g., via a bivalent or trivalent branched linker. 
     In some embodiments, the conjugate comprises one or more N-acetylgalactosamine (GalNAc) derivatives. Such a conjugate is also referred to herein as a GalNAc conjugate. In some embodiments, the conjugate targets the RNAi agent (e.g., dsRNA) to a particular cell, e.g., a liver cell, e.g., a hepatocyte. The GalNAc derivatives can be attached via a linker, e.g., a bivalent or trivalent branched linker. In particular embodiments, the conjugate is 
     
       
         
         
             
             
         
       
     
     In some embodiments, the RNAi agent is attached to the carbohydrate conjugate via a linker, e.g., a linker as shown in the following schematic, wherein X is O or S 
     
       
         
         
             
             
         
       
     
     In some embodiments, X is O. In some embodiments, X is S. 
     In some embodiments, the RNAi agent is conjugated to L96 as defined in Table 1 and shown below 
     
       
         
         
             
             
         
       
     
     In some embodiments, the RNAi agent is conjugated to a ligand that targets the RNAi (e.g., dsRNA) to a desired organ (e.g., the liver) or to a particular cell type (e.g., hepatocytes). In embodiments, the RNAi agent is conjugated to a ligand (e.g., a GalNAc ligand, e.g., L96) that targets the RNAi agent (e.g., dsRNA) to the liver. 
     In an aspect provided herein is a pharmaceutical composition for inhibiting the expression of a LECT2 gene in an organism, generally a human subject. The composition typically includes one or more of the iRNAs described herein and a pharmaceutically acceptable carrier or delivery vehicle. In one embodiment, the composition is used for treating a disorder related to LECT2 expression, e.g., amyloidosis, e.g., LECT2 amyloidosis. 
     In one aspect, an iRNA provided herein is a double-stranded ribonucleic acid (dsRNA) for inhibiting expression of LECT2, wherein said dsRNA comprises a sense strand and an antisense strand 15-30 base pairs in length and the antisense strand is complementary to at least 15 contiguous nucleotides of SEQ ID NO: 1. 
     In a further aspect, an iRNA provided herein is a double stranded RNAi (dsRNA) comprising a sense strand complementary to an antisense strand, wherein said antisense strand comprises a region of complementarity to a LECT2 RNA transcript, wherein each strand has about 14 to about 30 nucleotides, wherein said double stranded RNAi agent is 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 a ′- n   q ′5′  (III)
         wherein:   j, k, and 1 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 nucleotides which are either modified or unmodified or combinations thereof, each sequence comprising at least two differently modified nucleotides;   each N b  and N b ′ independently represents an oligonucleotide sequence comprising 0-10 nucleotides which are either modified or unmodified or combinations thereof;   each n p , n p ′, n q , and n q ′ independently represents an overhang nucleotide;   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;   modifications on N b  differ from the modification on Y and modifications on N b ′ differ from the modification on Y′.       

     In embodiments, the sense strand is conjugated to at least one ligand. 
     In embodiments, i is 1; j is 1; or both i and j are 1. 
     In embodiments, k is 1; 1 is 1; or both k and 1 are 1. 
     In embodiments, XXX is complementary to X′X′X′, YYY is complementary to Y′Y′Y′, and ZZZ is complementary to Z′Z′Z′. 
     In embodiments, the Y′Y′Y′ motif occurs at the 11, 12 and 13 positions of the antisense strand from the 5′-end. 
     In embodiments, the Y′ is 2′-O-methyl. 
     In embodiments, the duplex region is 15-30 nucleotide pairs in length. 
     In embodiments, the duplex region is 17-23 nucleotide pairs in length. 
     In embodiments, the duplex region is 19-21 nucleotide pairs in length. 
     In embodiments, the duplex region is 21-23 nucleotide pairs in length. 
     In embodiments, the modifications on the nucleotides are selected from the group consisting of a locked nucleic acid (LNA), an acyclic nucleotide, a hexitol or hexose nucleic acid (HNA), a cyclohexene nucleic acid (CeNA), 2′-methoxyethyl, 2′-O-alkyl, 2′-O-allyl, 2′-C— allyl, 2′-fluoro, 2′-deoxy, 2′-hydroxyl, and any combination thereof. 
     In embodiments, the modifications on the nucleotides are 2′-O-methyl, 2′-fluoro or both. 
     In embodiments, the ligand comprises a carbohydrate. 
     In embodiments, the ligand is attached via a linker. 
     In embodiments, the linker is a bivalent or trivalent branched linker. 
     In embodiments, the ligand is 
     
       
         
         
             
             
         
       
     
     In embodiments, the ligand and linker are as shown in Formula XXIV: 
     
       
         
         
             
             
         
       
     
     In embodiments, the ligand is attached to the 3′ end of the sense strand. 
     In embodiments, the dsRNA has (e.g., comprises) a nucleotide sequence (e.g., a sense and/or antisense sequence) selected from the group of sequences provided in Tables 2-3, 5-6 and 9-10. 
     In a further aspect, an iRNA provided herein is a double-stranded ribonucleic acid (dsRNA) for inhibiting expression of LECT2, wherein said dsRNA comprises a sense strand and an antisense strand, the antisense strand comprising a region of complementarity to a LECT2 RNA transcript, which antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from one of the antisense sequences listed in any one of Tables 2-3, 5-6 and 9-10. 
     In some embodiments, the dsRNA comprises at least one modified nucleotide. 
     In some embodiments, at least one of the modified nucleotides is chosen from the group consisting of: a 2′-O-methyl modified nucleotide, a nucleotide comprising a 5′-phosphorothioate group, and a terminal nucleotide linked to a cholesteryl derivative or dodecanoic acid bisdecylamide group. 
     In some embodiments, the modified nucleotide is chosen from the group consisting of: a 2′-deoxy-2′-fluoro modified nucleotide, a 2′-deoxy-modified nucleotide, a locked nucleotide, an acyclic nucleotide, an abasic nucleotide, 2′-amino-modified nucleotide, 2′-alkyl-modified nucleotide, morpholino nucleotide, a phosphoramidate, and a non-natural base comprising nucleotide. 
     In some embodiments, the region of complementarity is at least 17 nucleotides in length. 
     In some embodiments, the region of complementarity is between 19 and 21 nucleotides in length. 
     In some embodiments, the region of complementarity is 19 nucleotides in length. 
     In some embodiments, each strand is no more than 30 nucleotides in length. 
     In some embodiments, at least one strand comprises a 3′ overhang of at least 1 nucleotide. 
     In some embodiments, at least one strand comprises a 3′ overhang of at least 2 nucleotides. 
     In some embodiments, an iRNA (e.g., a dsRNA) described herein further comprises a ligand. 
     In some embodiments, the ligand is a GalNAc ligand. 
     In some embodiments, the ligand targets the iRNA (e.g., the dsRNA) to the liver (e.g., to hepatocytes). 
     In some embodiments, the ligand is conjugated to the 3′ end of the sense strand of the dsRNA. 
     In some embodiments, the region of complementarity consists of an antisense sequence selected from the antisense sequences provided in Tables 2-3, 5-6 and 9-10. 
     In embodiments, the region of complementarity consists of an antisense sequence selected from a duplex disclosed herein, wherein the duplex suppresses LECT2 mRNA or protein expression by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85% or 90%. 
     In some embodiments, the dsRNA comprises a sense strand comprising or consisting of a sense strand sequence selected from Table 2, 3, 5, 6, 9 or 10, and an antisense strand comprising or consisting of an antisense sequence selected from Table 2, 3, 5, 6, 9 or 10. In embodiments, the dsRNA comprises or consists of a pair of corresponding sense and antisense sequences selected from those of the duplexes disclosed in Tables 2-3 and 5-11. In certain embodiments, the dsRNA comprises or consists of a pair of corresponding sense and antisense sequences selected from those of the duplexes disclosed in Table 8. 
     In one aspect, the invention provides a cell containing at least one iRNA (e.g., dsRNAs) disclosed herein. The cell is typically a mammalian cell, such as a human cell. In embodiments, the cell is a liver cell (e.g., a hepatocyte). 
     In an aspect provided herein is a pharmaceutical composition for inhibiting expression of a LECT2 gene, the composition comprising an iRNA (e.g., a dsRNA) described herein. 
     In embodiments of the pharmaceutical compositions described herein, the iRNA (e.g., dsRNA) is administered in an unbuffered solution. In embodiments, the unbuffered solution is saline or water. 
     In embodiments of the pharmaceutical compositions described herein, the iRNA (e.g., dsRNA is administered with a buffer solution. In embodiments, the buffer solution comprises acetate, citrate, prolamine, carbonate, or phosphate or any combination thereof. In embodiments, the buffer solution is phosphate buffered saline (PBS). 
     In embodiments of the pharmaceutical compositions described herein, the iRNA (e.g., dsRNA) is targeted to the liver (e.g., to hepatocytes). 
     In embodiments of the pharmaceutical compositions described herein, the composition is administered intravenously. 
     In embodiments of the pharmaceutical compositions described herein, the composition is administered subcutaneously. 
     In embodiments, a pharmaceutical composition comprises an iRNA (e.g., a dsRNA) described herein that comprises a ligand (e.g., a GalNAc ligand) that targets the iRNA (e.g., dsRNA) to a liver cell, e.g., a hepatocyte. 
     In embodiments, a pharmaceutical composition comprises an iRNA (e.g., a dsRNA) described herein that comprises a ligand (e.g., a GalNAc ligand), and the pharmaceutical composition is administered subcutaneously. In embodiments, the ligand targets the iRNA (e.g., dsRNA) to a liver cell, e.g., a hepatocyte. 
     In certain embodiments, a pharmaceutical composition, e.g., a composition described herein, includes a lipid formulation. In some embodiments, the RNAi agent is in a LNP formulation, e.g., a MC3 formulation. In some embodiments, the LNP formulation targets the RNAi agent to a particular cell, e.g., a liver cell (e.g., a hepatocyte). In embodiments, the lipid formulation is a LNP11 formulation. In embodiments, the composition is administered intravenously. 
     In another embodiment, the pharmaceutical composition is formulated for administration according to a dosage regimen described herein, e.g., not more than once every four weeks, not more than once every three weeks, not more than once every two weeks, or not more than once every week. In another embodiment, the administration of the pharmaceutical composition can be maintained for a month or longer, e.g., one, two, three, or six months, or one year or longer. 
     In another embodiment, a composition containing an iRNA featured in the invention, e.g., a dsRNA targeting LECT2, is administered in conjunction with a second therapy for a disorder related to LECT2 expression (e.g., a LECT2 amyloidosis). An iRNA or composition comprising an iRNA provided herein can be administered before, after, or concurrent with a second therapy. In embodiments, the iRNA is administered before the second therapy. In embodiments, the iRNA is administered after the second therapy. In embodiments, the iRNA is administered concurrent with the second therapy. 
     In some embodiments, the second therapy is a non-iRNA therapeutic agent that is effective to treat the disorder or symptoms of the disorder. 
     In some embodiments, the disorder to be treated by the compositions or methods disclosed herein is a LECT2 amyloidosis that affects kidney function, e.g., through amyloid deposition in the kidney. In some such embodiments, the iRNA is administered in conjunction with a therapy that supports kidney function (e.g., dialysis). In embodiments, the iRNA is administered in conjunction with a diuretic, an ACE (angiotensin converting enzyme) inhibitor, an angiotensin receptor blocker, and/or dialysis, e.g., to support or manage kidney function. 
     In some embodiments, the disorder to be treated by the compositions or methods disclosed herein is a LECT2 amyloidosis involving amyloid deposits in the liver. In some such embodiments, the iRNA is administered in conjunction with a therapy that supports liver function. 
     In some embodiments, the disorder to be treated by the compositions or methods disclosed herein is a LECT2 amyloidosis, and the iRNA is administered in conjunction with removal of all or part of the organ(s) affected by the amyloidosis (e.g., resection of all or part of kidney or liver tissue affected by the amyloidosis). The removal is optionally conducted in conjunction with a replacement of all or part of the organ removed (e.g., in conjunction with a kidney or liver organ transplant). 
     In an aspect provided herein is a method of inhibiting LECT2 expression in a cell, the method comprising: (a) introducing into the cell an iRNA (e.g., a dsRNA) described herein and (b) maintaining the cell of step (a) for a time sufficient to obtain degradation of the mRNA transcript of a LECT2 gene, thereby inhibiting expression of the LECT2 gene in the cell. 
     In an aspect provided herein is a method for reducing or inhibiting the expression of a LECT2 gene in a cell (e.g., a liver cell, e.g., a hepatocyte). The method includes contacting the cell with a dsRNA as described herein, thereby inhibiting expression of a LECT2 gene. “Contacting,” as used herein, includes directly contacting a cell, as well as indirectly contacting a cell. For example, a cell within a subject (e.g., a liver cell) may be contacted when a composition comprising an RNAi is administered (e.g., intravenously or subcutaneously) to the subject. 
     In embodiments, the method includes
         (a) introducing into the cell a double-stranded ribonucleic acid (dsRNA), wherein the dsRNA includes at least two sequences that are complementary to each other. The dsRNA has a sense strand having a first sequence and an antisense strand having a second sequence; the antisense strand has a region of complementarity that is substantially complementary to at least a part of an mRNA encoding LECT2, and where the region of complementarity is 30 nucleotides or less, e.g., 15-30 nucleotides in length, and generally 19-24 nucleotides in length, and where the dsRNA upon contact with a cell expressing LECT2, inhibits expression of a LECT2 gene by at least 10%, e.g., at least 20%, at least 30%, at least 40% or more; and   (b) maintaining the cell of step (a) for a time sufficient to obtain degradation of the mRNA transcript of the LECT2 gene, thereby reducing or inhibiting expression of a LECT2 gene in the cell.       

     In embodiments of the foregoing methods of inhibiting LECT2 expression in a cell, the cell is treated ex vivo, in vitro, or in vivo. In embodiments, the cell is a hepatocyte. 
     In embodiments, the cell is present in a subject in need of treatment, prevention and/or management of a disorder related to LECT2 expression. 
     In embodiments, the disorder is a LECT2 amyloidosis, as described herein. 
     In embodiments, the expression of LECT2 is inhibited by at least 30%. 
     In embodiments, the iRNA (e.g., dsRNA) has an IC 50  in the range of 0.0005-1 nM, e.g., between 0.001 and 0.2 nM, between 0.002 and 0.1 nM, between 0.005 and 0.075 nM, or between 0.01 and 0.05 nM. In embodiments, the iRNA (e.g., dsRNA) has an IC 50  equal to or less than 0.02 nM, e.g., between 0.0005 and 0.02 nM, between 0.001 and 0.02 nM, between 0.005 and 0.02 nM, or between 0.01 and 0.02 nM. In embodiments, the iRNA (e.g., dsRNA) has an IC 50  in the range of 0.01-1 nM. 
     In embodiments, the cell (e.g., the hepatocyte) is a mammalian cell (e.g., a human, non-human primate, or rodent cell). 
     In one embodiment, the subject is a mammal (e.g., a human) having a LECT2 amyloidosis. 
     In one embodiment, the dsRNA introduced reduces or inhibits expression of a LECT2 gene in the cell. 
     In one embodiment, the dsRNA inhibits expression of a LECT2 gene, or inhibits amyloid deposition (e.g., by preventing amyloid deposition or reducing amyloid deposition, e.g., by reducing size, number, or extent of amyloid deposits). The inhibition optionally involves an inhibition of at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more compared to a reference, (e.g., a control that is untreated or treated with a non-targeting dsRNA (e.g., a dsRNA that does not target LECT2)). 
     In other aspects, the disclosure provides methods for treating pathological processes related to LECT2 expression (e.g., amyloid deposition). In one embodiment, the method includes administering to a subject, e.g., a patient in need of such treatment, an effective (e.g., a therapeutically or prophylactically effective) amount of a dsRNA provided herein. 
     In an aspect provided herein is a method of treating and/or preventing a disorder related to LECT2 expression (e.g., a LECT2 amyloidosis) comprising administering to a subject in need of such treatment a therapeutically effective amount of an iRNA (e.g., a dsRNA) described herein, or a composition comprising an iRNA (e.g., a dsRNA) described herein. 
     In an aspect provided herein is a method of treating a disorder related to LECT2 expression (e.g., LECT2 amyloidosis) comprising administering to a subject in need of such treatment a double-stranded ribonucleic acid (dsRNA), wherein said dsRNA comprises a sense strand and an antisense strand 15-30 base pairs in length and the antisense strand is complementary to at least 15 contiguous nucleotides of a LECT2 mRNA transcript, e.g., a human LECT2 mRNA transcript, e.g., SEQ ID NO: 1 or a nucleotide sequence having an A to G substitution at nucleotide position 373 of SEQ ID NO: 1. In one embodiment, the iRNA (e.g., dsRNA) targets mRNA that encodes valine at position 40 in the mature LECT2 protein (or amino acid 58 in the unprocessed protein). 
     In one embodiment provided herein is a method of treating a subject having a LECT2 amyloidosis, the method comprising administering to the subject a double-stranded ribonucleic acid (dsRNA), wherein said dsRNA comprises a sense strand and an antisense strand 15-30 base pairs in length and the antisense strand is complementary to at least 15 contiguous nucleotides of a LECT2 mRNA transcript, e.g., a human LECT2 mRNA transcript, e.g., SEQ ID NO: 1 or a nucleotide sequence having an A to G substitution at nucleotide position 373 of SEQ ID NO: 1. In one embodiment, the iRNA (e.g., dsRNA) targets mRNA that encodes valine at position 40 in the mature LECT2 protein (or amino acid 58 in the unprocessed protein). 
     In some embodiments, administration of the iRNA targeting LECT2 alleviates or relieves the severity of at least one symptom of a disorder related to LECT2 expression in the patient. In one embodiment, subject has a LECT2 amyloidosis. In another embodiment, the subject is at risk for developing a LECT2 amyloidosis. 
     In embodiments, the iRNA (e.g., dsRNA) is formulated as an LNP formulation. 
     In embodiments, the iRNA (e.g., dsRNA) is in the form of a GalNAc conjugate. 
     In embodiments, the iRNA (e.g., dsRNA) is administered at a dose of 0.05-50 mg/kg. 
     In embodiments, the iRNA (e.g., dsRNA) is administered at a concentration of 0.01 mg/kg-5 mg/kg bodyweight of the subject. 
     In embodiments, the iRNA (e.g., dsRNA) is formulated as an LNP formulation and is administered at a dose of 0.05-5 mg/kg. In embodiments, the iRNA (e.g., dsRNA) is formulated as an LNP formulation and is administered at a dose of 0.1 to 0.5 mg/kg. 
     In embodiments, the iRNA (e.g., dsRNA) is in the form of a GalNAc conjugate and is administered at a dose of 0.5-50 mg/kg. In embodiments, the iRNA (e.g., dsRNA) is in the form of a GalNAc conjugate and is administered at a dose of 1 to 10 mg/kg. 
     In embodiments, the method inhibits expression of a LECT2 gene, or inhibits amyloid deposition (e.g., by preventing amyloid deposition or reducing amyloid deposition, e.g., by reducing size, number, or extent of amyloid deposits). The inhibition optionally involves an inhibition of at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% compared to a reference (e.g., a control that is untreated or treated with a non-targeting dsRNA (e.g., a dsRNA that does not target LECT2)). 
     In embodiments, the iRNA (e.g., dsRNA) has an IC 50  in the range of 0.0005-1 nM, e.g., between 0.001 and 0.2 nM, between 0.002 and 0.1 nM, between 0.005 and 0.075 nM, or between 0.01 and 0.05 nM. In embodiments, the iRNA (e.g., dsRNA) has an IC 50  equal to or less than 0.02 nM, e.g., between 0.0005 and 0.02 nM, between 0.001 and 0.02 nM, between 0.005 and 0.02 nM, or between 0.01 and 0.02 nM. In embodiments, the iRNA (e.g., dsRNA) has an IC 50  in the range of 0.01-1 nM. 
     In embodiments, a method described herein ameliorates a symptom associated with a LECT2 related disorder (e.g., a LECT2 amyloidosis). 
     In embodiments, a method described herein inhibits expression of a LECT2 gene in the subject. 
     In embodiments, a method described herein inhibits amyloid deposition (e.g., by preventing amyloid deposition or reducing amyloid deposition, e.g., by reducing size, number, or extent of amyloid deposits). 
     In embodiments, the iRNA (e.g., dsRNA) or composition comprising the iRNA is administered according to a dosing regimen. 
     In embodiments, the subject is of Mexican descent (e.g., a Mexican American). 
     In embodiments, the subject carries the G allele of the LECT2 gene that encodes valine at position 40 in the mature protein (amino acid 58 in the unprocessed protein). In embodiments, the subject is homozygous for the G allele (G/G genotype). 
     In embodiments, a LECT2 protein expressed in the subject has valine at position 40 in the mature protein (or at amino acid 58 in the unprocessed protein). 
     In embodiments, the iRNA (e.g., dsRNA) or composition comprising the iRNA is administered repeatedly, e.g., according to a dosing regimen. 
     In embodiments, the iRNA (e.g., dsRNA) or composition comprising the iRNA is administered subcutaneously. In embodiments, the iRNA is in the form of a GalNAc conjugate. In embodiments, the iRNA (e.g., the dsRNA) is administered at a dose of 0.5-50 mg/kg. In embodiments, the iRNA (e.g., dsRNA) is in the form of a GalNAc conjugate and is administered at a dose of 1 to 10 mg/kg. 
     In an aspect provided herein is a vector encoding at least one strand of an iRNA (e.g., a dsRNA) as described herein. 
     In an aspect provided herein is a vector encoding at least one strand of a dsRNA, wherein said dsRNA comprises a region of complementarity to at least a part of an mRNA encoding LECT2, wherein said dsRNA is 30 base pairs or less in length, and wherein said dsRNA targets said mRNA for cleavage. 
     In embodiments, the region of complementarity is at least 15 nucleotides in length. 
     In embodiments, the region of complementarity is 19 to 21 nucleotides in length. 
     In one aspect, a vector is provided for inhibiting the expression of a LECT2 gene in a cell. In one embodiment, the vector comprises an iRNA as described herein. In one embodiment, the vector includes at least one regulatory sequence operably linked to a nucleotide sequence that encodes at least one strand of an iRNA as described herein. In one embodiment the vector comprises at least one strand of a LECT2 iRNA. 
     In an aspect provided herein is a cell comprising a vector as described herein. 
     In an aspect provided herein is a cell containing a vector for inhibiting the expression of a LECT2 gene in a cell. The vector includes a regulatory sequence operably linked to a nucleotide sequence that encodes at least one strand of an iRNA described herein. 
     All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. 
     The details of various embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and the drawings, and from the claims. 
    
    
     
       DESCRIPTION OF THE DRAWINGS 
         FIG. 1  depicts a human LECT2 mRNA transcript sequence (Ref. Seq. NM_002302.2 GI:59806344, record dated Apr. 17, 2013; SEQ ID NO: 1). 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     iRNA directs the sequence-specific degradation of mRNA through a process known as RNA interference (RNAi). Described herein are iRNAs and methods of using them for modulating (e.g., inhibiting) the expression of a LECT2 gene. Also provided are compositions and methods for treatment of disorders related to LECT2 expression, such as amyloidosis (e.g., LECT2 amyloidosis). 
     The iRNAs of the compositions featured herein include an RNA strand (the antisense strand) having a region which is 30 nucleotides or less in length, i.e., 15-30 nucleotides in length, generally 19-24 nucleotides in length, which region is substantially complementary to at least part of an mRNA transcript of a LECT2 gene (also referred to herein as an “LECT2-specific iRNA”). The use of such an iRNA enables the targeted degradation of mRNAs of genes that are implicated in disorders related to LECT2 expression, as described herein. Very low dosages of LECT2-specific iRNAs can specifically and efficiently mediate RNAi, resulting in significant inhibition of expression of a LECT2 gene. iRNAs targeting LECT2 can specifically and efficiently mediate RNAi, resulting in significant inhibition of expression of a LECT2 gene, which can be assessed, e.g., in cell based assays. 
     The following description discloses how to make and use compositions containing iRNAs to modulate (e.g., inhibit) the expression of a LECT2 gene, as well as compositions and methods for treating disorders related to expression of a LECT2 gene. 
     Embodiments of the pharmaceutical compositions featured herein include an iRNA having an antisense strand comprising a region which is 30 nucleotides or less in length, generally 19-24 nucleotides in length, which region is substantially complementary to at least part of an RNA transcript of a LECT2 gene. 
     In some aspects, pharmaceutical compositions containing a LECT2 iRNA and a pharmaceutically acceptable carrier, methods of using the compositions to inhibit expression of a LECT2 gene, and methods of using the pharmaceutical compositions to treat disorders related to expression of a LECT2 gene (e.g., LECT2 amyloidosis) are featured herein. 
     I. Definitions 
     For convenience, the meaning of certain terms and phrases used in the specification, examples, and appended claims, are provided below. If there is an apparent discrepancy between the usage of a term in other parts of this specification and its definition provided in this section, the definition in this section shall prevail. 
     As used herein, “LECT2” refers to leukocyte chemotactic factor 2 (also known as leukocyte cell-derived chemotaxin 2, chondromodulin-II, chm-II or chm2). See, e.g., Yamagoe S et al.  Genomics , Mar. 15, 1998; 48(3):324-9. LECT2 was first identified as a novel neutrophil chemotactic protein and is identical with chondromodulin II, a growth stimulator for chondrocytes and osteoblasts. The human LECT2 gene was mapped to chromosome 5q31.1-q32 . Ibid.    
     The sequence of a human LECT2 mRNA transcript can be found at NM_002302.2 (SEQ ID NO: 1). The sequence of a mouse LECT2 mRNA can be found at NM_010702.1 and at NM_010702.2, and the sequence of a rat LECT2 mRNA can be found at NM_001108405.1. 
     The human LECT2 protein is a secreted, 16 kDa protein. The LECT2 protein is secreted by the liver. It has high sequence similarity to the chondromodulin repeat regions of the chicken myb-induced myeloid 1 protein (world wide web address: genecards.org/cgi-bin/carddisp.pl?gene=LECT2; accessed Aug. 29, 2013). Polymorphism in the LECT2 gene has been associated with rheumatoid arthritis.  Ibid.    
     LECT2 is expressed in various tissues, including the brain and stomach as well as the liver. Koshimizu, Y &amp; Ohtomi, M. (2010)  Brain Res.  1311:1-11. In a study using indirect immunoperoxidase staining to investigate the expression of LECT2 in normal and diseased human organs and tissues other than liver, it was found that LECT2 was generally expressed in vascular, endothelial and smooth muscle cells, adipocytes, cerebral nerve cells, apical squamous epithelia, parathyroid cells, sweat and sebaceous glandular epithelia, Hassall bodies and some mononuclear cells in immunohematopoeietic tissue. This protein was generally negative, although occasionally positively stained in osteoblasts, chondrocytes, cardiac and skeletal muscle cells, smooth muscle cells of the gastrointestinal tract, and the epithelial cells of some tissues. Nagai et al. (1998)  Pathol Int.  48(11):882-6. 
     The human LECT2 gene codes for 151 amino acids including an 18 amino acid signal peptide. The secreted protein has 133 residues. A G/A polymorphism at nucleotide 172 in exon 3 of the gene (codon change GTC to ATC) has been identified and accounts for the presence of either valine or isoleucine at position 58 of the unprocessed protein (or position 40 of the mature protein). The G allele has an overall frequency of 0.477 and a frequency range of 0.6-0.7 in individuals of European descent. See Benson, M. D. et al. (2008)  Kidney International,  74: 218-222; Murphy, C. L. et al. (2010)  Am J Kidney Dis,  56(6):1100-1107. Patients with LECT2 amyloidosis typically are homozygous for the G allele. Without wishing to be bound by theory, it has been suggested that replacement of the buried isoleucine (A allele) side chain with valine (G allele) could destabilize the protein and possibly account for the amyloidogenic propensity of this LECT2 variant. Murphy, C. L. et al. (2010)  Am J Kidney Dis,  56(6):1100-1107. 
     As used herein, a “LECT2 amyloidosis” or “ALECT2” includes an amyloidosis involving deposits of amyloid or amyloid fibrils that contain a LECT2 protein (e.g., any polymorphic variant of a LECT2 protein) or a portion of a LECT2 protein. The LECT2 protein can be a variant (e.g., a mutant) LECT2 protein. The amyloidosis can be systemic or local. In embodiments, the LECT2 amyloidosis involves amyloid deposits in the kidney and/or liver. 
     “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. The skilled person is well aware that guanine, cytosine, adenine, and uracil may 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 may base pair with nucleotides containing adenine, cytosine, or uracil. Hence, nucleotides containing uracil, guanine, or adenine may 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. 
     As used herein, the term “iRNA,” “RNAi”, “iRNA agent,” or “RNAi agent” refers to an agent that contains RNA as that term is defined herein, and which mediates the targeted cleavage of an RNA transcript, e.g., via an RNA-induced silencing complex (RISC) pathway. In one embodiment, an iRNA as described herein effects inhibition of LECT2 expression. Inhibition of ALECT2 expression may be assessed based on a reduction in the level of ALECT2 mRNA or a reduction in the level of the ALECT2 protein. As used herein, “target sequence” refers to a contiguous portion of the nucleotide sequence of an mRNA molecule formed during the transcription of an ALECT2 gene, including mRNA that is a product of RNA processing of a primary transcription product. 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. For example, the target sequence will generally be from 9-36 nucleotides in length, e.g., 15-30 nucleotides in length, including all sub-ranges therebetween. As non-limiting examples, the target sequence can be from 15-30 nucleotides, 15-26 nucleotides, 15-23 nucleotides, 15-22 nucleotides, 15-21 nucleotides, 15-20 nucleotides, 15-19 nucleotides, 15-18 nucleotides, 15-17 nucleotides, 18-30 nucleotides, 18-26 nucleotides, 18-23 nucleotides, 18-22 nucleotides, 18-21 nucleotides, 18-20 nucleotides, 19-30 nucleotides, 19-26 nucleotides, 19-23 nucleotides, 19-22 nucleotides, 19-21 nucleotides, 19-20 nucleotides, 20-30 nucleotides, 20-26 nucleotides, 20-25 nucleotides, 20-24 nucleotides, 20-23 nucleotides, 20-22 nucleotides, 20-21 nucleotides, 21-30 nucleotides, 21-26 nucleotides, 21-25 nucleotides, 21-24 nucleotides, 21-23 nucleotides, or 21-22 nucleotides. 
     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. 
     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 may 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. Other conditions, such as physiologically relevant conditions as may 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 may 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, may yet be referred to as “fully complementary” for the purposes described herein. 
     “Complementary” sequences, as used herein, may also include, or be formed entirely from, non-Watson-Crick base pairs and/or base pairs formed from non-natural and modified nucleotides, in as far as the above requirements with respect to their ability to hybridize are fulfilled. Such non-Watson-Crick base pairs includes, but are not limited to, G:U Wobble or Hoogstein base pairing. 
     The terms “complementary,” “fully complementary” and “substantially complementary” herein may 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 an ALECT2 protein). For example, a polynucleotide is complementary to at least a part of a LECT2 mRNA if the sequence is substantially complementary to a non-interrupted portion of an mRNA encoding LECT2. As another example, a polynucleotide is complementary to at least a part of a LECT2 mRNA if the sequence is substantially complementary to a non-interrupted portion of an mRNA encoding LECT2. 
     The term “double-stranded RNA” or “dsRNA,” as used herein, refers to an iRNA that includes an RNA molecule or complex of molecules having a hybridized duplex region that comprises two anti-parallel and substantially complementary nucleic acid strands, which will be referred to as having “sense” and “antisense” orientations with respect to a target RNA. The duplex region can be of any length that permits specific degradation of a desired target RNA, e.g., through a RISC pathway, but will typically range from 9 to 36 base pairs in length, e.g., 15-30 base pairs in length. Considering a duplex between 9 and 36 base pairs, the duplex can be any length in this range, for example, 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 and any sub-range therein between, including, but not limited to 15-30 base pairs, 15-26 base pairs, 15-23 base pairs, 15-22 base pairs, 15-21 base pairs, 15-20 base pairs, 15-19 base pairs, 15-18 base pairs, 15-17 base pairs, 18-30 base pairs, 18-26 base pairs, 18-23 base pairs, 18-22 base pairs, 18-21 base pairs, 18-20 base pairs, 19-30 base pairs, 19-26 base pairs, 19-23 base pairs, 19-22 base pairs, 19-21 base pairs, 19-20 base pairs, 20-30 base pairs, 20-26 base pairs, 20-25 base pairs, 20-24 base pairs, 20-23 base pairs, 20-22 base pairs, 20-21 base pairs, 21-30 base pairs, 21-26 base pairs, 21-25 base pairs, 21-24 base pairs, 21-23 base pairs, or 21-22 base pairs. dsRNAs generated in the cell by processing with Dicer and similar enzymes are generally in the range of 19-22 base pairs in length. One strand of the duplex region of a dsDNA comprises a sequence that is substantially complementary to a region of a target RNA. The two strands forming the duplex structure can be from a single RNA molecule having at least one self-complementary region, or can be formed from two or more separate RNA molecules. Where the duplex region is formed from two strands of a single molecule, the molecule can have a duplex region separated by a single stranded chain of nucleotides (herein referred to as a “hairpin loop”) between the 3′-end of one strand and the 5′-end of the respective other strand forming the duplex structure. The hairpin loop can comprise at least one unpaired nucleotide; in some embodiments the hairpin loop can comprise 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 a hairpin loop, the connecting structure is referred to as a “linker.” The term “siRNA” is also used herein to refer to a dsRNA as described above. 
     In another embodiment, the iRNA 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 (e.g., sequences provided in Tables 2-3, 5-6 and 9-10) 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 aspect, the RNA agent is a “single-stranded antisense RNA molecule.” An single-stranded antisense RNA molecule is complementary to a sequence within the target mRNA. Single-stranded antisense RNA molecules 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. Alternatively, the single-stranded antisense molecules inhibit a target mRNA by hybridizing to the target and cleaving the target through an RNaseH cleavage event. The single-stranded antisense RNA molecule may be about 10 to about 30 nucleotides in length and have a sequence that is complementary to a target sequence. In one embodiment, the single-stranded antisense RNA molecule may comprise a sequence that is at least about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more contiguous nucleotides complementary to any of the target sites described herein, e.g., sequences provided in any one of Tables 2-3, 5-6 and 9-10. In another embodiment, the single-stranded antisense RNA molecule may comprise a sequence that is at least about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more contiguous nucleotides from any one of the antisense nucleotide sequences described herein, e.g., sequences provided in any one of Tables 2-3, 5-6 and 9-10. 
     The skilled artisan will recognize that the term “RNA molecule” or “ribonucleic acid molecule” encompasses not only RNA molecules as expressed or found in nature, but also analogs and derivatives of RNA comprising one or more ribonucleotide/ribonucleoside analogs or derivatives as described herein or as known in the art. Strictly speaking, a “ribonucleoside” includes a nucleoside base and a ribose sugar, and a “ribonucleotide” is a ribonucleoside with one, two or three phosphate moieties. However, the terms “ribonucleoside” and “ribonucleotide” can be considered to be equivalent as used herein. The RNA can be modified in the nucleobase structure, in the ribose structure, or in the ribose-phosphate backbone structure, e.g., as described herein below. However, the molecules comprising ribonucleoside analogs or derivatives must retain the ability to form a duplex. As non-limiting examples, an RNA molecule can also include at least one modified ribonucleoside including but not limited to a 2′-O-methyl modified nucleoside, a nucleoside comprising a 5′ phosphorothioate group, a terminal nucleoside linked to a cholesteryl derivative or dodecanoic acid bisdecylamide group, a locked nucleoside, an abasic nucleoside, an acyclic nucleoside, a 2′-deoxy-2′-fluoro modified nucleoside, a 2′-amino-modified nucleoside, 2′-alkyl-modified nucleoside, morpholino nucleoside, a phosphoramidate or a non-natural base comprising nucleoside, or any combination thereof. Alternatively, an RNA molecule can comprise at least two modified ribonucleosides, 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 15, at least 20 or more, up to the entire length of the dsRNA molecule. The modifications need not be the same for each of such a plurality of modified ribonucleosides in an RNA molecule. In one embodiment, modified RNAs contemplated for use in methods and compositions described herein are peptide nucleic acids (PNAs) that have the ability to form the required duplex structure and that permit or mediate the specific degradation of a target RNA, e.g., via a RISC pathway. 
     In one aspect, a modified ribonucleoside includes a deoxyribonucleoside. In such an instance, an iRNA agent can comprise one or more deoxynucleosides, including, for example, a deoxynucleoside overhang(s), or one or more deoxynucleosides within the double stranded portion of a dsRNA. In certain embodiments, the RNA molecule comprises a percentage of deoxyribonucleoses of at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95% or higher (but not 100%) deoxyribonucleosides, e.g., in one or both strands. In other embodiments, the term “iRNA” does not encompass a double stranded DNA molecule (e.g., a naturally-occurring double stranded DNA molecule or a 100% deoxynucleoside-containing DNA molecule). 
     In one aspect, an RNA interference agent includes a single stranded RNA that interacts with a target RNA 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.,  Genes Dev.  2001, 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 cleaves 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 that promotes the formation of a RISC complex to effect silencing of the target gene. 
     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) may 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 anti sense strand of a dsRNA has a 1-10 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 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. 
     The terms “blunt” or “blunt ended” as used herein in reference to a dsRNA mean that there are no unpaired nucleotides or nucleotide analogs at a given terminal end of a dsRNA, i.e., no nucleotide overhang. One or both ends of a dsRNA can be blunt. Where both ends of a dsRNA are blunt, the dsRNA is said to be blunt ended. To be clear, a “blunt ended” dsRNA is a dsRNA that is blunt at both ends, i.e., no nucleotide overhang at either end of the molecule. Most often such a molecule will be double-stranded over its entire length. 
     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. 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, as defined herein. Where the region of complementarity is not fully complementary to the target sequence, the mismatches may 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. 
     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 “SNALP” refers to a stable nucleic acid-lipid particle. A SNALP represents a vesicle of lipids coating a reduced aqueous interior comprising a nucleic acid such as an iRNA or a plasmid from which an iRNA is transcribed. SNALPs are described, e.g., in U.S. Patent Application Publication Nos. 2006/0240093, 2007/0135372, and in International Application No. WO 2009/082817. These applications are incorporated herein by reference in their entirety. 
     “Introducing into a cell,” when referring to an iRNA, means facilitating or effecting uptake or absorption into the cell, as is understood by those skilled in the art. Absorption or uptake of an iRNA can occur through unaided diffusive or active cellular processes, or by auxiliary agents or devices. The meaning of this term is not limited to cells in vitro; an iRNA may also be “introduced into a cell,” wherein the cell is part of a living organism. In such an instance, introduction into the cell will include the delivery to the organism. For example, for in vivo delivery, iRNA can be injected into a tissue site or administered systemically. In vivo delivery can also be by a β-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, which are hereby incorporated by reference in their entirety. In vitro introduction into a cell includes methods known in the art such as electroporation and lipofection. Further approaches are described herein below or known in the art. 
     As used herein, the term “modulate the expression of,” refers to at an least partial “inhibition” or partial “activation” of a LECT2 gene expression in a cell treated with an iRNA composition as described herein compared to the expression of LECT2 in a control cell. A control cell includes an untreated cell, or a cell treated with a non-targeting control iRNA. 
     The terms “activate,” “enhance,” “up-regulate the expression of,” “increase the expression of,” and the like, in so far as they refer to a LECT2 gene, herein refer to the at least partial activation of the expression of a LECT2 gene, as manifested by an increase in the amount of LECT2 mRNA, which may be isolated from or detected in a first cell or group of cells in which a LECT2 gene is transcribed and which has or have been treated such that the expression of a LECT2 gene is increased, as compared to a second cell or group of cells substantially identical to the first cell or group of cells but which has or have not been so treated (control cells). 
     In one embodiment, expression of a LECT2 gene is activated by at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% by administration of an iRNA as described herein. In some embodiments, a LECT2 gene is activated by at least about 60%, 70%, or 80% by administration of an iRNA featured in the invention. In some embodiments, expression of a LECT2 gene is activated by at least about 85%, 90%, or 95% or more by administration of an iRNA as described herein. In some embodiments, the LECT2 gene expression is increased by at least 1-fold, at least 2-fold, at least 5-fold, at least 10-fold, at least 50-fold, at least 100-fold, at least 500-fold, at least 1000 fold or more in cells treated with an iRNA as described herein compared to the expression in an untreated cell. Activation of expression by small dsRNAs is described, for example, in Li et al., 2006  Proc. Natl. Acad. Sci. U.S.A.  103:17337-42, and in US2007/0111963 and US2005/226848, each of which is incorporated herein by reference. 
     The terms “silence,” “inhibit expression of,” “down-regulate expression of,” “suppress expression of,” and the like, in so far as they refer to a LECT2 gene, herein refer to the at least partial suppression of the expression of a LECT2 gene, as assessed, e.g., based on LECT2 mRNA expression, LECT2 protein expression, or another parameter functionally linked to LECT2 gene expression. For example, inhibition of LECT2 expression may be manifested by a reduction of the amount of LECT2 mRNA which may be isolated from or detected in a first cell or group of cells in which a LECT2 gene is transcribed and which has or have been treated such that the expression of a LECT2 gene is inhibited, as compared to a control. The control may be a second cell or group of cells substantially identical to the first cell or group of cells, except that the second cell or group of cells have not been so treated (control cells). The degree of inhibition is usually expressed as a percentage of a control level, e.g., 
     
       
         
           
             
               
                 
                   
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     Alternatively, the degree of inhibition may be given in terms of a reduction of a parameter that is functionally linked to LECT2 gene expression, e.g., the amount of protein encoded by a LECT2 gene. The reduction of a parameter functionally linked to LECT2 gene expression may similarly be expressed as a percentage of a control level. In principle, LECT2 gene silencing may be determined in any cell expressing LECT2, either constitutively or by genomic engineering, and by any appropriate assay. 
     For example, in certain instances, expression of a LECT2 gene is suppressed by at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% by administration of an iRNA disclosed herein. In some embodiments, a LECT2 gene is suppressed by at least about 60%, 65%, 70%, 75%, or 80% by administration of an iRNA disclosed herein. In some embodiments, a LECT2 gene is suppressed by at least about 85%, 90%, 95%, 98%, 99%, or more by administration of an iRNA as described herein. 
     In the context of the present disclosure, the terms “treat,” “treatment,” and the like mean to prevent, relieve or alleviate at least one symptom associated with a disorder related to LECT2 expression, or to slow or reverse the progression or anticipated progression of such a disorder. For example, the methods featured herein, when employed to treat a LECT2 amyloidosis, may serve to inhibit amyloid deposition, to reduce or prevent one or more symptoms of the amyloidosis, or to reduce the risk or severity of associated conditions (e.g., nephrotic syndrome or hepatitis). Thus, unless the context clearly indicates otherwise, the terms “treat,” “treatment,” and the like are intended to encompass prophylaxis, e.g., prevention of disorders and/or symptoms of disorders related to LECT2 expression. 
     By “lower” in the context of a disease marker or symptom is meant any decrease, e.g., a statistically or clinically significant decrease in such level. The decrease can be, for example, at least 10%, at least 20%, at least 30%, at least 40%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%. The decrease can be down to a level accepted as within the range of normal for an individual without such disorder. 
     As used herein, the phrases “therapeutically effective amount” and “prophylactically effective amount” and the like refer to an amount that provides a therapeutic benefit in the treatment, prevention, or management of any disorder or pathological process related to LECT2 expression. The specific amount that is therapeutically effective may vary depending on factors known in the art, such as, for example, the type of disorder or pathological process, the patient&#39;s history and age, the stage of the disorder or pathological process, and the administration of other therapies. 
     As used herein, a “pharmaceutical composition” comprises a pharmacologically effective amount of an iRNA and a pharmaceutically acceptable carrier. As used herein, “pharmacologically effective amount,” “therapeutically effective amount” or simply “effective amount” refers to that amount of an iRNA effective to produce the intended pharmacological, therapeutic or preventive result. For example, in a method of treating a disorder related to LECT2 expression (e.g., a LECT2 amyloidosis), an effective amount includes an amount effective to reduce one or more symptoms associated with the LECT2 amyloidosis, an amount effective to inhibit amyloid deposition (e.g., LECT2 amyloid deposition), or an amount effective to reduce the risk of developing conditions associated with LECT2 amyloidosis. For example, if a given clinical treatment is considered effective when there is at least a 10% reduction in a measurable parameter associated with a disease or disorder, a therapeutically effective amount of a drug for the treatment of that disease or disorder is the amount necessary to obtain at least a 10% reduction in that parameter. For example, a therapeutically effective amount of an iRNA targeting LECT2 can reduce a level of LECT2 mRNA or a level of LECT2 protein by any measurable amount, e.g., by at least 10%, 20%, 30%, 40% or 50%. 
     The term “pharmaceutically acceptable carrier” refers to a carrier for administration of a therapeutic agent. Such carriers include, but are not limited to, saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof. The term specifically excludes cell culture medium. For drugs administered orally, pharmaceutically acceptable carriers include, but are not limited to pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservatives. Suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose, while corn starch and alginic acid are suitable disintegrating agents. Binding agents may include starch and gelatin, while the lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract. Agents included in drug formulations are described further herein below. 
     The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary from, for example, between 1% and 15% of the stated number or numerical range. 
     II. iRNA Agents 
     Described herein are iRNA agents that modulate (e.g., inhibit) the expression of a LECT2 gene. 
     In some embodiments, the iRNA agent activates the expression of a LECT2 gene in a cell or mammal. 
     In some embodiments, the iRNA agent includes double-stranded ribonucleic acid (dsRNA) molecules for inhibiting the expression of a LECT2 gene in a cell or in a subject (e.g., in a mammal, e.g., in a human), where 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 LECT2 gene, and where the region of complementarity is 30 nucleotides or less in length, generally 19-24 nucleotides in length, and where the dsRNA, upon contact with a cell expressing the LECT2 gene, inhibits the expression of the LECT2 gene, e.g., by at least 10%, 20%, 30%, 40%, or 50%. 
     The modulation (e.g., inhibition) of expression of the LECT2 gene can be assayed by, for example, a PCR or branched DNA (bDNA)-based method, or by a protein-based method, such as by Western blot. Expression of a LECT2 gene in cell culture, such as in COS cells, HeLa cells, primary hepatocytes, HepG2 cells, primary cultured cells or in a biological sample from a subject can be assayed by measuring LECT2 mRNA levels, such as by bDNA or TaqMan assay, or by measuring protein levels, such as by immunofluorescence analysis, using, for example, Western Blotting or flow cytometric techniques. 
     A dsRNA includes two RNA strands that are sufficiently complementary to hybridize to form a duplex structure under conditions in which the dsRNA will be used. One strand of a dsRNA (the anti sense strand) includes a region of complementarity that is substantially complementary, and generally fully complementary, to a target sequence, derived from the sequence of an mRNA formed during the expression of a LECT2 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. Generally, the duplex structure is between 15 and 30 inclusive, more generally between 18 and 25 inclusive, yet more generally between 19 and 24 inclusive, and most generally between 19 and 21 base pairs in length, inclusive. Similarly, the region of complementarity to the target sequence is between 15 and 30 inclusive, more generally between 18 and 25 inclusive, yet more generally between 19 and 24 inclusive, and most generally between 19 and 21 nucleotides in length, inclusive. 
     In some embodiments, the dsRNA is between 15 and 20 nucleotides in length, inclusive, and in other embodiments, the dsRNA is between 25 and 30 nucleotides in length, inclusive. As the ordinarily skilled person will recognize, the targeted 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 be a substrate for RNAi-directed cleavage (i.e., cleavage through a RISC pathway). dsRNAs having duplexes as short as 9 base pairs can, under some circumstances, mediate RNAi-directed RNA cleavage. Most often a target will be at least 15 nucleotides in length, e.g., 15-30 nucleotides in length. 
     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 9 to 36, e.g., 15-30 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, then, an miRNA is a dsRNA. In another embodiment, a dsRNA is not a naturally occurring miRNA. In another embodiment, an iRNA agent useful to target LECT2 expression is not generated in the target cell by cleavage of a larger dsRNA. 
     A dsRNA as described herein may further include one or more single-stranded nucleotide overhangs. The 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. 
     In one embodiment, a LECT2 gene is a human LECT2 gene. In another embodiment the LECT2 gene is a mouse or a rat LECT2 gene. 
     In specific embodiments, the dsRNA comprises a sense strand that comprises or consists of a sense sequence selected from the sense sequences provided in Tables 2-3, 5-6 and 9-10, and an antisense strand that comprises or consists of an antisense sequence selected from the antisense sequences provided in Tables 2-3, 5-6 and 9-10. 
     In one aspect, a dsRNA will include at least sense and antisense nucleotide sequences, whereby the sense strand is selected from the sequences provided in Tables 2-3, 5-6 and 9-10, and the corresponding antisense strand is selected from the sequences provided in Tables 2-3, 5-6 and 9-10. 
     In these aspects, 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 by the expression of a LECT2 gene. As such, a dsRNA will include two oligonucleotides, where one oligonucleotide is described as the sense strand, and the second oligonucleotide is described as the corresponding antisense strand. 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. 
     The skilled person is well aware that dsRNAs having a duplex structure of between 20 and 23, but specifically 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 be effective as well. 
     In the embodiments described above, by virtue of the nature of the oligonucleotide sequences provided in Tables 2-3, 5-6 and 9-10, dsRNAs described herein can include at least one strand of a length of minimally 19 nucleotides. It can be reasonably expected that shorter duplexes having one of the sequences of Tables 2, 3, 5, 6, 9 or 10 minus only a few nucleotides on one or both ends will be similarly effective as compared to the dsRNAs described above. 
     In some embodiments, the dsRNA has a partial sequence of at least 15, 16, 17, 18, 19, 20, or more contiguous nucleotides from one of the sequences of Tables 2, 3, 5, 6, 9 or 10. 
     In some embodiments, the dsRNA has an antisense sequence that comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides of an antisense sequence provided in Table 2 and a sense sequence that comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides of a corresponding sense sequence provided in Table 2. 
     In some embodiments, the dsRNA comprises an antisense sequence that comprises at least 15, 16, 17, 18, 19, 20, 21, 22, or 23 contiguous nucleotides of an antisense sequence provided in Table 3 and a sense sequence that comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides of a corresponding sense sequence provided in Table 3. 
     In some embodiments, the dsRNA comprises an antisense sequence that comprises at least 15, 16, 17, 18, 19, 20, 21, 22, or 23 contiguous nucleotides of an antisense sequence provided in Table 5 and a sense sequence that comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides of a corresponding sense sequence provided in Table 5. 
     In some embodiments, the dsRNA comprises an antisense sequence that comprises at least 15, 16, 17, 18, 19, 20, 21, 22, or 23 contiguous nucleotides of an antisense sequence provided in Table 6 and a sense sequence that comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides of a corresponding sense sequence provided in Table 6. 
     In some embodiments, the dsRNA comprises an antisense sequence that comprises at least 15, 16, 17, 18, 19, 20, 21, 22, or 23 contiguous nucleotides of an antisense sequence provided in Table 5 and a sense sequence that comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides of a corresponding sense sequence provided in Table 9. 
     In some embodiments, the dsRNA comprises an antisense sequence that comprises at least 15, 16, 17, 18, 19, 20, 21, 22, or 23 contiguous nucleotides of an antisense sequence provided in Table 6 and a sense sequence that comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides of a corresponding sense sequence provided in Table 10. 
     In some such embodiments, the dsRNA, although it comprises only a portion of the sequences provided in Table 2, 3, 5, 6, 9 or 10, is equally effective in inhibiting a level of LECT2 expression as is a dsRNA that comprises the full length sequences provided in Table 2, 3, 5, 6, 9 or 10. In some embodiments, the dsRNA differs in its inhibition of a level of expression of a LECT2 gene by not more than 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50% inhibition compared with a dsRNA comprising the full sequence disclosed herein. 
     The iRNAs provided in Tables 2-3, 5-6 and 9-10 identify a site in a LECT2 transcript that is susceptible to RISC-mediated cleavage. As such, the present invention further features iRNAs that target within one of such sequences. 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 15 contiguous nucleotides from one of the sequences provided in Tables 2-3, 5-6 and 9-10 coupled to additional nucleotide sequences taken from the region contiguous to the selected sequence in a LECT2 gene. 
     While a target sequence is generally 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 may 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 described herein or 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 Tables 2-3, 5-6 and 9-10, 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 Tables 2-3, 5-6 and 9-10, further optimization can be achieved by systematically either adding or removing nucleotides to generate longer or shorter sequences and testing those and 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 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, etc.) 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 not be 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 RNA strand which is complementary to a region of a LECT2 gene, the RNA strand 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 LECT2 gene. Consideration of the efficacy of iRNAs with mismatches in inhibiting expression of a LECT2 gene is important, especially if the particular region of complementarity in a LECT2 gene is known to have polymorphic sequence variation within the population. 
     In one embodiment, at least one end of a dsRNA has a single-stranded nucleotide overhang of 1 to 4, generally 1 or 2 nucleotides. dsRNAs having at least one nucleotide overhang have unexpectedly superior inhibitory properties relative to their blunt-ended counterparts. In yet another embodiment, the RNA of an iRNA (e.g., a dsRNA) is chemically modified to enhance stability or other beneficial characteristics. The nucleic acids featured in the invention may 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, (a) end modifications, e.g., 5′ end modifications (phosphorylation, conjugation, inverted linkages, etc.) 3′ end modifications (conjugation, DNA nucleotides, inverted linkages, etc.), (b) 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, (c) sugar modifications (e.g., at the 2′ position or 4′ position, or having an acyclic sugar) or replacement of the sugar, as well as (d) backbone modifications, including modification or replacement of the phosphodiester linkages. Specific examples of RNA compounds useful in this invention 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 particular embodiments, the modified RNA 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, each of which is herein incorporated 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, each of which is herein incorporated by reference. 
     In other RNA mimetics suitable or contemplated for use in iRNAs, 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, each of which is herein incorporated by reference. Further teaching of PNA compounds can be found, 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 may 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 may 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, 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 . 
     In other embodiments, an iRNA agent comprises one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) acyclic nucleotides (or nucleosides). In certain embodiments, the sense strand or the antisense strand, or both sense strand and antisense strand, include less than five acyclic nucleotides per strand (e.g., four, three, two or one acyclic nucleotides per strand). The one or more acyclic nucleotides can be found, for example, in the double-stranded region, of the sense or antisense strand, or both strands; at the 5′-end, the 3′-end, both of the 5′ and 3′-ends of the sense or antisense strand, or both strands, of the iRNA agent. In one embodiment, one or more acyclic nucleotides are present at positions 1 to 8 of the sense or antisense strand, or both. In one embodiment, one or more acyclic nucleotides are found in the antisense strand at positions 4 to 10 (e.g., positions 6-8) from the 5′-end of the antisense strand. In another embodiment, the one or more acyclic nucleotides are found at one or both 3′-terminal overhangs of the iRNA agent. 
     The term “acyclic nucleotide” or “acyclic nucleoside” as used herein refers to any nucleotide or nucleoside having an acyclic sugar, e.g., an acyclic ribose. An exemplary acyclic nucleotide or nucleoside can include a nucleobase, e.g., a naturally-occurring or a modified nucleobase (e.g., a nucleobase as described herein). In certain embodiments, a bond between any of the ribose carbons (C1, C2, C3, C4, or C5), is independently or in combination absent from the nucleotide. In one embodiment, the bond between C2-C3 carbons of the ribose ring is absent, e.g., an acyclic 2′-3′-seco-nucleotide monomer. In other embodiments, the bond between C1-C2, C3-C4, or C4-C5 is absent (e.g., a 1′-2′, 3′-4′ or 4′-5′-seco nucleotide monomer). Exemplary acyclic nucleotides are disclosed in U.S. Pat. No. 8,314,227, incorporated herein by reference in its entirely. For example, an acyclic nucleotide can include any of monomers D-J in FIGS. 1-2 of U.S. Pat. No. 8,314,227. In one embodiment, the acyclic nucleotide includes the following monomer: 
     
       
         
         
             
             
         
       
     
     wherein Base is a nucleobase, e.g., a naturally-occurring or a modified nucleobase (e.g., a nucleobase as described herein). 
     In certain embodiments, the acyclic nucleotide can be modified or derivatized, e.g., by coupling the acyclic nucleotide to another moiety, e.g., a ligand (e.g., a GalNAc, a cholesterol ligand), an alkyl, a polyamine, a sugar, a polypeptide, among others. 
     In other embodiments, the iRNA agent includes one or more acyclic nucleotides and one or more LNAs (e.g., an LNA as described herein). For example, one or more acyclic nucleotides and/or one or more LNAs can be present in the sense strand, the antisense strand, or both. The number of acyclic nucleotides in one strand can be the same or different from the number of LNAs in the opposing strand. In certain embodiments, the sense strand and/or the antisense strand comprises less than five LNAs (e.g., four, three, two or one LNAs) located in the double-stranded region or a 3′-overhang. In other embodiments, one or two LNAs are located in the double stranded region or the 3′-overhang of the sense strand. Alternatively, or in combination, the sense strand and/or antisense strand comprises less than five acyclic nucleotides (e.g., four, three, two or one acyclic nucleotides) in the double-stranded region or a 3′-overhang. In one embodiment, the sense strand of the iRNA agent comprises one or two LNAs in the 3′-overhang of the sense strand, and one or two acyclic nucleotides in the double-stranded region of the antisense strand (e.g., at positions 4 to 10 (e.g., positions 6-8) from the 5′-end of the antisense strand) of the iRNA agent. 
     In other embodiments, inclusion of one or more acyclic nucleotides (alone or in addition to one or more LNAs) in the iRNA agent results in one or more (or all) of: (i) a reduction in an off-target effect; (ii) a reduction in passenger strand participation in RNAi; (iii) an increase in specificity of the guide strand for its target mRNA; (iv) a reduction in a microRNA off-target effect; (v) an increase in stability; or (vi) an increase in resistance to degradation, of the iRNA molecule. 
     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 may 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 may 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, and each of which is herein incorporated by reference. 
     An iRNA may 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 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-deazaadenine 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. No. 3,687,808, as well as U.S. Pat. Nos. 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; 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, each of which is herein incorporated by reference, and U.S. Pat. No. 5,750,692, also herein incorporated by reference. 
     The RNA of an iRNA can also be modified to include one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) locked nucleic acids (LNA) (also referred to herein as “locked nucleotides”). In one embodiment, a locked nucleic acid is a nucleotide having a modified ribose moiety in which the ribose moiety comprises an extra bridge connecting, e.g., the 2′ and 4′ carbons. 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, increase thermal stability, 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). 
     Representative U.S. patents that teach the preparation of locked nucleic acids include, but are not limited to, the following: U.S. Pat. Nos. 6,268,490; 6,670,461; 6,794,499; 6,998,484; 7,053,207; 7,084,125; 7,399,845, and 8,314,227, each of which is herein incorporated by reference in its entirety. Exemplary LNAs include but are not limited to, a 2′, 4′-C methylene bicyclo nucleotide (see for example Wengel et al., International PCT Publication No. WO 00/66604 and WO 99/14226). 
     In other embodiments, the iRNA agents include one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) G-clamp nucleotides. A G-clamp nucleotide is a modified cytosine analog wherein the modifications confer the ability to hydrogen bond both Watson-Crick and Hoogsteen faces of a complementary guanine within a duplex, see for example Lin and Matteucci, 1998 , J. Am. Chem. Soc.,  120, 8531-8532. A single G-clamp analog substitution within an oligonucleotide can result in substantially enhanced helical thermal stability and mismatch discrimination when hybridized to complementary oligonucleotides. The inclusion of such nucleotides in the iRNA molecules can result in enhanced affinity and specificity to nucleic acid targets, complementary sequences, or template strands. 
     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. 
     IRNA Motifs 
     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, 0-5, 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′) l —N′ a - n   p ′3′  (II)
 
     wherein: 
     k and 1 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 nucleotides in 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 1 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, 0-5, 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, 0-5, 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, 0-5, 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—(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 a ′- n   q ′5′   (III)
 
     wherein: 
     j, k, and 1 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 l and l is 0; k is 0 and l is 1; or both k and 1 are 0; or both k and 1 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′—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, 0-5, 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, 0-5, 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. 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. 
     iRNA Conjugates 
     The iRNA agents disclosed herein can be in the form of conjugates. The conjugate may be attached at any suitable location in the iRNA molecule, e.g., at the 3′ end or the 5′ end of the sense or the anti sense strand. The conjugates are optionally attached via a linker. 
     In some embodiments, an iRNA agent described herein is chemically linked to one or more ligands, moieties or conjugates, which may confer functionality, e.g., by affecting (e.g., enhancing) 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 some 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. Typical 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 or hyaluronic acid); or a lipid. The ligand may 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 polyphosphazene. 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 α 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-glucosamine multivalent mannose, multivalent fucose, glycosylated polyaminoacids, multivalent galactose, transferrin, bisphosphonate, polyglutamate, polyaspartate, a lipid, cholesterol, a steroid, bile acid, folate, vitamin B12, biotin, or an RGD peptide or RGD peptide mimetic. 
     In some embodiments, the ligand is a GalNAc ligand that comprises one or more N-acetylgalactosamine (GalNAc) derivatives. In some embodiments, the GalNAc ligand is used to target the iRNA to the liver (e.g., to hepatocytes). Additional description of GalNAc ligands is provided in the section titled Carbohydrate Conjugates. 
     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 cancer cell, endothelial cell, or bone cell. Ligands may 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-glucosamine 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, jasplakinolide, 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. 
     Lipid Conjugates 
     In one embodiment, the ligand is a lipid or lipid-based molecule. Such a lipid or lipid-based molecule can typically bind a serum protein, such as human serum albumin (HSA). An HSA binding ligand allows for distribution of the conjugate to a target tissue. 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 modulate, e.g., control (e.g., inhibit) 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 one embodiment, the lipid based ligand binds HSA. For example, the ligand can bind HSA with a sufficient affinity such that distribution of the conjugate to a non-kidney tissue is enhanced. However, the affinity is typically not so strong that the HSA-ligand binding cannot be reversed. 
     In another embodiment, the lipid based ligand binds HSA weakly or not at all, such that distribution of the conjugate to the kidney is enhanced. 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 cancer cells. Also included are HSA and low density lipoprotein (LDL). 
     Cell Permeation Agents 
     In another aspect, the ligand is a cell-permeation agent, such as a helical cell-permeation agent. In one embodiment, the agent is amphipathic. An exemplary agent is a peptide such as tat or antennapedia. 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 typically an α-helical agent, and can have 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: 685). An RFGF analogue (e.g., amino acid sequence AALLPVLLAAP (SEQ ID NO: 686)) 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: 687)) and the  Drosophila  Antennapedia protein (RQIKIWFQNRRMKWKK (SEQ ID NO: 688)) 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). Typically, the peptide or peptidomimetic tethered to a dsRNA agent via an incorporated monomer unit is a cell targeting peptide such as 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 peptidomimetics 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. 
     An RGD peptide moiety can be used to target a particular cell type, e.g., a tumor cell, such as an endothelial tumor cell or a breast cancer tumor cell (Zitzmann et al.,  Cancer Res.,  62:5139-43, 2002). An RGD peptide can facilitate targeting of an dsRNA agent to tumors of a variety of other tissues, including the lung, kidney, spleen, or liver (Aoki et al.,  Cancer Gene Therapy  8:783-787, 2001). Typically, the RGD peptide will facilitate targeting of an iRNA agent to the kidney. The RGD peptide can be linear or cyclic, and can be modified, e.g., glycosylated or methylated to facilitate targeting to specific tissues. For example, a glycosylated RGD peptide can deliver a iRNA agent to a tumor cell expressing α ν β 3  (Haubner et al.,  Jour. Nucl. Med.,  42:326-336, 2001). 
     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, an 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). 
     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 comprises a monosaccharide. In one embodiment, the monosaccharide is an N-acetylgalactosamine (GalNAc). GalNAc conjugates, which comprise one or more N-acetylgalactosamine (GalNAc) derivatives, are described, for example, in U.S. Pat. No. 8,106,022, the entire content of which is hereby incorporated herein by reference. In some embodiments, the GalNAc conjugate serves as a ligand that targets the iRNA to particular cells. In some embodiments, the GalNAc conjugate targets the iRNA to liver cells, e.g., by serving as a ligand for the asialoglycoprotein receptor of liver cells (e.g., hepatocytes). 
     In some embodiments, the carbohydrate conjugate comprises one or more GalNAc derivatives. The GalNAc derivatives may be attached via a linker, e.g., a bivalent or trivalent branched linker. In some embodiments the GalNAc conjugate is conjugated to the 3′ end of the sense strand. In some embodiments, the GalNAc conjugate is conjugated to the iRNA agent (e.g., to the 3′ end of the sense strand) via a linker, e.g., a linker as described herein. 
     In some embodiments, the GalNAc conjugate is 
     
       
         
         
             
             
         
       
     
     In some embodiments, the RNAi agent is attached to the carbohydrate conjugate via a linker as shown in the following schematic, wherein X is O or S 
     
       
         
         
             
             
         
       
     
     In some embodiments, the RNAi agent is conjugated to L96 as defined in Table 1 and shown below 
     
       
         
         
             
             
         
       
     
     In some embodiments, a carbohydrate conjugate for use in the compositions and methods of the invention is selected from the group consisting of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Another representative carbohydrate conjugate for use in the embodiments described herein includes, but is not limited to, 
     
       
         
         
             
             
         
       
     
     when one of X or Y is an oligonucleotide, the other is a hydrogen. 
     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. 
     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. 
     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, heterocyclylalkenyl, 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. 
     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 (XXXI)-(XXXIV): 
     
       
         
         
             
             
         
       
     
     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 (XXXV): 
     
       
         
         
             
             
         
       
         
         
           
             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. 
     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). 
     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. 
     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. 
     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. 
     Ester-Based Cleavable 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. 
     Peptide-Based Cleavable Linking 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 alkynylene. 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. 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 is herein incorporated 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 may 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 the present invention, are iRNA compounds, e.g., dsRNAs, that 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 may 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 may 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. 
     Delivery of iRNA 
     The delivery of an iRNA to a subject in need thereof can be achieved in a number of different ways. In vivo delivery can be performed directly by administering a composition comprising an iRNA, e.g. a dsRNA, to a subject. Alternatively, delivery can be performed indirectly by administering one or more vectors that encode and direct the expression of the iRNA. These alternatives are discussed further below. 
     Direct Delivery 
     In general, any method of delivering a nucleic acid molecule can be adapted for use with an iRNA (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). However, there are three factors that are important to consider in order to successfully deliver an iRNA molecule in vivo: (a) biological stability of the delivered molecule, (2) preventing non-specific effects, and (3) 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 (as a non-limiting example, a tumor) 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 may otherwise be harmed by the agent or that may 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 other groups, e.g., a lipid or carbohydrate group as described herein. Such conjugates can be used to target iRNA to particular cells, e.g., liver cells, e.g., hepatocytes. For example, GalNAc conjugates or lipid (e.g., LNP) formulations can be used to target iRNA to particular cells, e.g., liver cells, e.g., hepatocytes. 
     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. 
     Vector Encoded iRNAs 
     In another aspect, iRNA targeting the LECT2 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 an inverted repeat joined by a linker polynucleotide sequence such that the dsRNA has a stem and loop structure. 
     An iRNA expression vector is typically a DNA plasmid or viral vector. An expression vector compatible with eukaryotic cells, e.g., 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 contain 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. 
     An iRNA expression plasmid can be transfected into a target cell as a complex with a cationic lipid carrier (e.g., Oligofectamine) or a non-cationic lipid-based carrier (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) SV40 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 may 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-β-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. 
     In a specific embodiment, 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 facilitates 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. 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. 
     Use of Adeno-associated virus (AAV) vectors is also contemplated (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 typical viral vector 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. 
     III. Pharmaceutical Compositions Containing iRNA 
     In one embodiment, the invention provides pharmaceutical compositions containing an iRNA, as described herein, and a pharmaceutically acceptable carrier. The pharmaceutical composition containing the iRNA is useful for treating a disease or disorder related to the expression or activity of a LECT2 gene (e.g., a LECT2 amyloidosis). Such pharmaceutical compositions are formulated based on the mode of delivery. For example, compositions can be formulated for systemic administration via parenteral delivery, e.g., by intravenous (IV) delivery. In some embodiments, a composition provided herein (e.g., an LNP formulation) is formulated for intravenous delivery. In some embodiments, a composition provided herein (e.g., a composition comprising a GalNAc conjugate) is formulated for subcutaneous delivery. 
     The pharmaceutical compositions featured herein are administered in a dosage sufficient to inhibit expression of a LECT2 gene. In general, a suitable dose of iRNA will be in the range of 0.01 to 200.0 milligrams per kilogram body weight of the recipient per day, generally in the range of 1 to 50 mg per kilogram body weight per day. For example, the dsRNA can be administered at 0.05 mg/kg, 0.5 mg/kg, 1 mg/kg, 1.5 mg/kg, 2 mg/kg, 3 mg/kg, 10 mg/kg, 20 mg/kg, 30 mg/kg, 40 mg/kg, or 50 mg/kg per single dose. The pharmaceutical composition may be administered once daily, or the iRNA may 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 can be used with the agents of the present invention. In this embodiment, the dosage unit contains a corresponding multiple of the daily dose. 
     The effect of a single dose on LECT2 levels 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. 
     The skilled artisan will appreciate that certain factors may 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 a suitable animal model. 
     A suitable animal model, e.g., a mouse containing a transgene expressing human LECT2, can be used to determine the therapeutically effective dose and/or an effective dosage regimen administration of LECT2 siRNA. 
     The present disclosure also includes pharmaceutical compositions and formulations that include the iRNA compounds featured herein. The pharmaceutical compositions of the present invention may be administered in a number of ways depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may 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 a tissue that produces erythrocytes. For example, the iRNA can be delivered to bone marrow, liver (e.g., hepatocytes of liver), lymph glands, spleen, lungs (e.g., pleura of lungs) or spine. In one embodiment, the iRNA is delivered to bone marrow. 
     Pharmaceutical compositions and formulations for topical administration may 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 may be necessary or desirable. Coated condoms, gloves and the like may 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 may be encapsulated within liposomes or may form complexes thereto, in particular to cationic liposomes. Alternatively, iRNAs may 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. 
     Liposomal Formulations 
     There are many organized surfactant structures besides microemulsions that have been studied and used for the formulation of drugs. These include monolayers, micelles, bilayers and vesicles. Vesicles, such as liposomes, have attracted great interest because of their specificity and the duration of action they offer from the standpoint of drug delivery. As used in the present invention, the term “liposome” means a vesicle composed of amphiphilic lipids arranged in a spherical bilayer or bilayers. 
     Liposomes are unilamellar or multilamellar vesicles which have a membrane formed from a lipophilic material and an aqueous interior. The aqueous portion contains the composition to be delivered. Cationic liposomes possess the advantage of being able to fuse to the cell wall. Non-cationic liposomes, although not able to fuse as efficiently with the cell wall, are taken up by macrophages in vivo. 
     In order to traverse 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. Therefore, it is desirable to use a liposome which is highly deformable and able to pass through such fine pores. 
     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 drugs in their internal compartments from metabolism and degradation (Rosoff, in  Pharmaceutical Dosage Forms , Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., 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. 
     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 liposomes start to merge with the cellular membranes and as the merging of the liposome and cell progresses, the liposomal contents are emptied into the cell where the active agent may act. 
     Liposomal formulations have been the focus of extensive investigation as the mode of delivery for many drugs. There is growing evidence that 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 a wide variety of drugs, both hydrophilic and hydrophobic, into the skin. 
     Several reports have detailed the ability of liposomes to deliver agents including high-molecular weight DNA into the skin. Compounds including analgesics, antibodies, hormones and high-molecular weight DNAs have been administered to the skin. The majority of applications resulted in the targeting of the upper epidermis 
     Liposomes fall into two broad classes. Cationic liposomes are positively charged liposomes which interact with the negatively charged DNA molecules to form a stable complex. The positively charged DNA/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 DNA rather than complex with it. Since both the DNA and the lipid are similarly charged, repulsion rather than complex formation occurs. Nevertheless, some DNA is entrapped within the aqueous interior of these liposomes. pH-sensitive liposomes have been used to deliver DNA 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. 
     Several studies have assessed the topical delivery of liposomal drug formulations to the skin. Application of liposomes containing interferon to guinea pig skin resulted in a reduction of skin herpes sores while delivery of interferon via other means (e.g., as a solution or as an emulsion) were ineffective (Weiner et al.,  Journal of Drug Targeting,  1992, 2, 405-410). Further, an additional study tested the efficacy of interferon administered as part of a liposomal formulation to the administration of interferon using an aqueous system, and concluded that the liposomal formulation was superior to aqueous administration (du Plessis et al.,  Antiviral Research,  1992, 18, 259-265). 
     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 cyclosporin-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 GM1, 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 GM1, 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 M1  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). 
     Many liposomes comprising lipids derivatized with one or more hydrophilic polymers, and methods of preparation thereof, are known in the art. Sunamoto et al. (Bull.  Chem. Soc. Jpn.,  1980, 53, 2778) described liposomes comprising a nonionic detergent, 2C 1215G , that contains a PEG moiety. Illum et al. ( FEBS Lett.,  1984, 167, 79) noted that hydrophilic coating of polystyrene particles with polymeric glycols results in significantly enhanced blood half-lives. Synthetic phospholipids modified by the attachment of carboxylic groups of polyalkylene glycols (e.g., PEG) are described by Sears (U.S. Pat. Nos. 4,426,330 and 4,534,899). Klibanov et al. ( FEBS Lett.,  1990, 268, 235) described experiments demonstrating that liposomes comprising phosphatidylethanolamine (PE) derivatized with PEG or PEG stearate have significant increases in blood circulation half-lives. Blume et al. ( Biochimica et Biophysica Acta,  1990, 1029, 91) extended such observations to other PEG-derivatized phospholipids, e.g., DSPE-PEG, formed from the combination of distearoylphosphatidylethanolamine (DSPE) and PEG. Liposomes having covalently bound PEG moieties on their external surface are described in European Patent No. EP 0 445 131 B1 and WO 90/04384 to Fisher. Liposome compositions containing 1-20 mole percent of PE derivatized with PEG, and methods of use thereof, are described by Woodle et al. (U.S. Pat. Nos. 5,013,556 and 5,356,633) and Martin et al. (U.S. Pat. No. 5,213,804 and European Patent No. EP 0 496 813 B1). Liposomes comprising a number of other lipid-polymer conjugates are disclosed in WO 91/05545 and U.S. Pat. No. 5,225,212 (both to Martin et al.) and in WO 94/20073 (Zalipsky et al.). Liposomes comprising PEG-modified ceramide lipids are described in WO 96/10391 (Choi et al). U.S. Pat. No. 5,540,935 (Miyazaki et al.) and U.S. Pat. No. 5,556,948 (Tagawa et al.) describe PEG-containing liposomes that can be further derivatized with functional moieties on their surfaces. 
     A number of liposomes comprising nucleic acids are known in the art. WO 96/40062 to Thierry et al. discloses methods for encapsulating high molecular weight nucleic acids in liposomes. U.S. Pat. No. 5,264,221 to Tagawa et al. discloses protein-bonded liposomes and asserts that the contents of such liposomes may include a dsRNA. U.S. Pat. No. 5,665,710 to Rahman et al. describes certain methods of encapsulating oligodeoxynucleotides in liposomes. WO 97/04787 to Love et al. discloses liposomes comprising dsRNAs targeted to the raf gene. 
     Transfersomes are yet another type of liposomes, and are highly deformable lipid aggregates which are attractive candidates for drug delivery vehicles. Transfersomes may 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). 
     Nucleic Acid Lipid Particles 
     In one embodiment, a LECT2 dsRNA featured in the invention is fully encapsulated in the lipid formulation, e.g., to form a SPLP, pSPLP, SNALP, or other nucleic acid-lipid particle. As used herein, the term “SNALP” refers to a stable nucleic acid-lipid particle, including SPLP. As used herein, the term “SPLP” refers to a nucleic acid-lipid particle comprising plasmid DNA encapsulated within a lipid vesicle. SNALPs and SPLPs typically contain a cationic lipid, a non-cationic lipid, and a lipid that prevents aggregation of the particle (e.g., a PEG-lipid conjugate). SNALPs and SPLPs 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). SPLPs 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; 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. 
     The cationic lipid may 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,6a5)—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 may 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 non-cationic lipid may be an anionic lipid or a neutral lipid including, but not limited to, distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylglycerol (DOPG), dipalmitoylphosphatidylglycerol (DPPG), dioleoyl-phosphatidylethanolamine (DOPE), palmitoyloleoylphosphatidylcholine (POPC), palmitoyloleoylphosphatidylethanolamine (POPE), dioleoyl-phosphatidylethanolamine 4-(N-maleimidomethyl)-cyclohexane-1-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 may 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 may 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 may 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 may 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 some embodiments, the iRNA is formulated in a lipid nanoparticle (LNP). 
     LNP01 
     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 herein incorporated by reference), Cholesterol (Sigma-Aldrich), and PEG-Ceramide C16 (Avanti Polar Lipids) can be used to prepare lipid-dsRNA nanoparticles (e.g., 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 provided in the following table. 
                     TABLE 4                  Exemplary lipid formulations                                 cationic lipid/non-cationic               lipid/cholesterol/               PEG-lipid conjugate           Cationic Lipid   Lipid:siRNA ratio                                 SNALP   1,2-Dilinolenyloxy-N,N-   DLinDMA/DPPC/           dimethylaminopropane    Cholesterol/PEG-cDMA           (DLinDMA)    (57.1/7.1/34.4/1.4)               lipid:siRNA ~7:1       S-XTC   2,2-Dilinoleyl-4-   XTC/DPPC/           dimethylaminoethyl-   Cholesterol/PEG-cDMA           [1,3]-dioxolane (XTC)   57.1/7.1/34.4/1.4               lipid:siRNA ~7:1       LNP05   2,2-Dilinoleyl-4-   XTC/DSPC/           dimethylaminoethyl-   Cholesterol/PEG-DMG           [1,3]-dioxolane (XTC)   57.5/7.5/31.5/3.5               lipid:siRNA ~6:1       LNP06   2,2-Dilinoleyl-4-   XTC/DSPC/           dimethylaminoethyl-   Cholesterol/PEG-DMG           [1,3]-dioxolane (XTC)   57.5/7.5/31.5/3.5               lipid:siRNA ~11:1       LNP07   2,2-Dilinoleyl-4-   XTC/DSPC/           dimethylaminoethyl-   Cholesterol/PEG-DMG           [1,3]-dioxolane (XTC)   60/7.5/31/1.5,               lipid:siRNA ~6:1       LNP08   2,2-Dilinoleyl-4-   XTC/DSPC/           dimethylaminoethyl-   Cholesterol/PEG-DMG           [1,3]-dioxolane (XTC)   60/7.5/31/1.5,               lipid:siRNA ~11:1       LNP09   2,2-Dilinoleyl-4-   XTC/DSPC/           dimethylaminoethyl-   Cholesterol/PEG-DMG           [1,3]-dioxolane (XTC)   50/10/38.5/1.5               Lipid:siRNA 10:1       LNP10   (3aR,5s,6aS)-N,N-   ALN100/DSPC/           dimethyl-2,2-   Cholesterol/PEG-DMG           di((9Z,12Z)-   50/10/38.5/1.5           octadeca-9,12-   Lipid:siRNA 10:1           dienyl)tetrahydro-3aH-               cyclopenta[d][1,3]dioxol-               5-amine               (ALN100)           LNP11   (6Z,9Z,28Z,31Z)-   MC-3/DSPC/           heptatriaconta-   Cholesterol/PEG-DMG           6,9,28,31-tetraen-19-yl 4-   50/10/38.5/1.5           (dimethylamino)butanoate    Lipid:siRNA 10:1           (MC3)           LNP12   1,1&#39;-(2-(4-(2-((2-(bis(2-   C12-200/DSPC/           hydroxy-   Cholesterol/PEG-DMG           dodecyl)amino)ethyl)(2-   50/10/38.5/1.5           hydroxydode-   Lipid:siRNA 10:1           cyl)amino)ethyl)piperazin-1-               ypethylazanediypdidodecan-               2-ol               (C12-200)           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 Ser. No. 61/185,712, 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. Provisional Ser. No. 61/244,834, filed Sep. 22, 2009, U.S. Provisional Ser. No. 61/185,800, filed Jun. 10, 2009, and International Application No. PCT/US10/28224, filed Jun. 10, 2010, 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 Cationic Lipids 
     Any of the compounds, e.g., cationic lipids and the like, used in the nucleic acid-lipid particles featured in the invention may be prepared by known organic synthesis techniques. 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 may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized, including bicyclic rings in which any of the above heterocycles are fused to a benzene ring. The heterocycle may 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, tetrahydropyrimidinyl, 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, —OR x , —NR x R y , —NR x C(═O)R y , —NR x SO 2 R y , —C(═O)R x , —C(═O)OR x , —C(═O)NR x R y , —SO n R x  and —SO n NR x R y , wherein n is 0, 1 or 2, R x  and R y  are the same or different and independently hydrogen, alkyl or heterocycle, and each of said alkyl and heterocycle substituents may be further substituted with one or more of oxo, halogen, —OH, —CN, alkyl, —OR x , heterocycle, —NR x R y , —NR x C(═O)R y , —NR x SO 2 R y , —C(═O)R x , —C(═O)OR x , —C(═O)NR x R y , —SO n R x  and —SO n NR x R y . 
     “Halogen” means fluoro, chloro, bromo and iodo. 
     In some embodiments, the methods featured in the invention may require the use of protecting groups. Protecting group methodology is well known to those skilled in the art (see, for example, P ROTECTIVE  G ROUPS IN  O RGANIC  S YNTHESIS , 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 one embodiments, nucleic acid-lipid particles featured in 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 may be made by the following Reaction Schemes 1 or 2, wherein all substituents are as defined above unless indicated otherwise. 
     
       
         
         
             
             
         
       
     
     Lipid A, where R 1  and R 2  are independently alkyl, alkenyl or alkynyl, each can be optionally substituted, and R 3  and R 4  are independently lower alkyl or R 3  and R 4  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 LiAlH4 (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 NaHCO3(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=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 C44H80NO 2  (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 may 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 enhancers 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 may 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 may include sterile aqueous solutions which may 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 may be generated from a variety of components that include, but are not limited to, preformed liquids, self-emulsifying solids and self-emulsifying semisolids. 
     The pharmaceutical formulations featured in the present invention, which may conveniently be presented in unit dosage form, may 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 featured in the present invention may 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 may also be formulated as suspensions in aqueous, non-aqueous or mixed media. Aqueous suspensions may further contain substances which increase the viscosity of the suspension including, for example, sodium carboxymethylcellulose, sorbitol and/or dextran. The suspension may also contain stabilizers. 
     Additional Formulations 
     Emulsions 
     The compositions of the present invention may 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 may 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 may contain additional components in addition to the dispersed phases, and the active drug which may 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 may also be present in emulsions as needed. Pharmaceutical emulsions may 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 may 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 may be incorporated into either phase of the emulsion. Emulsifiers may 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 may 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 tri stearate. 
     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 may 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 may 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. 
     In one embodiment of the present invention, the compositions of iRNAs and nucleic acids are formulated as microemulsions. A microemulsion may 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 (DAO750), 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 may, however, be prepared without the use of cosurfactants and alcohol-free self-emulsifying microemulsion systems are known in the art. The aqueous phase may 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 may 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 may form spontaneously when their components are brought together at ambient temperature. This may 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 may 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 may 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. 
     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 may 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 may 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: In connection with the present invention, 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). 
     Fatty acids: 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). 
     Bile salts: 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: 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 β-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). 
     Non-chelating non-surfactants: 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 include, 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 may 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 a  D1 Transfection Reagent (New England Biolabs; Ipswich, Mass., USA), LyoVec™/LipoGen™ (Invivogen; 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 may 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. 
     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). 
     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 may 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 may 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 may 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. 
     Other Components 
     The compositions of the present invention may additionally contain other adjunct components conventionally found in pharmaceutical compositions, at their art-established usage levels. Thus, for example, the compositions may contain additional, compatible, pharmaceutically-active materials such as, for example, antipruritics, astringents, local anesthetics or anti-inflammatory agents, or may 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 may contain substances that increase the viscosity of the suspension including, for example, sodium carboxymethylcellulose, sorbitol and/or dextran. The suspension may also contain stabilizers. 
     In some embodiments, pharmaceutical compositions featured in the invention include (a) one or more iRNA compounds and (b) one or more biologic agents which function by a non-RNAi mechanism. Examples of such biologic agents include agents that interfere with an interaction of LECT2 and at least one LECT2 binding partner. 
     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 typical. 
     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 in the invention lies generally within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may 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 may 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 may 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 diseases or disorders related to LECT2 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. 
     Methods of Treating Disorders Related to Expression of a LECT2 Gene 
     The present disclosure relates to the use of an iRNA targeting LECT2 to inhibit LECT2 expression and/or to treat a disease, disorder, or pathological process that is related to LECT2 expression. 
     In one aspect, a method of treatment of a disorder related to expression of LECT2 is provided, the method comprising administering an iRNA (e.g., a dsRNA) disclosed herein to a subject in need thereof. In some embodiments, the iRNA inhibits (decreases) LECT2 expression. In some embodiments, the iRNA increases LECT2 expression. 
     As used herein, “a disorder related to LECT2 expression,” a “disease related to LECT2 expression, a “pathological process related to LECT2 expression,” or the like includes any condition, disorder, or disease in which LECT2 expression is altered (e.g., decreased or increased relative to a normal level). In some embodiments, LECT2 expression is decreased. In some embodiments, LECT2 expression is increased. In embodiments, the decrease or increase in LECT2 expression is detectable in the blood (e.g., in the plasma) of the subject. In embodiments, the decrease or increase in LECT2 expression is detectable in a tissue sample from the subject (e.g., in a kidney sample or a liver sample). The decrease or increase may be assessed relative the level observed in the same individual prior to the development of the disorder or relative to other individual(s) who do not have the disorder. The decrease or increase may be limited to a particular organ, tissue, or region of the body (e.g., the kidney or the liver). 
     As used herein, a “subject” to be treated according to the methods described herein, includes a human or non-human animal, e.g., a mammal. The mammal may be, for example, a rodent (e.g., a rat or mouse) or a primate (e.g., a monkey). In some embodiments, the subject is a human. 
     A “subject in need thereof” includes a subject having, suspected of having, or at risk of developing a disorder related to LECT2 expression. In some embodiments, the subject has, or is suspected of having, a disorder related to LECT2 expression. In some embodiments, the subject is at risk of developing a disorder related to LECT2 expression. 
     In some embodiments, the subject is an animal that serves as a model for a disorder related to LECT2 expression, e.g., a LECT2 amyloidosis. 
     LECT2 Amyloidosis 
     In embodiments, the disorder related to LECT2 expression is an amyloidosis, e.g., a LECT2 amyloidosis. LECT2 amyloidosis has been described in several clinical studies. See, e.g., Benson, M. D. et al (2008)  Kidney International,  74: 218-222; Murphy, C. L. et al. (2010)  Am J Kidney Dis,  56(6):1100-1107; Larsen, C. P. et al. (2010)  Kidney Int.,  77(9):816-819; Holanda, D. G. et al. (20011)  Nephrol. Dial. Transplant.,  26 (1): 373-376; and Sethi, S. et al. (2012)  Kidney International  82, 226-234 (hereinafter Sethi et al.). 
     Clinical and pathological features of LECT2 amyloidosis mimic those of amyloid light chain (AL) amyloidosis. These symptoms include, e.g., symptoms of kidney disease and renal failure, e.g., fluid retention, swelling, and shortness of breath. Amyloidosis may affect the heart, peripheral nervous system, gastrointestinal tract, blood, lungs and skin. Heart complications include, e.g., heart failure and irregular heart beat. Other symptoms include, e.g., stroke, gastrointestinal disorders, enlarged liver, diminished spleen function, diminished function of the adrenal and other endocrine glands, skin color change or growths, lung problems, bleeding and bruising problems, fatigue and weight loss. In embodiments, the methods described herein are associated with improvement in one or more symptoms described herein. 
     Methods for diagnosis of amyloidosis, e.g., LECT2 amyloidosis, are described, e.g., in Leung, N. et al. (2010)  Blood , published online Sep. 4, 2012; DOE 10.1182/blood-2012-03-413682; Shiller, S. M. et al. (2011). Laboratory Methods for the Diagnosis of Hereditary Amyloidoses, Amyloidosis-Mechanisms and Prospects for Therapy, Dr. Svetlana Sarantseva (Ed.), ISBN: 978-953-307-253-1; Sethi et al. (see above) and in U.S. Patent Application Publication No. 20100323381. 
     Based on the results provided by Sethi et al., LECT2 amyloidosis accounts for a significant percentage of cases of renal amyloidosis. See Table 1 of Sethi et al., which shows that 26 out of 127 cases of renal amyloidosis studied by laser microdissection and mass spectrometry of renal biopsy and/or nephrectomy specimens were determined to be of the LECT2 amyloid type. Sethi et al. further report that apolipoprotein E protein and serum amyloid P component (SAP) were also present in all cases of LECT2 amyloidosis. 
     In embodiments, the amyloidosis, e.g., the LECT2 amyloidosis, involves systemic amyloid deposition. In embodiments, the amyloidosis, e.g., the LECT2 amyloidosis, is localized entirely or predominately to a particular tissue or organ (e.g., to the kidney or liver). 
     In embodiments, the amyloidosis, e.g., the LECT2 amyloidosis, is hereditary. 
     In embodiments, a LECT2 amyloidosis is diagnosed using analysis of a sample from the subject (e.g., a biopsy sample). In embodiments, the biopsy sample is a renal biopsy. In embodiments, the sample is a nephrectomy sample. In embodiments, the sample is from a liver biopsy or from other resected liver tissue. In embodiments, the sample is analyzed using methods selected from one or more of immunohistochemistry, LECT2 immunoassay, electron microscopy, laser microdissection, and mass spectrometry. In embodiments, the LECT2 amyloidosis is diagnosed using laser microdissection and mass spectrometry. 
     In embodiments, the amyloidosis, e.g., the LECT2 amyloidosis, affects the kidney, e.g., involves amyloid deposition in the kidney. In embodiments, kidney function is compromised as a result of the amyloidosis. In embodiments, the subject suffers from one or more of fluid retention, swelling, and shortness of breath. In embodiments, the subject has nephrotic syndrome. In embodiments, the subject suffers from proteinuria. In embodiments, the subject has renal failure. 
     In embodiments, the amyloidosis, e.g., the LECT2 amyloidosis, affects the liver, e.g., involves amyloid deposition in the liver. In embodiments, liver function is compromised as a result of the amyloidosis. In embodiments, the subject has hepatitis, e.g., chronic hepatitis. In embodiments, the hepatitis is a viral hepatitis. 
     LECT2 amyloidosis has been found to be particularly prevalent in Mexican Americans and has also been associated with homozygosity for the G allele of the LECT2 gene that encodes valine at position 40 in the mature protein (amino acid 58 in the unprocessed protein). See, e.g., Benson, M. D. et al. (2008)  Kidney International,  74: 218-222; Murphy, C. L. et al. (2010)  Am J Kidney Dis,  56(6):1100-1107. 
     In some embodiments, the subject is of Mexican descent. In some embodiments, the subject is a Mexican American. 
     In embodiments, the subject carries the G allele of the LECT2 gene that encodes valine at position 40 in the mature protein (amino acid 58 in the unprocessed protein). In embodiments, the subject is homozygous for the G allele (G/G genotype). In embodiments, a LECT2 protein expressed in the subject has valine at position 40 in the mature protein (or at amino acid 58 in the unprocessed protein). 
     In some embodiments, the method decreases LECT2 expression. In embodiments, the decrease in LECT2 expression is assessed relative to the level in the same individual prior to the treatment. In some embodiments, the method is shown to decrease LECT2 expression by comparing the levels of LECT2 expression in a treated subject (or group of subjects) with the levels in a control subject (or group of subjects), e.g., an untreated subject (or group of subjects) or a subject (or group of subjects) treated with a control treatment (e.g., an iRNA (e.g., a dsRNA) that does not target LECT2). 
     In embodiments, the method reduces amyloid deposition, e.g., deposition of amyloid comprising a LECT2 protein or a portion thereof. In embodiments, the protein is a wild type protein. In embodiments, the protein is a human LECT2 protein, or a portion thereof, that includes valine at position 40 (position 40 of the mature, secreted protein, or at amino acid 58 in the unprocessed protein, as described herein). In embodiments, the method decreases the size, number, and/or extent of amyloid deposits. 
     In embodiments, the method decreases one or more symptoms associated with amyloid deposition. 
     In some embodiments, the dsRNA is administered in a form that targets the dsRNA to a particular organ or tissue to inhibit amyloid deposition in the organ or tissue. In some embodiments, the dsRNA is targeted to the liver. In some embodiments, the dsRNA is conjugated to a ligand, e.g., a GalNAc ligand (e.g., a GalNAc ligand as described herein) that targets the dsRNA to the liver (e.g., to hepatocytes). 
     Also provided herein is a method of reducing amyloid deposition, the method comprising administering a dsRNA as disclosed herein to a subject in need thereof (e.g., a subject having, suspected of having, or at risk for developing a LECT2 amyloidosis). In embodiments, the method decreases (e.g., prevents or diminishes) the size, number, and/or extent of amyloid deposits. The size, number, and/or extent of amyloid deposits may be assessed using any method known in the art (e.g., immunoassay, immunohistochemistry, mass spectrometry). The reduction of amyloid deposition may involve a decrease in amyloid deposition (e.g., size, number, and/or extent of amyloid deposits) of at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more. 
     In the methods provided herein, the iRNA (e.g., dsRNA) and compositions thereof are administered in a therapeutically effective amount. Therapeutic effects of administration of a LECT2 siRNA can be established, for example, by comparison with an appropriate control. For example, inhibition of amyloid deposition may be established, for example, in a group of patients with amyloidosis (e.g., LECT2 amyloidosis) by comparison of any appropriate parameter (e.g., a parameter assessing the size, number, or extent of amyloid deposition) with the same parameter in an appropriate control group. A control group (e.g., a group of similar individuals or the same group of individuals in a crossover design) may include, for example, an untreated population, a population that has been treated with a conventional treatment; a population that has been treated with placebo or a non-targeting iRNA; and the like. 
     Rheumatoid Arthritis 
     Rheumatoid arthritis is also a disorder related to LECT2 expression. In particular, in a Japanese population, it was found that possession of one A allele of the LECT2 gene that encodes isoleucine at position 40 in the mature protein (or amino acid 58 in the unprocessed protein) was found to increase the overall risk of developing rheumatoid arthritis. Possessing two A alleles was strongly associated with disease severity. See Kameoka, Y. et al. (2000)  Arth Rheum,  43(6):1419-20. 
     In one embodiment of the methods provided herein, the disorder related to LECT2 expression is rheumatoid arthritis. In one embodiment, the dsRNA inhibits LECT2 expression in a subject having rheumatoid arthritis. In some such embodiments, the dsRNA inhibits LECT2 expression in synovial tissue and/or in synovial fluid-derived cells (e.g., mononuclear cells and fibroblasts). In some embodiments, the dsRNA targets an mRNA that encodes isoleucine at position 40 in the mature protein (amino acid 58 in the unprocessed protein). 
     Liver Injury 
     LECT2 expression can increase during acute liver injury. 
     In one embodiment of the methods provided herein, the disorder related to LECT2 expression is acute liver injury. In embodiments, the iRNA (e.g., dsRNA) modulates (e.g., increases or decreases) LECT2 expression. In embodiments, the iRNA modulates LECT2 expression in the liver. In embodiments, the iRNA decreases LECT2 expression in the liver. In embodiments, the iRNA increases LECT2 expression in the liver. 
     Combination Therapies 
     In embodiments, an iRNA (e.g., a dsRNA) disclosed herein is administered in combination with a second therapy (e.g., one or more additional therapies) known to be effective in treating a disorder related to LECT2 expression (e.g., a LECT2 amyloidosis) or a symptom of such a disorder. The iRNA may be administered before, after, or concurrent with the second therapy. In embodiments, the iRNA is administered before the second therapy. In embodiments, the iRNA is administered after the second therapy. In embodiments, the iRNA is administered concurrent with the second therapy. 
     The second therapy may be an additional therapeutic agent. The iRNA and the additional therapeutic agent can be administered in combination in the same composition or the additional therapeutic agent can be administered as part of a separate composition. 
     In some embodiments, the second therapy is a non-iRNA therapeutic agent that is effective to treat the disorder or symptoms of the disorder. 
     In some embodiments, the disorder to be treated by the compositions or methods disclosed herein is a LECT2 amyloidosis that affects kidney function, e.g., through amyloid deposition in the kidney. In some such embodiments, the iRNA is administered in conjunction with a therapy that supports kidney function (e.g., dialysis, a diuretic, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin receptor blocker (ARB), or dialysis). 
     In some embodiments, the disorder to be treated by the compositions or methods disclosed herein is a LECT2 amyloidosis involving amyloid deposits in the liver. In some such embodiments, the iRNA is administered in conjunction with a therapy that supports liver function. 
     In some embodiments, the disorder to be treated by the compositions or methods disclosed herein is a LECT2 amyloidosis, and the iRNA is administered in conjunction with removal of all or part of the organ(s) affected by the amyloidosis (e.g., resection of all or part of kidney or liver tissue affected by the amyloidosis). The removal is optionally conducted in conjunction with a replacement of all or part of the organ removed (e.g., in conjunction with a kidney or liver organ transplant). 
     Administration Dosages, Routes, and Timing 
     A subject (e.g., a human subject, e.g., a patient) can be administered a therapeutic amount of iRNA. The therapeutic amount can be, e.g., 0.05-50 mg/kg. For example, the therapeutic amount can be 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, 2.0, or 2.5, 3.0, 3.5, 4.0, 4.5, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 mg/kg dsRNA. 
     In some embodiments, the iRNA is formulated for delivery to a target organ, e.g., to the liver. 
     In some embodiments, the iRNA is formulated as a lipid formulation, e.g., an LNP formulation as described herein. In some such embodiments, the therapeutic amount is 0.05-5 mg/kg, e.g., 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 mg/kg dsRNA. In some embodiments, the lipid formulation, e.g., LNP formulation, is administered intravenously. In embodiments, the iRNA (e.g., dsRNA) is formulated as an LNP formulation and is administered (e.g., intravenously administered) at a dose of 0.1 to 0.5 mg/kg. 
     In some embodiments, the iRNA is administered by intravenous infusion over a period of time, such as over a 5 minute, 10 minute, 15 minute, 20 minute, or 25 minute period. 
     In some embodiments, the iRNA is in the form of a GalNAc conjugate as described herein. In some such embodiments, the therapeutic amount is 0.5-50 mg, e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, or 50 mg/kg dsRNA. In some embodiments, the GalNAc conjugate is administered subcutaneously. In embodiments, the iRNA (e.g., dsRNA) is in the form of a GalNAc conjugate and is administered (e.g., subcutaneously administered) at a dose of 1 to 10 mg/kg. 
     In some embodiments, the administration is repeated, for example, on a regular basis, such as, daily, 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 biweekly for three months, administration can be repeated once per month, for six months or a year or longer. 
     In some embodiments, the iRNA agent is administered in two or more doses. In some embodiments, the number or amount of subsequent doses is dependent on the achievement of a desired effect, e.g., inhibition of amyloid deposition, or the achievement of a therapeutic or prophylactic effect, e.g., reduction or prevention of one or more symptoms associated with the disorder. 
     In some embodiments, the iRNA agent is administered according to a schedule. For example, the iRNA agent may be administered once per week, twice per week, three times per week, four times per week, or five times per week. In some embodiments, the schedule involves regularly spaced administrations, e.g., hourly, every four hours, every six hours, every eight hours, every twelve hours, daily, every 2 days, every 3 days, every 4 days, every 5 days, weekly, biweekly, or monthly. In embodiments, the iRNA agent is administered at the frequency required to achieve a desired effect. 
     In embodiments, the schedule involves closely spaced administrations followed by a longer period of time during which the agent is not administered. For example, the schedule may involve an initial set of doses that are administered in a relatively short period of time (e.g., about every 6 hours, about every 12 hours, about every 24 hours, about every 48 hours, or about every 72 hours) followed by a longer time period (e.g., about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, or about 8 weeks) during which the iRNA agent is not administered. In one embodiment, the iRNA agent is initially administered hourly and is later administered at a longer interval (e.g., daily, weekly, biweekly, or monthly). In another embodiment, the iRNA agent is initially administered daily and is later administered at a longer interval (e.g., weekly, biweekly, or monthly). In certain embodiments, the longer interval increases over time or is determined based on the achievement of a desired effect. 
     Before administration of a full dose of the iRNA, patients can be administered a smaller dose, such as a 5% infusion dose, and monitored for adverse effects, such as an allergic reaction, or for elevated lipid levels or blood pressure. In another example, the patient can be monitored for unwanted effects. 
     Methods for Modulating Expression of a LECT2 Gene 
     In yet another aspect, the invention provides a method for modulating (e.g., inhibiting or activating) the expression of LECT2 gene, e.g., in a cell or in a subject. In some embodiments, the cell is ex vivo, in vitro, or in vivo. In some embodiments, the cell is in the liver (e.g., a hepatocyte). In some embodiments, the cell is in a subject (e.g., a mammal, such as, for example, a human). In some embodiments, the subject (e.g., the human) is at risk, or is diagnosed with a disorder related to expression of LECT2 expression, as described herein. 
     In one embodiment, the method includes contacting the cell with an iRNA as described herein, in an amount effective to decrease the expression of a LECT2 gene in the cell. “Contacting,” as used herein, includes directly contacting a cell, as well as indirectly contacting a cell. For example, a cell within a subject may be contacted when a composition comprising an iRNA is administered (e.g., intravenously or subcutaneously) to the subject. 
     The expression of a LECT2 gene may be assessed based on the level of expression of a LECT2 mRNA, a LECT2 protein, or the level of another parameter functionally linked to the level of expression of a LECT2 gene. In some embodiments, the expression of LECT2 is inhibited by at least 5%, 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%, or at least 95%. In some embodiments, the iRNA has an IC 50  in the range of 0.001-0.01 nM, 0.001-0.10 nM, 0.001-1.0 nM, 0.001-10 nM, 0.01-0.05 nM, 0.01-0.50 nM, 0.02-0.60 nM, 0.01-1.0 nM, 0.01-1.5 nM, 0.01-10 nM. The IC 50  value may be normalized relative to an appropriate control value, e.g., the IC 50  of a non-targeting iRNA. 
     In some embodiments, the method includes introducing into the cell an iRNA as described herein and maintaining the cell for a time sufficient to obtain degradation of the mRNA transcript of a LECT2 gene, thereby inhibiting the expression of the LECT2 gene in the cell. 
     In one embodiment, the method includes administering a composition described herein, e.g., a composition comprising an iRNA that targets LECT2, to the mammal such that expression of the target LECT2 gene is decreased, such as for an extended duration, e.g., at least two, three, four days or more, e.g., one week, two weeks, three weeks, or four weeks or longer. In some embodiments, the decrease in expression of LECT2 is detectable within 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, or 24 hours of the first administration. 
     In another embodiment, the method includes administering a composition as described herein to a mammal such that expression of the target LECT2 gene is increased by e.g., at least 10% compared to an untreated animal. In some embodiments, the activation of LECT2 occurs over an extended duration, e.g., at least two, three, four days or more, e.g., one week, two weeks, three weeks, four weeks, or more. Without wishing to be bound by theory, an iRNA can activate LECT2 expression by stabilizing the LECT2 mRNA transcript, interacting with a promoter in the genome, and/or inhibiting an inhibitor of LECT2 expression. 
     The iRNAs useful for the methods and compositions featured in the invention specifically target RNAs (primary or processed) of a LECT2 gene. Compositions and methods for inhibiting the expression of a LECT2 gene using iRNAs can be prepared and performed as described elsewhere herein. 
     In one embodiment, the method includes administering 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 LECT2 gene of the subject, e.g., the mammal, e.g., the human, to be treated. The composition may be administered by any appropriate means known in the art including, but not limited to oral, intraperitoneal, or parenteral routes, including intracranial (e.g., intraventricular, intraparenchymal and intrathecal), intravenous, intramuscular, subcutaneous, transdermal, airway (aerosol), nasal, rectal, and topical (including buccal and sublingual) administration. 
     In certain embodiments, the composition is administered by intravenous infusion or injection. In some such embodiments, the composition comprises a lipid formulated siRNA (e.g., an LNP formulation, such as an LNP11 formulation) for intravenous infusion. 
     In other embodiments, the composition is administered subcutaneously. In some such embodiments, the composition comprises an iRNA conjugated to a GalNAc ligand. In some such embodiments, the ligand targets the iRNA to the liver (e.g., to hepatocytes). 
     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. LECT2 siRNA 
     Nucleic acid sequences provided herein are represented using standard nomenclature. See the abbreviations of Table 1. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 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&#39;-3&#39;-phosphodiester bonds. 
               
            
           
           
               
               
            
               
                 Abbreviation 
                 Nucleotide(s) 
               
               
                   
               
               
                 A 
                 Adenosine-3&#39;-phosphate 
               
               
                 Ab 
                 beta-L-adenosine-3    phosphate 
               
               
                 Abs 
                 beta-L-adenosine-3    phosphorothioate 
               
               
                 Af 
                 2&#39;-fluoroadenosine-3&#39;-phosphate 
               
               
                 Afs 
                 2&#39;-fluoroadenosine-3&#39;-phosphorothioate 
               
               
                 As 
                 adenosine-3&#39;-phosphorothioate 
               
               
                 C 
                 cytidine-3&#39;-phosphate 
               
               
                 Cb 
                 beta-L-cytidine-3&#39;-phosphate 
               
               
                 Cbs 
                 beta-L-cytidine-3&#39;-phosphorothioate 
               
               
                 Cf 
                 2&#39;-fluorocytidine-3&#39;-phosphate 
               
               
                 Cfs 
                 2&#39;-fluorocytidine-3&#39;-phosphorothioate 
               
               
                 (Chd) 
                 2&#39;-O-hexadecyl-cytidine-3&#39;-phosphate 
               
               
                 (Chds) 
                 2&#39;-O-hexadecyl-cytidine-3&#39;-phosphorothioate 
               
               
                 Cs 
                 cytidine-3&#39;-phosphorothioate 
               
               
                 G 
                 guanosine-3&#39;-phosphate 
               
               
                 Gb 
                 beta-L-guanosine-3    phosphate 
               
               
                 Gbs 
                 beta-L-guanosine-3    phosphorothioate 
               
               
                 Gf 
                 2&#39;-fluoroguanosine-3&#39;-phosphate 
               
               
                 Gfs 
                 2&#39;-fluoroguanosine-3&#39;-phosphorothioate 
               
               
                 Gs 
                 guanosine-3&#39;-phosphorothioate 
               
               
                 T 
                 5&#39;-methyluridine-3&#39;-phosphate 
               
               
                 Tb 
                 beta-L-thymidine-3&#39;-phosphate 
               
               
                 Tbs 
                 beta-L-thymidine-3&#39;-phosphorothioate 
               
               
                 Tf 
                 2&#39;-fluoro-5-methyluridine-3&#39;-phosphate 
               
               
                 Tfs 
                 2&#39;-fluoro-5-methyluridine-3&#39;-phosphorothioate 
               
               
                 Ts 
                 5-methyluridine-3&#39;-phosphorothioate 
               
               
                 U 
                 Uridine-3&#39;-phosphate 
               
               
                 Ub 
                 beta-L-uridine-3    phosphate 
               
               
                 Ubs 
                 beta-L-uridine-3    phosphorothioate 
               
               
                 Uf 
                 2&#39;-fluorouridine-3&#39;-phosphate 
               
               
                 Ufs 
                 2&#39;-fluorouridine-3&#39;-phosphorothioate 
               
               
                 (Uhd) 
                 2&#39;-O-hexadecyl-uridine-3&#39;-phosphate 
               
               
                 (Uhds) 
                 2&#39;-O-hexadecyl-uridine-3&#39;-phosphorothioate 
               
               
                 Us 
                 uridine-3&#39;-phosphorothioate 
               
               
                 N 
                 any nucleotide (G, A, C, T or U) 
               
               
                 a 
                 2&#39;-O-methyladenosine-3&#39;-phosphate 
               
               
                 as 
                 2&#39;-O-methyladenosine-3&#39;-phosphorothioate 
               
               
                 c 
                 2&#39;-O-methylcytidine-3&#39;-phosphate 
               
               
                 cs 
                 2&#39;-O-methylcytidine-3&#39;-phosphorothioate 
               
               
                 g 
                 2&#39;-O-methylguanosine-3&#39;-phosphate 
               
               
                 gs 
                 2&#39;-O-methylguanosine-3&#39;-phosphorothioate 
               
               
                 t 
                 2&#39;-O-methyl-5-methyluridine-3&#39;-phosphate 
               
               
                 ts 
                 2&#39;-O-methyl-5-methyluridine-3&#39;-phosphorothioate 
               
               
                 u 
                 2&#39;-O-methyluridine-3&#39;-phosphate 
               
               
                 us 
                 2&#39;-O-methyluridine-3&#39;-phosphorothioate 
               
               
                 dA 
                 2    deoxyadenosine-3    phosphate 
               
               
                 dAs 
                 2    deoxyadenosine-3    phosphorothioate 
               
               
                 dC 
                 2    deoxycytidine-3    phosphate 
               
               
                 dCs 
                 2    deoxycytidine-3    phosphorothioate 
               
               
                 dG 
                 2    deoxyguanosine-3    phosphate 
               
               
                 dGs 
                 2    deoxyguanosine-3    phosphorothioate 
               
               
                 dT 
                 2&#39;-deoxythymidine 
               
               
                 dTs 
                 2    deoxythymidine-3    phosphorothioate 
               
               
                 dU 
                 2    deoxyuridine 
               
               
                 s 
                 phosphorothioate linkage 
               
               
                 L961 
                 N-[tris(GalNAc-alkyl)-amidodecanoyl)]- 
               
               
                   
                 4-hydroxyprolinol Hyp- 
               
               
                   
                 (GalNAc-alkyl)3 
               
               
                 (Aeo) 
                 2&#39;-O-methoxyethyladenosine-3&#39;-phosphate 
               
               
                 (Aeos) 
                 2&#39;-O-methoxyethyladenosine-3&#39;-phosphorothioate 
               
               
                 (Geo) 
                 2&#39;-O-methoxyethylguanosine-3&#39;-phosphate 
               
               
                 (Geos) 
                 2&#39;-O-methoxyethylguanosine-3&#39;-phosphorothioate 
               
               
                 (Teo) 
                 2&#39;-O-methoxyethyl-5-methyluridine-3&#39;-phosphate 
               
               
                 (Teos) 
                 2&#39;-O-methoxyethyl-5-methyluridine-3&#39;-phosphorothioate 
               
               
                 (m5Ceo) 
                 2&#39;-O-methoxyethyl-5-methylcytidine-3&#39;-phosphate 
               
               
                 (m5Ceos) 
                 2&#39;-O-methoxyethyl-5-methylcytidine-3&#39;-phosphorothioate 
               
               
                   
               
            
           
         
       
     
       1 The chemical structure of L96 is as follows: 
     
       
         
         
             
             
         
       
     
     Experimental Methods 
     Bioinformatics 
     Transcripts 
     siRNA design was carried out to identify siRNAs targeting human, cynomolgus monkey ( Macaca fascicularis ; henceforth “cyno”), mouse, and rat LECT2 transcripts. Design used the following transcripts from the NCBI RefSeq collection, annotated in the NCBI Gene database (http://www.ncbi.nlm.nih.gov/gene/): Human, NM_002302.2; mouse, NM_010702.1; rat, NM_001108405.1. For cyno, design used a transcript sequenced from a liver-derived cDNA library. Due to high primate/rodent sequence divergence, siRNA duplexes were designed in several separate batches, including but not limited to batches containing duplexes matching human and cyno transcripts only; human, cyno, and mouse transcripts only; and human, cyno, mouse, and rat transcripts only. Most siRNA duplexes were designed that shared 100% identity in the designated region with the listed human transcript and other species transcripts considered in each design batch (above). In some instances, mismatches between duplex and mRNA target were allowed at the first antisense (last sense) position when the antisense strand:target mRNA complementary basepair was a GC or CG pair (see Table 3, oligos with label G21U, G21A, C21A). In these cases, duplexes were designed with UA or AU pairs at the first antisense:last sense pair. Thus the duplexes maintained complementarity but were mismatched with respect to target (U:C, U:G, A:C, or A:G). 
     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 353 candidate human/cyno, 24 human/cyno/mouse, and 10 human/cyno/mouse/rat siRNAs were used in comprehensive searches against the appropriate transcriptomes (defined as the set of NM and XM_records within the human, cyno, 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 is used to create 2 heptamers and one octomer. A ‘heptamer1’ was created by adding a 3′ A to the hexamer; we create heptamer2 by adding a 5′ A to the hexamer; we create the octomer by adding an A to both 5′ and 3′ ends of the hexamer. The frequency of octomers and heptamers in the human, cyno, 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 octomer frequency was normalized to the heptamer frequency using the median value from the range of octomer frequencies. A ‘mirSeedScore’ was then calculated by calculating the sum of ((3× normalized octomer count)+(2× heptamer2 count)+(1× heptamer1 count)). 
     Both siRNA 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 then moderately (or higher) specific duplexes whose antisense oligos possessed characteristics of duplexes with high predicted efficacy, including maximal UA content in the seed region and low overall GC content, were selected. 23 human/cyno/mouse sense:antisense oligo pairs, including 6 where the first antisense position was swapped to UA (above), were selected. Similarly, 24 human/cyno, and 5 human/cyno/mouse/rat, oligo pairs were selected. The selected antisense oligos were then extended to 23 nucleotides in length, and sense oligos to 21 nucleotides in length. The 48 oligo pairs that still fully matched at least human and cyno transcripts (excluding the first position for UA-swapped sequences) were then selected for synthesis and annealing into duplexes. (Table 3) 
     We also selected a set of 198 pairs of 19mer oligos that matched at least the human LECT2 transcript. These were selected to have at least one mismatch to all other annotated human transcripts, and possess good predicted efficacy as above. (Table 2) 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Human LECT2 siRNA Single Strands and Duplex Sequences 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 SEQ 
                   
                   
                   
                   
               
               
                   
                 ID 
                   
                   
                   
                   
               
               
                 SEQ ID 
                 NO: 
                   
                 Start Position 
                   
                   
               
               
                 NO: 
                 (anti- 
                   
                 on transcript 
                   
                   
               
               
                 (sense) 
                 sense) 
                 Oligo Name 
                 NM_002302.2 
                 Sense Sequence (5′-3′) 
                 Antisense Sequence (5′-3′) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 2 
                 3 
                 NM_002302.2_1- 
                 1 
                 AAAUCAAAUAGCUAUCCAU 
                 AUGGAUAGCUAUUUGAUUU 
               
               
                   
                   
                 19_s 
                   
                   
                   
               
               
                   
               
               
                 4 
                 5 
                 NM_002302.2_7- 
                 7 
                 AAUAGCUAUCCAUGGAAUA 
                 UAUUCCAUGGAUAGCUAUU 
               
               
                   
                   
                 25_s 
                   
                   
                   
               
               
                   
               
               
                 6 
                 7 
                 NM_002302.2_13- 
                 13 
                 UAUCCAUGGAAUAUUAGAA 
                 UUCUAAUAUUCCAUGGAUA 
               
               
                   
                   
                 31_s 
                   
                   
                   
               
               
                   
               
               
                 8 
                 9 
                 NM_002302.2_18- 
                 18 
                 AUGGAAUAUUAGAACUUGA 
                 UCAAGUUCUAAUAUUCCAU 
               
               
                   
                   
                 36_s 
                   
                   
                   
               
               
                   
               
               
                 10 
                 11 
                 NM_002302.2_21- 
                 21 
                 GAAUAUUAGAACUUGACUU 
                 AAGUCAAGUUCUAAUAUUC 
               
               
                   
                   
                 39_s 
                   
                   
                   
               
               
                   
               
               
                 12 
                 13 
                 NM_002302.2_28- 
                 28 
                 AGAACUUGACUUGCUCCAU 
                 AUGGAGCAAGUCAAGUUCU 
               
               
                   
                   
                 46_s 
                   
                   
                   
               
               
                   
               
               
                 14 
                 15 
                 NM_002302.2_29- 
                 29 
                 GAACUUGACUUGCUCCAUC 
                 GAUGGAGCAAGUCAAGUUC 
               
               
                   
                   
                 47_s 
                   
                   
                   
               
               
                   
               
               
                 16 
                 17 
                 NM_002302.2_34- 
                 34 
                 UGACUUGCUCCAUCCUCUU 
                 AAGAGGAUGGAGCAAGUCA 
               
               
                   
                   
                 52_s 
                   
                   
                   
               
               
                   
               
               
                 18 
                 19 
                 NM_002302.2_43- 
                 43 
                 CCAUCCUCUUAAACUUUUU 
                 AAAAAGUUUAAGAGGAUGG 
               
               
                   
                   
                 61_s 
                   
                   
                   
               
               
                   
               
               
                 20 
                 21 
                 NM_002302.2_47- 
                 47 
                 CCUCUUAAACUUUUUGUGU 
                 ACACAAAAAGUUUAAGAGG 
               
               
                   
                   
                 65_s 
                   
                   
                   
               
               
                   
               
               
                 22 
                 23 
                 NM_002302.2_49- 
                 49 
                 UCUUAAACUUUUUGUGUCU 
                 AGACACAAAAAGUUUAAGA 
               
               
                   
                   
                 67_s 
                   
                   
                   
               
               
                   
               
               
                 24 
                 25 
                 NM_002302.2_56- 
                 56 
                 CUUUUUGUGUCUCACACUA 
                 UAGUGUGAGACACAAAAAG 
               
               
                   
                   
                 74_s 
                   
                   
                   
               
               
                   
               
               
                 26 
                 27 
                 NM_002302.2_62- 
                 62 
                 GUGUCUCACACUAAAGAAA 
                 UUUCUUUAGUGUGAGACAC 
               
               
                   
                   
                 80_s 
                   
                   
                   
               
               
                   
               
               
                 28 
                 29 
                 NM_002302.2_67- 
                 67 
                 UCACACUAAAGAAAUGAGA 
                 UCUCAUUUCUUUAGUGUGA 
               
               
                   
                   
                 85_s 
                   
                   
                   
               
               
                   
               
               
                 30 
                 31 
                 NM_002302.2_69- 
                 69 
                 ACACUAAAGAAAUGAGAGA 
                 UCUCUCAUUUCUUUAGUGU 
               
               
                   
                   
                 87_s 
                   
                   
                   
               
               
                   
               
               
                 32 
                 33 
                 NM_002302.2_76- 
                 76 
                 AGAAAUGAGAGAUGCAGAA 
                 UUCUGCAUCUCUCAUUUCU 
               
               
                   
                   
                 94_s 
                   
                   
                   
               
               
                   
               
               
                 34 
                 35 
                 NM_002302.2_82- 
                 82 
                 GAGAGAUGCAGAAUUCUAA 
                 UUAGAAUUCUGCAUCUCUC 
               
               
                   
                   
                 100_s 
                   
                   
                   
               
               
                   
               
               
                 36 
                 37 
                 NM_002302.2_87- 
                 87 
                 AUGCAGAAUUCUAAGGCUA 
                 UAGCCUUAGAAUUCUGCAU 
               
               
                   
                   
                 105_s 
                   
                   
                   
               
               
                   
               
               
                 38 
                 39 
                 NM_002302.2_92- 
                 92 
                 GAAUUCUAAGGCUAAAUAG 
                 CUAUUUAGCCUUAGAAUUC 
               
               
                   
                   
                 110_s 
                   
                   
                   
               
               
                   
               
               
                 40 
                 41 
                 NM_002302.2_95- 
                 95 
                 UUCUAAGGCUAAAUAGCUA 
                 UAGCUAUUUAGCCUUAGAA 
               
               
                   
                   
                 113_s 
                   
                   
                   
               
               
                   
               
               
                 42 
                 43 
                 NM_002302.2_103- 
                 103 
                 CUAAAUAGCUAGGAAGUAU 
                 AUACUUCCUAGCUAUUUAG 
               
               
                   
                   
                 121_s 
                   
                   
                   
               
               
                   
               
               
                 44 
                 45 
                 NM_002302.2_107- 
                 107 
                 AUAGCUAGGAAGUAUUCAU 
                 AUGAAUACUUCCUAGCUAU 
               
               
                   
                   
                 125_s 
                   
                   
                   
               
               
                   
               
               
                 46 
                 47 
                 NM_002302.2_114- 
                 114 
                 GGAAGUAUUCAUUCAAACU 
                 AGUUUGAAUGAAUACUUCC 
               
               
                   
                   
                 132_s 
                   
                   
                   
               
               
                   
               
               
                 48 
                 49 
                 NM_002302.2_123- 
                 123 
                 CAUUCAAACUUGAAUAUUC 
                 GAAUAUUCAAGUUUGAAUG 
               
               
                   
                   
                 141_s 
                   
                   
                   
               
               
                   
               
               
                 50 
                 51 
                 NM_002302.2_131- 
                 131 
                 CUUGAAUAUUCUUCAAAGA 
                 UCUUUGAAGAAUAUUCAAG 
               
               
                   
                   
                 149_s 
                   
                   
                   
               
               
                   
               
               
                 52 
                 53 
                 NM_002302.2_141- 
                 141 
                 CUUCAAAGAGAGUGUGGGG 
                 CCCCACACUCUCUUUGAAG 
               
               
                   
                   
                 159_s 
                   
                   
                   
               
               
                   
               
               
                 54 
                 55 
                 NM_002302.2_144- 
                 144 
                 CAAAGAGAGUGUGGGGGCA 
                 UGCCCCCACACUCUCUUUG 
               
               
                   
                   
                 162_s 
                   
                   
                   
               
               
                   
               
               
                 56 
                 57 
                 NM_002302.2_152- 
                 152 
                 GUGUGGGGGCAACUCUAAU 
                 AUUAGAGUUGCCCCCACAC 
               
               
                   
                   
                 170_s 
                   
                   
                   
               
               
                   
               
               
                 58 
                 59 
                 NM_002302.2_156- 
                 156 
                 GGGGGCAACUCUAAUCAGA 
                 UCUGAUUAGAGUUGCCCCC 
               
               
                   
                   
                 174_s 
                   
                   
                   
               
               
                   
               
               
                 60 
                 61 
                 NM_002302.2_162- 
                 162 
                 AACUCUAAUCAGAGGAAGA 
                 UCUUCCUCUGAUUAGAGUU 
               
               
                   
                   
                 180_s 
                   
                   
                   
               
               
                   
               
               
                 62 
                 63 
                 NM_002302.2_168- 
                 168 
                 AAUCAGAGGAAGAAACUAA 
                 UUAGUUUCUUCCUCUGAUU 
               
               
                   
                   
                 186_s 
                   
                   
                   
               
               
                   
               
               
                 64 
                 65 
                 NM_002302.2_169- 
                 169 
                 AUCAGAGGAAGAAACUAAA 
                 UUUAGUUUCUUCCUCUGAU 
               
               
                   
                   
                 187_s 
                   
                   
                   
               
               
                   
               
               
                 66 
                 67 
                 NM_002302.2_178- 
                 178 
                 AGAAACUAAAGGAAGUAAA 
                 UUUACUUCCUUUAGUUUCU 
               
               
                   
                   
                 196_s 
                   
                   
                   
               
               
                   
               
               
                 68 
                 69 
                 NM_002302.2_179- 
                 179 
                 GAAACUAAAGGAAGUAAAA 
                 UUUUACUUCCUUUAGUUUC 
               
               
                   
                   
                 197_s 
                   
                   
                   
               
               
                   
               
               
                 70 
                 71 
                 NM_002302.2_184- 
                 184 
                 UAAAGGAAGUAAAACCAGA 
                 UCUGGUUUUACUUCCUUUA 
               
               
                   
                   
                 202_s 
                   
                   
                   
               
               
                   
               
               
                 72 
                 73 
                 NM_002302.2_190- 
                 190 
                 AAGUAAAACCAGAUGUUUU 
                 AAAACAUCUGGUUUUACUU 
               
               
                   
                   
                 208_s 
                   
                   
                   
               
               
                   
               
               
                 74 
                 75 
                 NM_002302.2_198- 
                 198 
                 CCAGAUGUUUUCCACCAAA 
                 UUUGGUGGAAAACAUCUGG 
               
               
                   
                   
                 216_s 
                   
                   
                   
               
               
                   
               
               
                 76 
                 77 
                 NM_002302.2_199- 
                 199 
                 CAGAUGUUUUCCACCAAAG 
                 CUUUGGUGGAAAACAUCUG 
               
               
                   
                   
                 217_s 
                   
                   
                   
               
               
                   
               
               
                 78 
                 79 
                 NM_002302.2_208- 
                 208 
                 UCCACCAAAGCCCUCCUUU 
                 AAAGGAGGGCUUUGGUGGA 
               
               
                   
                   
                 226_s 
                   
                   
                   
               
               
                   
               
               
                 80 
                 81 
                 NM_002302.2_209- 
                 209 
                 CCACCAAAGCCCUCCUUUU 
                 AAAAGGAGGGCUUUGGUGG 
               
               
                   
                   
                 227_s 
                   
                   
                   
               
               
                   
               
               
                 82 
                 83 
                 NM_002302.2_218- 
                 218 
                 CCCUCCUUUUGGCUGGUCU 
                 AGACCAGCCAAAAGGAGGG 
               
               
                   
                   
                 236_s 
                   
                   
                   
               
               
                   
               
               
                 84 
                 85 
                 NM_002302.2_228- 
                 228 
                 GGCUGGUCUGAUUUCUACC 
                 GGUAGAAAUCAGACCAGCC 
               
               
                   
                   
                 246_s 
                   
                   
                   
               
               
                   
               
               
                 86 
                 87 
                 NM_002302.2 232- 
                 232 
                 GGUCUGAUUUCUACCGCAC 
                 GUGCGGUAGAAAUCAGACC 
               
               
                   
                   
                 250_s 
                   
                   
                   
               
               
                   
               
               
                 88 
                 89 
                 NM_002302.2_237- 
                 237 
                 GAUUUCUACCGCACUGGCA 
                 UGCCAGUGCGGUAGAAAUC 
               
               
                   
                   
                 255_s 
                   
                   
                   
               
               
                   
               
               
                 90 
                 91 
                 NM_002302.2_243- 
                 243 
                 UACCGCACUGGCAGGGCCA 
                 UGGCCCUGCCAGUGCGGUA 
               
               
                   
                   
                 261_s 
                   
                   
                   
               
               
                   
               
               
                 92 
                 93 
                 NM_002302.2_245- 
                 245 
                 CCGCACUGGCAGGGCCAUG 
                 CAUGGCCCUGCCAGUGCGG 
               
               
                   
                   
                 263_s 
                   
                   
                   
               
               
                   
               
               
                 94 
                 95 
                 NM_002302.2_252- 
                 252 
                 GGCAGGGCCAUGGGCUAAU 
                 AUUAGCCCAUGGCCCUGCC 
               
               
                   
                   
                 270_s 
                   
                   
                   
               
               
                   
               
               
                 96 
                 97 
                 NM_002302.2_258- 
                 258 
                 GCCAUGGGCUAAUAUAUGU 
                 ACAUAUAUUAGCCCAUGGC 
               
               
                   
                   
                 276_s 
                   
                   
                   
               
               
                   
               
               
                 98 
                 99 
                 NM_002302.2_259- 
                 259 
                 CCAUGGGCUAAUAUAUGUG 
                 CACAUAUAUUAGCCCAUGG 
               
               
                   
                   
                 277_s 
                   
                   
                   
               
               
                   
               
               
                 100 
                 101 
                 NM_002302.2_266- 
                 266 
                 CUAAUAUAUGUGCUGGCAA 
                 UUGCCAGCACAUAUAUUAG 
               
               
                   
                   
                 284_s 
                   
                   
                   
               
               
                   
               
               
                 102 
                 103 
                 NM_002302.2_271- 
                 271 
                 AUAUGUGCUGGCAAGUCUU 
                 AAGACUUGCCAGCACAUAU 
               
               
                   
                   
                 289_s 
                   
                   
                   
               
               
                   
               
               
                 104 
                 105 
                 NM_002302.2_278- 
                 278 
                 CUGGCAAGUCUUCCAAUGA 
                 UCAUUGGAAGACUUGCCAG 
               
               
                   
                   
                 296_s 
                   
                   
                   
               
               
                   
               
               
                 106 
                 107 
                 NM_002302.2_281- 
                 281 
                 GCAAGUCUUCCAAUGAGAU 
                 AUCUCAUUGGAAGACUUGC 
               
               
                   
                   
                 299_s 
                   
                   
                   
               
               
                   
               
               
                 108 
                 109 
                 NM_002302.2_286- 
                 286 
                 UCUUCCAAUGAGAUCCGGA 
                 UCCGGAUCUCAUUGGAAGA 
               
               
                   
                   
                 304_s 
                   
                   
                   
               
               
                   
               
               
                 110 
                 111 
                 NM_002302.2_293- 
                 293 
                 AUGAGAUCCGGACGUGUGA 
                 UCACACGUCCGGAUCUCAU 
               
               
                   
                   
                 311_s 
                   
                   
                   
               
               
                   
               
               
                 112 
                 113 
                 NM_002302.2_297- 
                 297 
                 GAUCCGGACGUGUGACCGC 
                 GCGGUCACACGUCCGGAUC 
               
               
                   
                   
                 315_s 
                   
                   
                   
               
               
                   
               
               
                 114 
                 115 
                 NM_002302.2_301- 
                 301 
                 CGGACGUGUGACCGCCAUG 
                 CAUGGCGGUCACACGUCCG 
               
               
                   
                   
                 319_s 
                   
                   
                   
               
               
                   
               
               
                 116 
                 117 
                 NM_002302.2_304- 
                 304 
                 ACGUGUGACCGCCAUGGCU 
                 AGCCAUGGCGGUCACACGU 
               
               
                   
                   
                 322_s 
                   
                   
                   
               
               
                   
               
               
                 118 
                 119 
                 NM_002302.2_312- 
                 312 
                 CCGCCAUGGCUGUGGACAG 
                 CUGUCCACAGCCAUGGCGG 
               
               
                   
                   
                 330_s 
                   
                   
                   
               
               
                   
               
               
                 120 
                 121 
                 NM_002302.2_315- 
                 315 
                 CCAUGGCUGUGGACAGUAC 
                 GUACUGUCCACAGCCAUGG 
               
               
                   
                   
                 333_s 
                   
                   
                   
               
               
                   
               
               
                 122 
                 123 
                 NM_002302.2_319- 
                 319 
                 GGCUGUGGACAGUACUCUG 
                 CAGAGUACUGUCCACAGCC 
               
               
                   
                   
                 337_s 
                   
                   
                   
               
               
                   
               
               
                 124 
                 125 
                 NM_002302.2_330- 
                 330 
                 GUACUCUGCUCAAAGAAGU 
                 ACUUCUUUGAGCAGAGUAC 
               
               
                   
                   
                 348_s 
                   
                   
                   
               
               
                   
               
               
                 126 
                 127 
                 NM_002302.2_334- 
                 334 
                 UCUGCUCAAAGAAGUCAGA 
                 UCUGACUUCUUUGAGCAGA 
               
               
                   
                   
                 352_s 
                   
                   
                   
               
               
                   
               
               
                 128 
                 129 
                 NM_002302.2_340- 
                 340 
                 CAAAGAAGUCAGAGGCCUC 
                 GAGGCCUCUGACUUCUUUG 
               
               
                   
                   
                 358_s 
                   
                   
                   
               
               
                   
               
               
                 130 
                 131 
                 NM_002302.2_345- 
                 345 
                 AAGUCAGAGGCCUCACCAG 
                 CUGGUGAGGCCUCUGACUU 
               
               
                   
                   
                 363_s 
                   
                   
                   
               
               
                   
               
               
                 132 
                 133 
                 NM_002302.2_351- 
                 351 
                 GAGGCCUCACCAGGGUGUG 
                 CACACCCUGGUGAGGCCUC 
               
               
                   
                   
                 369_s 
                   
                   
                   
               
               
                   
               
               
                 134 
                 135 
                 NM_002302.2_354- 
                 354 
                 GCCUCACCAGGGUGUGGAC 
                 GUCCACACCCUGGUGAGGC 
               
               
                   
                   
                 372_s 
                   
                   
                   
               
               
                   
               
               
                 136 
                 137 
                 NM_002302.2_360- 
                 360 
                 CCAGGGUGUGGACAUCUUG 
                 CAAGAUGUCCACACCCUGG 
               
               
                   
                   
                 378_s 
                   
                   
                   
               
               
                   
               
               
                 138 
                 139 
                 NM_002302.2_364- 
                 364 
                 GGUGUGGACAUCUUGUGCU 
                 AGCACAAGAUGUCCACACC 
               
               
                   
                   
                 382_s 
                   
                   
                   
               
               
                   
               
               
                 140 
                 141 
                 NM_002302.2_371- 
                 371 
                 ACAUCUUGUGCUCUGCUGG 
                 CCAGCAGAGCACAAGAUGU 
               
               
                   
                   
                 389_s 
                   
                   
                   
               
               
                   
               
               
                 142 
                 143 
                 NM_002302.2_378- 
                 378 
                 GUGCUCUGCUGGAUCUACU 
                 AGUAGAUCCAGCAGAGCAC 
               
               
                   
                   
                 396_s 
                   
                   
                   
               
               
                   
               
               
                 144 
                 145 
                 NM_002302.2_383- 
                 383 
                 CUGCUGGAUCUACUGUGUA 
                 UACACAGUAGAUCCAGCAG 
               
               
                   
                   
                 401_s 
                   
                   
                   
               
               
                   
               
               
                 146 
                 147 
                 NM_002302.2_388- 
                 388 
                 GGAUCUACUGUGUACGCAC 
                 GUGCGUACACAGUAGAUCC 
               
               
                   
                   
                 406_s 
                   
                   
                   
               
               
                   
               
               
                 148 
                 149 
                 NM_002302.2_392- 
                 392 
                 CUACUGUGUACGCACCAUU 
                 AAUGGUGCGUACACAGUAG 
               
               
                   
                   
                 410_s 
                   
                   
                   
               
               
                   
               
               
                 150 
                 151 
                 NM_002302.2_395- 
                 395 
                 CUGUGUACGCACCAUUCAC 
                 GUGAAUGGUGCGUACACAG 
               
               
                   
                   
                 413_s 
                   
                   
                   
               
               
                   
               
               
                 152 
                 153 
                 NM_002302.2_403- 
                 403 
                 GCACCAUUCACUGGAAUGA 
                 UCAUUCCAGUGAAUGGUGC 
               
               
                   
                   
                 421_s 
                   
                   
                   
               
               
                   
               
               
                 154 
                 155 
                 NM_002302.2_406- 
                 406 
                 CCAUUCACUGGAAUGAUUG 
                 CAAUCAUUCCAGUGAAUGG 
               
               
                   
                   
                 424_s 
                   
                   
                   
               
               
                   
               
               
                 156 
                 157 
                 NM_002302.2_413- 
                 413 
                 CUGGAAUGAUUGUGGGCCA 
                 UGGCCCACAAUCAUUCCAG 
               
               
                   
                   
                 431_s 
                   
                   
                   
               
               
                   
               
               
                 158 
                 159 
                 NM_002302.2_416- 
                 416 
                 GAAUGAUUGUGGGCCAGGA 
                 UCCUGGCCCACAAUCAUUC 
               
               
                   
                   
                 434_s 
                   
                   
                   
               
               
                   
               
               
                 160 
                 161 
                 NM_002302.2_420- 
                 420 
                 GAUUGUGGGCCAGGAGAAA 
                 UUUCUCCUGGCCCACAAUC 
               
               
                   
                   
                 438_s 
                   
                   
                   
               
               
                   
               
               
                 162 
                 163 
                 NM_002302.2_426- 
                 426 
                 GGGCCAGGAGAAACCUUAU 
                 AUAAGGUUUCUCCUGGCCC 
               
               
                   
                   
                 444_s 
                   
                   
                   
               
               
                   
               
               
                 164 
                 165 
                 NM_002302.2_430- 
                 430 
                 CAGGAGAAACCUUAUCAAA 
                 UUUGAUAAGGUUUCUCCUG 
               
               
                   
                   
                 448_s 
                   
                   
                   
               
               
                   
               
               
                 166 
                 167 
                 NM_002302.2_436- 
                 436 
                 AAACCUUAUCAAAACAAGA 
                 UCUUGUUUUGAUAAGGUUU 
               
               
                   
                   
                 454_s 
                   
                   
                   
               
               
                   
               
               
                 168 
                 169 
                 NM_002302.2_442- 
                 442 
                 UAUCAAAACAAGAAUGCUA 
                 UAGCAUUCUUGUUUUGAUA 
               
               
                   
                   
                 460_s 
                   
                   
                   
               
               
                   
               
               
                 170 
                 171 
                 NM_002302.2_448- 
                 448 
                 AACAAGAAUGCUAUCAAUA 
                 UAUUGAUAGCAUUCUUGUU 
               
               
                   
                   
                 466_s 
                   
                   
                   
               
               
                   
               
               
                 172 
                 173 
                 NM_002302.2_450- 
                 450 
                 CAAGAAUGCUAUCAAUAAU 
                 AUUAUUGAUAGCAUUCUUG 
               
               
                   
                   
                 468_s 
                   
                   
                   
               
               
                   
               
               
                 174 
                 175 
                 NM_002302.2_462- 
                 462 
                 CAAUAAUGGUGUUCGAAUA 
                 UAUUCGAACACCAUUAUUG 
               
               
                   
                   
                 480_s 
                   
                   
                   
               
               
                   
               
               
                 176 
                 177 
                 NM_002302.2_465- 
                 465 
                 UAAUGGUGUUCGAAUAUCU 
                 AGAUAUUCGAACACCAUUA 
               
               
                   
                   
                 483_s 
                   
                   
                   
               
               
                   
               
               
                 178 
                 179 
                 NM_002302.2_471- 
                 471 
                 UGUUCGAAUAUCUGGAAGA 
                 UCUUCCAGAUAUUCGAACA 
               
               
                   
                   
                 489_s 
                   
                   
                   
               
               
                   
               
               
                 180 
                 181 
                 NM_002302.2_478- 
                 478 
                 AUAUCUGGAAGAGGUUUUU 
                 AAAAACCUCUUCCAGAUAU 
               
               
                   
                   
                 496_s 
                   
                   
                   
               
               
                   
               
               
                 182 
                 183 
                 NM_002302.2_480- 
                 480 
                 AUCUGGAAGAGGUUUUUGU 
                 ACAAAAACCUCUUCCAGAU 
               
               
                   
                   
                 498_s 
                   
                   
                   
               
               
                   
               
               
                 184 
                 185 
                 NM_002302.2_487- 
                 487 
                 AGAGGUUUUUGUGUCAAAA 
                 UUUUGACACAAAAACCUCU 
               
               
                   
                   
                 505_s 
                   
                   
                   
               
               
                   
               
               
                 186 
                 187 
                 NM_002302.2_490- 
                 490 
                 GGUUUUUGUGUCAAAAUGU 
                 ACAUUUUGACACAAAAACC 
               
               
                   
                   
                 508_s 
                   
                   
                   
               
               
                   
               
               
                 188 
                 189 
                 NM_002302.2_497- 
                 497 
                 GUGUCAAAAUGUUCUACAU 
                 AUGUAGAACAUUUUGACAC 
               
               
                   
                   
                 515_s 
                   
                   
                   
               
               
                   
               
               
                 190 
                 191 
                 NM_002302.2_500- 
                 500 
                 UCAAAAUGUUCUACAUUAA 
                 UUAAUGUAGAACAUUUUGA 
               
               
                   
                   
                 518_s 
                   
                   
                   
               
               
                   
               
               
                 192 
                 193 
                 NM_002302.2_506- 
                 506 
                 UGUUCUACAUUAAGCCAAU 
                 AUUGGCUUAAUGUAGAACA 
               
               
                   
                   
                 524_s 
                   
                   
                   
               
               
                   
               
               
                 194 
                 195 
                 NM_002302.2_528- 
                 528 
                 GUAUAAAGGUCCUAUUAAG 
                 CUUAAUAGGACCUUUAUAC 
               
               
                   
                   
                 546_s 
                   
                   
                   
               
               
                   
               
               
                 196 
                 197 
                 NM_002302.2_529- 
                 529 
                 UAUAAAGGUCCUAUUAAGA 
                 UCUUAAUAGGACCUUUAUA 
               
               
                   
                   
                 547_s 
                   
                   
                   
               
               
                   
               
               
                 198 
                 199 
                 NM_002302.2_538- 
                 538 
                 CCUAUUAAGAAGGGAGAAA 
                 UUUCUCCCUUCUUAAUAGG 
               
               
                   
                   
                 556_s 
                   
                   
                   
               
               
                   
               
               
                 200 
                 201 
                 NM_002302.2_539- 
                 539 
                 CUAUUAAGAAGGGAGAAAA 
                 UUUUCUCCCUUCUUAAUAG 
               
               
                   
                   
                 557_s 
                   
                   
                   
               
               
                   
               
               
                 202 
                 203 
                 NM_002302.2_544- 
                 544 
                 AAGAAGGGAGAAAAACUUG 
                 CAAGUUUUUCUCCCUUCUU 
               
               
                   
                   
                 562_s 
                   
                   
                   
               
               
                   
               
               
                 204 
                 205 
                 NM_002302.2_552- 
                 552 
                 AGAAAAACUUGGAACUCUA 
                 UAGAGUUCCAAGUUUUUCU 
               
               
                   
                   
                 570_s 
                   
                   
                   
               
               
                   
               
               
                 206 
                 207 
                 NM_002302.2_555- 
                 555 
                 AAAACUUGGAACUCUAUUG 
                 CAAUAGAGUUCCAAGUUUU 
               
               
                   
                   
                 573_s 
                   
                   
                   
               
               
                   
               
               
                 208 
                 209 
                 NM_002302.2_559- 
                 559 
                 CUUGGAACUCUAUUGCCCU 
                 AGGGCAAUAGAGUUCCAAG 
               
               
                   
                   
                 577_s 
                   
                   
                   
               
               
                   
               
               
                 210 
                 211 
                 NM_002302.2_566- 
                 566 
                 CUCUAUUGCCCUUGCAGAA 
                 UUCUGCAAGGGCAAUAGAG 
               
               
                   
                   
                 584_s 
                   
                   
                   
               
               
                   
               
               
                 212 
                 213 
                 NM_002302.2_573- 
                 573 
                 GCCCUUGCAGAAAGUUUAU 
                 AUAAACUUUCUGCAAGGGC 
               
               
                   
                   
                 591_s 
                   
                   
                   
               
               
                   
               
               
                 214 
                 215 
                 NM_002302.2_574- 
                 574 
                 CCCUUGCAGAAAGUUUAUC 
                 GAUAAACUUUCUGCAAGGG 
               
               
                   
                   
                 592_s 
                   
                   
                   
               
               
                   
               
               
                 216 
                 217 
                 NM_002302.2_581- 
                 581 
                 AGAAAGUUUAUCCUGGCAU 
                 AUGCCAGGAUAAACUUUCU 
               
               
                   
                   
                 599_s 
                   
                   
                   
               
               
                   
               
               
                 218 
                 219 
                 NM_002302.2_585- 
                 585 
                 AGUUUAUCCUGGCAUACAA 
                 UUGUAUGCCAGGAUAAACU 
               
               
                   
                   
                 603_s 
                   
                   
                   
               
               
                   
               
               
                 220 
                 221 
                 NM_002302.2_592- 
                 592 
                 CCUGGCAUACAAUCGCAUG 
                 CAUGCGAUUGUAUGCCAGG 
               
               
                   
                   
                 610_s 
                   
                   
                   
               
               
                   
               
               
                 222 
                 223 
                 NM_002302.2_598- 
                 598 
                 AUACAAUCGCAUGUGCACA 
                 UGUGCACAUGCGAUUGUAU 
               
               
                   
                   
                 616_s 
                   
                   
                   
               
               
                   
               
               
                 224 
                 225 
                 NM_002302.2_603- 
                 603 
                 AUCGCAUGUGCACAUUGAA 
                 UUCAAUGUGCACAUGCGAU 
               
               
                   
                   
                 621_s 
                   
                   
                   
               
               
                   
               
               
                 226 
                 227 
                 NM_002302.2_606- 
                 606 
                 GCAUGUGCACAUUGAAAAC 
                 GUUUUCAAUGUGCACAUGC 
               
               
                   
                   
                 624_s 
                   
                   
                   
               
               
                   
               
               
                 228 
                 229 
                 NM_002302.2_611- 
                 611 
                 UGCACAUUGAAAACUGUGA 
                 UCACAGUUUUCAAUGUGCA 
               
               
                   
                   
                 629_s 
                   
                   
                   
               
               
                   
               
               
                 230 
                 231 
                 NM_002302.2_616- 
                 616 
                 AUUGAAAACUGUGACUCGA 
                 UCGAGUCACAGUUUUCAAU 
               
               
                   
                   
                 634_s 
                   
                   
                   
               
               
                   
               
               
                 232 
                 233 
                 NM_002302.2_620- 
                 620 
                 AAAACUGUGACUCGAGUGA 
                 UCACUCGAGUCACAGUUUU 
               
               
                   
                   
                 638_s 
                   
                   
                   
               
               
                   
               
               
                 234 
                 235 
                 NM_002302.2_625- 
                 625 
                 UGUGACUCGAGUGACCCUA 
                 UAGGGUCACUCGAGUCACA 
               
               
                   
                   
                 643_s 
                   
                   
                   
               
               
                   
               
               
                 236 
                 237 
                 NM_002302.2_633- 
                 633 
                 GAGUGACCCUACUGCAUAC 
                 GUAUGCAGUAGGGUCACUC 
               
               
                   
                   
                 651_s 
                   
                   
                   
               
               
                   
               
               
                 238 
                 239 
                 NM_002302.2_637- 
                 637 
                 GACCCUACUGCAUACCUGU 
                 ACAGGUAUGCAGUAGGGUC 
               
               
                   
                   
                 655_s 
                   
                   
                   
               
               
                   
               
               
                 240 
                 241 
                 NM_002302.2_640- 
                 640 
                 CCUACUGCAUACCUGUAAA 
                 UUUACAGGUAUGCAGUAGG 
               
               
                   
                   
                 658_s 
                   
                   
                   
               
               
                   
               
               
                 242 
                 243 
                 NM_002302.2_644- 
                 644 
                 CUGCAUACCUGUAAAUCGA 
                 UCGAUUUACAGGUAUGCAG 
               
               
                   
                   
                 662_s 
                   
                   
                   
               
               
                   
               
               
                 244 
                 245 
                 NM_002302.2_651- 
                 651 
                 CCUGUAAAUCGAAGGCCAA 
                 UUGGCCUUCGAUUUACAGG 
               
               
                   
                   
                 669_s 
                   
                   
                   
               
               
                   
               
               
                 246 
                 247 
                 NM_002302.2_657- 
                 657 
                 AAUCGAAGGCCAAUGGUCA 
                 UGACCAUUGGCCUUCGAUU 
               
               
                   
                   
                 675_s 
                   
                   
                   
               
               
                   
               
               
                 248 
                 249 
                 NM_002302.2_663- 
                 663 
                 AGGCCAAUGGUCAGAUCUU 
                 AAGAUCUGACCAUUGGCCU 
               
               
                   
                   
                 681_s 
                   
                   
                   
               
               
                   
               
               
                 250 
                 251 
                 NM_002302.2_667- 
                 667 
                 CAAUGGUCAGAUCUUCAAA 
                 UUUGAAGAUCUGACCAUUG 
               
               
                   
                   
                 685_s 
                   
                   
                   
               
               
                   
               
               
                 252 
                 253 
                 NM_002302.2_674- 
                 674 
                 CAGAUCUUCAAAAUAAAAA 
                 UUUUUAUUUUGAAGAUCUG 
               
               
                   
                   
                 692_s 
                   
                   
                   
               
               
                   
               
               
                 254 
                 255 
                 NM_002302.2_686- 
                 686 
                 AUAAAAAGUCAUCUUAAAA 
                 UUUUAAGAUGACUUUUUAU 
               
               
                   
                   
                 704_s 
                   
                   
                   
               
               
                   
               
               
                 256 
                 257 
                 NM_002302.2_691- 
                 691 
                 AAGUCAUCUUAAAAACCUG 
                 CAGGUUUUUAAGAUGACUU 
               
               
                   
                   
                 709_s 
                   
                   
                   
               
               
                   
               
               
                 258 
                 259 
                 NM_002302.2_698- 
                 698 
                 CUUAAAAACCUGGAUGCAU 
                 AUGCAUCCAGGUUUUUAAG 
               
               
                   
                   
                 716_s 
                   
                   
                   
               
               
                   
               
               
                 260 
                 261 
                 NM_002302.2_699- 
                 699 
                 UUAAAAACCUGGAUGCAUA 
                 UAUGCAUCCAGGUUUUUAA 
               
               
                   
                   
                 717_s 
                   
                   
                   
               
               
                   
               
               
                 262 
                 263 
                 NM_002302.2_706- 
                 706 
                 CCUGGAUGCAUACCCUUCU 
                 AGAAGGGUAUGCAUCCAGG 
               
               
                   
                   
                 724_s 
                   
                   
                   
               
               
                   
               
               
                 264 
                 265 
                 NM_002302.2_709- 
                 709 
                 GGAUGCAUACCCUUCUCUU 
                 AAGAGAAGGGUAUGCAUCC 
               
               
                   
                   
                 727_s 
                   
                   
                   
               
               
                   
               
               
                 266 
                 267 
                 NM_002302.2_716- 
                 716 
                 UACCCUUCUCUUCAAGAAA 
                 UUUCUUGAAGAGAAGGGUA 
               
               
                   
                   
                 734_s 
                   
                   
                   
               
               
                   
               
               
                 268 
                 269 
                 NM_002302.2_719- 
                 719 
                 CCUUCUCUUCAAGAAAUUU 
                 AAAUUUCUUGAAGAGAAGG 
               
               
                   
                   
                 737_s 
                   
                   
                   
               
               
                   
               
               
                 270 
                 271 
                 NM_002302.2_728- 
                 728 
                 CAAGAAAUUUGUGUUCACA 
                 UGUGAACACAAAUUUCUUG 
               
               
                   
                   
                 746_s 
                   
                   
                   
               
               
                   
               
               
                 272 
                 273 
                 NM_002302.2_730- 
                 730 
                 AGAAAUUUGUGUUCACAAA 
                 UUUGUGAACACAAAUUUCU 
               
               
                   
                   
                 748_s 
                   
                   
                   
               
               
                   
               
               
                 274 
                 275 
                 NM_002302.2_736- 
                 736 
                 UUGUGUUCACAAAGGAAAA 
                 UUUUCCUUUGUGAACACAA 
               
               
                   
                   
                 754_s 
                   
                   
                   
               
               
                   
               
               
                 276 
                 277 
                 NM_002302.2_743- 
                 743 
                 CACAAAGGAAAAAUGCAUG 
                 CAUGCAUUUUUCCUUUGUG 
               
               
                   
                   
                 761_s 
                   
                   
                   
               
               
                   
               
               
                 278 
                 279 
                 NM_002302.2_745- 
                 745 
                 CAAAGGAAAAAUGCAUGAA 
                 UUCAUGCAUUUUUCCUUUG 
               
               
                   
                   
                 763_s 
                   
                   
                   
               
               
                   
               
               
                 280 
                 281 
                 NM_002302.2_750- 
                 750 
                 GAAAAAUGCAUGAAGGGAU 
                 AUCCCUUCAUGCAUUUUUC 
               
               
                   
                   
                 768_s 
                   
                   
                   
               
               
                   
               
               
                 282 
                 283 
                 NM_002302.2_755- 
                 755 
                 AUGCAUGAAGGGAUGGAUA 
                 UAUCCAUCCCUUCAUGCAU 
               
               
                   
                   
                 773_s 
                   
                   
                   
               
               
                   
               
               
                 284 
                 285 
                 NM_002302.2_763- 
                 763 
                 AGGGAUGGAUACCCCAUUU 
                 AAAUGGGGUAUCCAUCCCU 
               
               
                   
                   
                 781_s 
                   
                   
                   
               
               
                   
               
               
                 286 
                 287 
                 NM_002302.2_764- 
                 764 
                 GGGAUGGAUACCCCAUUUU 
                 AAAAUGGGGUAUCCAUCCC 
               
               
                   
                   
                 782_s 
                   
                   
                   
               
               
                   
               
               
                 288 
                 289 
                 NM_002302.2_773- 
                 773 
                 ACCCCAUUUUCCAUGACAU 
                 AUGUCAUGGAAAAUGGGGU 
               
               
                   
                   
                 791_s 
                   
                   
                   
               
               
                   
               
               
                 290 
                 291 
                 NM_002302.2_774- 
                 774 
                 CCCCAUUUUCCAUGACAUG 
                 CAUGUCAUGGAAAAUGGGG 
               
               
                   
                   
                 792_s 
                   
                   
                   
               
               
                   
               
               
                 292 
                 293 
                 NM_002302.2_783- 
                 783 
                 CCAUGACAUGAUUAUUACA 
                 UGUAAUAAUCAUGUCAUGG 
               
               
                   
                   
                 801_s 
                   
                   
                   
               
               
                   
               
               
                 294 
                 295 
                 NM_002302.2_786- 
                 786 
                 UGACAUGAUUAUUACACAU 
                 AUGUGUAAUAAUCAUGUCA 
               
               
                   
                   
                 804_s 
                   
                   
                   
               
               
                   
               
               
                 296 
                 297 
                 NM_002302.2_792- 
                 792 
                 GAUUAUUACACAUUGCAUG 
                 CAUGCAAUGUGUAAUAAUC 
               
               
                   
                   
                 810_s 
                   
                   
                   
               
               
                   
               
               
                 298 
                 299 
                 NM_002302.2_798- 
                 798 
                 UACACAUUGCAUGCCUGUA 
                 UACAGGCAUGCAAUGUGUA 
               
               
                   
                   
                 816_s 
                   
                   
                   
               
               
                   
               
               
                 300 
                 301 
                 NM_002302.2_803- 
                 803 
                 AUUGCAUGCCUGUAUCAAA 
                 UUUGAUACAGGCAUGCAAU 
               
               
                   
                   
                 821_s 
                   
                   
                   
               
               
                   
               
               
                 302 
                 303 
                 NM_002302.2_804- 
                 804 
                 UUGCAUGCCUGUAUCAAAA 
                 UUUUGAUACAGGCAUGCAA 
               
               
                   
                   
                 822_s 
                   
                   
                   
               
               
                   
               
               
                 304 
                 305 
                 NM_002302.2_815- 
                 815 
                 UAUCAAAACAUCUCACGUA 
                 UACGUGAGAUGUUUUGAUA 
               
               
                   
                   
                 833_s 
                   
                   
                   
               
               
                   
               
               
                 306 
                 307 
                 NM_002302.2_823- 
                 823 
                 CAUCUCACGUACCUCAUAA 
                 UUAUGAGGUACGUGAGAUG 
               
               
                   
                   
                 841_s 
                   
                   
                   
               
               
                   
               
               
                 308 
                 309 
                 NM_002302.2_828- 
                 828 
                 CACGUACCUCAUAAACAUA 
                 UAUGUUUAUGAGGUACGUG 
               
               
                   
                   
                 846_s 
                   
                   
                   
               
               
                   
               
               
                 310 
                 311 
                 NM_002302.2_830- 
                 830 
                 CGUACCUCAUAAACAUAUA 
                 UAUAUGUUUAUGAGGUACG 
               
               
                   
                   
                 848_s 
                   
                   
                   
               
               
                   
               
               
                 312 
                 313 
                 NM_002302.2_840- 
                 840 
                 AAACAUAUACACCUAUGUA 
                 UACAUAGGUGUAUAUGUUU 
               
               
                   
                   
                 858_s 
                   
                   
                   
               
               
                   
               
               
                 314 
                 315 
                 NM_002302.2_848- 
                 848 
                 ACACCUAUGUACCCACAAA 
                 UUUGUGGGUACAUAGGUGU 
               
               
                   
                   
                 866_s 
                   
                   
                   
               
               
                   
               
               
                 316 
                 317 
                 NM_002302.2_849- 
                 849 
                 CACCUAUGUACCCACAAAA 
                 UUUUGUGGGUACAUAGGUG 
               
               
                   
                   
                 867_s 
                   
                   
                   
               
               
                   
               
               
                 318 
                 319 
                 NM_002302.2_858- 
                 858 
                 ACCCACAAAAAUUUUUUAA 
                 UUAAAAAAUUUUUGUGGGU 
               
               
                   
                   
                 876_s 
                   
                   
                   
               
               
                   
               
               
                 320 
                 321 
                 NM_002302.2_863- 
                 863 
                 CAAAAAUUUUUUAAUUAAA 
                 UUUAAUUAAAAAAUUUUUG 
               
               
                   
                   
                 881_s 
                   
                   
                   
               
               
                   
               
               
                 322 
                 323 
                 NM_002302.2_872- 
                 872 
                 UUUAAUUAAAAAAAGGAAA 
                 UUUCCUUUUUUUAAUUAAA 
               
               
                   
                   
                 890_s 
                   
                   
                   
               
               
                   
               
               
                 324 
                 325 
                 NM_002302.2_877- 
                 877 
                 UUAAAAAAAGGAAAUUUGA 
                 UCAAAUUUCCUUUUUUUAA 
               
               
                   
                   
                 895_s 
                   
                   
                   
               
               
                   
               
               
                 326 
                 327 
                 NM_002302.2_883- 
                 883 
                 AAAGGAAAUUUGAGUUUAA 
                 UUAAACUCAAAUUUCCUUU 
               
               
                   
                   
                 901_s 
                   
                   
                   
               
               
                   
               
               
                 328 
                 329 
                 NM_002302.2_886- 
                 886 
                 GGAAAUUUGAGUUUAAAUA 
                 UAUUUAAACUCAAAUUUCC 
               
               
                   
                   
                 904_s 
                   
                   
                   
               
               
                   
               
               
                 330 
                 331 
                 NM_002302.2_889- 
                 889 
                 AAUUUGAGUUUAAAUAGAA 
                 UUCUAUUUAAACUCAAAUU 
               
               
                   
                   
                 907_s 
                   
                   
                   
               
               
                   
               
               
                 332 
                 333 
                 NM_002302.2_895- 
                 895 
                 AGUUUAAAUAGAAACAUGA 
                 UCAUGUUUCUAUUUAAACU 
               
               
                   
                   
                 913_s 
                   
                   
                   
               
               
                   
               
               
                 334 
                 335 
                 NM_002302.2_899- 
                 899 
                 UAAAUAGAAACAUGAUAAA 
                 UUUAUCAUGUUUCUAUUUA 
               
               
                   
                   
                 917_s 
                   
                   
                   
               
               
                   
               
               
                 336 
                 337 
                 NM_002302.2_905- 
                 905 
                 GAAACAUGAUAAAUGCAAG 
                 CUUGCAUUUAUCAUGUUUC 
               
               
                   
                   
                 923_s 
                   
                   
                   
               
               
                   
               
               
                 338 
                 339 
                 NM_002302.2_912- 
                 912 
                 GAUAAAUGCAAGAAAGAAA 
                 UUUCUUUCUUGCAUUUAUC 
               
               
                   
                   
                 930_s 
                   
                   
                   
               
               
                   
               
               
                 340 
                 341 
                 NM_002302.2_915- 
                 915 
                 AAAUGCAAGAAAGAAAACA 
                 UGUUUUCUUUCUUGCAUUU 
               
               
                   
                   
                 933_s 
                   
                   
                   
               
               
                   
               
               
                 342 
                 343 
                 NM_002302.2_920- 
                 920 
                 CAAGAAAGAAAACAUUUUG 
                 CAAAAUGUUUUCUUUCUUG 
               
               
                   
                   
                 938_s 
                   
                   
                   
               
               
                   
               
               
                 344 
                 345 
                 NM_002302.2_926- 
                 926 
                 AGAAAACAUUUUGAUUUUA 
                 UAAAAUCAAAAUGUUUUCU 
               
               
                   
                   
                 944_s 
                   
                   
                   
               
               
                   
               
               
                 346 
                 347 
                 NM_002302.2_932- 
                 932 
                 CAUUUUGAUUUUAACUCAU 
                 AUGAGUUAAAAUCAAAAUG 
               
               
                   
                   
                 950_s 
                   
                   
                   
               
               
                   
               
               
                 348 
                 349 
                 NM_002302.2_938- 
                 938 
                 GAUUUUAACUCAUUGUCAC 
                 GUGACAAUGAGUUAAAAUC 
               
               
                   
                   
                 956_s 
                   
                   
                   
               
               
                   
               
               
                 350 
                 351 
                 NM_002302.2_939- 
                 939 
                 AUUUUAACUCAUUGUCACU 
                 AGUGACAAUGAGUUAAAAU 
               
               
                   
                   
                 957_s 
                   
                   
                   
               
               
                   
               
               
                 352 
                 353 
                 NM_002302.2_948- 
                 948 
                 CAUUGUCACUCUGAUGUUC 
                 GAACAUCAGAGUGACAAUG 
               
               
                   
                   
                 966_s 
                   
                   
                   
               
               
                   
               
               
                 354 
                 355 
                 NM_002302.2_950- 
                 950 
                 UUGUCACUCUGAUGUUCAU 
                 AUGAACAUCAGAGUGACAA 
               
               
                   
                   
                 968_s 
                   
                   
                   
               
               
                   
               
               
                 356 
                 357 
                 NM_002302.2_956- 
                 956 
                 CUCUGAUGUUCAUGUGAAC 
                 GUUCACAUGAACAUCAGAG 
               
               
                   
                   
                 974_s 
                   
                   
                   
               
               
                   
               
               
                 358 
                 359 
                 NM_002302.2_960- 
                 960 
                 GAUGUUCAUGUGAACUGGU 
                 ACCAGUUCACAUGAACAUC 
               
               
                   
                   
                 978_s 
                   
                   
                   
               
               
                   
               
               
                 360 
                 361 
                 NM_002302.2_966- 
                 966 
                 CAUGUGAACUGGUUGCUUC 
                 GAAGCAACCAGUUCACAUG 
               
               
                   
                   
                 984_s 
                   
                   
                   
               
               
                   
               
               
                 362 
                 363 
                 NM_002302.2_973- 
                 973 
                 ACUGGUUGCUUCGGGCUCU 
                 AGAGCCCGAAGCAACCAGU 
               
               
                   
                   
                 991_s 
                   
                   
                   
               
               
                   
               
               
                 364 
                 365 
                 NM_002302.2_977- 
                 977 
                 GUUGCUUCGGGCUCUUUGA 
                 UCAAAGAGCCCGAAGCAAC 
               
               
                   
                   
                 995_s 
                   
                   
                   
               
               
                   
               
               
                 366 
                 367 
                 NM_002302.2_980- 
                 980 
                 GCUUCGGGCUCUUUGAUCU 
                 AGAUCAAAGAGCCCGAAGC 
               
               
                   
                   
                 998_s 
                   
                   
                   
               
               
                   
               
               
                 368 
                 369 
                 NM_002302.2_984- 
                 984 
                 CGGGCUCUUUGAUCUGUCA 
                 UGACAGAUCAAAGAGCCCG 
               
               
                   
                   
                 1002_s 
                   
                   
                   
               
               
                   
               
               
                 370 
                 371 
                 NM_002302.2_989- 
                 989 
                 UCUUUGAUCUGUCACCUAU 
                 AUAGGUGACAGAUCAAAGA 
               
               
                   
                   
                 1007_s 
                   
                   
                   
               
               
                   
               
               
                 372 
                 373 
                 NM_002302.2_994- 
                 994 
                 GAUCUGUCACCUAUGGAAU 
                 AUUCCAUAGGUGACAGAUC 
               
               
                   
                   
                 1012_s 
                   
                   
                   
               
               
                   
               
               
                 374 
                 375 
                 NM_002302.2_1001- 
                 1001 
                 CACCUAUGGAAUCUGAGUG 
                 CACUCAGAUUCCAUAGGUG 
               
               
                   
                   
                 1019_s 
                   
                   
                   
               
               
                   
               
               
                 376 
                 377 
                 NM_002302.2_1008- 
                 1008 
                 GGAAUCUGAGUGGUUUUAU 
                 AUAAAACCACUCAGAUUCC 
               
               
                   
                   
                 1026_s 
                   
                   
                   
               
               
                   
               
               
                 378 
                 379 
                 NM_002302.2_1013- 
                 1013 
                 CUGAGUGGUUUUAUUUUUU 
                 AAAAAAUAAAACCACUCAG 
               
               
                   
                   
                 1031_s 
                   
                   
                   
               
               
                   
               
               
                 380 
                 381 
                 NM_002302.2_1015- 
                 1015 
                 GAGUGGUUUUAUUUUUUAG 
                 CUAAAAAAUAAAACCACUC 
               
               
                   
                   
                 1033_s 
                   
                   
                   
               
               
                   
               
               
                 382 
                 383 
                 NM_002302.2_1019- 
                 1019 
                 GGUUUUAUUUUUUAGAUUU 
                 AAAUCUAAAAAAUAAAACC 
               
               
                   
                   
                 1037_s 
                   
                   
                   
               
               
                   
               
               
                 384 
                 385 
                 NM_002302.2_1025- 
                 1025 
                 AUUUUUUAGAUUUCUCAGU 
                 ACUGAGAAAUCUAAAAAAU 
               
               
                   
                   
                 1043_s 
                   
                   
                   
               
               
                   
               
               
                 386 
                 387 
                 NM_002302.2_1031- 
                 1031 
                 UAGAUUUCUCAGUCCCAAA 
                 UUUGGGACUGAGAAAUCUA 
               
               
                   
                   
                 1049_s 
                   
                   
                   
               
               
                   
               
               
                 388 
                 389 
                 NM_002302.2_1038- 
                 1038 
                 CUCAGUCCCAAAGAUCUAA 
                 UUAGAUCUUUGGGACUGAG 
               
               
                   
                   
                 1056_s 
                   
                   
                   
               
               
                   
               
               
                 390 
                 391 
                 NM_002302.2_1043- 
                 1043 
                 UCCCAAAGAUCUAAGAUAA 
                 UUAUCUUAGAUCUUUGGGA 
               
               
                   
                   
                 1061_s 
                   
                   
                   
               
               
                   
               
               
                 392 
                 393 
                 NM_002302.2_1046- 
                 1046 
                 CAAAGAUCUAAGAUAAAUA 
                 UAUUUAUCUUAGAUCUUUG 
               
               
                   
                   
                 1064_s 
                   
                   
                   
               
               
                   
               
               
                 394 
                 395 
                 NM_002302.2_1053- 
                 1053 
                 CUAAGAUAAAUAAACAAGA 
                 UCUUGUUUAUUUAUCUUAG 
               
               
                   
                   
                 1071_s 
                   
                   
                   
               
               
                   
               
               
                 396 
                 397 
                 NM_002302.2_1055- 
                 1055 
                 AAGAUAAAUAAACAAGAGA 
                 UCUCUUGUUUAUUUAUCUU 
               
               
                   
                   
                 1073_s 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Human LECT2 siRNA Single Strands and Duplex Sequences 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                   
                 Start 
                   
                   
                   
               
               
                   
                 SEQ 
                   
                 Position 
                   
                   
                   
               
               
                   
                 ID 
                   
                 on 
                   
                   
                   
               
               
                 SEQ ID 
                 NO: 
                   
                 transcript 
                   
                   
                   
               
               
                 NO: 
                 (anti- 
                   
                 NM_ 
                 Sense Sequence 
                 Antisense Sequence 
                   
               
               
                 (sense) 
                 sense) 
                 Duplex Name 
                 002302.2 
                 (5′-3′) 
                 (5′-3′) 
                 Species 1   
               
               
                   
               
               
                 398 
                 399 
                 NM_002302.2_512- 
                 512 
                 AUUAAGCCAAUUAAGUAUAAA 
                 UUUAUACUUAAUUGGCUUAAUGU 
                 HCMR 
               
               
                   
                   
                 534_s 
                   
                   
                   
                   
               
               
                   
               
               
                 400 
                 401 
                 NM_002302.2_511- 
                 511 
                 CAUUAAGCCAAUUAAGUAUAA 
                 UUAUACUUAAUUGGCUUAAUGUA 
                 HCMR 
               
               
                   
                   
                 533_s 
                   
                   
                   
                   
               
               
                   
               
               
                 402 
                 403 
                 NM_002302.2_508- 
                 508 
                 CUACAUUAAGCCAAUUAAGUA 
                 UACUUAAUUGGCUUAAUGUAGAA 
                 HCMR 
               
               
                   
                   
                 530_s 
                   
                   
                   
                   
               
               
                   
               
               
                 404 
                 405 
                 NM_002302.2_509- 
                 509 
                 UACAUUAAGCCAAUUAAGUAU 
                 AUACUUAAUUGGCUUAAUGUAGA 
                 HCMR 
               
               
                   
                   
                 531_s 
                   
                   
                   
                   
               
               
                   
               
               
                 406 
                 407 
                 NM_002302.2_510- 
                 510 
                 ACAUUAAGCCAAUUAAGUAUA 
                 UAUACUUAAUUGGCUUAAUGUAG 
                 HCMR 
               
               
                   
                   
                 532_s 
                   
                   
                   
                   
               
               
                   
               
               
                 408 
                 409 
                 NM_002302.2_320- 
                 320 
                 UGUGGACAGUACUCUGCUCAA 
                 UUGAGCAGAGUACUGUCCACAGC 
                 HCM 
               
               
                   
                   
                 342_s 
                   
                   
                   
                   
               
               
                   
               
               
                 410 
                 411 
                 NM_002302.2_515- 
                 515 
                 AAGCCAAUUAAGUAUAAAGGU 
                 ACCUUUAUACUUAAUUGGCUUAA 
                 HCM 
               
               
                   
                   
                 537_s 
                   
                   
                   
                   
               
               
                   
               
               
                 412 
                 413 
                 NM_002302.2_513- 
                 513 
                 UUAAGCCAAUUAAGUAUAAAG 
                 CUUUAUACUUAAUUGGCUUAAUG 
                 HCM 
               
               
                   
                   
                 535_s 
                   
                   
                   
                   
               
               
                   
               
               
                 414 
                 415 
                 NM_002302.2_317- 
                 317 
                 GGCUGUGGACAGUACUCUGCU 
                 AGCAGAGUACUGUCCACAGCCAU 
                 HCM 
               
               
                   
                   
                 339_s 
                   
                   
                   
                   
               
               
                   
               
               
                 416 
                 417 
                 NM_002302.2_319- 
                 319 
                 CUGUGGACAGUACUCUGCUCA 
                 UGAGCAGAGUACUGUCCACAGCC 
                 HCM 
               
               
                   
                   
                 341_s 
                   
                   
                   
                   
               
               
                   
               
               
                 418 
                 419 
                 NM_002302.2_321- 
                 321 
                 GUGGACAGUACUCUGCUCAAA 
                 UUUGAGCAGAGUACUGUCCACAG 
                 HCM 
               
               
                   
                   
                 343_s 
                   
                   
                   
                   
               
               
                   
               
               
                 420 
                 421 
                 NM_002302.2_318- 
                 318 
                 GCUGUGGACAGUACUCUGCUC 
                 GAGCAGAGUACUGUCCACAGCCA 
                 HCM 
               
               
                   
                   
                 340_s 
                   
                   
                   
                   
               
               
                   
               
               
                 422 
                 423 
                 NM_002302.2_514- 
                 514 
                 UAAGCCAAUUAAGUAUAAAGG 
                 CCUUUAUACUUAAUUGGCUUAAU 
                 HCM 
               
               
                   
                   
                 536_s 
                   
                   
                   
                   
               
               
                   
               
               
                 424 
                 425 
                 NM_002302.2_324- 
                 324 
                 GACAGUACUCUGCUCAAAGAA 
                 UUCUUUGAGCAGAGUACUGUCCA 
                 HCM 
               
               
                   
                   
                 346_s 
                   
                   
                   
                   
               
               
                   
               
               
                 426 
                 427 
                 NM_002302.2_323- 
                 323 
                 GGACAGUACUCUGCUCAAAGA 
                 UCUUUGAGCAGAGUACUGUCCAC 
                 HCM 
               
               
                   
                   
                 345_s 
                   
                   
                   
                   
               
               
                   
               
               
                 428 
                 429 
                 NM_002302.2_322- 
                 322 
                 UGGACAGUACUCUGCUCAAAG 
                 CUUUGAGCAGAGUACUGUCCACA 
                 HCM 
               
               
                   
                   
                 344_s 
                   
                   
                   
                   
               
               
                   
               
               
                 430 
                 431 
                 NM_002302.2_513- 
                 513 
                 UUAAGCCAAUUAAGUAUAAAU 
                 AUUUAUACUUAAUUGGCUUAAUG 
                 HCM 
               
               
                   
                   
                 535_G21U_s 
                   
                   
                   
                   
               
               
                   
               
               
                 432 
                 433 
                 NM_002302.2_318- 
                 318 
                 GCUGUGGACAGUACUCUGCUA 
                 UAGCAGAGUACUGUCCACAGCCA 
                 HCM 
               
               
                   
                   
                 340_C21A_s 
                   
                   
                   
                   
               
               
                   
               
               
                 434 
                 435 
                 NM_002302.2_514- 
                 514 
                 UAAGCCAAUUAAGUAUAAAGA 
                 UCUUUAUACUUAAUUGGCUUAAU 
                 HCM 
               
               
                   
                   
                 536_G21A_s 
                   
                   
                   
                   
               
               
                   
               
               
                 436 
                 437 
                 NM_002302.2_322- 
                 322 
                 UGGACAGUACUCUGCUCAAAU 
                 AUUUGAGCAGAGUACUGUCCACA 
                 HCM 
               
               
                   
                   
                 344_G21U_s 
                   
                   
                   
                   
               
               
                   
               
               
                 438 
                 439 
                 NM_002302.2_516- 
                 516 
                 AGCCAAUUAAGUAUAAAGGUA 
                 UACCUUUAUACUUAAUUGGCUUA 
                 HCM 
               
               
                   
                   
                 538_C21A_s 
                   
                   
                   
                   
               
               
                   
               
               
                 440 
                 441 
                 NM_002302.2_516- 
                 516 
                 AGCCAAUUAAGUAUAAAGGUC 
                 GACCUUUAUACUUAAUUGGCUUA 
                 HCM 
               
               
                   
                   
                 538_s 
                   
                   
                   
                   
               
               
                   
               
               
                 442 
                 443 
                 NM_002302.2_507- 
                 507 
                 UCUACAUUAAGCCAAUUAAGU 
                 ACUUAAUUGGCUUAAUGUAGAAC 
                 HC 
               
               
                   
                   
                 529_s 
                   
                   
                   
                   
               
               
                   
               
               
                 444 
                 445 
                 NM_002302.2_506- 
                 506 
                 UUCUACAUUAAGCCAAUUAAG 
                 CUUAAUUGGCUUAAUGUAGAACA 
                 HC 
               
               
                   
                   
                 528_s 
                   
                   
                   
                   
               
               
                   
               
               
                 446 
                 447 
                 NM_002302.2_505- 
                 505 
                 GUUCUACAUUAAGCCAAUUAA 
                 UUAAUUGGCUUAAUGUAGAACAU 
                 HC 
               
               
                   
                   
                 527_s 
                   
                   
                   
                   
               
               
                   
               
               
                 448 
                 449 
                 NM_002302.2_504- 
                 504 
                 UGUUCUACAUUAAGCCAAUUA 
                 UAAUUGGCUUAAUGUAGAACAUU 
                 HC 
               
               
                   
                   
                 526_s 
                   
                   
                   
                   
               
               
                   
               
               
                 450 
                 451 
                 NM_002302.2_314- 
                 314 
                 CAUGGCUGUGGACAGUACUCU 
                 AGAGUACUGUCCACAGCCAUGGC 
                 HC 
               
               
                   
                   
                 336_s 
                   
                   
                   
                   
               
               
                   
               
               
                 452 
                 453 
                 NM_002302.2_316- 
                 316 
                 UGGCUGUGGACAGUACUCUGC 
                 GCAGAGUACUGUCCACAGCCAUG 
                 HC 
               
               
                   
                   
                 338_s 
                   
                   
                   
                   
               
               
                   
               
               
                 454 
                 455 
                 NM_002302.2_506- 
                 506 
                 UUCUACAUUAAGCCAAUUAAA 
                 UUUAAUUGGCUUAAUGUAGAACA 
                 HC 
               
               
                   
                   
                 528_G21A_s 
                   
                   
                   
                   
               
               
                   
               
               
                 456 
                 457 
                 NM_002302.2_316- 
                 316 
                 UGGCUGUGGACAGUACUCUGA 
                 UCAGAGUACUGUCCACAGCCAUG 
                 HC 
               
               
                   
                   
                 338_C21A_s 
                   
                   
                   
                   
               
               
                   
               
               
                 458 
                 459 
                 NM_002302.2_263- 
                 263 
                 GCUAAUAUAUGUGCUGGCAAA 
                 UUUGCCAGCACAUAUAUUAGCCC 
                 HC 
               
               
                   
                   
                 285_G21A_s 
                   
                   
                   
                   
               
               
                   
               
               
                 460 
                 461 
                 NM_002302.2_571- 
                 571 
                 GCCCUUGCAGAAAGUUUAUCA 
                 UGAUAAACUUUCUGCAAGGGCAA 
                 HC 
               
               
                   
                   
                 593_C21A_s 
                   
                   
                   
                   
               
               
                   
               
               
                 462 
                 463 
                 NM_002302.2_130- 
                 130 
                 UUGAAUAUUCUUCAAAGAGAA 
                 UUCUCUUUGAAGAAUAUUCAAGU 
                 HC 
               
               
                   
                   
                 152_G21A_s 
                   
                   
                   
                   
               
               
                   
               
               
                 464 
                 465 
                 NM_002302.2_263- 
                 263 
                 GCUAAUAUAUGUGCUGGCAAG 
                 CUUGCCAGCACAUAUAUUAGCCC 
                 HC 
               
               
                   
                   
                 285_s 
                   
                   
                   
                   
               
               
                   
               
               
                 466 
                 467 
                 NM_002302.2_118- 
                 118 
                 AUUCAUUCAAACUUGAAUAUU 
                 AAUAUUCAAGUUUGAAUGAAUAC 
                 HC 
               
               
                   
                   
                 140_s 
                   
                   
                   
                   
               
               
                   
               
               
                 468 
                 469 
                 NM_002302.2_107- 
                 107 
                 AGCUAGGAAGUAUUCAUUCAA 
                 UUGAAUGAAUACUUCCUAGCUAU 
                 HC 
               
               
                   
                   
                 129_s 
                   
                   
                   
                   
               
               
                   
               
               
                 470 
                 471 
                 NM_002302.2_665- 
                 665 
                 CAAUGGUCAGAUCUUCAAAAU 
                 AUUUUGAAGAUCUGACCAUUGGC 
                 HC 
               
               
                   
                   
                 687_s 
                   
                   
                   
                   
               
               
                   
               
               
                 472 
                 473 
                 NM_002302.2_668- 
                 668 
                 UGGUCAGAUCUUCAAAAUAAA 
                 UUUAUUUUGAAGAUCUGACCAUU 
                 HC 
               
               
                   
                   
                 690_s 
                   
                   
                   
                   
               
               
                   
               
               
                 474 
                 475 
                 NM_002302.2_427- 
                 427 
                 CCAGGAGAAACCUUAUCAAAA 
                 UUUUGAUAAGGUUUCUCCUGGCC 
                 HC 
               
               
                   
                   
                 449_s 
                   
                   
                   
                   
               
               
                   
               
               
                 476 
                 477 
                 NM_002302.2_572- 
                 572 
                 CCCUUGCAGAAAGUUUAUCCU 
                 AGGAUAAACUUUCUGCAAGGGCA 
                 HC 
               
               
                   
                   
                 594_s 
                   
                   
                   
                   
               
               
                   
               
               
                 478 
                 479 
                 NM_002302.2_123- 
                 123 
                 UUCAAACUUGAAUAUUCUUCA 
                 UGAAGAAUAUUCAAGUUUGAAUG 
                 HC 
               
               
                   
                   
                 145_s 
                   
                   
                   
                   
               
               
                   
               
               
                 480 
                 481 
                 NM_002302.2_106- 
                 106 
                 UAGCUAGGAAGUAUUCAUUCA 
                 UGAAUGAAUACUUCCUAGCUAUU 
                 HC 
               
               
                   
                   
                 128_s 
                   
                   
                   
                   
               
               
                   
               
               
                 482 
                 483 
                 NM_002302.2_571- 
                 571 
                 GCCCUUGCAGAAAGUUUAUCC 
                 GGAUAAACUUUCUGCAAGGGCAA 
                 HC 
               
               
                   
                   
                 593_s 
                   
                   
                   
                   
               
               
                   
               
               
                 484 
                 485 
                 NM_002302.2_130- 
                 130 
                 UUGAAUAUUCUUCAAAGAGAG 
                 CUCUCUUUGAAGAAUAUUCAAGU 
                 HC 
               
               
                   
                   
                 152_s 
                   
                   
                   
                   
               
               
                   
               
               
                 486 
                 487 
                 NM_002302.2_664- 
                 664 
                 CCAAUGGUCAGAUCUUCAAAA 
                 UUUUGAAGAUCUGACCAUUGGCC 
                 HC 
               
               
                   
                   
                 686_s 
                   
                   
                   
                   
               
               
                   
               
               
                 488 
                 489 
                 NM_002302.2_666- 
                 666 
                 AAUGGUCAGAUCUUCAAAAUA 
                 UAUUUUGAAGAUCUGACCAUUGG 
                 HC 
               
               
                   
                   
                 688_s 
                   
                   
                   
                   
               
               
                   
               
               
                 490 
                 491 
                 NM_002302.2_421- 
                 421 
                 UGUGGGCCAGGAGAAACCUUA 
                 UAAGGUUUCUCCUGGCCCACAAU 
                 HC 
               
               
                   
                   
                 443_s 
                   
                   
                   
                   
               
               
                   
               
               
                 492 
                 493 
                 NM_002302.2_368- 
                 368 
                 GACAUCUUGUGCUCUGCUGGA 
                 UCCAGCAGAGCACAAGAUGUCCA 
                 HC 
               
               
                   
                   
                 390_s 
               
               
                   
               
               
                   1 H: human; C: cynomolgus monkey; M: mouse; R: rat 
               
            
           
         
       
     
     Example 2. In Vitro Screening of LECT2 siRNA 
     Experimental Methods 
     Cell Culture and Transfections: 
     Primary Cynomolgus monkey hepatocytes (PCH) (Celsis #MO03055, lot CBT) were transfected 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 siRNA duplexes per well into a 96-well plate and incubated at room temperature for 15 minutes. 80 μl of InVitroGRO CP Rat media (InVitro Technologies) containing ˜2×10 4  PCH cells 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 and dose response experiments were done over a range of doses from 10 nM to 36 fM final duplex concentration over 8, 6-fold dilutions. 
     RNA Isolation: 
     Total RNA was isolated 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 minute 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 magnetic stand and the supernatant was removed without disturbing the beads. After removing supernatant, the lysed cells were added to the remaining beads and mixed for 5 minutes. After removing supernatant, magnetic beads were washed 2 times with 150 μl Wash Buffer A and mixed for 1 minute. Beads were capture again and supernatant removed. Beads were then washed with 150 μl Wash Buffer B, captured and supernatant was removed. Beads were next washed with 150 μl Elution Buffer, captured and supernatant removed. 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. Beads were captured on magnet for 5 minutes. 40 μl of supernatant was removed and added to another 96 well plate. 
     cDNA Synthesis 
     cDNA was synthesized 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 3.41 of H 2 O per reaction were added into 10 μl total RNA. cDNA was 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: 
     2 μl of cDNA were added to a master mix containing 0.5 μl of custom designed Cynomolgus monkey GAPDH TaqMan Probe (F-GCATCCTGGGCTACACTGA (SEQ ID NO: 494), R-TGGGTGTCGCTGTTGAAGTC (SEQ ID NO: 495), Probe-CCAGGTGGTCTCCTCC (SEQ ID NO: 496)), 0.5 μl human Lect2 (Hs01040204_m1—which is cross reactive with Cynomolgus monkey Lect2) 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 LightCycler480 Real Time PCR system (Roche) using the ΔΔCt(RQ) assay. Each duplex was tested in two independent transfections and each transfection was assayed in duplicate, unless otherwise noted in the summary tables. 
     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. IC 50  s were calculated using a 4 parameter fit model using XLFit and normalized to cells transfected with AD-1955 or naïve cells. 
     The modified and unmodified LECT2 siRNA sequences are shown in Tables 5 and 6, respectively. Nucleic acid sequences provided herein are represented using standard nomenclature (see the abbreviations of Table 1). In some instances, mismatches between duplex and mRNA target were allowed at the first antisense (last sense) position when the antisense strand:target mRNA complementary basepair was a GC or CG pair (see Tables 5 and 6, oligos with label G21U, G21A, C21A). In these cases, duplexes were designed with UA or AU pairs at the first antisense:last sense pair. Thus the duplexes maintained complementarity but were mismatched with respect to target (U:C, U:G, A:C, or A:G). 
     
       
         
           
               
             
               
                 TABLE 5 
               
               
                   
               
               
                 Modified LECT2 siRNA Sequences 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 Sense 
                   
                 SEQ 
                   
               
               
                 Duplex 
                 Oligo 
                   
                 ID 
                 Antisense 
               
               
                 Name 
                 Name 
                 Sense Sequence 
                 NO 
                 Oligo Name 
               
               
                   
               
               
                 AD-61249 
                 A-122943 
                 UfsasGfcUfaGfgAfAfGfuAfuUfcAfuUfcAfL96 
                 497 
                 A-122944 
               
               
                   
               
               
                 AD-61260 
                 A-122931 
                 AfsgsCfuAfgGfaAfGfUfaUfuCfaUfuCfaAfL96 
                 499 
                 A-122932 
               
               
                   
               
               
                 AD-61254 
                 A-122929 
                 AfsusUfcAfuUfcAfAfAfcUfuGfaAfuAfuUfL96 
                 501 
                 A-122930 
               
               
                   
               
               
                 AD-61243 
                 A-122941 
                 UfsusCfaAfaCfuUfGfAfaUfaUfuCfuUfcAfL96 
                 503 
                 A-122942 
               
               
                   
               
               
                 AD-61261 
                 A-122947 
                 UfsusGfaAfuAfuUfCfUfuCfaAfaGfaGfaGfL96 
                 505 
                 A-122948 
               
               
                   
               
               
                 AD-61242 
                 A-122925 
                 UfsusGfaAfuAfuUfCfUfuCfaAfaGfaGfaAfL96 
                 507 
                 A-122926 
               
               
                   
               
               
                 AD-61248 
                 A-122927 
                 GfscsUfaAfuAfuAfUfGfuGfcUfgGfcAfaGfL96 
                 509 
                 A-122928 
               
               
                   
               
               
                 AD-61277 
                 A-122921 
                 GfscsUfaAfuAfuAfUfGfuGfcUfgGfcAfaAfL96 
                 511 
                 A-122922 
               
               
                   
               
               
                 AD-61253 
                 A-122913 
                 CfsasUfgGfcUfgUfGfGfaCfaGfuAfcUfcUfL96 
                 513 
                 A-122914 
               
               
                   
               
               
                 AD-61259 
                 A-122915 
                 UfsgsGfcUfgUfgGfAfCfaGfuAfcUfcUfgCfL96 
                 515 
                 A-122916 
               
               
                   
               
               
                 AD-61271 
                 A-122919 
                 UfsgsGfcUfgUfgGfAfCfaGfuAfcUfcUfgAfL96 
                 517 
                 A-122920 
               
               
                   
               
               
                 AD-61239 
                 A-122877 
                 GfsgsCfuGfuGfgAfCfAfgUfaCfuCfuGfcUfL96 
                 519 
                 A-122878 
               
               
                   
               
               
                 AD-61257 
                 A-122883 
                 GfscsUfgUfgGfaCfAfGfuAfcUfcUfgCfuCfL96 
                 521 
                 A-122884 
               
               
                   
               
               
                 AD-61246 
                 A-122895 
                 GfscsUfgUfgGfaCfAfGfuAfcUfcUfgCfuAfL96 
                 523 
                 A-122896 
               
               
                   
               
               
                 AD-61245 
                 A-122879 
                 CfsusGfuGfgAfcAfGfUfaCfuCfuGfcUfcAfL96 
                 525 
                 A-122880 
               
               
                   
               
               
                 AD-61268 
                 A-122871 
                 UfsgsUfgGfaCfaGfUfAfcUfcUfgCfuCfaAfL96 
                 527 
                 A-122872 
               
               
                   
               
               
                 AD-61251 
                 A-122881 
                 GfsusGfgAfcAfgUfAfCfuCfuGfcUfcAfaAfL96 
                 529 
                 A-122882 
               
               
                   
               
               
                 AD-61281 
                 A-122891 
                 UfsgsGfaCfaGfuAfCfUfcUfgCfuCfaAfaGfL96 
                 531 
                 A-122892 
               
               
                   
               
               
                 AD-61258 
                 A-122899 
                 UfsgsGfaCfaGfuAfCfUfcUfgCfuCfaAfaUfL96 
                 533 
                 A-122900 
               
               
                   
               
               
                 AD-61275 
                 A-122889 
                 GfsgsAfcAfgUfaCfUfCfuGfcUfcAfaAfgAfL96 
                 535 
                 A-122890 
               
               
                   
               
               
                 AD-61269 
                 A-122887 
                 GfsasCfaGfuAfcUfCfUfgCfuCfaAfaGfaAfL96 
                 537 
                 A-122888 
               
               
                   
               
               
                 AD-61279 
                 A-122955 
                 UfsgsUfgGfgCfcAfGfGfaGfaAfaCfcUfuAfL96 
                 539 
                 A-122956 
               
               
                   
               
               
                 AD-61278 
                 A-122937 
                 CfscsAfgGfaGfaAfAfCfcUfuAfuCfaAfaAfL96 
                 541 
                 A-122938 
               
               
                   
               
               
                 AD-61247 
                 A-122911 
                 UfsgsUfuCfuAfcAfUfUfaAfgCfcAfaUfuAfL96 
                 543 
                 A-122912 
               
               
                   
               
               
                 AD-61241 
                 A-122909 
                 GfsusUfcUfaCfaUfUfAfaGfcCfaAfuUfaAfL96 
                 545 
                 A-122910 
               
               
                   
               
               
                 AD-61282 
                 A-122907 
                 UfsusCfuAfcAfuUfAfAfgCfcAfaUfuAfaGfL96 
                 547 
                 A-122908 
               
               
                   
               
               
                 AD-61265 
                 A-122917 
                 UfsusCfuAfcAfuUfAfAfgCfcAfaUfuAfaAfL96 
                 549 
                 A-122918 
               
               
                   
               
               
                 AD-61276 
                 A-122905 
                 UfscsUfaCfaUfuAfAfGfcCfaAfuUfaAfgUfL96 
                 551 
                 A-122906 
               
               
                   
               
               
                 AD-61250 
                 A-122865 
                 CfsusAfcAfuUfaAfGfCfcAfaUfuAfaGfuAfL96 
                 553 
                 A-122866 
               
               
                   
               
               
                 AD-61256 
                 A-122867 
                 UfsasCfaUfuAfaGfCfCfaAfuUfaAfgUfaUfL96 
                 555 
                 A-122868 
               
               
                   
               
               
                 AD-61262 
                 A-122869 
                 AfscsAfuUfaAfgCfCfAfaUfuAfaGfuAfuAfL96 
                 557 
                 A-122870 
               
               
                   
               
               
                 AD-61244 
                 A-122863 
                 CfsasUfuAfaGfcCfAfAfuUfaAfgUfaUfaAfL96 
                 559 
                 A-122864 
               
               
                   
               
               
                 AD-61238 
                 A-122861 
                 AfsusUfaAfgCfcAfAfUfuAfaGfuAfuAfaAfL96 
                 561 
                 A-122862 
               
               
                   
               
               
                 AD-61280 
                 A-122875 
                 UfsusAfaGfcCfaAfUfUfaAfgUfaUfaAfaGfL96 
                 563 
                 A-122876 
               
               
                   
               
               
                 AD-61240 
                 A-122893 
                 UfsusAfaGfcCfaAfUfUfaAfgUfaUfaAfaUfL96 
                 565 
                 A-122894 
               
               
                   
               
               
                 AD-61263 
                 A-122885 
                 UfsasAfgCfcAfaUfUfAfaGfuAfuAfaAfgGfL96 
                 567 
                 A-122886 
               
               
                   
               
               
                 AD-61252 
                 A-122897 
                 UfsasAfgCfcAfaUfUfAfaGfuAfuAfaAfgAfL96 
                 569 
                 A-122898 
               
               
                   
               
               
                 AD-61274 
                 A-122873 
                 AfsasGfcCfaAfuUfAfAfgUfaUfaAfaGfgUfL96 
                 571 
                 A-122874 
               
               
                   
               
               
                 AD-61270 
                 A-122903 
                 AfsgsCfcAfaUfuAfAfGfuAfuAfaAfgGfuCfL96 
                 573 
                 A-122904 
               
               
                   
               
               
                 AD-61264 
                 A-122901 
                 AfsgsCfcAfaUfuAfAfGfuAfuAfaAfgGfuAfL96 
                 575 
                 A-122902 
               
               
                   
               
               
                 AD-61255 
                 A-122945 
                 GfscsCfcUfuGfcAfGfAfaAfgUfuUfaUfcCfL96 
                 577 
                 A-122946 
               
               
                   
               
               
                 AD-61283 
                 A-122923 
                 GfscsCfcUfuGfcAfGfAfaAfgUfuUfaUfcAfL96 
                 579 
                 A-122924 
               
               
                   
               
               
                 AD-61284 
                 A-122939 
                 CfscsCfuUfgCfaGfAfAfaGfuUfuAfuCfcUfL96 
                 581 
                 A-122940 
               
               
                   
               
               
                 AD-61267 
                 A-122950 
                 CfscsAfaUfgGfuCfAfGfaUfcUfuCfaAfaAfL96 
                 583 
                 A-122952 
               
               
                   
               
               
                 AD-61266 
                 A-122933 
                 CfsasAfuGfgUfcAfGfAfuCfuUfcAfaAfaUfL96 
                 585 
                 A-122934 
               
               
                   
               
               
                 AD-61273 
                 A-122953 
                 AfsasUfgGfuCfaGfAfUfcUfuCfaAfaAfuAfL96 
                 587 
                 A-122954 
               
               
                   
               
               
                 AD-61272 
                 A-122935 
                 UfsgsGfuCfaGfaUfCfUfuCfaAfaAfuAfaAfL96 
                 589 
                 A-122936 
               
               
                   
               
               
                   
                   
                   
                 SEQ 
                 Antisense 
               
               
                   
                 Duplex 
                   
                 ID 
                 position in 
               
               
                   
                 Name 
                 Antisense Sequence 
                 NO 
                 NM_002302 
               
               
                   
               
               
                   
                 AD-61249 
                 usGfsaAfuGfaAfuAfcuuCfcUfaGfcUfasusu 
                 498 
                 106-128 
               
               
                   
               
               
                   
                 AD-61260 
                 usUfsgAfaUfgAfaUfacuUfcCfuAfgCfusasu 
                 500 
                 107-129 
               
               
                   
               
               
                   
                 AD-61254 
                 asAfsuAfuUfcAfaGfuuuGfaAfuGfaAfusasc 
                 502 
                 118-140 
               
               
                   
               
               
                   
                 AD-61243 
                 usGfsaAfgAfaUfaUfucaAfgUfuUfgAfasusg 
                 504 
                 123-145 
               
               
                   
               
               
                   
                 AD-61261 
                 csUfscUfcUfuUfgAfagaAfuAfuUfcAfasgsu 
                 506 
                 130-152 
               
               
                   
               
               
                   
                 AD-61242 
                 usUfscUfcUfuUfgAfagaAfuAfuUfcAfasgsu 
                 508 
                 130-152_G21A 
               
               
                   
               
               
                   
                 AD-61248 
                 csUfsuGfcCfaGfcAfcauAfuAfuUfaGfcscsc 
                 510 
                 263-285 
               
               
                   
               
               
                   
                 AD-61277 
                 usUfsuGfcCfaGfcAfcauAfuAfuUfaGfcscsc 
                 512 
                 263-285_G21A 
               
               
                   
               
               
                   
                 AD-61253 
                 asGfsaGfuAfcUfgUfccaCfaGfcCfaUfgsgsc 
                 514 
                 314-336 
               
               
                   
               
               
                   
                 AD-61259 
                 gsCfsaGfaGfuAfcUfgucCfaCfaGfcCfasusg 
                 516 
                 316-338 
               
               
                   
               
               
                   
                 AD-61271 
                 usCfsaGfaGfuAfcUfgucCfaCfaGfcCfasusg 
                 518 
                 316-338_C21A 
               
               
                   
               
               
                   
                 AD-61239 
                 asGfscAfgAfgUfaCfuguCfcAfcAfgCfcsasu 
                 520 
                 317-339 
               
               
                   
               
               
                   
                 AD-61257 
                 gsAfsgCfaGfaGfuAfcugUfcCfaCfaGfcscsa 
                 522 
                 318-340 
               
               
                   
               
               
                   
                 AD-61246 
                 usAfsgCfaGfaGfuAfcugUfcCfaCfaGfcscsa 
                 524 
                 318-340_C21A 
               
               
                   
               
               
                   
                 AD-61245 
                 usGfsaGfcAfgAfgUfacuGfuCfcAfcAfgscsc 
                 526 
                 319-341 
               
               
                   
               
               
                   
                 AD-61268 
                 usUfsgAfgCfaGfaGfuacUfgUfcCfaCfasgsc 
                 528 
                 320-342 
               
               
                   
               
               
                   
                 AD-61251 
                 usUfsuGfaGfcAfgAfguaCfuGfuCfcAfcsasg 
                 530 
                 321-343 
               
               
                   
               
               
                   
                 AD-61281 
                 csUfsuUfgAfgCfaGfaguAfcUfgUfcCfascsa 
                 532 
                 322-344 
               
               
                   
               
               
                   
                 AD-61258 
                 asUfsuUfgAfgCfaGfaguAfcUfgUfcCfascsa 
                 534 
                 322-344_G21U 
               
               
                   
               
               
                   
                 AD-61275 
                 usCfsuUfuGfaGfcAfgagUfaCfuGfuCfcsasc 
                 536 
                 323-345 
               
               
                   
               
               
                   
                 AD-61269 
                 usUfscUfuUfgAfgCfagaGfuAfcUfgUfcscsa 
                 538 
                 324-346 
               
               
                   
               
               
                   
                 AD-61279 
                 usAfsaGfgUfuUfcUfccuGfgCfcCfaCfasasu 
                 540 
                 421-443 
               
               
                   
               
               
                   
                 AD-61278 
                 usUfsuUfgAfuAfaGfguuUfcUfcCfuGfgscsc 
                 542 
                 427-449 
               
               
                   
               
               
                   
                 AD-61247 
                 usAfsaUfuGfgCfuUfaauGfuAfgAfaCfasusu 
                 544 
                 504-526 
               
               
                   
               
               
                   
                 AD-61241 
                 usUfsaAfuUfgGfcUfuaaUfgUfaGfaAfcsasu 
                 546 
                 505-527 
               
               
                   
               
               
                   
                 AD-61282 
                 csUfsuAfaUfuGfgCfuuaAfuGfuAfgAfascsa 
                 548 
                 506-528 
               
               
                   
               
               
                   
                 AD-61265 
                 usUfsuAfaUfuGfgCfuuaAfuGfuAfgAfascsa 
                 550 
                 506-528_G21A 
               
               
                   
               
               
                   
                 AD-61276 
                 asCfsuUfaAfuUfgGfcuuAfaUfgUfaGfasasc 
                 552 
                 507-529 
               
               
                   
               
               
                   
                 AD-61250 
                 usAfscUfuAfaUfuGfgcuUfaAfuGfuAfgsasa 
                 554 
                 508-530 
               
               
                   
               
               
                   
                 AD-61256 
                 asUfsaCfuUfaAfuUfggcUfuAfaUfgUfasgsa 
                 556 
                 509-531 
               
               
                   
               
               
                   
                 AD-61262 
                 usAfsuAfcUfuAfaUfuggCfuUfaAfuGfusasg 
                 558 
                 510-532 
               
               
                   
               
               
                   
                 AD-61244 
                 usUfsaUfaCfuUfaAfuugGfcUfuAfaUfgsusa 
                 560 
                 511-533 
               
               
                   
               
               
                   
                 AD-61238 
                 usUfsuAfuAfcUfuAfauuGfgCfuUfaAfusgsu 
                 562 
                 512-534 
               
               
                   
               
               
                   
                 AD-61280 
                 csUfsuUfaUfaCfuUfaauUfgGfcUfuAfasusg 
                 564 
                 513-535 
               
               
                   
               
               
                   
                 AD-61240 
                 asUfsuUfaUfaCfuUfaauUfgGfcUfuAfasusg 
                 566 
                 513-535_G21U 
               
               
                   
               
               
                   
                 AD-61263 
                 csCfsuUfuAfuAfcUfuaaUfuGfgCfuUfasasu 
                 568 
                 514-536 
               
               
                   
               
               
                   
                 AD-61252 
                 usCfsuUfuAfuAfcUfuaaUfuGfgCfuUfasasu 
                 570 
                 514-536_G21A 
               
               
                   
               
               
                   
                 AD-61274 
                 asCfscUfuUfaUfaCfuuaAfuUfgGfcUfusasa 
                 572 
                 515-537 
               
               
                   
               
               
                   
                 AD-61270 
                 gsAfscCfuUfuAfuAfcuuAfaUfuGfgCfususa 
                 574 
                 516-538 
               
               
                   
               
               
                   
                 AD-61264 
                 usAfscCfuUfuAfuAfcuuAfaUfuGfgCfususa 
                 576 
                 516-538_C21A 
               
               
                   
               
               
                   
                 AD-61255 
                 gsGfsaUfaAfaCfuUfucuGfcAfaGfgGfcsasa 
                 578 
                 571-593 
               
               
                   
               
               
                   
                 AD-61283 
                 usGfsaUfaAfaCfuUfucuGfcAfaGfgGfcsasa 
                 580 
                 571-593_C21A 
               
               
                   
               
               
                   
                 AD-61284 
                 asGfsgAfuAfaAfcUfuucUfgCfaAfgGfgscsa 
                 582 
                 572-594 
               
               
                   
               
               
                   
                 AD-61267 
                 usUfsuUfgAfaGfaUfcugAfcCfaUfuGfgscsc 
                 584 
                 664-686 
               
               
                   
               
               
                   
                 AD-61266 
                 asUfsuUfuGfaAfgAfucuGfaCfcAfuUfgsgsc 
                 586 
                 665-687 
               
               
                   
               
               
                   
                 AD-61273 
                 usAfsuUfuUfgAfaGfaucUfgAfcCfaUfusgsg 
                 588 
                 666-688 
               
               
                   
               
               
                   
                 AD-61272 
                 usUfsuAfuUfuUfgAfagaUfcUfgAfcCfasusu 
                 590 
                 668-690 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 Unmodified LECT2 siRNA Sequences 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                 Sense 
                 Anti- 
                   
                   
                 Antisense 
               
               
                   
                 Sense 
                   
                 SEQ 
                 Position 
                 sense 
                   
                 SEQ 
                 position 
               
               
                   
                 Oligo 
                   
                 ID 
                 in 
                 Oligo 
                   
                 ID 
                 in 
               
               
                 Duplex Name 
                 Name 
                 Sense Sequence 
                 NO 
                 NM_002302 
                 Name 
                 Antisense Sequence 
                 NO 
                 NM_002302 
               
               
                   
               
               
                 AD-61249UM 
                 A-122943 
                 UAGCUAGGAAGUAUUCAUUCA 
                 591 
                 108-128 
                 A-122944 
                 UGAAUGAAUACUUCCUAGCUAUU 
                 592 
                 106-128 
               
               
                   
               
               
                 AD-61260 UM 
                 A-122931 
                 AGCUAGGAAGUAUUCAUUCAA 
                 593 
                 109-129 
                 A-122932 
                 UUGAAUGAAUACUUCCUAGCUAU 
                 594 
                 107-129 
               
               
                   
               
               
                 AD-61254 UM 
                 A-122929 
                 AUUCAUUCAAACUUGAAUAUU 
                 595 
                 120-140 
                 A-122930 
                 AAUAUUCAAGUUUGAAUGAAUAC 
                 596 
                 118-140 
               
               
                   
               
               
                 AD-61243 UM 
                 A-122941 
                 UUCAAACUUGAAUAUUCUUCA 
                 597 
                 125-145 
                 A-122942 
                 UGAAGAAUAUUCAAGUUUGAAUG 
                 598 
                 123-145 
               
               
                   
               
               
                 AD-61261 UM 
                 A-122947 
                 UUGAAUAUUCUUCAAAGAGAG 
                 599 
                 132-152 
                 A-122948 
                 CUCUCUUUGAAGAAUAUUCAAGU 
                 600 
                 130-152 
               
               
                   
               
               
                 AD-61242 UM 
                 A-122925 
                 UUGAAUAUUCUUCAAAGAGAA 
                 601 
                 132-152_ 
                 A-122926 
                 UUCUCUUUGAAGAAUAUUCAAGU 
                 602 
                 130-152_ 
               
               
                   
                   
                   
                   
                 G21A 
                   
                   
                   
                 G21A 
               
               
                   
               
               
                 AD-61248 UM 
                 A-122927 
                 GCUAAUAUAUGUGCUGGCAAG 
                 603 
                 265-285 
                 A-122928 
                 CUUGCCAGCACAUAUAUUAGCCC 
                 604 
                 263-285 
               
               
                   
               
               
                 AD-61277 UM 
                 A-122921 
                 GCUAAUAUAUGUGCUGGCAAA 
                 605 
                 265-285_ 
                 A-122922 
                 UUUGCCAGCACAUAUAUUAGCCC 
                 606 
                 263-285_ 
               
               
                   
                   
                   
                   
                 G21A 
                   
                   
                   
                 G21A 
               
               
                   
               
               
                 AD-61253 UM 
                 A-122913 
                 CAUGGCUGUGGACAGUACUCU 
                 607 
                 316-336 
                 A-122914 
                 AGAGUACUGUCCACAGCCAUGGC 
                 608 
                 314-336 
               
               
                   
               
               
                 AD-61259 UM 
                 A-122915 
                 UGGCUGUGGACAGUACUCUGC 
                 609 
                 318-338 
                 A-122916 
                 GCAGAGUACUGUCCACAGCCAUG 
                 610 
                 316-338 
               
               
                   
               
               
                 AD-61271 UM 
                 A-122919 
                 UGGCUGUGGACAGUACUCUGA 
                 611 
                 318-338_ 
                 A-122920 
                 UCAGAGUACUGUCCACAGCCAUG 
                 612 
                 316-338_ 
               
               
                   
                   
                   
                   
                 C21A 
                   
                   
                   
                 C21A 
               
               
                   
               
               
                 AD-61239 UM 
                 A-122877 
                 GGCUGUGGACAGUACUCUGCU 
                 613 
                 319-339 
                 A-122878 
                 AGCAGAGUACUGUCCACAGCCAU 
                 614 
                 317-339 
               
               
                   
               
               
                 AD-61257 UM 
                 A-122883 
                 GCUGUGGACAGUACUCUGCUC 
                 615 
                 320-340 
                 A-122884 
                 GAGCAGAGUACUGUCCACAGCCA 
                 616 
                 318-340 
               
               
                   
               
               
                 AD-61246 UM 
                 A-122895 
                 GCUGUGGACAGUACUCUGCUA 
                 617 
                 320-340_ 
                 A-122896 
                 UAGCAGAGUACUGUCCACAGCCA 
                 618 
                 318-340_ 
               
               
                   
                   
                   
                   
                 C21A 
                   
                   
                   
                 C21A 
               
               
                   
               
               
                 AD-61245 UM 
                 A-122879 
                 CUGUGGACAGUACUCUGCUCA 
                 619 
                 321-341 
                 A-122880 
                 UGAGCAGAGUACUGUCCACAGCC 
                 620 
                 319-341 
               
               
                   
               
               
                 AD-61268 UM 
                 A-122871 
                 UGUGGACAGUACUCUGCUCAA 
                 621 
                 322-342 
                 A-122872 
                 UUGAGCAGAGUACUGUCCACAGC 
                 622 
                 320-342 
               
               
                   
               
               
                 AD-61251 UM 
                 A-122881 
                 GUGGACAGUACUCUGCUCAAA 
                 623 
                 323-343 
                 A-122882 
                 UUUGAGCAGAGUACUGUCCACAG 
                 624 
                 321-343 
               
               
                   
               
               
                 AD-61281 UM 
                 A-122891 
                 UGGACAGUACUCUGCUCAAAG 
                 625 
                 324-344 
                 A-122892 
                 CUUUGAGCAGAGUACUGUCCACA 
                 626 
                 322-344 
               
               
                   
               
               
                 AD-61258 UM 
                 A-122899 
                 UGGACAGUACUCUGCUCAAAU 
                 627 
                 324-344_ 
                 A-122900 
                 AUUUGAGCAGAGUACUGUCCACA 
                 628 
                 322-344_ 
               
               
                   
                   
                   
                   
                 G21U 
                   
                   
                   
                 G21U 
               
               
                   
               
               
                 AD-61275 UM 
                 A-122889 
                 GGACAGUACUCUGCUCAAAGA 
                 629 
                 325-345 
                 A-122890 
                 UCUUUGAGCAGAGUACUGUCCAC 
                 630 
                 323-345 
               
               
                   
               
               
                 AD-61269 UM 
                 A-122887 
                 GACAGUACUCUGCUCAAAGAA 
                 631 
                 326-346 
                 A-122888 
                 UUCUUUGAGCAGAGUACUGUCCA 
                 632 
                 324-346 
               
               
                   
               
               
                 AD-61279 UM 
                 A-122955 
                 UGUGGGCCAGGAGAAACCUUA 
                 633 
                 423-443 
                 A-122956 
                 UAAGGUUUCUCCUGGCCCACAAU 
                 634 
                 421-443 
               
               
                   
               
               
                 AD-61278 UM 
                 A-122937 
                 CCAGGAGAAACCUUAUCAAAA 
                 635 
                 429-449 
                 A-122938 
                 UUUUGAUAAGGUUUCUCCUGGCC 
                 636 
                 427-449 
               
               
                   
               
               
                 AD-61247 UM 
                 A-122911 
                 UGUUCUACAUUAAGCCAAUUA 
                 637 
                 506-526 
                 A-122912 
                 UAAUUGGCUUAAUGUAGAACAUU 
                 638 
                 504-526 
               
               
                   
               
               
                 AD-61241 UM 
                 A-122909 
                 GUUCUACAUUAAGCCAAUUAA 
                 639 
                 507-527 
                 A-122910 
                 UUAAUUGGCUUAAUGUAGAACAU 
                 640 
                 505-527 
               
               
                   
               
               
                 AD-61282 UM 
                 A-122907 
                 UUCUACAUUAAGCCAAUUAAG 
                 641 
                 508-528 
                 A-122908 
                 CUUAAUUGGCUUAAUGUAGAACA 
                 642 
                 506-528 
               
               
                   
               
               
                 AD-61265 UM 
                 A-122917 
                 UUCUACAUUAAGCCAAUUAAA 
                 643 
                 508-528_ 
                 A-122918 
                 UUUAAUUGGCUUAAUGUAGAACA 
                 644 
                 506-528_ 
               
               
                   
                   
                   
                   
                 G21A 
                   
                   
                   
                 G21A 
               
               
                   
               
               
                 AD-61276 UM 
                 A-122905 
                 UCUACAUUAAGCCAAUUAAGU 
                 645 
                 509-529 
                 A-122906 
                 ACUUAAUUGGCUUAAUGUAGAAC 
                 646 
                 507-529 
               
               
                   
               
               
                 AD-61250 UM 
                 A-122865 
                 CUACAUUAAGCCAAUUAAGUA 
                 647 
                 510-530 
                 A-122866 
                 UACUUAAUUGGCUUAAUGUAGAA 
                 648 
                 508-530 
               
               
                   
               
               
                 AD-61256 UM 
                 A-122867 
                 UACAUUAAGCCAAUUAAGUAU 
                 649 
                 511-531 
                 A-122868 
                 AUACUUAAUUGGCUUAAUGUAGA 
                 650 
                 509-531 
               
               
                   
               
               
                 AD-61262 UM 
                 A-122869 
                 ACAUUAAGCCAAUUAAGUAUA 
                 651 
                 512-532 
                 A-122870 
                 UAUACUUAAUUGGCUUAAUGUAG 
                 652 
                 510-532 
               
               
                   
               
               
                 AD-61244 UM 
                 A-122863 
                 CAUUAAGCCAAUUAAGUAUAA 
                 653 
                 513-533 
                 A-122864 
                 UUAUACUUAAUUGGCUUAAUGUA 
                 654 
                 511-533 
               
               
                   
               
               
                 AD-61238 UM 
                 A-122861 
                 AUUAAGCCAAUUAAGUAUAAA 
                 655 
                 514-534 
                 A-122862 
                 UUUAUACUUAAUUGGCUUAAUGU 
                 656 
                 512-534 
               
               
                   
               
               
                 AD-61280 UM 
                 A-122875 
                 UUAAGCCAAUUAAGUAUAAAG 
                 657 
                 515-535 
                 A-122876 
                 CUUUAUACUUAAUUGGCUUAAUG 
                 658 
                 513-535 
               
               
                   
               
               
                 AD-61240 UM 
                 A-122893 
                 UUAAGCCAAUUAAGUAUAAAU 
                 659 
                 515-535_ 
                 A-122894 
                 AUUUAUACUUAAUUGGCUUAAUG 
                 660 
                 513-535_ 
               
               
                   
                   
                   
                   
                 G21U 
                   
                   
                   
                 G21U 
               
               
                   
               
               
                 AD-61263 UM 
                 A-122885 
                 UAAGCCAAUUAAGUAUAAAGG 
                 661 
                 516-536 
                 A-122886 
                 CCUUUAUACUUAAUUGGCUUAAU 
                 662 
                 514-536 
               
               
                   
               
               
                 AD-61252 UM 
                 A-122897 
                 UAAGCCAAUUAAGUAUAAAGA 
                 663 
                 516-536_ 
                 A-122898 
                 UCUUUAUACUUAAUUGGCUUAAU 
                 664 
                 514-536_ 
               
               
                   
                   
                   
                   
                 G21A 
                   
                   
                   
                 G21A 
               
               
                   
               
               
                 AD-61274 UM 
                 A-122873 
                 AAGCCAAUUAAGUAUAAAGGU 
                 665 
                 517-537 
                 A-122874 
                 ACCUUUAUACUUAAUUGGCUUAA 
                 666 
                 515-537 
               
               
                   
               
               
                 AD-61270 UM 
                 A-122903 
                 AGCCAAUUAAGUAUAAAGGUC 
                 667 
                 518-538 
                 A-122904 
                 GACCUUUAUACUUAAUUGGCUUA 
                 668 
                 516-538 
               
               
                   
               
               
                 AD-61264 UM 
                 A-122901 
                 AGCCAAUUAAGUAUAAAGGUA 
                 669 
                 518-538_ 
                 A-122902 
                 UACCUUUAUACUUAAUUGGCUUA 
                 670 
                 516-538_ 
               
               
                   
                   
                   
                   
                 C21A 
                   
                   
                   
                 C21A 
               
               
                   
               
               
                 AD-61255 UM 
                 A-122945 
                 GCCCUUGCAGAAAGUUUAUCC 
                 671 
                 573-593 
                 A-122946 
                 GGAUAAACUUUCUGCAAGGGCAA 
                 672 
                 571-593 
               
               
                   
               
               
                 AD-61283 UM 
                 A-122923 
                 GCCCUUGCAGAAAGUUUAUCA 
                 673 
                 573-593_ 
                 A-122924 
                 UGAUAAACUUUCUGCAAGGGCAA 
                 674 
                 571-593_ 
               
               
                   
                   
                   
                   
                 C21A 
                   
                   
                   
                 C21A 
               
               
                   
               
               
                 AD-61284 UM 
                 A-122939 
                 CCCUUGCAGAAAGUUUAUCCU 
                 675 
                 574-594 
                 A-122940 
                 AGGAUAAACUUUCUGCAAGGGCA 
                 676 
                 572-594 
               
               
                   
               
               
                 AD-61267 UM 
                 A-122950 
                 CCAAUGGUCAGAUCUUCAAAA 
                 677 
                 666-686 
                 A-122952 
                 UUUUGAAGAUCUGACCAUUGGCC 
                 678 
                 664-686 
               
               
                   
               
               
                 AD-61266 UM 
                 A-122933 
                 CAAUGGUCAGAUCUUCAAAAU 
                 679 
                 667-687 
                 A-122934 
                 AUUUUGAAGAUCUGACCAUUGGC 
                 680 
                 665-687 
               
               
                   
               
               
                 AD-61273 UM 
                 A-122953 
                 AAUGGUCAGAUCUUCAAAAUA 
                 681 
                 668-688 
                 A-122954 
                 UAUUUUGAAGAUCUGACCAUUGG 
                 682 
                 666-688 
               
               
                   
               
               
                 AD-61272 UM 
                 A-122935 
                 UGGUCAGAUCUUCAAAAUAAA 
                 683 
                 670-690 
                 A-122936 
                 UUUAUUUUGAAGAUCUGACCAUU 
                 684 
                 668-690 
               
               
                   
               
            
           
         
       
     
     Results 
     The results of single dose screen in primary monkey hepatocytes are shown in Table 7. The single dose experiments were performed at 10 nM and 0.1 nM final duplex concentration and the data are expressed as percent message remaining relative to AD-1955 non-targeting control. 
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 LECT2 siRNA Single Dose Screen in Primary  
               
               
                 Monkey Hepatocytes 
               
            
           
           
               
               
               
               
               
            
               
                   
                 10 nM_ 
                 0.1 nM_ 
                 10 nM_ 
                 0.1 nM_ 
               
               
                 DuplexID 
                 AVG 
                 AVG 
                 STDEV 
                 STDEV 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 AD-61278 
                 1.8 
                 22.3 
                 0.78 
                 6.56 
               
               
                 AD-61268 
                 4.6 
                 43.2 
                 2.72 
                 9.01 
               
               
                 AD-61251 
                 4.8 
                 41.0 
                 1.50 
                 9.73 
               
               
                 AD-61260 
                 5.6 
                 48.9 
                 0.40 
                 4.98 
               
               
                 AD-61258 
                 5.9 
                 50.8 
                 0.70 
                 0.29 
               
               
                 AD-61277 
                 6.2 
                 33.4 
                 0.14 
                 8.56 
               
               
                 AD-61241 
                 6.3 
                 32.3 
                 4.28 
                 8.26 
               
               
                 AD-61242 
                 6.8 
                 64.2 
                 0.58 
                 14.00 
               
               
                 AD-61273 
                 7.0 
                 18.0 
                 0.46 
                 0.16 
               
               
                 AD-61243 
                 7.0 
                 34.9 
                 3.27 
                 6.84 
               
               
                 AD-61267 
                 7.2 
                 20.1 
                 1.52 
                 0.31 
               
               
                 AD-61266 
                 7.3 
                 20.0 
                 1.12 
                 0.57 
               
               
                 AD-61256 
                 7.3 
                 18.6 
                 1.44 
                 2.53 
               
               
                 AD-61284 
                 7.6 
                 31.0 
                 1.42 
                 0.58 
               
               
                 AD-61246 
                 7.6 
                 74.2 
                 0.62 
                 8.28 
               
               
                 AD-61272 
                 7.8 
                 15.3 
                 0.17 
                 0.99 
               
               
                 AD-61244 
                 7.9 
                 20.5 
                 0.14 
                 3.97 
               
               
                 AD-61275 
                 8.3 
                 63.8 
                 3.06 
                 5.57 
               
               
                 AD-61265 
                 9.8 
                 34.4 
                 1.42 
                 0.65 
               
               
                 AD-61281 
                 10.2 
                 48.2 
                 0.28 
                 12.35 
               
               
                 AD-61254 
                 10.4 
                 63.6 
                 1.65 
                 15.68 
               
               
                 AD-61257 
                 10.5 
                 66.5 
                 1.36 
                 16.73 
               
               
                 AD-61238 
                 11.0 
                 42.2 
                 1.69 
                 2.24 
               
               
                 AD-61240 
                 11.6 
                 30.7 
                 0.31 
                 2.28 
               
               
                 AD-61250 
                 11.8 
                 57.0 
                 1.24 
                 15.15 
               
               
                 AD-61262 
                 13.7 
                 57.7 
                 2.37 
                 10.92 
               
               
                 AD-61249 
                 13.8 
                 74.7 
                 0.57 
                 1.53 
               
               
                 AD-61283 
                 14.3 
                 59.2 
                 ND 
                 13.47 
               
               
                 AD-61282 
                 14.7 
                 44.6 
                 0.11 
                 1.13 
               
               
                 AD-61261 
                 15.6 
                 58.0 
                 0.65 
                 25.10 
               
               
                 AD-61264 
                 16.2 
                 66.7 
                 0.75 
                 2.89 
               
               
                 AD-61239 
                 16.6 
                 78.5 
                 6.08 
                 4.68 
               
               
                 AD-61274 
                 17.9 
                 66.9 
                 3.54 
                 13.94 
               
               
                 AD-61253 
                 18.8 
                 90.1 
                 0.23 
                 4.49 
               
               
                 AD-61280 
                 18.8 
                 56.8 
                 4.16 
                 9.66 
               
               
                 AD-61276 
                 21.0 
                 71.0 
                 0.87 
                 3.88 
               
               
                 AD-61269 
                 21.1 
                 85.8 
                 2.52 
                 10.42 
               
               
                 AD-61279 
                 21.5 
                 67.6 
                 0.58 
                 1.60 
               
               
                 AD-61255 
                 22.1 
                 87.0 
                 4.14 
                 1.78 
               
               
                 AD-61248 
                 25.7 
                 85.8 
                 2.95 
                 9.58 
               
               
                 AD-61270 
                 27.4 
                 77.8 
                 3.94 
                 12.22 
               
               
                 AD-61252 
                 28.1 
                 82.3 
                 0.89 
                 0.07 
               
               
                 AD-61245 
                 41.9 
                 90.1 
                 6.65 
                 3.46 
               
               
                 AD-61271 
                 46.5 
                 82.5 
                 4.44 
                 26.55 
               
               
                 AD-61263 
                 53.2 
                 82.4 
                 4.04 
                 11.61 
               
               
                 AD-61247 
                 56.7 
                 93.6 
                 1.25 
                 4.20 
               
               
                 AD-61259 
                 78.1 
                 90.2 
                 0.96 
                 7.14 
               
               
                 AD-1955 
                 100.6 
                   
                 11.1 
               
               
                   
               
            
           
         
       
     
     A subset of LECT2 siRNA duplexes tested in the single dose screen were further tested in a dose response screen in primary monkey hepatocytes. The results are shown in Table 8. The dose response experiments were performed over a range of doses from 10 nM to 36 fM final duplex concentration. The data are expressed as IC50 values. 
     
       
         
           
               
             
               
                 TABLE 8 
               
             
            
               
                   
               
               
                 LECT2 SiRNA Dose Response Screen in Primary  
               
               
                 Monkey Hepatocytes 
               
            
           
           
               
               
               
            
               
                   
                 Duplex ID 
                 IC50 (nM) 
               
               
                   
                   
               
            
           
           
               
               
               
            
               
                   
                 AD-61272 
                 0.0024 
               
               
                   
                 AD-61273 
                 0.0006 
               
               
                   
                 AD-61266 
                 0.003 
               
               
                   
                 AD-61267 
                 0.0026 
               
               
                   
                 AD-61278 
                 0.0124 
               
               
                   
                 AD-61284 
                 0.0522 
               
               
                   
                 AD-61240 
                 0.0084 
               
               
                   
                 AD-61251 
                 0.0621 
               
               
                   
                 AD-61268 
                 0.117 
               
               
                   
                 AD-61256 
                 0.0163 
               
               
                   
                 AD-61244 
                 0.0165 
               
               
                   
                   
               
            
           
         
       
     
     Example 3. LECT2 siRNA Gene Walk 
     Experimental Methods 
     Bioinformatics: 
     A set of 93 overlapping siRNAs targeting the human LECT2 gene (NCBI refseqID NM_002302.2; NCBI Gene ID 3950 “leukocyte cell-derived chemotaxin 2”) were designed using custom R and Python scripts. The LECT2 REF SEQ mRNA has a length of 1077 bases. 
     In Vitro Screening: 
     Cell Culture and Transfections: 
     Primary cynomolgus monkey hepatocytes (PCHs, Celsis #MO03055, lot CBT) were transfected 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 siRNA duplexes per well into a 96-well plate and incubated at room temperature for 15 minutes. 80 ul of phenol red-free Williams Medium E (Life Technologies #A1217601) containing ˜2×10 4  PCH cells 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. 
     Total RNA was isolated 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 minute 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 magnetic stand and the supernatant was removed without disturbing the beads. After removing supernatant, the lysed cells were added to the remaining beads and mixed for 5 minutes. After removing supernatant, magnetic beads were washed 2 times with 150 μl Wash Buffer A and mixed for 1 minute. Beads were capture again and supernatant removed. Beads were then washed with 150 μl Wash Buffer B, captured and supernatant was removed. Beads were next washed with 150 μl Elution Buffer, captured and supernatant removed. 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. Beads were captured on magnet for 5 minutes. 40 μl of supernatant was removed and added to another 96 well plate. 
     cDNA Synthesis: 
     cDNA was synthesized 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 into 10 μl total RNA. cDNA was 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: 
     2 μl of cDNA were added to a master mix containing 0.5 μl of custom designed Cynomolgus monkey GAPDH TaqMan Probe (F-GCATCCTGGGCTACACTGA (SEQ ID NO: 494), R-TGGGTGTCGCTGTTGAAGTC (SEQ ID NO: 495), Probe-CCAGGTGGTCTCCTCC (SEQ ID NO: 496)), 0.5 μl human Lect2 (Hs01040204_m1—which is cross reactive with Cynomolgus monkey Lect2) 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 LightCycler480 Real Time PCR system (Roche) using the ΔΔCt(RQ) assay. Each duplex was tested in two independent transfections and each transfection was assayed in duplicate, unless otherwise noted in the summary tables. 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. 
     The modified and unmodified LECT2 siRNA sequences are shown in Tables 9 and 10, respectively. Nucleic acid sequences provided herein are represented using standard nomenclature (see the abbreviations of Table 1). 
     
       
         
           
               
             
               
                 TABLE 9 
               
             
            
               
                   
               
               
                 Modified LECT2 siRNA Sequences 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                 SEQ 
                   
                   
                 SEQ 
               
               
                   
                   
                 Sense Oligo 
                   
                 ID 
                 Antisense 
                   
                 ID 
               
               
                 Target 
                 Duplex Name 
                 Name 
                 Sense Oligo Sequence 
                 NO 
                 Oligo Name 
                 Antisense Oligo Sequence 
                 NO 
               
               
                   
               
               
                 LECT2 
                 AD-65819.1 
                 A-131907.1 
                 GAAUAUUAGAACUUGACUUdTdT 
                 690 
                 A-131908.1 
                 AAGUCAAGUUCUAAUAUUCdTdT 
                 691 
               
               
                   
               
               
                 LECT2 
                 AD-65825.1 
                 A-131909.1 
                 AACUUGACUUGCUCCAUCCdTdT 
                 692 
                 A-131910.1 
                 GGAUGGAGCAAGUCAAGUUdTdT 
                 693 
               
               
                   
               
               
                 LECT2 
                 AD-65831.1 
                 A-131911.1 
                 CCAUCCUCUUAAACUUUUUdTdT 
                 694 
                 A-131912.1 
                 AAAAAGUUUAAGAGGAUGGdTdT 
                 695 
               
               
                   
               
               
                 LECT2 
                 AD-65837.1 
                 A-131913.1 
                 UAAACUUUUUGUGUCUCACdTdT 
                 696 
                 A-131914.1 
                 GUGAGACACAAAAAGUUUAdTdT 
                 697 
               
               
                   
               
               
                 LECT2 
                 AD-65843.1 
                 A-131915.1 
                 GUCUCACACUAAAGAAAUGdTdT 
                 698 
                 A-131916.1 
                 CAUUUCUUUAGUGUGAGACdTdT 
                 699 
               
               
                   
               
               
                 LECT2 
                 AD-65849.1 
                 A-131917.1 
                 AAAGAAAUGAGAGAUGCAGdTdT 
                 700 
                 A-131918.1 
                 CUGCAUCUCUCAUUUCUUUdTdT 
                 701 
               
               
                   
               
               
                 LECT2 
                 AD-65855.1 
                 A-131919.1 
                 AUGCAGAAUUCUAAGGCUAdTdT 
                 702 
                 A-131920.1 
                 UAGCCUUAGAAUUCUGCAUdTdT 
                 703 
               
               
                   
               
               
                 LECT2 
                 AD-65861.1 
                 A-131921.1 
                 UCUAAGGCUAAAUAGCUAGdTdT 
                 704 
                 A-131922.1 
                 CUAGCUAUUUAGCCUUAGAdTdT 
                 705 
               
               
                   
               
               
                 LECT2 
                 AD-65820.1 
                 A-131923.1 
                 AUAGCUAGGAAGUAUUCAUdTdT 
                 706 
                 A-131924.1 
                 AUGAAUACUUCCUAGCUAUdTdT 
                 707 
               
               
                   
               
               
                 LECT2 
                 AD-65826.1 
                 A-131925.1 
                 AUUCAUUCAAACUUGAAUAdTdT 
                 708 
                 A-131926.1 
                 UAUUCAAGUUUGAAUGAAUdTdT 
                 709 
               
               
                   
               
               
                 LECT2 
                 AD-65832.1 
                 A-131927.1 
                 CUUGAAUAUUCUUCAAAGAdTdT 
                 710 
                 A-131928.1 
                 UCUUUGAAGAAUAUUCAAGdTdT 
                 711 
               
               
                   
               
               
                 LECT2 
                 AD-65838.1 
                 A-131929.1 
                 CUUCAAAGAGAGUGUGGGGdTdT 
                 712 
                 A-131930.1 
                 CCCCACACUCUCUUUGAAGdTdT 
                 713 
               
               
                   
               
               
                 LECT2 
                 AD-65844.1 
                 A-131931.1 
                 GUGUGGGGGCAACUCUAAUdTdT 
                 714 
                 A-131932.1 
                 AUUAGAGUUGCCCCCACACdTdT 
                 715 
               
               
                   
               
               
                 LECT2 
                 AD-65850.1 
                 A-131933.1 
                 AACUCUAAUCAGAGGAAGAdTdT 
                 716 
                 A-131934.1 
                 UCUUCCUCUGAUUAGAGUUdTdT 
                 717 
               
               
                   
               
               
                 LECT2 
                 AD-65856.1 
                 A-131935.1 
                 AGGAAGAAACUAAAGGAAGdTdT 
                 718 
                 A-131936.1 
                 CUUCCUUUAGUUUCUUCCUdTdT 
                 719 
               
               
                   
               
               
                 LECT2 
                 AD-65862.1 
                 A-131937.1 
                 UAAAGGAAGUAAAACCAGAdTdT 
                 720 
                 A-131938.1 
                 UCUGGUUUUACUUCCUUUAdTdT 
                 721 
               
               
                   
               
               
                 LECT2 
                 AD-65821.1 
                 A-131939.1 
                 AAACCAGAUGUUUUCCACCdTdT 
                 722 
                 A-131940.1 
                 GGUGGAAAACAUCUGGUUUdTdT 
                 723 
               
               
                   
               
               
                 LECT2 
                 AD-65827.1 
                 A-131941.1 
                 UCCACCAAAGCCCUCCUUUdTdT 
                 724 
                 A-131942.1 
                 AAAGGAGGGCUUUGGUGGAdTdT 
                 725 
               
               
                   
               
               
                 LECT2 
                 AD-65833.1 
                 A-131943.1 
                 CCUCCUUUUGGCUGGUCUGdTdT 
                 726 
                 A-131944.1 
                 CAGACCAGCCAAAAGGAGGdTdT 
                 727 
               
               
                   
               
               
                 LECT2 
                 AD-65839.1 
                 A-131945.1 
                 GGCUGGUCUGAUUUCUACCdTdT 
                 728 
                 A-131946.1 
                 GGUAGAAAUCAGACCAGCCdTdT 
                 729 
               
               
                   
               
               
                 LECT2 
                 AD-65845.1 
                 A-131947.1 
                 UUUCUACCGCACUGGCAGGdTdT 
                 730 
                 A-131948.1 
                 CCUGCCAGUGCGGUAGAAAdTdT 
                 731 
               
               
                   
               
               
                 LECT2 
                 AD-65851.1 
                 A-131949.1 
                 GGCAGGGCCAUGGGCUAAUdTdT 
                 732 
                 A-131950.1 
                 AUUAGCCCAUGGCCCUGCCdTdT 
                 733 
               
               
                   
               
               
                 LECT2 
                 AD-65857.1 
                 A-131951.1 
                 GGGCUAAUAUAUGUGCUGGdTdT 
                 734 
                 A-131952.1 
                 CCAGCACAUAUAUUAGCCCdTdT 
                 735 
               
               
                   
               
               
                 LECT2 
                 AD-65863.1 
                 A-131953.1 
                 AUGUGCUGGCAAGUCUUCCdTdT 
                 736 
                 A-131954.1 
                 GGAAGACUUGCCAGCACAUdTdT 
                 737 
               
               
                   
               
               
                 LECT2 
                 AD-65822.1 
                 A-131955.1 
                 AAGUCUUCCAAUGAGAUCCdTdT 
                 738 
                 A-131956.1 
                 GGAUCUCAUUGGAAGACUUdTdT 
                 739 
               
               
                   
               
               
                 LECT2 
                 AD-65828.1 
                 A-131957.1 
                 AGAUCCGGACGUGUGACCGdTdT 
                 740 
                 A-131958.1 
                 CGGUCACACGUCCGGAUCUdTdT 
                 741 
               
               
                   
               
               
                 LECT2 
                 AD-65834.1 
                 A-131959.1 
                 GUGUGACCGCCAUGGCUGUdTdT 
                 742 
                 A-131960.1 
                 ACAGCCAUGGCGGUCACACdTdT 
                 743 
               
               
                   
               
               
                 LECT2 
                 AD-65840.1 
                 A-131961.1 
                 AUGGCUGUGGACAGUACUCdTdT 
                 744 
                 A-131962.1 
                 GAGUACUGUCCACAGCCAUdTdT 
                 745 
               
               
                   
               
               
                 LECT2 
                 AD-65846.1 
                 A-131963.1 
                 AGUACUCUGCUCAAAGAAGdTdT 
                 746 
                 A-131964.1 
                 CUUCUUUGAGCAGAGUACUdTdT 
                 747 
               
               
                   
               
               
                 LECT2 
                 AD-65852.1 
                 A-131965.1 
                 CAAAGAAGUCAGAGGCCUCdTdT 
                 748 
                 A-131966.1 
                 GAGGCCUCUGACUUCUUUGdTdT 
                 749 
               
               
                   
               
               
                 LECT2 
                 AD-65858.1 
                 A-131967.1 
                 CAGAGGCCUCACCAGGGUGdTdT 
                 750 
                 A-131968.1 
                 CACCCUGGUGAGGCCUCUGdTdT 
                 751 
               
               
                   
               
               
                 LECT2 
                 AD-65864.1 
                 A-131969.1 
                 CCAGGGUGUGGACAUCUUGdTdT 
                 752 
                 A-131970.1 
                 CAAGAUGUCCACACCCUGGdTdT 
                 753 
               
               
                   
               
               
                 LECT2 
                 AD-65823.1 
                 A-131971.1 
                 ACAUCUUGUGCUCUGCUGGdTdT 
                 754 
                 A-131972.1 
                 CCAGCAGAGCACAAGAUGUdTdT 
                 755 
               
               
                   
               
               
                 LECT2 
                 AD-65829.1 
                 A-131973.1 
                 CUGCUGGAUCUACUGUGUAdTdT 
                 756 
                 A-131974.1 
                 UACACAGUAGAUCCAGCAGdTdT 
                 757 
               
               
                   
               
               
                 LECT2 
                 AD-65835.1 
                 A-131975.1 
                 CUGUGUACGCACCAUUCACdTdT 
                 758 
                 A-131976.1 
                 GUGAAUGGUGCGUACACAGdTdT 
                 759 
               
               
                   
               
               
                 LECT2 
                 AD-65841.1 
                 A-131977.1 
                 CCAUUCACUGGAAUGAUUGdTdT 
                 760 
                 A-131978.1 
                 CAAUCAUUCCAGUGAAUGGdTdT 
                 761 
               
               
                   
               
               
                 LECT2 
                 AD-65847.1 
                 A-131979.1 
                 AAUGAUUGUGGGCCAGGAGdTdT 
                 762 
                 A-131980.1 
                 CUCCUGGCCCACAAUCAUUdTdT 
                 763 
               
               
                   
               
               
                 LECT2 
                 AD-65853.1 
                 A-131981.1 
                 GGGCCAGGAGAAACCUUAUdTdT 
                 764 
                 A-131982.1 
                 AUAAGGUUUCUCCUGGCCCdTdT 
                 765 
               
               
                   
               
               
                 LECT2 
                 AD-65859.1 
                 A-131983.1 
                 CCUUAUCAAAACAAGAAUGdTdT 
                 766 
                 A-131984.1 
                 CAUUCUUGUUUUGAUAAGGdTdT 
                 767 
               
               
                   
               
               
                 LECT2 
                 AD-65865.1 
                 A-131985.1 
                 CAAGAAUGCUAUCAAUAAUdTdT 
                 768 
                 A-131986.1 
                 AUUAUUGAUAGCAUUCUUGdTdT 
                 769 
               
               
                   
               
               
                 LECT2 
                 AD-65824.1 
                 A-131987.1 
                 AUCAAUAAUGGUGUUCGAAdTdT 
                 770 
                 A-131988.1 
                 UUCGAACACCAUUAUUGAUdTdT 
                 771 
               
               
                   
               
               
                 LECT2 
                 AD-65830.1 
                 A-131989.1 
                 GUUCGAAUAUCUGGAAGAGdTdT 
                 772 
                 A-131990.1 
                 CUCUUCCAGAUAUUCGAACdTdT 
                 773 
               
               
                   
               
               
                 LECT2 
                 AD-65836.1 
                 A-131991.1 
                 UCUGGAAGAGGUUUUUGUGdTdT 
                 774 
                 A-131992.1 
                 CACAAAAACCUCUUCCAGAdTdT 
                 775 
               
               
                   
               
               
                 LECT2 
                 AD-65842.1 
                 A-131993.1 
                 UUUUUGUGUCAAAAUGUUCdTdT 
                 776 
                 A-131994.1 
                 GAACAUUUUGACACAAAAAdTdT 
                 777 
               
               
                   
               
               
                 LECT2 
                 AD-65848.1 
                 A-131995.1 
                 AUGUUCUACAUUAAGCCAAdTdT 
                 778 
                 A-131996.1 
                 UUGGCUUAAUGUAGAACAUdTdT 
                 779 
               
               
                   
               
               
                 LECT2 
                 AD-65854.1 
                 A-131997.1 
                 UAAGCCAAUUAAGUAUAAAdTdT 
                 780 
                 A-131998.1 
                 UUUAUACUUAAUUGGCUUAdTdT 
                 781 
               
               
                   
               
               
                 LECT2 
                 AD-65860.1 
                 A-131999.1 
                 AAGUAUAAAGGUCCUAUUAdTdT 
                 782 
                 A-132000.1 
                 UAAUAGGACCUUUAUACUUdTdT 
                 783 
               
               
                   
               
               
                 LECT2 
                 AD-65866.1 
                 A-132001.1 
                 CCUAUUAAGAAGGGAGAAAdTdT 
                 784 
                 A-132002.1 
                 UUUCUCCCUUCUUAAUAGGdTdT 
                 785 
               
               
                   
               
               
                 LECT2 
                 AD-65872.1 
                 A-132003.1 
                 AGGGAGAAAAACUUGGAACdTdT 
                 786 
                 A-132004.1 
                 GUUCCAAGUUUUUCUCCCUdTdT 
                 787 
               
               
                   
               
               
                 LECT2 
                 AD-65878.1 
                 A-132005.1 
                 CUUGGAACUCUAUUGCCCUdTdT 
                 788 
                 A-132006.1 
                 AGGGCAAUAGAGUUCCAAGdTdT 
                 789 
               
               
                   
               
               
                 LECT2 
                 AD-65884.1 
                 A-132007.1 
                 UUGCCCUUGCAGAAAGUUUdTdT 
                 790 
                 A-132008.1 
                 AAACUUUCUGCAAGGGCAAdTdT 
                 791 
               
               
                   
               
               
                 LECT2 
                 AD-65890.1 
                 A-132009.1 
                 AGAAAGUUUAUCCUGGCAUdTdT 
                 792 
                 A-132010.1 
                 AUGCCAGGAUAAACUUUCUdTdT 
                 793 
               
               
                   
               
               
                 LECT2 
                 AD-65896.1 
                 A-132011.1 
                 CCUGGCAUACAAUCGCAUGdTdT 
                 794 
                 A-132012.1 
                 CAUGCGAUUGUAUGCCAGGdTdT 
                 795 
               
               
                   
               
               
                 LECT2 
                 AD-65902.1 
                 A-132013.1 
                 AUCGCAUGUGCACAUUGAAdTdT 
                 796 
                 A-132014.1 
                 UUCAAUGUGCACAUGCGAUdTdT 
                 797 
               
               
                   
               
               
                 LECT2 
                 AD-65907.1 
                 A-132015.1 
                 CAUUGAAAACUGUGACUCGdTdT 
                 798 
                 A-132016.1 
                 CGAGUCACAGUUUUCAAUGdTdT 
                 799 
               
               
                   
               
               
                 LECT2 
                 AD-65867.1 
                 A-132017.1 
                 GUGACUCGAGUGACCCUACdTdT 
                 800 
                 A-132018.1 
                 GUAGGGUCACUCGAGUCACdTdT 
                 801 
               
               
                   
               
               
                 LECT2 
                 AD-65873.1 
                 A-132019.1 
                 UGACCCUACUGCAUACCUGdTdT 
                 802 
                 A-132020.1 
                 CAGGUAUGCAGUAGGGUCAdTdT 
                 803 
               
               
                   
               
               
                 LECT2 
                 AD-65879.1 
                 A-132021.1 
                 CAUACCUGUAAAUCGAAGGdTdT 
                 804 
                 A-132022.1 
                 CCUUCGAUUUACAGGUAUGdTdT 
                 805 
               
               
                   
               
               
                 LECT2 
                 AD-65891.1 
                 A-132025.1 
                 UGGUCAGAUCUUCAAAAUAdTdT 
                 806 
                 A-132026.1 
                 UAUUUUGAAGAUCUGACCAdTdT 
                 807 
               
               
                   
               
               
                 LECT2 
                 AD-65897.1 
                 A-132027.1 
                 CUUCAAAAUAAAAAGUCAUdTdT 
                 808 
                 A-132028.1 
                 AUGACUUUUUAUUUUGAAGdTdT 
                 809 
               
               
                   
               
               
                 LECT2 
                 AD-65903.1 
                 A-132029.1 
                 AAGUCAUCUUAAAAACCUGdTdT 
                 810 
                 A-132030.1 
                 CAGGUUUUUAAGAUGACUUdTdT 
                 811 
               
               
                   
               
               
                 LECT2 
                 AD-65908.1 
                 A-132031.1 
                 AAAACCUGGAUGCAUACCCdTdT 
                 812 
                 A-132032.1 
                 GGGUAUGCAUCCAGGUUUUdTdT 
                 813 
               
               
                   
               
               
                 LECT2 
                 AD-65868.1 
                 A-132033.1 
                 GCAUACCCUUCUCUUCAAGdTdT 
                 814 
                 A-132034.1 
                 CUUGAAGAGAAGGGUAUGCdTdT 
                 815 
               
               
                   
               
               
                 LECT2 
                 AD-65874.1 
                 A-132035.1 
                 CUUCAAGAAAUUUGUGUUCdTdT 
                 816 
                 A-132036.1 
                 GAACACAAAUUUCUUGAAGdTdT 
                 817 
               
               
                   
               
               
                 LECT2 
                 AD-65880.1 
                 A-132037.1 
                 UUGUGUUCACAAAGGAAAAdTdT 
                 818 
                 A-132038.1 
                 UUUUCCUUUGUGAACACAAdTdT 
                 819 
               
               
                   
               
               
                 LECT2 
                 AD-65886.1 
                 A-132039.1 
                 AAGGAAAAAUGCAUGAAGGdTdT 
                 820 
                 A-132040.1 
                 CCUUCAUGCAUUUUUCCUUdTdT 
                 821 
               
               
                   
               
               
                 LECT2 
                 AD-65892.1 
                 A-132041.1 
                 UGCAUGAAGGGAUGGAUACdTdT 
                 822 
                 A-132042.1 
                 GUAUCCAUCCCUUCAUGCAdTdT 
                 823 
               
               
                   
               
               
                 LECT2 
                 AD-65898.1 
                 A-132043.1 
                 UGGAUACCCCAUUUUCCAUdTdT 
                 824 
                 A-132044.1 
                 AUGGAAAAUGGGGUAUCCAdTdT 
                 825 
               
               
                   
               
               
                 LECT2 
                 AD-65904.1 
                 A-132045.1 
                 UUUCCAUGACAUGAUUAUUdTdT 
                 826 
                 A-132046.1 
                 AAUAAUCAUGUCAUGGAAAdTdT 
                 827 
               
               
                   
               
               
                 LECT2 
                 AD-65909.1 
                 A-132047.1 
                 CAUGAUUAUUACACAUUGCdTdT 
                 828 
                 A-132048.1 
                 GCAAUGUGUAAUAAUCAUGdTdT 
                 829 
               
               
                   
               
               
                 LECT2 
                 AD-65869.1 
                 A-132049.1 
                 CACAUUGCAUGCCUGUAUCdTdT 
                 830 
                 A-132050.1 
                 GAUACAGGCAUGCAAUGUGdTdT 
                 831 
               
               
                   
               
               
                 LECT2 
                 AD-65875.1 
                 A-132051.1 
                 CCUGUAUCAAAACAUCUCAdTdT 
                 832 
                 A-132052.1 
                 UGAGAUGUUUUGAUACAGGdTdT 
                 833 
               
               
                   
               
               
                 LECT2 
                 AD-65881.1 
                 A-132053.1 
                 CAUCUCACGUACCUCAUAAdTdT 
                 834 
                 A-132054.1 
                 UUAUGAGGUACGUGAGAUGdTdT 
                 835 
               
               
                   
               
               
                 LECT2 
                 AD-65887.1 
                 A-132055.1 
                 CCUCAUAAACAUAUACACCdTdT 
                 836 
                 A-132056.1 
                 GGUGUAUAUGUUUAUGAGGdTdT 
                 837 
               
               
                   
               
               
                 LECT2 
                 AD-65893.1 
                 A-132057.1 
                 AUACACCUAUGUACCCACAdTdT 
                 838 
                 A-132058.1 
                 UGUGGGUACAUAGGUGUAUdTdT 
                 839 
               
               
                   
               
               
                 LECT2 
                 AD-65899.1 
                 A-132059.1 
                 GUACCCACAAAAAUUUUUUdTdT 
                 840 
                 A-132060.1 
                 AAAAAAUUUUUGUGGGUACdTdT 
                 841 
               
               
                   
               
               
                 LECT2 
                 AD-65905.1 
                 A-132061.1 
                 UAAAAAAAGGAAAUUUGAGdTdT 
                 842 
                 A-132062.1 
                 CUCAAAUUUCCUUUUUUUAdTdT 
                 843 
               
               
                   
               
               
                 LECT2 
                 AD-65910.1 
                 A-132063.1 
                 AAUUUGAGUUUAAAUAGAAdTdT 
                 844 
                 A-132064.1 
                 UUCUAUUUAAACUCAAAUUdTdT 
                 845 
               
               
                   
               
               
                 LECT2 
                 AD-65870.1 
                 A-132065.1 
                 AUAGAAACAUGAUAAAUGCdTdT 
                 846 
                 A-132066.1 
                 GCAUUUAUCAUGUUUCUAUdTdT 
                 847 
               
               
                   
               
               
                 LECT2 
                 AD-65876.1 
                 A-132067.1 
                 GAUAAAUGCAAGAAAGAAAdTdT 
                 848 
                 A-132068.1 
                 UUUCUUUCUUGCAUUUAUCdTdT 
                 849 
               
               
                   
               
               
                 LECT2 
                 AD-65882.1 
                 A-132069.1 
                 GAAAGAAAACAUUUUGAUUdTdT 
                 850 
                 A-132070.1 
                 AAUCAAAAUGUUUUCUUUCdTdT 
                 851 
               
               
                   
               
               
                 LECT2 
                 AD-65894.1 
                 A-132073.1 
                 ACUCAUUGUCACUCUGAUGdTdT 
                 852 
                 A-132074.1 
                 CAUCAGAGUGACAAUGAGUdTdT 
                 853 
               
               
                   
               
               
                 LECT2 
                 AD-65900.1 
                 A-132075.1 
                 CUCUGAUGUUCAUGUGAACdTdT 
                 854 
                 A-132076.1 
                 GUUCACAUGAACAUCAGAGdTdT 
                 855 
               
               
                   
               
               
                 LECT2 
                 AD-65906.1 
                 A-132077.1 
                 CAUGUGAACUGGUUGCUUCdTdT 
                 856 
                 A-132078.1 
                 GAAGCAACCAGUUCACAUGdTdT 
                 857 
               
               
                   
               
               
                 LECT2 
                 AD-65911.1 
                 A-132079.1 
                 GUUGCUUCGGGCUCUUUGAdTdT 
                 858 
                 A-132080.1 
                 UCAAAGAGCCCGAAGCAACdTdT 
                 859 
               
               
                   
               
               
                 LECT2 
                 AD-65871.1 
                 A-132081.1 
                 UCUUUGAUCUGUCACCUAUdTdT 
                 860 
                 A-132082.1 
                 AUAGGUGACAGAUCAAAGAdTdT 
                 861 
               
               
                   
               
               
                 LECT2 
                 AD-65877.1 
                 A-132083.1 
                 CACCUAUGGAAUCUGAGUGdTdT 
                 862 
                 A-132084.1 
                 CACUCAGAUUCCAUAGGUGdTdT 
                 863 
               
               
                   
               
               
                 LECT2 
                 AD-65883.1 
                 A-132085.1 
                 AAUCUGAGUGGUUUUAUUUdTdT 
                 864 
                 A-132086.1 
                 AAAUAAAACCACUCAGAUUdTdT 
                 865 
               
               
                   
               
               
                 LECT2 
                 AD-65889.1 
                 A-132087.1 
                 UUUUUUAGAUUUCUCAGUCdTdT 
                 866 
                 A-132088.1 
                 GACUGAGAAAUCUAAAAAAdTdT 
                 867 
               
               
                   
               
               
                 LECT2 
                 AD-65895.1 
                 A-132089.1 
                 CUCAGUCCCAAAGAUCUAAdTdT 
                 868 
                 A-132090.1 
                 UUAGAUCUUUGGGACUGAGdTdT 
                 869 
               
               
                   
               
               
                 LECT2 
                 AD-65901.1 
                 A-132091.1 
                 GAUCUAAGAUAAAUAAACAdTdT 
                 870 
                 A-132092.1 
                 UGUUUAUUUAUCUUAGAUCdTdT 
                 871 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 10 
               
               
                   
               
               
                 Unmodified LECT2 siRNA Sequences 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                 SEQ 
                   
               
               
                   
                 Duplex 
                 Sense Oligo 
                   
                 ID 
                 Position in 
               
               
                 Target 
                 Name 
                 Name 
                 Sense Sequence 
                 NO 
                 NM_002302.2 
               
               
                   
               
               
                 LECT2 
                 AD-65819.1 
                 A-131907.1 
                 GAAUAUUAGAACUUGACUU 
                 872 
                 011-29 
               
               
                   
               
               
                 LECT2 
                 AD-65825.1 
                 A-131909.1 
                 AACUUGACUUGCUCCAUCC 
                 874 
                 020-38 
               
               
                   
               
               
                 LECT2 
                 AD-65831.1 
                 A-131911.1 
                 CCAUCCUCUUAAACUUUUU 
                 876 
                 033-51 
               
               
                   
               
               
                 LECT2 
                 AD-65837.1 
                 A-131913.1 
                 UAAACUUUUUGUGUCUCAC 
                 878 
                 042-60 
               
               
                   
               
               
                 LECT2 
                 AD-65843.1 
                 A-131915.1 
                 GUCUCACACUAAAGAAAUG 
                 880 
                 054-72 
               
               
                   
               
               
                 LECT2 
                 AD-65849.1 
                 A-131917.1 
                 AAAGAAAUGAGAGAUGCAG 
                 882 
                 064-82 
               
               
                   
               
               
                 LECT2 
                 AD-65855.1 
                 A-131919.1 
                 AUGCAGAAUUCUAAGGCUA 
                 884 
                 077-95 
               
               
                   
               
               
                 LECT2 
                 AD-65861.1 
                 A-131921.1 
                 UCUAAGGCUAAAUAGCUAG 
                 886 
                  086-104 
               
               
                   
               
               
                 LECT2 
                 AD-65820.1 
                 A-131923.1 
                 AUAGCUAGGAAGUAUUCAU 
                 888 
                  097-115 
               
               
                   
               
               
                 LECT2 
                 AD-65826.1 
                 A-131925.1 
                 AUUCAUUCAAACUUGAAUA 
                 890 
                  110-128 
               
               
                   
               
               
                 LECT2 
                 AD-65832.1 
                 A-131927.1 
                 CUUGAAUAUUCUUCAAAGA 
                 892 
                  121-139 
               
               
                   
               
               
                 LECT2 
                 AD-65838.1 
                 A-131929.1 
                 CUUCAAAGAGAGUGUGGGG 
                 894 
                  131-149 
               
               
                   
               
               
                 LECT2 
                 AD-65844.1 
                 A-131931.1 
                 GUGUGGGGGCAACUCUAAU 
                 896 
                  142-160 
               
               
                   
               
               
                 LECT2 
                 AD-65850.1 
                 A-131933.1 
                 AACUCUAAUCAGAGGAAGA 
                 898 
                  152-170 
               
               
                   
               
               
                 LECT2 
                 AD-65856.1 
                 A-131935.1 
                 AGGAAGAAACUAAAGGAAG 
                 900 
                  164-182 
               
               
                   
               
               
                 LECT2 
                 AD-65862.1 
                 A-131937.1 
                 UAAAGGAAGUAAAACCAGA 
                 902 
                  174-192 
               
               
                   
               
               
                 LECT2 
                 AD-65821.1 
                 A-131939.1 
                 AAACCAGAUGUUUUCCACC 
                 904 
                  185-203 
               
               
                   
               
               
                 LECT2 
                 AD-65827.1 
                 A-131941.1 
                 UCCACCAAAGCCCUCCUUU 
                 906 
                  198-216 
               
               
                   
               
               
                 LECT2 
                 AD-65833.1 
                 A-131943.1 
                 CCUCCUUUUGGCUGGUCUG 
                 908 
                  209-227 
               
               
                   
               
               
                 LECT2 
                 AD-65839.1 
                 A-131945.1 
                 GGCUGGUCUGAUUUCUACC 
                 910 
                  218-236 
               
               
                   
               
               
                 LECT2 
                 AD-65845.1 
                 A-131947.1 
                 UUUCUACCGCACUGGCAGG 
                 912 
                  229-247 
               
               
                   
               
               
                 LECT2 
                 AD-65851.1 
                 A-131949.1 
                 GGCAGGGCCAUGGGCUAAU 
                 914 
                  242-260 
               
               
                   
               
               
                 LECT2 
                 AD-65857.1 
                 A-131951.1 
                 GGGCUAAUAUAUGUGCUGG 
                 916 
                  253-271 
               
               
                   
               
               
                 LECT2 
                 AD-65863.1 
                 A-131953.1 
                 AUGUGCUGGCAAGUCUUCC 
                 918 
                  263-281 
               
               
                   
               
               
                 LECT2 
                 AD-65822.1 
                 A-131955.1 
                 AAGUCUUCCAAUGAGAUCC 
                 920 
                  273-291 
               
               
                   
               
               
                 LECT2 
                 AD-65828.1 
                 A-131957.1 
                 AGAUCCGGACGUGUGACCG 
                 922 
                  286-304 
               
               
                   
               
               
                 LECT2 
                 AD-65834.1 
                 A-131959.1 
                 GUGUGACCGCCAUGGCUGU 
                 924 
                  296-314 
               
               
                   
               
               
                 LECT2 
                 AD-65840.1 
                 A-131961.1 
                 AUGGCUGUGGACAGUACUC 
                 926 
                  307-325 
               
               
                   
               
               
                 LECT2 
                 AD-65846.1 
                 A-131963.1 
                 AGUACUCUGCUCAAAGAAG 
                 928 
                  319-337 
               
               
                   
               
               
                 LECT2 
                 AD-65852.1 
                 A-131965.1 
                 CAAAGAAGUCAGAGGCCUC 
                 930 
                  330-348 
               
               
                   
               
               
                 LECT2 
                 AD-65858.1 
                 A-131967.1 
                 CAGAGGCCUCACCAGGGUG 
                 932 
                  339-357 
               
               
                   
               
               
                 LECT2 
                 AD-65864.1 
                 A-131969.1 
                 CCAGGGUGUGGACAUCUUG 
                 934 
                  350-368 
               
               
                   
               
               
                 LECT2 
                 AD-65823.1 
                 A-131971.1 
                 ACAUCUUGUGCUCUGCUGG 
                 936 
                  361-379 
               
               
                   
               
               
                 LECT2 
                 AD-65829.1 
                 A-131973.1 
                 CUGCUGGAUCUACUGUGUA 
                 938 
                  373-391 
               
               
                   
               
               
                 LECT2 
                 AD-65835.1 
                 A-131975.1 
                 CUGUGUACGCACCAUUCAC 
                 940 
                  385-403 
               
               
                   
               
               
                 LECT2 
                 AD-65841.1 
                 A-131977.1 
                 CCAUUCACUGGAAUGAUUG 
                 942 
                  396-414 
               
               
                   
               
               
                 LECT2 
                 AD-65847.1 
                 A-131979.1 
                 AAUGAUUGUGGGCCAGGAG 
                 944 
                  407-425 
               
               
                   
               
               
                 LECT2 
                 AD-65853.1 
                 A-131981.1 
                 GGGCCAGGAGAAACCUUAU 
                 946 
                  416-434 
               
               
                   
               
               
                 LECT2 
                 AD-65859.1 
                 A-131983.1 
                 CCUUAUCAAAACAAGAAUG 
                 948 
                  429-447 
               
               
                   
               
               
                 LECT2 
                 AD-65865.1 
                 A-131985.1 
                 CAAGAAUGCUAUCAAUAAU 
                 950 
                  440-458 
               
               
                   
               
               
                 LECT2 
                 AD-65824.1 
                 A-131987.1 
                 AUCAAUAAUGGUGUUCGAA 
                 952 
                  450-468 
               
               
                   
               
               
                 LECT2 
                 AD-65830.1 
                 A-131989.1 
                 GUUCGAAUAUCUGGAAGAG 
                 954 
                  462-480 
               
               
                   
               
               
                 LECT2 
                 AD-65836.1 
                 A-131991.1 
                 UCUGGAAGAGGUUUUUGUG 
                 956 
                  471-489 
               
               
                   
               
               
                 LECT2 
                 AD-65842.1 
                 A-131993.1 
                 UUUUUGUGUCAAAAUGUUC 
                 958 
                  482-500 
               
               
                   
               
               
                 LECT2 
                 AD-65848.1 
                 A-131995.1 
                 AUGUUCUACAUUAAGCCAA 
                 960 
                  495-513 
               
               
                   
               
               
                 LECT2 
                 AD-65854.1 
                 A-131997.1 
                 UAAGCCAAUUAAGUAUAAA 
                 962 
                  506-524 
               
               
                   
               
               
                 LECT2 
                 AD-65860.1 
                 A-131999.1 
                 AAGUAUAAAGGUCCUAUUA 
                 964 
                  516-534 
               
               
                   
               
               
                 LECT2 
                 AD-65866.1 
                 A-132001.1 
                 CCUAUUAAGAAGGGAGAAA 
                 966 
                  528-546 
               
               
                   
               
               
                 LECT2 
                 AD-65872.1 
                 A-132003.1 
                 AGGGAGAAAAACUUGGAAC 
                 968 
                  538-556 
               
               
                   
               
               
                 LECT2 
                 AD-65878.1 
                 A-132005.1 
                 CUUGGAACUCUAUUGCCCU 
                 970 
                  549-567 
               
               
                   
               
               
                 LECT2 
                 AD-65884.1 
                 A-132007.1 
                 UUGCCCUUGCAGAAAGUUU 
                 972 
                  561-579 
               
               
                   
               
               
                 LECT2 
                 AD-65890.1 
                 A-132009.1 
                 AGAAAGUUUAUCCUGGCAU 
                 974 
                  571-589 
               
               
                   
               
               
                 LECT2 
                 AD-65896.1 
                 A-132011.1 
                 CCUGGCAUACAAUCGCAUG 
                 976 
                  582-600 
               
               
                   
               
               
                 LECT2 
                 AD-65902.1 
                 A-132013.1 
                 AUCGCAUGUGCACAUUGAA 
                 978 
                  593-611 
               
               
                   
               
               
                 LECT2 
                 AD-65907.1 
                 A-132015.1 
                 CAUUGAAAACUGUGACUCG 
                 980 
                  605-623 
               
               
                   
               
               
                 LECT2 
                 AD-65867.1 
                 A-132017.1 
                 GUGACUCGAGUGACCCUAC 
                 982 
                  616-634 
               
               
                   
               
               
                 LECT2 
                 AD-65873.1 
                 A-132019.1 
                 UGACCCUACUGCAUACCUG 
                 984 
                  626-644 
               
               
                   
               
               
                 LECT2 
                 AD-65879.1 
                 A-132021.1 
                 CAUACCUGUAAAUCGAAGG 
                 986 
                  637-655 
               
               
                   
               
               
                 LECT2 
                 AD-65891.1 
                 A-132025.1 
                 UGGUCAGAUCUUCAAAAUA 
                 988 
                  660-678 
               
               
                   
               
               
                 LECT2 
                 AD-65897.1 
                 A-132027.1 
                 CUUCAAAAUAAAAAGUCAU 
                 990 
                  669-687 
               
               
                   
               
               
                 LECT2 
                 AD-65903.1 
                 A-132029.1 
                 AAGUCAUCUUAAAAACCUG 
                 992 
                  681-699 
               
               
                   
               
               
                 LECT2 
                 AD-65908.1 
                 A-132031.1 
                 AAAACCUGGAUGCAUACCC 
                 994 
                  692-710 
               
               
                   
               
               
                 LECT2 
                 AD-65868.1 
                 A-132033.1 
                 GCAUACCCUUCUCUUCAAG 
                 996 
                  703-721 
               
               
                   
               
               
                 LECT2 
                 AD-65874.1 
                 A-132035.1 
                 CUUCAAGAAAUUUGUGUUC 
                 998 
                  715-733 
               
               
                   
               
               
                 LECT2 
                 AD-65880.1 
                 A-132037.1 
                 UUGUGUUCACAAAGGAAAA 
                 1000 
                  726-744 
               
               
                   
               
               
                 LECT2 
                 AD-65886.1 
                 A-132039.1 
                 AAGGAAAAAUGCAUGAAGG 
                 1002 
                  737-755 
               
               
                   
               
               
                 LECT2 
                 AD-65892.1 
                 A-132041.1 
                 UGCAUGAAGGGAUGGAUAC 
                 1004 
                  746-764 
               
               
                   
               
               
                 LECT2 
                 AD-65898.1 
                 A-132043.1 
                 UGGAUACCCCAUUUUCCAU 
                 1006 
                  758-776 
               
               
                   
               
               
                 LECT2 
                 AD-65904.1 
                 A-132045.1 
                 UUUCCAUGACAUGAUUAUU 
                 1008 
                  770-788 
               
               
                   
               
               
                 LECT2 
                 AD-65909.1 
                 A-132047.1 
                 CAUGAUUAUUACACAUUGC 
                 1010 
                  779-797 
               
               
                   
               
               
                 LECT2 
                 AD-65869.1 
                 A-132049.1 
                 CACAUUGCAUGCCUGUAUC 
                 1012 
                  790-808 
               
               
                   
               
               
                 LECT2 
                 AD-65875.1 
                 A-132051.1 
                 CCUGUAUCAAAACAUCUCA 
                 1014 
                  801-819 
               
               
                   
               
               
                 LECT2 
                 AD-65881.1 
                 A-132053.1 
                 CAUCUCACGUACCUCAUAA 
                 1016 
                  813-831 
               
               
                   
               
               
                 LECT2 
                 AD-65887.1 
                 A-132055.1 
                 CCUCAUAAACAUAUACACC 
                 1018 
                  824-842 
               
               
                   
               
               
                 LECT2 
                 AD-65893.1 
                 A-132057.1 
                 AUACACCUAUGUACCCACA 
                 1020 
                  836-854 
               
               
                   
               
               
                 LECT2 
                 AD-65899.1 
                 A-132059.1 
                 GUACCCACAAAAAUUUUUU 
                 1022 
                  846-864 
               
               
                   
               
               
                 LECT2 
                 AD-65905.1 
                 A-132061.1 
                 UAAAAAAAGGAAAUUUGAG 
                 1024 
                  856-874 
               
               
                   
               
               
                 LECT2 
                 AD-65910.1 
                 A-132063.1 
                 AAUUUGAGUUUAAAUAGAA 
                 1026 
                  867-885 
               
               
                   
               
               
                 LECT2 
                 AD-65870.1 
                 A-132065.1 
                 AUAGAAACAUGAUAAAUGC 
                 1028 
                  880-898 
               
               
                   
               
               
                 LECT2 
                 AD-65876.1 
                 A-132067.1 
                 GAUAAAUGCAAGAAAGAAA 
                 1030 
                  890-908 
               
               
                   
               
               
                 LECT2 
                 AD-65882.1 
                 A-132069.1 
                 GAAAGAAAACAUUUUGAUU 
                 1032 
                  901-919 
               
               
                   
               
               
                 LECT2 
                 AD-65894.1 
                 A-132073.1 
                 ACUCAUUGUCACUCUGAUG 
                 1034 
                  923-941 
               
               
                   
               
               
                 LECT2 
                 AD-65900.1 
                 A-132075.1 
                 CUCUGAUGUUCAUGUGAAC 
                 1036 
                  934-952 
               
               
                   
               
               
                 LECT2 
                 AD-65906.1 
                 A-132077.1 
                 CAUGUGAACUGGUUGCUUC 
                 1038 
                  944-962 
               
               
                   
               
               
                 LECT2 
                 AD-65911.1 
                 A-132079.1 
                 GUUGCUUCGGGCUCUUUGA 
                 1040 
                  955_973 
               
               
                   
               
               
                 LECT2 
                 AD-65871.1 
                 A-132081.1 
                 UCUUUGAUCUGUCACCUAU 
                 1042 
                  967-985 
               
               
                   
               
               
                 LECT2 
                 AD-65877.1 
                 A-132083.1 
                 CACCUAUGGAAUCUGAGUG 
                 1044 
                  979-997 
               
               
                   
               
               
                 LECT2 
                 AD-65883.1 
                 A-132085.1 
                 AAUCUGAGUGGUUUUAUUU 
                 1046 
                   988-1006 
               
               
                   
               
               
                 LECT2 
                 AD-65889.1 
                 A-132087.1 
                 UUUUUUAGAUUUCUCAGUC 
                 1048 
                   999-1017 
               
               
                   
               
               
                 LECT2 
                 AD-65895.1 
                 A-132089.1 
                 CUCAGUCCCAAAGAUCUAA 
                 1050 
                  1011-1029 
               
               
                   
               
               
                 LECT2 
                 AD-65901.1 
                 A-132091.1 
                 GAUCUAAGAUAAAUAAACA 
                 1052 
                  1023-1041 
               
               
                   
               
               
                   
                   
                   
                   
                 SEQ 
                   
               
               
                   
                   
                 Antisense 
                   
                 ID 
                 Position in 
               
               
                   
                 Target 
                 Oligo Name 
                 Antisense Sequence 
                 NO 
                 NM_002302.2 
               
               
                   
               
               
                   
                 LECT2 
                 A-131908.1 
                 AAGUCAAGUUCUAAUAUUC 
                 873 
                 11-29 
               
               
                   
               
               
                   
                 LECT2 
                 A-131910.1 
                 GGAUGGAGCAAGUCAAGUU 
                 875 
                 20-38 
               
               
                   
               
               
                   
                 LECT2 
                 A-131912.1 
                 AAAAAGUUUAAGAGGAUGG 
                 877 
                 33-51 
               
               
                   
               
               
                   
                 LECT2 
                 A-131914.1 
                 GUGAGACACAAAAAGUUUA 
                 879 
                 42-60 
               
               
                   
               
               
                   
                 LECT2 
                 A-131916.1 
                 CAUUUCUUUAGUGUGAGAC 
                 881 
                 54-72 
               
               
                   
               
               
                   
                 LECT2 
                 A-131918.1 
                 CUGCAUCUCUCAUUUCUUU 
                 883 
                 64-82 
               
               
                   
               
               
                   
                 LECT2 
                 A-131920.1 
                 UAGCCUUAGAAUUCUGCAU 
                 885 
                 77-95 
               
               
                   
               
               
                   
                 LECT2 
                 A-131922.1 
                 CUAGCUAUUUAGCCUUAGA 
                 887 
                  86-104 
               
               
                   
               
               
                   
                 LECT2 
                 A-131924.1 
                 AUGAAUACUUCCUAGCUAU 
                 889 
                  97-115 
               
               
                   
               
               
                   
                 LECT2 
                 A-131926.1 
                 UAUUCAAGUUUGAAUGAAU 
                 891 
                 110-128 
               
               
                   
               
               
                   
                 LECT2 
                 A-131928.1 
                 UCUUUGAAGAAUAUUCAAG 
                 893 
                 121-139 
               
               
                   
               
               
                   
                 LECT2 
                 A-131930.1 
                 CCCCACACUCUCUUUGAAG 
                 895 
                 131-149 
               
               
                   
               
               
                   
                 LECT2 
                 A-131932.1 
                 AUUAGAGUUGCCCCCACAC 
                 897 
                 142-160 
               
               
                   
               
               
                   
                 LECT2 
                 A-131934.1 
                 UCUUCCUCUGAUUAGAGUU 
                 899 
                 152-170 
               
               
                   
               
               
                   
                 LECT2 
                 A-131936.1 
                 CUUCCUUUAGUUUCUUCCU 
                 901 
                 164-182 
               
               
                   
               
               
                   
                 LECT2 
                 A-131938.1 
                 UCUGGUUUUACUUCCUUUA 
                 903 
                 174-192 
               
               
                   
               
               
                   
                 LECT2 
                 A-131940.1 
                 GGUGGAAAACAUCUGGUUU 
                 905 
                 185-203 
               
               
                   
               
               
                   
                 LECT2 
                 A-131942.1 
                 AAAGGAGGGCUUUGGUGGA 
                 907 
                 198-216 
               
               
                   
               
               
                   
                 LECT2 
                 A-131944.1 
                 CAGACCAGCCAAAAGGAGG 
                 909 
                 209-227 
               
               
                   
               
               
                   
                 LECT2 
                 A-131946.1 
                 GGUAGAAAUCAGACCAGCC 
                 911 
                 218-236 
               
               
                   
               
               
                   
                 LECT2 
                 A-131948.1 
                 CCUGCCAGUGCGGUAGAAA 
                 913 
                 229-247 
               
               
                   
               
               
                   
                 LECT2 
                 A-131950.1 
                 AUUAGCCCAUGGCCCUGCC 
                 915 
                 242-260 
               
               
                   
               
               
                   
                 LECT2 
                 A-131952.1 
                 CCAGCACAUAUAUUAGCCC 
                 917 
                 253-271 
               
               
                   
               
               
                   
                 LECT2 
                 A-131954.1 
                 GGAAGACUUGCCAGCACAU 
                 919 
                 263-281 
               
               
                   
               
               
                   
                 LECT2 
                 A-131956.1 
                 GGAUCUCAUUGGAAGACUU 
                 921 
                 273-291 
               
               
                   
               
               
                   
                 LECT2 
                 A-131958.1 
                 CGGUCACACGUCCGGAUCU 
                 923 
                 286-304 
               
               
                   
               
               
                   
                 LECT2 
                 A-131960.1 
                 ACAGCCAUGGCGGUCACAC 
                 925 
                 296-314 
               
               
                   
               
               
                   
                 LECT2 
                 A-131962.1 
                 GAGUACUGUCCACAGCCAU 
                 927 
                 307-325 
               
               
                   
               
               
                   
                 LECT2 
                 A-131964.1 
                 CUUCUUUGAGCAGAGUACU 
                 929 
                 319-337 
               
               
                   
               
               
                   
                 LECT2 
                 A-131966.1 
                 GAGGCCUCUGACUUCUUUG 
                 931 
                 330-348 
               
               
                   
               
               
                   
                 LECT2 
                 A-131968.1 
                 CACCCUGGUGAGGCCUCUG 
                 933 
                 339-357 
               
               
                   
               
               
                   
                 LECT2 
                 A-131970.1 
                 CAAGAUGUCCACACCCUGG 
                 935 
                 350-368 
               
               
                   
               
               
                   
                 LECT2 
                 A-131972.1 
                 CCAGCAGAGCACAAGAUGU 
                 937 
                 361-379 
               
               
                   
               
               
                   
                 LECT2 
                 A-131974.1 
                 UACACAGUAGAUCCAGCAG 
                 939 
                 373-391 
               
               
                   
               
               
                   
                 LECT2 
                 A-131976.1 
                 GUGAAUGGUGCGUACACAG 
                 941 
                 385-403 
               
               
                   
               
               
                   
                 LECT2 
                 A-131978.1 
                 CAAUCAUUCCAGUGAAUGG 
                 943 
                 396-414 
               
               
                   
               
               
                   
                 LECT2 
                 A-131980.1 
                 CUCCUGGCCCACAAUCAUU 
                 945 
                 407-425 
               
               
                   
               
               
                   
                 LECT2 
                 A-131982.1 
                 AUAAGGUUUCUCCUGGCCC 
                 947 
                 416-434 
               
               
                   
               
               
                   
                 LECT2 
                 A-131984.1 
                 CAUUCUUGUUUUGAUAAGG 
                 949 
                 429-447 
               
               
                   
               
               
                   
                 LECT2 
                 A-131986.1 
                 AUUAUUGAUAGCAUUCUUG 
                 951 
                 440-458 
               
               
                   
               
               
                   
                 LECT2 
                 A-131988.1 
                 UUCGAACACCAUUAUUGAU 
                 953 
                 450-468 
               
               
                   
               
               
                   
                 LECT2 
                 A-131990.1 
                 CUCUUCCAGAUAUUCGAAC 
                 955 
                 462-480 
               
               
                   
               
               
                   
                 LECT2 
                 A-131992.1 
                 CACAAAAACCUCUUCCAGA 
                 957 
                 471-489 
               
               
                   
               
               
                   
                 LECT2 
                 A-131994.1 
                 GAACAUUUUGACACAAAAA 
                 959 
                 482-500 
               
               
                   
               
               
                   
                 LECT2 
                 A-131996.1 
                 UUGGCUUAAUGUAGAACAU 
                 961 
                 495-513 
               
               
                   
               
               
                   
                 LECT2 
                 A-131998.1 
                 UUUAUACUUAAUUGGCUUA 
                 963 
                 506-524 
               
               
                   
               
               
                   
                 LECT2 
                 A-132000.1 
                 UAAUAGGACCUUUAUACUU 
                 965 
                 516-534 
               
               
                   
               
               
                   
                 LECT2 
                 A-132002.1 
                 UUUCUCCCUUCUUAAUAGG 
                 967 
                 528-546 
               
               
                   
               
               
                   
                 LECT2 
                 A-132004.1 
                 GUUCCAAGUUUUUCUCCCU 
                 969 
                 538-556 
               
               
                   
               
               
                   
                 LECT2 
                 A-132006.1 
                 AGGGCAAUAGAGUUCCAAG 
                 971 
                 549-567 
               
               
                   
               
               
                   
                 LECT2 
                 A-132008.1 
                 AAACUUUCUGCAAGGGCAA 
                 973 
                 561-579 
               
               
                   
               
               
                   
                 LECT2 
                 A-132010.1 
                 AUGCCAGGAUAAACUUUCU 
                 975 
                 571-589 
               
               
                   
               
               
                   
                 LECT2 
                 A-132012.1 
                 CAUGCGAUUGUAUGCCAGG 
                 977 
                 582-600 
               
               
                   
               
               
                   
                 LECT2 
                 A-132014.1 
                 UUCAAUGUGCACAUGCGAU 
                 979 
                 593-611 
               
               
                   
               
               
                   
                 LECT2 
                 A-132016.1 
                 CGAGUCACAGUUUUCAAUG 
                 981 
                 605-623 
               
               
                   
               
               
                   
                 LECT2 
                 A-132018.1 
                 GUAGGGUCACUCGAGUCAC 
                 983 
                 616-634 
               
               
                   
               
               
                   
                 LECT2 
                 A-132020.1 
                 CAGGUAUGCAGUAGGGUCA 
                 985 
                 626-644 
               
               
                   
               
               
                   
                 LECT2 
                 A-132022.1 
                 CCUUCGAUUUACAGGUAUG 
                 987 
                 637-655 
               
               
                   
               
               
                   
                 LECT2 
                 A-132026.1 
                 UAUUUUGAAGAUCUGACCA 
                 989 
                 660-678 
               
               
                   
               
               
                   
                 LECT2 
                 A-132028.1 
                 AUGACUUUUUAUUUUGAAG 
                 991 
                 669-687 
               
               
                   
               
               
                   
                 LECT2 
                 A-132030.1 
                 CAGGUUUUUAAGAUGACUU 
                 993 
                 681-699 
               
               
                   
               
               
                   
                 LECT2 
                 A-132032.1 
                 GGGUAUGCAUCCAGGUUUU 
                 995 
                 692-710 
               
               
                   
               
               
                   
                 LECT2 
                 A-132034.1 
                 CUUGAAGAGAAGGGUAUGC 
                 997 
                 703-721 
               
               
                   
               
               
                   
                 LECT2 
                 A-132036.1 
                 GAACACAAAUUUCUUGAAG 
                 999 
                 715-733 
               
               
                   
               
               
                   
                 LECT2 
                 A-132038.1 
                 UUUUCCUUUGUGAACACAA 
                 1001 
                 726-744 
               
               
                   
               
               
                   
                 LECT2 
                 A-132040.1 
                 CCUUCAUGCAUUUUUCCUU 
                 1003 
                 737-755 
               
               
                   
               
               
                   
                 LECT2 
                 A-132042.1 
                 GUAUCCAUCCCUUCAUGCA 
                 1005 
                 746-764 
               
               
                   
               
               
                   
                 LECT2 
                 A-132044.1 
                 AUGGAAAAUGGGGUAUCCA 
                 1007 
                 758-776 
               
               
                   
               
               
                   
                 LECT2 
                 A-132046.1 
                 AAUAAUCAUGUCAUGGAAA 
                 1009 
                 770-788 
               
               
                   
               
               
                   
                 LECT2 
                 A-132048.1 
                 GCAAUGUGUAAUAAUCAUG 
                 1011 
                 779-797 
               
               
                   
               
               
                   
                 LECT2 
                 A-132050.1 
                 GAUACAGGCAUGCAAUGUG 
                 1013 
                 790-808 
               
               
                   
               
               
                   
                 LECT2 
                 A-132052.1 
                 UGAGAUGUUUUGAUACAGG 
                 1015 
                 801-819 
               
               
                   
               
               
                   
                 LECT2 
                 A-132054.1 
                 UUAUGAGGUACGUGAGAUG 
                 1017 
                 813-831 
               
               
                   
               
               
                   
                 LECT2 
                 A-132056.1 
                 GGUGUAUAUGUUUAUGAGG 
                 1019 
                 824-842 
               
               
                   
               
               
                   
                 LECT2 
                 A-132058.1 
                 UGUGGGUACAUAGGUGUAU 
                 1021 
                 836-854 
               
               
                   
               
               
                   
                 LECT2 
                 A-132060.1 
                 AAAAAAUUUUUGUGGGUAC 
                 1023 
                 846-864 
               
               
                   
               
               
                   
                 LECT2 
                 A-132062.1 
                 CUCAAAUUUCCUUUUUUUA 
                 1025 
                 856-874 
               
               
                   
               
               
                   
                 LECT2 
                 A-132064.1 
                 UUCUAUUUAAACUCAAAUU 
                 1027 
                 867-885 
               
               
                   
               
               
                   
                 LECT2 
                 A-132066.1 
                 GCAUUUAUCAUGUUUCUAU 
                 1029 
                 880-898 
               
               
                   
               
               
                   
                 LECT2 
                 A-132068.1 
                 UUUCUUUCUUGCAUUUAUC 
                 1031 
                 890-908 
               
               
                   
               
               
                   
                 LECT2 
                 A-132070.1 
                 AAUCAAAAUGUUUUCUUUC 
                 1033 
                 901-919 
               
               
                   
               
               
                   
                 LECT2 
                 A-132074.1 
                 CAUCAGAGUGACAAUGAGU 
                 1035 
                 923-941 
               
               
                   
               
               
                   
                 LECT2 
                 A-132076.1 
                 GUUCACAUGAACAUCAGAG 
                 1037 
                 934-952 
               
               
                   
               
               
                   
                 LECT2 
                 A-132078.1 
                 GAAGCAACCAGUUCACAUG 
                 1039 
                 944-962 
               
               
                   
               
               
                   
                 LECT2 
                 A-132080.1 
                 UCAAAGAGCCCGAAGCAAC 
                 1041 
                 955_973 
               
               
                   
               
               
                   
                 LECT2 
                 A-132082.1 
                 AUAGGUGACAGAUCAAAGA 
                 1043 
                 967-985 
               
               
                   
               
               
                   
                 LECT2 
                 A-132084.1 
                 CACUCAGAUUCCAUAGGUG 
                 1045 
                 979-997 
               
               
                   
               
               
                   
                 LECT2 
                 A-132086.1 
                 AAAUAAAACCACUCAGAUU 
                 1047 
                  988-1006 
               
               
                   
               
               
                   
                 LECT2 
                 A-132088.1 
                 GACUGAGAAAUCUAAAAAA 
                 1049 
                  999-1017 
               
               
                   
               
               
                   
                 LECT2 
                 A-132090.1 
                 UUAGAUCUUUGGGACUGAG 
                 1051 
                 1011-1029 
               
               
                   
               
               
                   
                 LECT2 
                 A-132092.1 
                 UGUUUAUUUAUCUUAGAUC 
                 1053 
                 1023-1041 
               
               
                   
               
            
           
         
       
     
     Results 
     The results of single dose screen in primary monkey hepatocytes using modified LECT2 siRNA sequences are shown in Table 11. The single dose experiments were performed at 10 nM final duplex concentration and the data are expressed as percent message remaining relative to AD-1955 non-targeting control. 
     
       
         
           
               
             
               
                 TABLE 11 
               
             
            
               
                   
               
               
                 Lect2 Single Dose Screen in Primary 
               
               
                 Monkey Hepatocytes 
               
            
           
           
               
               
               
            
               
                 Duplex Name 
                 10 nM avg 
                 10 nM stdev 
               
               
                   
               
            
           
           
               
               
               
            
               
                 AD-65819.1 
                 11.7 
                 8.5 
               
               
                 AD-65825.1 
                 50.7 
                 28.0 
               
               
                 AD-65831.1 
                 75.3 
                 49.5 
               
               
                 AD-65837.1 
                 75.5 
                 32.7 
               
               
                 AD-65843.1 
                 5.5 
                 3.0 
               
               
                 AD-65849.1 
                 104.5 
                 64.9 
               
               
                 AD-65855.1 
                 114.1 
                 36.7 
               
               
                 AD-65861.1 
                 81.5 
                 49.6 
               
               
                 AD-65820.1 
                 3.3 
                 1.4 
               
               
                 AD-65826.1 
                 43.6 
                 18.4 
               
               
                 AD-65832.1 
                 6.5 
                 2.2 
               
               
                 AD-65838.1 
                 61.8 
                 11.9 
               
               
                 AD-65844.1 
                 4.2 
                 2.1 
               
               
                 AD-65850.1 
                 85.8 
                 24.0 
               
               
                 AD-65856.1 
                 105.4 
                 24.0 
               
               
                 AD-65862.1 
                 50.4 
                 15.5 
               
               
                 AD-65821.1 
                 56.1 
                 32.5 
               
               
                 AD-65827.1 
                 37.8 
                 5.7 
               
               
                 AD-65833.1 
                 4.7 
                 2.6 
               
               
                 AD-65839.1 
                 5.2 
                 1.6 
               
               
                 AD-65845.1 
                 65.1 
                 19.1 
               
               
                 AD-65851.1 
                 46.1 
                 5.4 
               
               
                 AD-65857.1 
                 35.0 
                 5.4 
               
               
                 AD-65863.1 
                 58.0 
                 14.4 
               
               
                 AD-65822.1 
                 82.7 
                 10.4 
               
               
                 AD-65828.1 
                 95.9 
                 29.0 
               
               
                 AD-65834.1 
                 7.9 
                 2.9 
               
               
                 AD-65840.1 
                 98.3 
                 39.1 
               
               
                 AD-65846.1 
                 33.8 
                 16.1 
               
               
                 AD-65852.1 
                 32.8 
                 4.4 
               
               
                 AD-65858.1 
                 73.4 
                 29.3 
               
               
                 AD-65864.1 
                 7.0 
                 3.0 
               
               
                 AD-65823.1 
                 54.5 
                 18.8 
               
               
                 AD-65829.1 
                 17.1 
                 14.8 
               
               
                 AD-65835.1 
                 100.4 
                 31.8 
               
               
                 AD-65841.1 
                 11.1 
                 10.4 
               
               
                 AD-65847.1 
                 165.1 
                 39.2 
               
               
                 AD-65853.1 
                 1.7 
                 0.3 
               
               
                 AD-65859.1 
                 39.9 
                 6.3 
               
               
                 AD-65865.1 
                 76.5 
                 17.0 
               
               
                 AD-65824.1 
                 66.0 
                 10.5 
               
               
                 AD-65830.1 
                 106.0 
                 16.1 
               
               
                 AD-65836.1 
                 67.5 
                 19.2 
               
               
                 AD-65842.1 
                 147.3 
                 38.9 
               
               
                 AD-65848.1 
                 20.1 
                 4.5 
               
               
                 AD-65854.1 
                 40.4 
                 12.1 
               
               
                 AD-65860.1 
                 62.8 
                 19.0 
               
               
                 AD-65866.1 
                 49.8 
                 8.9 
               
               
                 AD-65872.1 
                 45.6 
                 15.8 
               
               
                 AD-65878.1 
                 11.4 
                 5.6 
               
               
                 AD-65884.1 
                 6.1 
                 2.5 
               
               
                 AD-65890.1 
                 47.1 
                 23.0 
               
               
                 AD-65896.1 
                 108.3 
                 58.2 
               
               
                 AD-65902.1 
                 9.8 
                 3.3 
               
               
                 AD-65907.1 
                 19.6 
                 4.7 
               
               
                 AD-65867.1 
                 39.9 
                 8.8 
               
               
                 AD-65873.1 
                 14.8 
                 5.1 
               
               
                 AD-65879.1 
                 113.2 
                 7.1 
               
               
                 AD-65891.1 
                 2.5 
                 1.5 
               
               
                 AD-65897.1 
                 15.0 
                 6.7 
               
               
                 AD-65903.1 
                 44.8 
                 14.0 
               
               
                 AD-65908.1 
                 77.1 
                 23.6 
               
               
                 AD-65868.1 
                 32.7 
                 3.9 
               
               
                 AD-65874.1 
                 119.4 
                 35.4 
               
               
                 AD-65880.1 
                 117.6 
                 30.6 
               
               
                 AD-65886.1 
                 127.8 
                 45.3 
               
               
                 AD-65892.1 
                 80.0 
                 20.6 
               
               
                 AD-65898.1 
                 75.1 
                 29.3 
               
               
                 AD-65904.1 
                 123.8 
                 31.5 
               
               
                 AD-65909.1 
                 97.9 
                 10.0 
               
               
                 AD-65869.1 
                 34.3 
                 8.4 
               
               
                 AD-65875.1 
                 76.5 
                 12.1 
               
               
                 AD-65881.1 
                 35.7 
                 6.4 
               
               
                 AD-65887.1 
                 88.8 
                 32.6 
               
               
                 AD-65893.1 
                 141.7 
                 5.5 
               
               
                 AD-65899.1 
                 149.8 
                 29.1 
               
               
                 AD-65905.1 
                 167.5 
                 36.8 
               
               
                 AD-65910.1 
                 58.5 
                 20.7 
               
               
                 AD-65870.1 
                 92.3 
                 33.3 
               
               
                 AD-65876.1 
                 86.8 
                 22.2 
               
               
                 AD-65882.1 
                 65.5 
                 10.6 
               
               
                 AD-65894.1 
                 69.4 
                 20.5 
               
               
                 AD-65900.1 
                 125.0 
                 57.8 
               
               
                 AD-65906.1 
                 153.4 
                 54.0 
               
               
                 AD-65911.1 
                 114.4 
                 24.2 
               
               
                 AD-65871.1 
                 59.6 
                 26.4 
               
               
                 AD-65877.1 
                 58.1 
                 18.5 
               
               
                 AD-65883.1 
                 60.3 
                 16.6 
               
               
                 AD-65889.1 
                 74.1 
                 25.1 
               
               
                 AD-65895.1 
                 94.0 
                 11.8 
               
               
                 AD-65901.1 
                 92.4 
                 6.2 
               
               
                 AD-1955 
                 100.1 
                 24.7 
               
               
                   
               
            
           
         
       
     
     EQUIVALENTS 
     Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.