Patent Publication Number: US-2012041051-A1

Title: Compositions And Methods For Inhibiting Expression Of MIG-12 Gene

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
     This application claims the benefit of U.S. Provisional Application No. 61/155,649, filed Feb. 26, 2009, which is hereby incorporated in its entirety by reference. 
    
    
     REFERENCE TO SEQUENCE LISTING 
     This application includes a Sequence Listing submitted electronically as a text file named “16641PCT_Sequence_Listing.txt”, created on Feb. 25, 2010, with a size of approximately 460 kilobytes. The sequence listing is incorporated by reference. 
     FIELD OF THE INVENTION 
     The invention relates to a double-stranded ribonucleic acid (dsRNA) targeting a MIG1 interacting G12-like protein (MIG12) gene, and methods of using the dsRNA to inhibit expression of MIG12. 
     BACKGROUND OF THE INVENTION 
     MIG1 interacting G12-like protein (MIG12) is expressed in macrophages, fibroblasts and the liver, and its expression is regulated by cholesterol and the statins. MIG12 belongs to the Spot 14 family of proteins. Spot 14 protein is believed to be involved in the transduction of hormonal and dietary signals for induction of hepatic lipogenesis. MIG12 is also expressed in the embryonic ventral midline and co-operates with the midline 1 (MID1) gene product to stabilize microtubules. Defects in MID1/MIG12-mediated microtubule regulation are believed to contribute to the development of Opitz syndrome, a multiple congenital anomaly disorder. 
     Double-stranded RNA molecules (dsRNA) have been shown to block gene expression in a highly conserved regulatory mechanism known as RNA interference (RNAi). WO 99/32619 (Fire et al.) disclosed the use of a dsRNA of at least 25 nucleotides in length to inhibit the expression of genes in  C. elegans . dsRNA has also been shown to degrade target RNA in other organisms, including plants (see, e.g., WO 99/53050, Waterhouse et al.; and WO 99/61631, Heifetz et al.),  Drosophila  (see, e.g., Yang, D., et al.,  Curr. Biol . (2000) 10:1191-1200), and mammals (see WO 00/44895, Limmer; and DE 101 00 586.5, Kreutzer et al.). 
     SUMMARY OF THE INVENTION 
     The invention provides compositions containing double-stranded ribonucleic acid (dsRNA) and methods for inhibiting the expression of a MIG12 gene, such as in a cell or mammal. The invention also provides compositions and methods for treating pathological conditions and diseases caused by the expression of a MIG12 gene, such as a lipid disorder or metabolic disorder (e.g., atherosclerosis or diabetes). The dsRNAs included in the compositions featured herein include a dsRNA having an RNA strand (the antisense strand) having a region that is less than 30 nucleotides in length, generally 19-24 nucleotides in length, and that is substantially complementary to at least part of an mRNA transcript of a MIG12 gene. 
     In one embodiment, a dsRNA for inhibiting expression of a MIG12 gene includes at least two sequences that are complementary to each other. The dsRNA 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 MIG12, and the region of complementarity is less than 30 nucleotides in length, and at least 15 nucleotides in length. Generally, the dsRNA is 19 to 24, e.g., 19 to 21 nucleotides in length. In some embodiments the dsRNA is from about 10 to about 15 nucleotides in length, and in other embodiments the dsRNA is from about 25 to about 30 nucleotides in length. The dsRNA, upon contacting with a cell expressing MIG12, inhibits the expression of a MIG12 gene by at least 20%, at least 25%, at least 30%, at least 35% or at least 40%, such as when assayed by a method as described herein. In one embodiment, the MIG12 dsRNA is formulated in a stable nucleic acid particle (SNALP). 
     In one embodiment, a dsRNA featured herein includes a double-stranded ribonucleic acid (dsRNA) for inhibiting expression of MIG12 mRNA, wherein said dsRNA comprises a sense strand and an antisense strand, the antisense strand comprising a region complementary to a part of a mRNA encoding MIG12, wherein said region of complementarity is at least 15 nucleotides in length. 
     In another embodiment, a dsRNA featured herein includes a first sequence of the dsRNA that is selected from the group consisting of the sense sequences of Tables 2, 3 and 4, and a second sequence that is selected from the group consisting of the antisense sequences of Tables 2, 3 and 4. The dsRNA molecules featured herein can include naturally occurring nucleotides or can include at least one modified nucleotide, such as 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 abasic nucleotide, 2′-amino-modified nucleotide, 2′-alkyl-modified nucleotide, morpholino nucleotide, a phosphoramidate, and a non-natural base comprising nucleotide. Generally, such a modified sequence will be based on a first sequence of said dsRNA selected from the group consisting of the sense sequences of Tables 2, 3 and 4, and a second sequence selected from the group consisting of the antisense sequences of Tables 2, 3 and 4. 
     In another embodiment, a composition containing a dsRNA targeting MIG12 is administered to a subject when Low Density Lipoprotein cholesterol (LDLc) levels reach or surpass a predetermined minimal level, such as greater than 130 mg/dL, 150 mg/dL, 200 mg/dL, 300 mg/dL, or 400 mg/dL. In another embodiment, the subject has an LDLc level greater than about 150 mg/dL. 
     In one embodiment, a single administration of the dsRNA lowers LDLc levels by at least 10%, e.g., by at least 15%, 20%, 25%, 30%, 40%, 50%, or 60%, or more. In another embodiment, the lowered LDLc level is maintained for at least 5, 10, 20, 30, or 40 days or longer. 
     In one embodiment, the subject is selected, at least in part, on the basis of needing (as opposed to merely selecting a patient on the grounds of who happens to be in need of) LDL lowering, LDL lowering without lowering of HDL, ApoB lowering, or total cholesterol lowering without HDL lowering. 
     In one embodiment, a dsRNA featured in the invention targets a wildtype MIG12 RNA transcript, and in another embodiment, the dsRNA features a mutant transcript (e.g., a MIG12 RNA carrying an allelic variant). For example, a dsRNA of the invention can target a polymorphism, such as a single nucleotide polymorphism (SNP), of MIG12. In another embodiment, the dsRNA targets both a wildtype and a mutant MIG12 transcript. In yet another embodiment, the dsRNA targets a transcript variant of MIG12. 
     In one embodiment, a dsRNA featured in the invention targets a non-coding region of a MIG12 RNA transcript, such as the 5′ or 3′ untranslated region. 
     In one aspect, the invention provides a cell containing at least one of the dsRNAs featured in the invention. The cell is generally a mammalian cell, such as a human cell. 
     In another aspect, the invention provides a pharmaceutical composition for inhibiting the expression of a MIG12 gene in an organism, generally a human subject. The composition typically includes one or more of the dsRNAs described herein and a pharmaceutically acceptable carrier or delivery vehicle. In one embodiment, the composition is used for treating a lipid disorder, such as atherosclerosis. 
     In another embodiment, the pharmaceutical composition is formulated for administration of 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 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 a dsRNA featured in the invention, i.e., a dsRNA targeting MIG12, is administered with a non-dsRNA therapeutic agent, such as an agent known to treat a lipid disorder, or a symptom of a lipid disorder. For example, a dsRNA featured in the invention can be administered with an agent for treatment of atherosclerosis or hypercholesterolemia or other disorders associated with cholesterol metabolism. 
     In another embodiment, a MIG12 dsRNA is administered to a patient, and then the non-dsRNA agent is administered to the patient (or vice versa). In another embodiment, a MIG12 dsRNA and the non-dsRNA therapeutic agent are administered at the same time. In one embodiment, the agent is, for example, an agent that affects cholesterol metabolism, such as an HMG-CoA reductase inhibitor (e.g., a statin). 
     In another embodiment, a composition containing a dsRNA featured in the invention, i.e., a dsRNA targeting MIG12, is administered with a non-dsRNA therapeutic agent, such as an agent known to treat an Opitz syndrome, or a symptom of an Opitz syndrome. For example, a dsRNA featured in the invention can be administered with an agent for treatment of facial anomalies (e.g., ocular hypertelorism, prominent forehead, widow&#39;s peak, broad nasal bridge, and/or anteverted nares), laryngo-tracheo-esophageal (LTE) defects, genitourinary abnormalities (hypospadias, cryptorchidism, and/or hypoplastic/bifid scrotum), developmental delay, mental retardation, cleft lip and/or palate, congenital heart defects, imperforate or ectopic anus, and/or midline brain defects (e.g., Dandy-Walker malformation, and/or agenesis or hypoplasia of the corpus callosum and/or cerebellar vermis). 
     In another embodiment, a MIG12 dsRNA is administered to a patient, and then the non-dsRNA agent is administered to the patient (or vice versa). In another embodiment, a MIG12 dsRNA and the non-dsRNA therapeutic agent are administered at the same time. In one embodiment, the non-dsRNA agent is, e.g., an antireflux agent, such as to treat Opitz syndrome. 
     In another aspect, the invention provides a method for inhibiting the expression of a MIG12 gene in a cell by performing the following steps:
         (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 MIG12, and where the region of complementarity is less than 30 nucleotides in length, generally 19-24 nucleotides in length, and where the dsRNA, upon contact with a cell expressing MIG12, inhibits expression of a MIG12 gene by at least 40%; and   (b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of MIG12 gene, thereby inhibiting expression of a MIG12 gene in the cell.       

     In one embodiment, the method is for inhibiting gene expression in a macrophage, a fibroblast, or a liver cell. 
     In another embodiment, the method is for inhibiting gene expression in a neuronal cell. 
     In other aspects, the invention provides methods for treating, preventing or managing pathological processes mediated by MIG12 expression, such as a lipid disorder. In one embodiment, the method includes administering to a patient in need of such treatment, prevention or management a therapeutically or prophylactically effective amount of one or more of the dsRNAs featured in the invention. In one embodiment the patient has diabetes or atherosclerosis. In another embodiment, administration of the dsRNA targeting MIG12 alleviates or relieves the severity of at least one symptom of a MIG12-mediated disorder in the patient, such as high LDLc level, high ApoB level, or high total cholesterol level. In another embodiment, administration of the MIG12 dsRNA does not lower the level of HDL cholesterol in the patient. 
     In another embodiment, the invention provides methods for treating, preventing or managing Opitz syndrome. In one embodiment, the method includes administering to a patient in need of such treatment, prevention or management a therapeutically or prophylactically effective amount of one or more of the dsRNAs featured in the invention. In one embodiment the patient has X-linked Opitz syndrome. In another embodiment, administration of the dsRNA targeting MIG12 alleviates or relieves the severity of at least one symptom of a MIG12-mediated disorder in the patient, such as a facial anomaly (e.g., ocular hypertelorism), laryngo-tracheo-esophageal (LTE) defect, or genitourinary abnormality (e.g., hypospadias). 
     In one embodiment of the methods for altering MIG12 levels in a human, the dsRNA compositions described herein are administered to the human at about 0.01, 0.1, 0.5, 1.0, 2.5, or 5.0 mg/kg. In related embodiments, the dsRNA is administered to the human at about 1.0 mg/kg. In certain embodiments, the human has levels of Low Density Lipoprotein cholesterol (LDLc) above 130 mg/dL. 
     In one aspect, the invention provides a vector for inhibiting the expression of a MIG12 gene in a cell. In one embodiment, the vector includes at least one regulatory sequence operably linked to a nucleotide sequence that encodes at least one strand of a dsRNA featured in the invention. 
     In another aspect, the invention provides a cell containing a vector for inhibiting the expression of a MIG12 gene in a cell. The vector includes a regulatory sequence operably linked to a nucleotide sequence that encodes at least one strand of one of the dsRNAs featured in the invention. 
     In yet another aspect, the invention provides a composition containing a MIG12 dsRNA, in combination with a second dsRNA targeting a second gene involved in a pathological disease, and useful for treating the disease, e.g., a lipid disorder or metabolic disorder. 
     In yet another aspect, the invention provides a composition containing a MIG12 dsRNA or vector encoding a part of said MIG12 dsRNA, wherein said composition is formulated in a LNP formulation, a LNP01 formulation, a XTC-SNALP formulation, or a SNALP formulation. 
     The details of one or more 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  is the sequence of human MIG12 mRNA (Ref. Seq. NM — 001098791.1, SEQ ID NO:1299). 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The invention provides dsRNAs and methods of using the dsRNAs for inhibiting the expression of a MIG12 gene in a cell or a mammal where the dsRNA targets a MIG12 gene. 
     The invention also provides compositions and methods for treating pathological conditions and diseases, such as a lipid disorder or metabolic disorder, in a mammal caused by the expression of a MIG12 gene. dsRNA directs the sequence-specific degradation of mRNA through a process known as RNA interference (RNAi). 
     The dsRNAs of the compositions featured herein include an RNA strand (the antisense strand) having a region which is less than 30 nucleotides in length, generally 19-24 nucleotides in length, and is substantially complementary to at least part of an mRNA transcript of a MIG12 gene. The use of these dsRNAs enables the targeted degradation of mRNAs of genes that are implicated in pathologies associated with MIG12 expression in mammals. Very low dosages of MIG12 dsRNAs in particular can specifically and efficiently mediate RNAi, resulting in significant inhibition of expression of a MIG12 gene. Using cell-based assays, the present inventors have demonstrated that dsRNAs targeting MIG12 can specifically and efficiently mediate RNAi, resulting in significant inhibition of expression of a MIG12 gene. Thus, methods and compositions including these dsRNAs are useful for treating pathological processes that can be mediated by down regulating MIG12, such as in the treatment of a lipid disorder, e.g., atherosclerosis, or a genetic disorder, such as Opitz syndrome. 
     The following detailed description discloses how to make and use the compositions containing dsRNAs to inhibit the expression of a MIG12 gene, as well as compositions (e.g., pharmaceutical compositions) and methods for treating diseases and disorders caused by the expression of this gene. 
     Accordingly, in some aspects, pharmaceutical compositions containing a MIG12 dsRNA and a pharmaceutically acceptable carrier, methods of using the compositions to inhibit expression of a MIG12 gene, and methods of using the pharmaceutical compositions to treat diseases caused by expression of a MIG12 gene are featured in the invention. 
     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. 
     “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, “MID1 interacting G12-like protein” (“MIG12”) refers to a gene in a cell. MIG12 is also known as MID11P1, THRSPL, FLJ10386, G12-like, STRAIT11499, S14 Related (S14-R), or Spot 14 Related. The sequence of a human MIG12 mRNA transcript can be found at NM — 021242.4 (variant 1), NM — 001098790.1 (variant 2), and NM — 001098791.1 (variant 3). The sequence of mouse MIG12 mRNA can be found at NM — 026524.3, and the sequence of rat MIG12 mRNA can be found at NM — 206950.1. 
     As used herein, “target sequence” refers to a contiguous portion of the nucleotide sequence of an mRNA molecule formed during the transcription of a MIG12 gene, including mRNA that is a product of RNA processing of a primary transcription product. 
     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. 
     This includes base-pairing of the oligonucleotide or polynucleotide comprising the first nucleotide sequence to the oligonucleotide or polynucleotide comprising the second nucleotide sequence over the entire length of the first and second nucleotide sequence. 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 4, 3 or 2 mismatched base pairs upon hybridization, while retaining the ability to hybridize under the conditions most relevant to their ultimate application. 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 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 a dsRNA 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 MIG12). For example, a polynucleotide is complementary to at least a part of a MIG12 mRNA if the sequence is substantially complementary to a non-interrupted portion of an mRNA encoding MIG12. 
     The term “double-stranded RNA” or “dsRNA,” as used herein, refers to a complex of ribonucleic acid molecules, having a duplex structure comprising two anti-parallel and substantially complementary, as defined above, nucleic acid strands. The two strands forming the duplex structure may be different portions of one larger RNA molecule, or they may be separate RNA molecules. Where the two strands are part of one larger molecule, and therefore are connected by an uninterrupted chain of nucleotides between the 3′-end of one strand and the 5′-end of the respective other strand forming the duplex structure, the connecting RNA chain is referred to as a “hairpin loop.” Where the two strands are connected covalently by means other than an uninterrupted chain of nucleotides between the 3′-end of one strand and the 5′-end of the respective other strand forming the duplex structure, the connecting structure is referred to as a “linker.” The RNA strands may have the same or a different number of nucleotides. The maximum number of base pairs is the number of nucleotides in the shortest strand of the dsRNA minus any overhangs that are present in the duplex. In addition to the duplex structure, a dsRNA may comprise one or more nucleotide overhangs. The term “siRNA” is also used herein to refer to a dsRNA as described above. 
     As used herein, a “nucleotide overhang” refers to the unpaired nucleotide or nucleotides that protrude from the duplex structure of a dsRNA when a 3′-end of one strand of the dsRNA extends beyond the 5′-end of the other strand, or vice versa. “Blunt” or “blunt end” means that there are no unpaired nucleotides at that end of the dsRNA, i.e., no nucleotide overhang. A “blunt ended” dsRNA is a dsRNA that is double-stranded over its entire length, i.e., no nucleotide overhang at either end of the molecule. 
     The term “antisense strand” refers to the strand of 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 6, 5, 4, 3, or 2 nucleotides of the 5′ and/or 3′ terminus. 
     The term “sense strand,” as used herein, refers to the strand of a dsRNA that includes a region that is substantially complementary to a region of the antisense strand. 
     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 agent or a plasmid from which an iRNA agent is transcribed. SNALP are described, e.g., in U.S. Patent Application Publication Nos. 20060240093, 20070135372, and U.S. Ser. No. 61/045,228 filed on Apr. 15, 2008. These applications are hereby incorporated by reference. 
     “Introducing into a cell,” when referring to a dsRNA, means facilitating uptake or absorption into the cell, as is understood by those skilled in the art. Absorption or uptake of dsRNA 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; a dsRNA may also be “introduced into a cell,” wherein the cell is part of a living organism. In such instance, introduction into the cell will include the delivery to the organism. For example, for in vivo delivery, dsRNA can be injected into a tissue site or administered systemically. In vivo delivery can also be by a beta-glucan delivery system, such as those described in U.S. Pat. Nos. 5,032,401 and 5,607,677, and U.S. Publication No. 2005/0281781. U.S. Pat. Nos. 5,032,401 and 5,607,677, and U.S. Publication No. 2005/0281781 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. 
     The terms “silence,” “inhibit the expression of,” “down-regulate the expression of,” “suppress the expression of,” and the like, in as far as they refer to a MIG12 gene, herein refer to the at least partial suppression of the expression of a MIG12 gene, as manifested by a reduction of the amount of MIG-12 mRNA which may be isolated or detected from a first cell or group of cells in which a MIG12 gene is transcribed and which has or have been treated such that the expression of a MIG12 gene is inhibited, as compared to a second cell or group of cells substantially identical to the first cell or group of cells but which has or have not been so treated (control cells). The degree of inhibition is usually expressed in terms of 
     
       
         
           
             
               
                 
                   
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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 MIG12 gene expression, e.g., the amount of protein encoded by a MIG12 gene, or the number of cells displaying a certain phenotype, e.g., stabilization of microtubules. In principle, MIG12 gene silencing may be determined in any cell expressing MIG-12, either constitutively or by genomic engineering, and by any appropriate assay. However, when a reference is needed in order to determine whether a given siRNA inhibits the expression of the MIG-12 gene by a certain degree and therefore is encompassed by the instant invention, the assays provided in the Examples below shall serve as such reference. 
     For example, in certain instances, expression of a MIG12 gene is suppressed by at least about 20%, 25%, 30%, 35%, 40%, 45%, or 50% by administration of the double-stranded oligonucleotide featured in the invention. In some embodiments, a MIG12 gene is suppressed by at least about 60%, 70%, or 80% by administration of the double-stranded oligonucleotide featured in the invention. In some embodiments, a MIG12 gene is suppressed by at least about 85%, 90%, or 95% by administration of the double-stranded oligonucleotide featured in the invention. 
     As used herein in the context of MIG12 expression, the terms “treat,” “treatment,” and the like, refer to relief from or alleviation of pathological processes mediated by MIG12 expression. In the context of the present invention insofar as it relates to any of the other conditions recited herein below (other than pathological processes mediated by MIG12 expression), the terms “treat,” “treatment,” and the like mean to relieve or alleviate at least one symptom associated with such condition, or to slow or reverse the progression of such condition, such as slowing the progression of a lipid disorder, such as atherosclerosis; or slowing the progression of an Opitz syndrome, such as an X-linked Opitz syndrome. 
     An Opitz syndrome is a multiple congenital anomaly disorder that affects several structures along the midline of the body and is characterized by ocular hypertelorism (wide-spaced eyes), defects of the larynx, trachea, and/or esophagus (causing breathing problems and dysphagia (difficulty in swallowing)), and in males, hypospadias (the urethra opening on the underside of the penis). Mild mental retardation is observed in less than 50% of affected individuals. About half people with Opitz syndrome also have cleft lip and/or plate. 
     Opitz syndrome manifests in various forms, which are distinguished by their genetic causes and patterns of inheritance. A mutation in the MID1 gene on the X chromosome causes the X-linked form of Opitz syndrome (MIG12 is also located on the X chromosome). A mutation in an as-yet unidentified gene on chromosome 22 causes the autosomal dominant form of Opitz syndrome. Opitz syndrome is also known as BBBG Syndrome, Hypertelorism with Esophageal Abnormalities and Hypospadias, Hypertelorism-Hypospadias Syndrome, Hypospadias-Dysphagia Syndrome, Opitz BBB Syndrome, Opitz BBBG Syndrome, Opitz BBB/G Compound Syndrome, Opitz G Syndrome, Opitz Hypertelorism-Hypospadias Syndrome, Opitz Oculogenitolaryngeal Syndrome, Opitz-Frias Syndrome, and Telecanthus-Hypospadias Syndrome. 
     Symptoms of Opitz syndrome include facial anomalies (e.g., ocular hypertelorism, prominent forehead, widow&#39;s peak, broad nasal bridge, and/or anteverted nares), laryngo-tracheo-esophageal (LTE) defects, genitourinary abnormalities (hypospadias, cryptorchidism, and/or hypoplastic/bifid scrotum), developmental delay, mental retardation, cleft lip and/or palate, congenital heart defects, imperforate or ectopic anus, and/or midline brain defects (e.g., Dandy-Walker malformation, and/or agenesis or hypoplasia of the corpus callosum and/or cerebellar vermis). 
     As used herein, the phrases “therapeutically effective amount” and “prophylactically effective amount” refer to an amount that provides a therapeutic benefit in the treatment, prevention, or management of pathological processes mediated by MIG12 expression or an overt symptom of pathological processes mediated by MIG12 expression. The specific amount that is therapeutically effective can be readily determined by an ordinary medical practitioner, and may vary depending on factors known in the art, such as, for example, the type of pathological processes mediated by MIG12 expression, the patient&#39;s history and age, the stage of pathological processes mediated by MIG12 expression, and the administration of other anti-pathological processes mediated by MIG12 expression agents. 
     As used herein, a “pharmaceutical composition” comprises a pharmacologically effective amount of a dsRNA and a pharmaceutically acceptable carrier. As used herein, “pharmacologically effective amount,” “therapeutically effective amount” or simply “effective amount” refers to that amount of an RNA effective to produce the intended pharmacological, therapeutic or preventive result. For example, if a given clinical treatment is considered effective when there is at least a 25% 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 effect at least a 25% reduction in that parameter. For example, a therapeutically effective amount of a dsRNA targeting MIG12 can reduce MIG12 protein levels by at least 25%. In another example, a therapeutically effective amount of a dsRNA targeting MIG12 can improve liver function by at least 25%. 
     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. 
     As used herein, a “transformed cell” is a cell into which a vector has been introduced from which a dsRNA molecule may be expressed. 
     II. Double-Stranded Ribonucleic Acid (dsRNA) 
     As described in more detail herein, the invention provides double-stranded ribonucleic acid (dsRNA) molecules for inhibiting the expression of a MIG12 gene in a cell or mammal, e.g., in a human having an Opitz syndrome, where the dsRNA includes a sense strand having a first sequence and an antisense strand comprising a second sequence complementary to mRNA encoding MIG12, wherein said first sequence is complementary to said second sequence at a region of complementarity and wherein each strand is 15 to 30 base pairs in length. In some embodiments, the dsRNA of the invention inhibits the expression of said MIG12 gene by at least 30% as assayed by, for example, a PCR or branched DNA (bDNA)-based method, or by a protein-based method, such as by Western blot. For example, expression of a MIG12 gene in cell culture, such as in COS cells, can be assayed by measuring MIG12 mRNA levels, such as by bDNA or TaqMan assay, or by measuring protein levels, such as by immunofluorescence analysis. 
     The dsRNA includes two RNA strands that are sufficiently complementary to hybridize to form a duplex structure. One strand of the dsRNA (the antisense strand) includes a region of complementarity that is complementary to a target sequence, derived from the sequence of an mRNA formed during the expression of a MIG12 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. The region of complementarity is generally at least 15 nucleotides in length, or between 19 and 21 nucleotides in length, or 19, 20, or 21 nucleotides in length. In some embodiments the region of complementarity includes at least 15 contiguous nucleotides of one of the antisense sequences listed in Tables 2, 3 or 4. In other embodiments the region of complementarity includes one of the antisense sequences listed in Tables 2, 3 or 4. 
     Generally, the duplex structure is between 15 and 30, more generally between 18 and 25, (e.g., 18, 19, 20, 21, 22, 23, 24 and 25) base pairs in length, yet more generally between 19 and 24, and most generally between 19 and 21 base pairs in length. Similarly, the region of complementarity to the target sequence is between 15 and 30, more generally between 18 and 25 (e.g., 18, 19, 20, 21, 22, 23, 24 or 25) base pairs in length, yet more generally between 19 and 24, and most generally between 19 and 21 nucleotides in length. In one embodiment, the duplex is 19 base pairs in length. In another embodiment, the duplex is 21 base pairs in length. When two different dsRNAs are used in combination, the duplex lengths, lengths of regions of complementarity, and lengths of strands can be identical or they can differ from each other. 
     In some embodiments, the dsRNA is between 10 and 15 nucleotides in length, and in other embodiments, the dsRNA is between 25 and 30 nucleotides in length. The dsRNA featured in the invention 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 MIG12 gene is a human MIG12 gene. In specific embodiments, the first sequence is a sense strand of the dsRNA that includes a sense sequence from Tables 2, 3 and 4, and the second sequence is selected from the group consisting of the antisense sequences of Tables 2, 3 and 4. Alternative antisense agents that target elsewhere in the target sequence provided in Tables 2, 3 and 4 can readily be determined using the target sequence and the flanking MIG12 sequence. 
     The dsRNA will include at least two nucleotide sequences selected from the groups of sequences provided in Tables 2, 3 and 4. One of the two sequences is complementary to the other of the two sequences, with one of the sequences being substantially complementary to a sequence of an mRNA generated in the expression of a MIG12 gene. As such, the dsRNA will include two oligonucleotides, where one oligonucleotide is described as the sense strand in Tables 2, 3 and 4, and the second oligonucleotide is described as the antisense strand in Tables 2, 3 and 4. 
     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 dsRNAs can be effective as well. In the embodiments described above, by virtue of the nature of the oligonucleotide sequences provided in Tables 2, 3 and 4, the dsRNAs featured in the invention can include at least one strand of a length of minimally 21 nt. It can be reasonably expected that shorter dsRNAs having one of the sequences of Tables 2, 3 and 4 minus only a few nucleotides on one or both ends may be similarly effective as compared to the dsRNAs described above. Hence, dsRNAs having 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 and 4, and differing in their ability to inhibit the expression of a MIG12 gene by not more than 5, 10, 15, 20, 25, or 30% inhibition from a dsRNA comprising the full sequence, are contemplated by the invention. Further, dsRNAs that cleave within a desired MIG12 target sequence can readily be made using the corresponding MIG12 antisense sequence and a complementary sense sequence. 
     In addition, the dsRNAs provided in Tables 2, 3 and 4 identify a site in a MIG12 that is susceptible to RNAi based cleavage. As such, the present invention further features dsRNAs that target within the sequence targeted by one of the agents of the present invention. As used herein, a second dsRNA is said to target within the sequence of a first dsRNA if the second dsRNA cleaves the message anywhere within the mRNA that is complementary to the antisense strand of the first dsRNA. Such a second dsRNA will generally consist of at least 15 contiguous nucleotides from one of the sequences provided in Tables 2, 3 and 4 coupled to additional nucleotide sequences taken from the region contiguous to the selected sequence in a MIG12 gene. 
     Additional dsRNA of the invention include those that cleave a target mRNA at the same location as a dsRNA described in any of the tables. In general, a RISC complex will cleave a target mRNA between the nucleotides complementary to nucleotides 10 and 11 of the antisense strand of a dsRNA, e.g., siRNA, of the invention. Cleavage sites can be assayed using, e.g., a 5′ RACE assay. For example, the duplex described by the first two sequences listed in Table 2, below, includes the sense and antisense strands with the sequence of SEQ ID NOs 355 and 373, respectively. Treatment of a cell with this duplex results in cleavage of human MIG12 mRNA at the nucleotides complementary to nucleotides 10 and 11 of the antisense strand, e.g., nucleotides 363 and 364. Therefore, also included in the invention are those dsRNAs that cleave at that location. 
     The dsRNA featured in the invention can contain one or more mismatches to the target sequence. In one embodiment, the dsRNA featured in the invention contains no more than 3 mismatches. If the antisense strand of the dsRNA 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 dsRNA contains mismatches to the target sequence, it is preferable that the mismatch be restricted to 5 nucleotides from either end, for example 5, 4, 3, 2, or 1 nucleotide from either the 5′ or 3′ end of the region of complementarity. For example, for a 23 nucleotide dsRNA strand which is complementary to a region of a MIG12 gene, the dsRNA generally does not contain any mismatch within the central 13 nucleotides. The methods described within the invention can be used to determine whether a dsRNA containing a mismatch to a target sequence is effective in inhibiting the expression of a MIG12 gene. Consideration of the efficacy of dsRNAs with mismatches in inhibiting expression of a MIG12 gene is important, especially if the particular region of complementarity in a MIG12 gene is known to have polymorphic sequence variation within the population. 
     In one embodiment, at least one end of the dsRNA has a single-stranded nucleotide overhang of 1, 2, 3, or 4 nucleotides. In another embodiment, the overhang includes dTdT. dsRNAs having at least one nucleotide overhang have unexpectedly superior inhibitory properties than their blunt-ended counterparts. Moreover, the present inventors have discovered that the presence of only one nucleotide overhang strengthens the interference activity of the dsRNA, without affecting its overall stability. dsRNA having only one overhang has proven particularly stable and effective in vivo, as well as in a variety of cells, cell culture mediums, blood, and serum. Generally, the single-stranded overhang is located at the 3′-terminal end of the antisense strand or, alternatively, at the 3′-terminal end of the sense strand. The dsRNA may also have a blunt end, generally located at the 5′-end of the antisense strand. Such dsRNAs have improved stability and inhibitory activity, thus allowing administration at low dosages, i.e., less than 5 mg/kg body weight of the recipient per day. In one embodiment, the antisense strand of the dsRNA has a 1-10 nucleotide overhang at the 3′ end and/or the 5′ end. In one embodiment, the sense strand of the 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. 
     In yet another embodiment, the dsRNA is chemically modified to enhance stability. 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. Specific examples of dsRNA compounds useful in this invention include dsRNAs containing modified backbones or no natural internucleoside linkages. As defined in this specification, dsRNAs having modified backbones include those that retain a phosphorus atom in the backbone and 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 dsRNAs that do not have a phosphorus atom in their internucleoside backbone can also be considered to be oligonucleosides. 
     Modified dsRNA 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; and 5,625,050, each of which is herein incorporated by reference 
     Modified dsRNA 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 ore 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 suitable dsRNA mimetics, 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, a dsRNA 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 a dsRNA 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 in Nielsen et al., Science, 1991, 254, 1497-1500. 
     Most embodiments featured in the invention include dsRNAs 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 dsRNAs featured herein have morpholino backbone structures of the above-referenced U.S. Pat. No. 5,034,506. 
     Modified dsRNAs may also contain one or more substituted sugar moieties. The dsRNAs featured herein can 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 a dsRNA, or a group for improving the pharmacodynamic properties of a dsRNA, and other substituents having similar properties. In some embodiments, the modification includes a 2′-methoxyethoxy (2′-O—CH 2 CH 2 OCH 3 , also known as 2′-O-(2-methoxyethyl) or 2′-MOE) (Martin et al.,  Helv. Chim. Acta,  1995, 78:486-504) i.e., an alkoxy-alkoxy group. Another exemplary modification is 2′-dimethylaminooxyethoxy, i.e., a O(CH 2 ) 2 ON(CH 3 ) 2  group, also known as 2′-DMAOE, as described in examples hereinbelow, 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 , also described in examples hereinbelow. 
     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 dsRNA, 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. DsRNAs 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. 
     DsRNAs 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-daazaadenine and 3-deazaguanine and 3-deazaadenine. Further nucleobases include those disclosed in U.S. Pat. No. 3,687,808, 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; and 5,681,941, each of which is herein incorporated by reference, and U.S. Pat. No. 5,750,692, also herein incorporated by reference. 
     Another modification of the dsRNAs featured in the invention involves chemically linking to the dsRNA one or more moieties or conjugates which enhance the activity, cellular distribution or cellular uptake of the dsRNA. 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-5-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-β-hexadecyl-rac-glycero-3-Hphosphonate (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). 
     Representative U.S. patents that teach the preparation of such dsRNA 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, 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 a dsRNA. The present invention also includes dsRNA compounds which are chimeric compounds. “Chimeric” dsRNA compounds or “chimeras,” in the context of this invention, are dsRNA compounds, particularly dsRNAs, which contain two or more chemically distinct regions, each made up of at least one monomer unit, i.e., a nucleotide in the case of a dsRNA compound. These dsRNAs typically contain at least one region wherein the dsRNA is modified so as to confer upon the dsRNA increased resistance to nuclease degradation, increased cellular uptake, and/or increased binding affinity for the target nucleic acid. An additional region of the dsRNA 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 dsRNA inhibition of gene expression. Consequently, comparable results can often be obtained with shorter dsRNAs when chimeric dsRNAs are used, compared to phosphorothioate deoxydsRNAs 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 dsRNA may be modified by a non-ligand group. A number of non-ligand molecules have been conjugated to dsRNAs in order to enhance the activity, cellular distribution or cellular uptake of the dsRNA, and procedures for performing such conjugations are available in the scientific literature. Such non-ligand moieties have included lipid moieties, such as cholesterol (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-5-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 dsRNA conjugates have been listed above. Typical conjugation protocols involve the synthesis of dsRNAs 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 dsRNA still bound to the solid support or following cleavage of the dsRNA in solution phase. Purification of the dsRNA conjugate by HPLC typically affords the pure conjugate. 
     Vector Encoded dsRNAs 
     In another aspect, MIG12 dsRNA molecules are 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). These transgenes can be introduced as a linear construct, a circular plasmid, or a viral vector, which can be incorporated and inherited as a transgene integrated into the host genome. 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 strands of a dsRNA can be transcribed by promoters on two separate expression vectors and co-transfected into a target cell. Alternatively each individual strand of the 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. 
     The recombinant dsRNA expression vectors are generally DNA plasmids or viral vectors. dsRNA expressing viral vectors can be constructed based on, but not limited to, adeno-associated virus (for a review, see Muzyczka, et al.,  Curr. Topics Micro. Immunol . (1992) 158:97-129)); adenovirus (see, for example, Berkner, et al., BioTechniques (1998) 6:616), Rosenfeld et al. (1991, Science 252:431-434), and Rosenfeld et al. (1992),  Cell  68:143-155)); or alphavirus as well as others known in the art. Retroviruses have been used to introduce a variety of genes into many different cell types, including epithelial cells, in vitro and/or in vivo (see, e.g., Eglitis, et al.,  Science  (1985) 230:1395-1398; Danos and Mulligan,  Proc. Natl. Acad. Sci. USA  (1998) 85:6460-6464; Wilson et al., 1988, Proc. Natl. Acad. Sci. USA 85:3014-3018; Armentano et al., 1990, Proc. Natl. Acad. Sci. USA 87:61416145; Huber et al., 1991, Proc. Natl. Acad. Sci. USA 88:8039-8043; Ferry et al., 1991, Proc. Natl. Acad. Sci. USA 88:8377-8381; Chowdhury et al., 1991, Science 254:1802-1805; van Beusechem. et al., 1992, Proc. Nad. Acad. Sci. USA 89:7640-19; Kay et al., 1992, Human Gene Therapy 3:641-647; Dai et al., 1992, Proc. Natl. Acad. Sci. USA 89:10892-10895; Hwu et al., 1993, J. Immunol. 150:4104-4115; U.S. Pat. No. 4,868,116; U.S. Pat. No. 4,980,286; PCT Application WO 89/07136; PCT Application WO 89/02468; PCT Application WO 89/05345; and PCT Application WO 92/07573). Recombinant retroviral vectors capable of transducing and expressing genes inserted into the genome of a cell can be produced by transfecting the recombinant retroviral genome into suitable packaging cell lines such as PA317 and Psi-CRIP (Comette et al., 1991, Human Gene Therapy 2:5-10; Cone et al., 1984, Proc. Natl. Acad. Sci. USA 81:6349). Recombinant adenoviral vectors can be used to infect a wide variety of cells and tissues in susceptible hosts (e.g., rat, hamster, dog, and chimpanzee) (Hsu et al., 1992, J. Infectious Disease, 166:769), and also have the advantage of not requiring mitotically active cells for infection. 
     Any viral vector capable of accepting the coding sequences for the dsRNA molecule(s) to be expressed can be used, for example vectors derived from adenovirus (AV); adeno-associated virus (AAV); retroviruses (e.g, lentiviruses (LV), Rhabdoviruses, murine leukemia virus); herpes virus, and the like. 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 featured in the invention can be pseudotyped with surface proteins from vesicular stomatitis virus (VSV), rabies, Ebola, Mokola, and the like. AAV vectors featured in the invention can be made to target different cells by engineering the vectors to express different capsid protein serotypes. For example, an AAV vector expressing a serotype 2 capsid on a serotype 2 genome is called AAV 2/2. This serotype 2 capsid gene in the AAV 2/2 vector can be replaced by a serotype 5 capsid gene to produce an AAV 2/5 vector. Techniques for constructing AAV vectors which express different capsid protein serotypes are within the skill in the art; see, e.g., Rabinowitz J E et al. (2002), J Virol 76:791-801, the entire disclosure of which is herein incorporated by reference. 
     Selection of recombinant viral vectors suitable for use in the invention, methods for inserting nucleic acid sequences for expressing the dsRNA into the vector, and methods of delivering the viral vector to the cells of interest are within the skill in the art. See, for example, Dornburg R (1995), Gene Therap. 2: 301-310; Eglitis M A (1988), Biotechniques 6: 608-614; Miller A D (1990), Hum Gene Therap. 1: 5-14; Anderson W F (1998), Nature 392: 25-30; and Rubinson D A et al., Nat. Genet. 33: 401-406, the entire disclosures of which are herein incorporated by reference. 
     Viral vectors can be derived from AV and AAV. In one embodiment, the dsRNA featured in the invention is 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. 
     A suitable AV vector for expressing the dsRNA 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. 
     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. No. 5,252,479; U.S. Pat. No. 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. 
     The promoter driving dsRNA expression in either a DNA plasmid or viral vector featured in the invention may be a eukaryotic RNA polymerase I (e.g., ribosomal RNA promoter), RNA polymerase II (e.g., CMV early promoter or actin promoter or Ul snRNA promoter) or generally RNA polymerase III promoter (e.g., U6 snRNA or 7SK RNA promoter) or a prokaryotic promoter, for example the T7 promoter, provided the expression plasmid also encodes T7 RNA polymerase required for transcription from a T7 promoter. The promoter can also direct transgene expression to the pancreas (see, e.g., the insulin regulatory sequence for pancreas (Bucchini et al., 1986, Proc. Natl. Acad. Sci. USA 83:2511-2515)). 
     In addition, expression of the transgene can be precisely regulated, for example, by using an inducible regulatory sequence and expression systems such as a 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 transgene expression in cells or in mammals include regulation by ecdysone, by estrogen, progesterone, tetracycline, chemical inducers of dimerization, and isopropyl-beta-D1-thiogalactopyranoside (EPTG). A person skilled in the art would be able to choose the appropriate regulatory/promoter sequence based on the intended use of the dsRNA transgene. 
     Generally, recombinant vectors capable of expressing dsRNA molecules are delivered as described below, and persist in target cells. Alternatively, viral vectors can be used that provide for transient expression of dsRNA molecules. Such vectors can be repeatedly administered as necessary. Once expressed, the dsRNAs bind to target RNA and modulate its function or expression. Delivery of dsRNA 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. 
     dsRNA expression DNA plasmids are typically transfected into target cells as a complex with cationic lipid carriers (e.g., Oligofectamine) or non-cationic lipid-based carriers (e.g., Transit-TKO™). Multiple lipid transfections for dsRNA-mediated knockdowns targeting different regions of a single MIG12 gene or multiple MIG12 genes 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. 
     MIG12 specific dsRNA molecules can also be inserted into vectors and used as gene therapy vectors for human patients. Gene therapy vectors can be delivered to a subject by, for example, intravenous injection, local administration (see U.S. Pat. No. 5,328,470) or by stereotactic injection (see e.g., Chen et al. (1994) Proc. Natl. Acad. Sci. USA 91:3054-3057). The pharmaceutical preparation of the gene therapy vector can include the gene therapy 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 dsRNA 
     In one embodiment, the invention provides pharmaceutical compositions containing a dsRNA, as described herein, and a pharmaceutically acceptable carrier. The pharmaceutical composition containing the dsRNA is useful for treating a disease or disorder associated with the expression or activity of a MIG12 gene, such as pathological processes mediated by MIG12 expression. Such pharmaceutical compositions are formulated based on the mode of delivery. One example is compositions that are formulated for systemic administration via parenteral delivery, e.g., by intravenous (IV) delivery. Another example is compositions that are formulated for direct delivery into the brain parenchyma, e.g., by infusion into the brain, such as by continuous pump infusion. 
     The pharmaceutical compositions featured herein are administered in dosages sufficient to inhibit expression of MIG12 genes. In general, a suitable dose of dsRNA will be in the range of 0.01 to 200.0 milligrams of dsRNA 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 0.0059 mg/kg, 0.01 mg/kg, 0.0295 mg/kg, 0.05 mg/kg, 0.0590 mg/kg, 0.163 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 0.543 mg/kg, 0.5900 mg/kg, 0.6 mg/kg, 0.7 mg/kg, 0.8 mg/kg, 0.9 mg/kg, 1 mg/kg, 1.1 mg/kg, 1.2 mg/kg, 1.3 mg/kg, 1.4 mg/kg, 1.5 mg/kg, 1.628 mg/kg, 2 mg/kg, 3 mg/kg, 5.0 mg/kg, 10 mg/kg, 20 mg/kg, 30 mg/kg, 40 mg/kg, or 50 mg/kg per single dose. 
     In one embodiment, the dosage is between 0.01 and 0.2 mg/kg. For example, the dsRNA can be administered at a dose of 0.01 mg/kg, 0.02 mg/kg, 0.03 mg/kg, 0.04 mg/kg, 0.05 mg/kg, 0.06 mg/kg, 0.07 mg/kg 0.08 mg/kg 0.09 mg/kg, 0.10 mg/kg, 0.11 mg/kg, 0.12 mg/kg, 0.13 mg/kg, 0.14 mg/kg, 0.15 mg/kg, 0.16 mg/kg, 0.17 mg/kg, 0.18 mg/kg, 0.19 mg/kg, or 0.20 mg/kg. 
     In one embodiment, the dosage is between 0.005 mg/kg and 1.628 mg/kg. For example, the dsRNA can be administered at a dose of 0.0059 mg/kg, 0.0295 mg/kg, 0.0590 mg/kg, 0.163 mg/kg, 0.543 mg/kg, 0.5900 mg/kg, or 1.628 mg/kg. 
     In one embodiment, the dosage is between 0.2 mg/kg and 1.5 mg/kg. For example, the dsRNA can be administered at a dose of 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 0.6 mg/kg, 0.7 mg/kg, 0.8 mg/kg, 0.9 mg/kg, 1 mg/kg, 1.1 mg/kg, 1.2 mg/kg, 1.3 mg/kg, 1.4 mg/kg, or 1.5 mg/kg. 
     The pharmaceutical composition may be administered once daily, or the dsRNA 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 dsRNA 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 dsRNA over a several day period. Sustained release formulations are well known in the art and are particularly useful for delivery of agents at a particular site, such as could be used with the agents of the present invention. In this embodiment, the dosage unit contains a corresponding multiple of the daily dose. 
     The effect of a single dose on MIG12 levels is 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 dsRNAs encompassed by the invention can be made using conventional methodologies or on the basis of in vivo testing using an appropriate animal model, as described elsewhere herein. 
     Advances in mouse genetics have generated a number of mouse models for the study of various human diseases, such as pathological processes mediated by MIG12 expression. Such models are used for in vivo testing of dsRNA, as well as for determining a therapeutically effective dose. A suitable mouse model is, for example, a mouse containing a plasmid expressing human MIG12. Another suitable mouse model is a transgenic mouse carrying a transgene that expresses human MIG12. 
     The present invention also includes pharmaceutical compositions and formulations which include the dsRNA compounds featured in the invention. 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 dsRNA can be delivered in a manner to target a particular tissue, such as the liver (e.g., the hepatocytes of the liver). 
     The present invention includes pharmaceutical compositions that can be delivered by injection directly into the brain. The injection can be by stereotactic injection into a particular region of the brain (e.g., the substantia nigra, cortex, hippocampus, striatum, or globus pallidus), or the dsRNA can be delivered into multiple regions of the central nervous system (e.g., into multiple regions of the brain, and/or into the spinal cord). The dsRNA can also be delivered into diffuse regions of the brain (e.g., diffuse delivery to the cortex of the brain). 
     In one embodiment, a dsRNA targeting MIG12 can be delivered by way of a cannula or other delivery device having one end implanted in a tissue, e.g., the brain, e.g., the substantia nigra, cortex, hippocampus, striatum, corpus callosum or globus pallidus of the brain. The cannula can be connected to a reservoir of the dsRNA composition. The flow or delivery can be mediated by a pump, e.g., an osmotic pump or minipump, such as an Alzet pump (Durect, Cupertino, Calif.). In one embodiment, a pump and reservoir are implanted in an area distant from the tissue, e.g., in the abdomen, and delivery is effected by a conduit leading from the pump or reservoir to the site of release. Infusion of the dsRNA composition into the brain can be over several hours or for several days, e.g., for 1, 2, 3, 5, or 7 days or more. Devices for delivery to the brain are described, for example, in U.S. Pat. Nos. 6,093,180, and 5,814,014. 
     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 dsRNAs 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). DsRNAs featured in the invention may be encapsulated within liposomes or may form complexes thereto, in particular to cationic liposomes. Alternatively, dsRNAs 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 1-10  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. 
     In one embodiment, a MIG12 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 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-(1-(2,3-dioleoyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTAP), N-(1-(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.C1), 1,2-Dilinoleoyl-3-trimethylaminopropane chloride salt (DLin-TAP.C1), 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), 2,2-Dilinoleyl-4-dimethylaminomethyl-[1,3]-dioxolane (DLin-K-DMA), 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. 
     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), palmitoyloleoyl-phosphatidylethanolamine (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. 
     Lipid 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 siRNA concentration in the formulation, as well as the entrapped fraction, is estimated using a dye exclusion assay. A sample of the formulated siRNA 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 siRNA 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” siRNA content (as measured by the signal in the absence of surfactant) from the total siRNA content. Percent entrapped siRNA 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 Pub. 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. Particularly preferred are formulations that target the liver when treating hepatic disorders such as hepatic carcinoma. 
     The pharmaceutical formulations of 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 of 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 of the present invention 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. 
     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 (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 (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 (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 (Rieger, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 285). 
     Naturally occurring emulsifiers used in emulsion formulations include lanolin, beeswax, phosphatides, lecithin and acacia. Absorption bases possess hydrophilic properties such that they can soak up water to form w/o emulsions yet retain their semisolid consistencies, such as anhydrous lanolin and hydrophilic petrolatum. Finely divided solids have also been used as good emulsifiers especially in combination with surfactants and in viscous preparations. These include polar inorganic solids, such as heavy metal hydroxides, nonswelling clays such as bentonite, attapulgite, hectorite, kaolin, montmorillonite, colloidal aluminum silicate and colloidal magnesium aluminum silicate, pigments and nonpolar solids such as carbon or glyceryl tristearate. 
     A large variety of non-emulsifying materials are also included in emulsion formulations and contribute to the properties of emulsions. These include fats, oils, waxes, fatty acids, fatty alcohols, fatty esters, humectants, hydrophilic colloids, preservatives and antioxidants (Block, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 335; Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 199). 
     Hydrophilic colloids or hydrocolloids include naturally occurring gums and synthetic polymers such as polysaccharides (for example, acacia, agar, alginic acid, carrageenan, guar gum, karaya gum, and tragacanth), cellulose derivatives (for example, carboxymethylcellulose and carboxypropylcellulose), and synthetic polymers (for example, carbomers, cellulose ethers, and carboxyvinyl polymers). These disperse or swell in water to form colloidal solutions that stabilize emulsions by forming strong interfacial films around the dispersed-phase droplets and by increasing the viscosity of the external phase. 
     Since emulsions often contain a number of ingredients such as carbohydrates, proteins, sterols and phosphatides that 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 (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 (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 dsRNAs 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 (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, co-surfactant 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 (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 (M0310), 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 co-surfactant, 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 (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 (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 dsRNAs. 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 dsRNAs and nucleic acids from the gastrointestinal tract, as well as improve the local cellular uptake of dsRNAs 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 dsRNAs 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. 
     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 cross intact mammalian skin, lipid vesicles must pass through a series of fine pores, each with a diameter less than 50 nm, under the influence of a suitable transdermal gradient. 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/po-lyoxyethylene-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 G M1 , or (B) is derivatized with one or more hydrophilic polymers, such as a polyethylene glycol (PEG) moiety. While not wishing to be bound by any particular theory, it is thought in the art that, at least for sterically stabilized liposomes containing gangliosides, sphingomyelin, or PEG-derivatized lipids, the enhanced circulation half-life of these sterically stabilized liposomes derives from a reduced uptake into cells of the reticuloendothelial system (RES) (Allen et al., FEBS Letters, 1987, 223, 42; Wu et al., Cancer Research, 1993, 53, 3765). 
     Various liposomes comprising one or more glycolipids are known in the art. Papahadjopoulos et al. (Ann. N.Y. Acad. Sci., 1987, 507, 64) reported the ability of monosialoganglioside G M1 , 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-dimyristoylphosphat-idylcholine 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). 
     SNALPs 
     In one embodiment, a dsRNA featured in the invention is fully encapsulated in the lipid formulation 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 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-(1-(2,3-dioleoyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTAP), N-(1-(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.C1), 1,2-Dilinoleoyl-3-trimethylaminopropane chloride salt (DLin-TAP.C1), 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, 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), palmitoyloleoyl-phosphatidylethanolamine (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. 
     LNP01 
     In one embodiment, the lipidoid ND98.4HCl (MW 1487) (Formula I), Cholesterol (Sigma-Aldrich), and PEG-Ceramide C16 (Avanti Polar Lipids) can be used to prepare lipid-siRNA nanoparticles (i.e., LNP01 particles). Stock solutions of each in ethanol can be prepared as follows: ND98, 133 mg/ml; Cholesterol, 25 mg/ml, PEG-Ceramide C16, 100 mg/ml. The ND98, Cholesterol, and PEG-Ceramide C16 stock solutions can then be combined in a, e.g., 42:48:10 molar ratio. The combined lipid solution can be mixed with aqueous siRNA (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-siRNA 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-siRNA formulations are as follows: 
     
       
         
           
               
               
               
               
             
               
                   
                   
               
               
                   
                   
                 cationic lipid/non-cationic 
                   
               
               
                   
                   
                 lipid//choleseterol/PEG-lipid 
               
               
                   
                   
                 conjugate 
               
               
                   
                 Cationic Lipid 
                 Lipid:siRNA ratio 
                 Process 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                 SNALP 
                 1,2-Dilinolenyloxy-N,N- 
                 DLinDMA/DPPC/Cholesterol/PEG- 
                   
               
               
                   
                 dimethylaminopropane (DLinDMA) 
                 cDMA 
               
               
                   
                   
                 (57.1/7.1/34.4/1.4) 
               
               
                   
                   
                 lipid:siRNA ~7:1 
               
               
                 SNALP- 
                 2,2-Dilinoleyl-4-dimethylaminoethyl- 
                 XTC/DPPC/Cholesterol/PEG- 
               
               
                 XTC 
                 [1,3]-dioxolane (XTC) 
                 cDMA 
               
               
                   
                   
                 57.1/7.1/34.4/1.4 
               
               
                   
                   
                 lipid:siRNA ~7:1 
               
               
                 LNP05 
                 2,2-Dilinoleyl-4-dimethylaminoethyl- 
                 XTC/DSPC/Cholesterol/PEG-DMG 
                 Extrusion 
               
               
                   
                 [1,3]-dioxolane (XTC) 
                 57.5/7.5/31.5/3.5 
               
               
                   
                   
                 lipid:siRNA ~6:1 
               
               
                 LNP06 
                 2,2-Dilinoleyl-4-dimethylaminoethyl- 
                 XTC/DSPC/Cholesterol/PEG-DMG 
                 Extrusion 
               
               
                   
                 [1,3]-dioxolane (XTC) 
                 57.5/7.5/31.5/3.5 
               
               
                   
                   
                 lipid:siRNA ~11:1 
               
               
                 LNP07 
                 2,2-Dilinoleyl-4-dimethylaminoethyl- 
                 XTC/DSPC/Cholesterol/PEG-DMG 
                 In-line 
               
               
                   
                 [1,3]-dioxolane (XTC) 
                 60/7.5/31/1.5, 
                 mixing 
               
               
                   
                   
                 lipid:siRNA ~6:1 
               
               
                 LNP08 
                 2,2-Dilinoleyl-4-dimethylaminoethyl- 
                 XTC/DSPC/Cholesterol/PEG-DMG 
                 In-line 
               
               
                   
                 [1,3]-dioxolane (XTC) 
                 60/7.5/31/1.5, 
                 mixing 
               
               
                   
                   
                 lipid:siRNA ~11:1 
               
               
                 LNP09 
                 2,2-Dilinoleyl-4-dimethylaminoethyl- 
                 XTC/DSPC/Cholesterol/PEG-DMG 
                 In-line 
               
               
                   
                 [1,3]-dioxolane (XTC) 
                 50/10/38.5/1.5 
                 mixing 
               
               
                   
                   
                 Lipid:siRNA 10:1 
               
               
                 LNP10 
                 (3aR,5s,6aS)-N,N-dimethyl-2,2- 
                 ALN100/DSPC/Cholesterol/PEG- 
                 In-line 
               
               
                   
                 di((9Z,12Z)-octadeca-9,12- 
                 DMG 
                 mixing 
               
               
                   
                 dienyl)tetrahydro-3aH- 
                 50/10/38.5/1.5 
               
               
                   
                 cyclopenta[d][1,3]dioxol-5-amine 
                 Lipid:siRNA 10:1 
               
               
                   
                 (ALN100) 
               
               
                 LNP11 
                 (6Z,9Z,28Z,31Z)-heptatriaconta- 
                 MC-3/DSPC/Cholesterol/PEG- 
                 In-line 
               
               
                   
                 6,9,28,31-tetraen-19-yl 4- 
                 DMG 
                 mixing 
               
               
                   
                 (dimethylamino)butanoate (MC3) 
                 50/10/38.5/1.5 
               
               
                   
                   
                 Lipid:siRNA 10:1 
               
               
                 LNP12 
                 1,1′-(2-(4-(2-((2-(bis(2- 
                 Tech G1/DSPC/Cholesterol/PEG- 
                 In-line 
               
               
                   
                 hydroxydodecyl)amino)ethyl)(2- 
                 DMG 
                 mixing 
               
               
                   
                 hydroxydodecyl)amino)ethyl)piperazin- 
                 50/10/38.5/1.5 
               
               
                   
                 1-yl)ethylazanediyl)didodecan-2-ol 
                 Lipid:siRNA 10:1 
               
               
                   
                 (Tech G1) 
               
               
                   
               
            
           
         
       
     
     Penetration Enhancers 
     In one embodiment, the present invention employs various penetration enhancers to effect the efficient delivery of nucleic acids, particularly dsRNAs, 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 (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 dsRNAs 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) (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 1-10  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.) (Lee et al., Critical Reviews in Therapeutic Drug Carryier 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 (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) (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 dsRNAs through the mucosa is enhanced. With regards to their use as penetration enhancers in the present invention, chelating agents have the added advantage of also serving as DNase inhibitors, as most characterized DNA nucleases require a divalent metal ion for catalysis and are thus inhibited by chelating agents (Jarrett, J. Chromatogr., 1993, 618, 315-339). Suitable chelating agents include but are not limited to disodium ethylenediaminetetraacetate (EDTA), citric acid, salicylates (e.g., sodium salicylate, 5-methoxysalicylate and homovanilate), N-acyl derivatives of collagen, laureth-9 and N-amino acyl derivatives of beta-diketones (enamines) (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 dsRNAs through the alimentary mucosa (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 dsRNAs 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. 
     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 which 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 dsRNA compounds and (b) one or more anti-cytokine biologic agents which function by a non-RNAi mechanism. Examples of such biologics include, biologics that target IL1β (e.g., anakinra), IL6 (e.g., tocilizumab), or TNF (e.g., etanercept, infliximab, adlimumab, or certolizumab). 
     Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50. Compounds that exhibit high therapeutic indices are preferred. 
     The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of compositions featured 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 dsRNAs featured in the invention can be administered in combination with other known agents effective in treatment of pathological processes mediated by MIG12 expression. In any event, the administering physician can adjust the amount and timing of dsRNA administration on the basis of results observed using standard measures of efficacy known in the art or described herein. 
     Methods for Treating Diseases Caused by Expression of a MIG12 Gene 
     The invention relates in particular to the use of a dsRNA targeting MIG12 and compositions containing at least one such dsRNA for the treatment of a MIG12-mediated disorder or disease. For example, a composition containing a dsRNA targeting a MIG12 gene is used for treatment of lipid or metabolic disorders, such as hypercholesterolemia, dyslipidemia, diabetes, diabetes type I, diabetes type II, coronary artery disease, atherosclerosis, myocardial infarction, coronary artery bypass graft, percutaneous transluminal angioplasties, coronary stenosis, cerebrovascular disease transient ischemic attack, ischemic stroke, carotid endarterectomies, peripheral arterial disease, and other disorders associated with cholesterol metabolism. 
     The invention further relates to the use of a dsRNA or a pharmaceutical composition thereof, e.g., for treating a lipid disorder, in combination with other pharmaceuticals and/or other therapeutic methods, e.g., with known pharmaceuticals and/or known therapeutic methods, such as, for example, those which are currently employed for treating these disorders. For example, in certain embodiments, administration of a dsRNA targeting MIG12 is administered in combination with, e.g., an HMG-CoA reductase inhibitor (e.g., a statin, such as atrovastatin, lovastatin, pravastatin or simvastatin), a fibrate, a bile acid sequestrant, niacin, an antiplatelet agent, an angiotensin converting enzyme inhibitor, an angiotensin II receptor antagonist (e.g., losartan potassium, such as Merck &amp; Co.&#39;s Cozaar®), an acylCoA cholesterol acetyltransferase (ACAT) inhibitor, a cholesterol absorption inhibitor, a cholesterol ester transfer protein (CETP) inhibitor, a microsomal triglyceride transfer protein (MTTP) inhibitor, a cholesterol modulator, a bile acid modulator, a peroxisome proliferation activated receptor (PPAR) agonist, a gene-based therapy, a composite vascular protectant (e.g., AGI-1067, from Atherogenics), a glycoprotein IIb/IIIa inhibitor, aspirin or an aspirin-like compound, an IBAT inhibitor (e.g., S-8921, from Shionogi), a squalene synthase inhibitor, or a monocyte chemoattractant protein (MCP)-I inhibitor. Exemplary HMG-CoA reductase inhibitors include atorvastatin (Pfizer&#39;s Lipitor®/Tahor/Sortis/Torvast/Cardyl), pravastatin (Bristol-Myers Squibb&#39;s Pravachol, Sankyo&#39;s Mevalotin/Sanaprav), simvastatin (Merck&#39;s Zocor®/Sinvacor, Boehringer Ingelheim&#39;s Denan, Banyu&#39;s Lipovas), lovastatin (Merck&#39;s Mevacor/Mevinacor, Bexal&#39;s Lovastatina, Cepa; Schwarz Pharma&#39;s Liposcler), fluvastatin (Novartis&#39;Lescol®/Locol/Lochol, Fujisawa&#39;s Cranoc, Solvay&#39;s Digaril), cerivastatin (Bayer&#39;s Lipobay/GlaxoSmithKline&#39;s Baycol), rosuvastatin (AstraZeneca&#39;s Crestor®), and pitivastatin (itavastatin/risivastatin) (Nissan Chemical, Kowa Kogyo, Sankyo, and Novartis). Exemplary fibrates include, e.g., bezafibrate (e.g., Roche&#39;s Befizal®/Cedur®/Bezalip®, Kissei&#39;s Bezatol), clofibrate (e.g., Wyeth&#39;s Atromid-S®), fenofibrate (e.g., Fournier&#39;s Lipidil/Lipantil, Abbott&#39;s Tricor®, Takeda&#39;s Lipantil, generics), gemfibrozil (e.g., Pfizer&#39;s Lopid/Lipur) and ciprofibrate (Sanofi-Synthelabo&#39;s Modalim®). Exemplary bile acid sequestrants include, e.g., cholestyramine (Bristol-Myers Squibb&#39;s Questran® and Questran Light™), colestipol (e.g., Pharmacia&#39;s Colestid), and colesevelam (Genzyme/Sankyo&#39;s WelChol™). Exemplary niacin therapies include, e.g, immediate release formulations, such as Aventis&#39; Nicobid, Upsher-Smith&#39;s Niacor, Aventis&#39; Nicolar, and Sanwakagaku&#39;s Perycit. Niacin extended release formulations include, e.g., Kos Pharmaceuticals&#39; Niaspan and Upsher-Smith&#39;s SIo-Niacin. Exemplary antiplatelet agents include, e.g., aspirin (e.g., Bayer&#39;s aspirin), clopidogrel (Sanofi-Synthelabo/Bristol-Myers Squibb&#39;s Plavix), and ticlopidine (e.g., Sanofi-Synthelabo&#39;s Ticlid and Daiichi&#39;s Panaldine). Other aspirin-like compounds useful in combination with a dsRNA targeting PCSK9 include, e.g., Asacard (slow-release aspirin, by Pharmacia) and Pamicogrel (Kanebo/Angelini Ricerche/CEPA). Exemplary angiotensin-converting enzyme inhibitors include, e.g., ramipril (e.g., Aventis&#39; Altace) and enalapril (e.g., Merck &amp; Co.&#39;s Vasotec). Exemplary acyl CoA cholesterol acetyltransferase (ACAT) inhibitors include, e.g., avasimibe (Pfizer), eflucimibe (BioM{acute over (ε)}rieux Pierre Fabre/Eli Lilly), CS-505 (Sankyo and Kyoto), and SMP-797 (Sumito). Exemplary cholesterol absorption inhibitors include, e.g., ezetimibe (Merck/Schering-Plough Pharmaceuticals Zetia®) and Pamaqueside (Pfizer). Exemplary CETP inhibitors include, e.g., Torcetrapib (also called CP-529414, Pfizer), JTT-705 (Japan Tobacco), and CETi-I (Avant Immunotherapeutics). Exemplary microsomal triglyceride transfer protein (MTTP) inhibitors include, e.g, implitapide (Bayer), R-103757 (Janssen), and CP-346086 (Pfizer). Other exemplary cholesterol modulators include, e.g., NO-1886 (Otsuka/TAP Pharmaceutical), CI-1027 (Pfizer), and WAY-135433 (Wyeth-Ayerst). Exemplary bile acid modulators include, e.g., HBS-107 (Hisamitsu/Banyu), Btg-511 (British Technology Group), BARI-1453 (Aventis), S-8921 (Shionogi), SD-5613 (Pfizer), and AZD-7806 (AstraZeneca). Exemplary peroxisome proliferation activated receptor (PPAR) agonists include, e.g., tesaglitazar (AZ-242) (AstraZeneca), Netoglitazone (MCC-555) (Mitsubishi/Johnson &amp; Johnson), GW-409544 (Ligand Pharmaceuticals/GlaxoSmithKline), GW-501516 (Ligand Pharmaceuticals/GlaxoSmithKline), LY-929 (Ligand Pharmaceuticals and Eli Lilly), LY-465608 (Ligand Pharmaceuticals and Eli Lilly), LY-518674 (Ligand Pharmaceuticals and Eli Lilly), and MK-767 (Merck and Kyorin). Exemplary gene-based therapies include, e.g., AdGWEGF121.10 (GenVec), ApoAl (UCB Pharma/Groupe Fournier), EG-004 (Trinam) (Ark Therapeutics), and ATP-binding cassette transporter-Al (ABCA1) (CV Therapeutics/Incyte, Aventis, Xenon). Exemplary Glycoprotein Ilb/IIIa inhibitors include, e.g., roxifiban (also called DMP754, Bristol-Myers Squibb), Gantofiban (Merck KGaA/Yamanouchi), and Cromafiban (Millennium Pharmaceuticals). Exemplary squalene synthase inhibitors include, e.g., BMS-1884941 (Bristol-Myers Squibb), CP-210172 (Pfizer), CP-295697 (Pfizer), CP-294838 (Pfizer), and TAK-475 (Takeda). An exemplary MCP-I inhibitor is, e.g., RS-504393 (Roche Bioscience). The anti-atherosclerotic agent BO-653 (Chugai Pharmaceuticals), and the nicotinic acid derivative Nyclin (Yamanouchi Pharmacuticals) are also appropriate for administering in combination with a dsRNA featured in the invention. Exemplary combination therapies suitable for administration with a dsRNA targeting PCSK9 include, e.g., advicor (Niacin/lovastatin from Kos Pharmaceuticals), amlodipine/atorvastatin (Pfizer), and ezetimibe/simvastatin (e.g., Vytorin® 10/10, 10/20, 10/40, and 10/80 tablets by Merck/Schering-Plough Pharmaceuticals). Agents for treating hypercholesterolemia, and suitable for administration in combination with a dsRNA targeting PCSK9 include, e.g., lovastatin, niacin Altoprev® Extended-Release Tablets (Andrx Labs), lovastatin Caduet® Tablets (Pfizer), amlodipine besylate, atorvastatin calcium Crestor®Tablets (AstraZeneca), rosuvastatin calcium Lescol® Capsules (Novartis), fluvastatin sodium Lescol® (Reliant, Novartis), fluvastatin sodium Lipitor® Tablets (Parke-Davis), atorvastatin calcium Lofibra® Capsules (Gate), Niaspan Extended-Release Tablets (Kos), niacin Pravachol Tablets (Bristol-Myers Squibb), pravastatin sodium TriCor® Tablets (Abbott), fenofibrate Vytorin® 10/10 Tablets (Merck/Schering-Plough Pharmaceuticals), ezetimibe, simvastatin WelChol™ Tablets (Sankyo), colesevelam hydrochloride Zetia® Tablets (Schering), ezetimibe Zetia® Tablets (Merck/Schering-Plough Pharmaceuticals), and ezetimibe Zocor® Tablets (Merck). 
     In one embodiment, a dsRNA targeting MIG12 is administered in combination with an ezetimibe/simvastatin combination (e.g., Vytorin® (Merck/Schering-Plough Pharmaceuticals)). 
     The invention further relates to the use of a dsRNA or a pharmaceutical composition containing a dsRNA for treatment of a metabolic disorder, such as diabetes, in combination with other pharmaceuticals and/or other therapeutic methods, e.g., with known pharmaceuticals and/or known therapeutic methods, such as, for example, those which are currently employed for treating metabolic disorders (e.g., diabetes). For example, in certain embodiments, administration of a dsRNA targeting MIG12 is administered in combination with, e.g., insulin (e.g., insulin injections); a biguanide (e.g., metformin); a sulfonylurea (e.g., glibenclamide, glipizide, tolbautamide, chloropamidem, tolazamide, glimepride, glicazide or glyburide); an alpha-glucosidase inhibitor (e.g., acarbose); a PPAR gamma agonist (e.g., thiazolidinedione and derivatives such as rosiglitazone or pioglitazone); an oxadiazolidinedione; a meglitinide; a D-phenylalanine derivative; repaglinide; a PPAR (Peroxisome proliferator-activated receptor) ligand including the PPAR-alpha, PPAR-gamma and PPAR-delta subtypes; an RxR (retinoid X receptor) agonist, such as ALRT-268, LG-1268 or LG-1069; a PPAR alpha agonist (e.g., clofibrate and gemfibrozil); an alpha agonist (non-thiazolinedione); a glycogen phosphorylase inhibitor; a glucagon-like peptide; a dipeptidylpeptidase IV inhibitor; an HMG-CoA reductase inhibitor (e.g., a statin, such as atrovastatin, lovastatin, pravastatin or simvastatin); a GLP-1 antagonist; a DPP-IV (dipeptidyl peptidase-IV) inhibitor; a PTPase (protein tyrosine phosphatase) inhibitor; or a compound lowering food intake. 
     A composition containing a dsRNA targeting a MIG12 gene is also used for treatment of an Opitz syndrome or one or more symptoms of an Opitz syndrome. Symptoms include, for example, facial anomalies (e.g., ocular hypertelorism, prominent forehead, widow&#39;s peak, broad nasal bridge, and/or anteverted nares), laryngo-tracheo-esophageal (LTE) defects, genitourinary abnormalities (hypospadias, cryptorchidism, and/or hypoplastic/bifid scrotum), developmental delay, mental retardation, cleft lip and/or palate, congenital heart defects, imperforate or ectopic anus, and/or midline brain defects (e.g., Dandy-Walker malformation, and/or agenesis or hypoplasia of the corpus callosum and/or cerebellar vermis). 
     The invention further relates to the use of a dsRNA or a pharmaceutical composition thereof, e.g., for treating an Opitz syndrome, in combination with other pharmaceuticals and/or other therapeutic methods, e.g., with known pharmaceuticals and/or known therapeutic methods, such as, for example, those which are currently employed for treating these disorders. In one example, a dsRNA targeting MIG12 can be administered in combination with a pharmaceutical or therapeutic method for treating a symptom of a MIG12 disease, such as a surgical intervention (e.g., surgical treatment of medically significant LTE abnormalities, hypospadias, cleft lip/palate, imperforate anus, and/or heart defects) and antireflux agents. 
     The dsRNA and an additional therapeutic agent can be administered in the same combination, e.g., parenterally, or the additional therapeutic agent can be administered as part of a separate composition or by another method described herein. 
     The invention features a method of administering a dsRNA targeting MIG12 to a patient having a disease or disorder mediated by MIG12 expression, such as a lipid disorder, or a disorder associated with cholesterol metabolism, e.g., diabetes or atherosclerosis. Administration of the dsRNA can lower LDL levels, lower ApoB level, or lower total cholesterol level, for example, in a patient with a lipid disorder, or a disorder associated with cholesterol metabolism. 
     The invention features a method of administering a dsRNA targeting MIG12 to a patient having a disease or disorder mediated by MIG12 expression, such as an Opitz syndrome, e.g., an X-linked Opitz syndrome. Administration of the dsRNA can stabilize and improve CNS function, for example, in a patient with X-linked Opitz syndrome. 
     Patients can be administered a therapeutic amount of dsRNA, such as 0.5 mg/kg, 1.0 mg/kg, 1.5 mg/kg, 2.0 mg/kg, or 2.5 mg/kg dsRNA. The dsRNA can be 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. The administration is repeated, for example, on a regular basis, such as 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. Administration of the dsRNA can reduce MIG12 levels in the blood or urine of the patient by at least 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80% or 90% or more. 
     Before administration of a full dose of the dsRNA, patients can be administered a smaller dose, such as a 5% infusion reaction, 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 immunostimulatory effects, such as increased cytokine (e.g., TNF-alpha or INF-alpha) levels. 
     Many MIG12-associated diseases and disorders are hereditary. Therefore, a patient in need of a MIG12 dsRNA can be identified by taking a family history. A healthcare provider, such as a doctor, nurse, or family member, can take a family history before prescribing or administering a MIG12 dsRNA. A DNA test may also be performed on the patient to identify a mutation in the MIG12 gene, before a MIG12 dsRNA is administered to the patient. 
     Owing to the inhibitory effects on MIG12 expression, a composition according to the invention or a pharmaceutical composition prepared therefrom can enhance the quality of life. 
     Methods for Inhibiting Expression of a MIG12 Gene 
     In yet another aspect, the invention provides a method for inhibiting the expression of a MIG12 gene in a mammal. The method includes administering a composition featured in the invention to the mammal such that expression of the target MIG12 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. The effect of the decreased target MIG12 gene preferably results in a decrease in LDLc levels in the blood, and more particularly in the serum, of the mammal. In some embodiments, LDLc levels are decreased by at least 10%, 15%, 20%, 25%, 30%, 40%, 50%, or 60%, or more, as compared to pretreatment levels. 
     Preferably, the dsRNAs useful for the methods and compositions featured in the invention specifically target RNAs (primary or processed) of the target MIG12 gene. Compositions and methods for inhibiting the expression of these MIG12 genes using dsRNAs can be performed as described elsewhere herein. 
     In one embodiment, the method includes administering a composition containing a dsRNA, where the dsRNA has a nucleotide sequence that is complementary to at least a part of an RNA transcript of the MIG12 gene of the mammal to be treated. When the organism to be treated is a mammal such as a human, the composition may be administered by any 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 compositions are administered by intravenous infusion or injection. 
     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 dsRNAs 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 
     dsRNA Synthesis 
     Source of Reagents 
     Where the source of a reagent is not specifically given herein, such reagent may be obtained from any supplier of reagents for molecular biology at a quality/purity standard for application in molecular biology. 
     siRNA Synthesis 
     Single-stranded RNAs were produced by solid phase synthesis on a scale of 1 μmole using an Expedite 8909 synthesizer (Applied Biosystems, Applera Deutschland GmbH, Darmstadt, Germany) and controlled pore glass (CPG, 500 Å, Proligo Biochemie GmbH, Hamburg, Germany) as solid support. RNA and RNA containing 2′-O-methyl nucleotides were generated by solid phase synthesis employing the corresponding phosphoramidites and 2′-O-methyl phosphoramidites, respectively (Proligo Biochemie GmbH, Hamburg, Germany). These building blocks were incorporated at selected sites within the sequence of the oligoribonucleotide chain using standard nucleoside phosphoramidite chemistry such as described in Current protocols in nucleic acid chemistry, Beaucage, S. L. et al. (Edrs.), John Wiley &amp; Sons, Inc., New York, N.Y., USA. Phosphorothioate linkages were introduced by replacement of the iodine oxidizer solution with a solution of the Beaucage reagent (Chruachem Ltd, Glasgow, UK) in acetonitrile (1%). Further ancillary reagents were obtained from Mallinckrodt Baker (Griesheim, Germany). 
     Deprotection and purification of the crude oligoribonucleotides by anion exchange HPLC were carried out according to established procedures. Yields and concentrations were determined by UV absorption of a solution of the respective RNA at a wavelength of 260 nm using a spectral photometer (DU 640B, Beckman Coulter GmbH, Unterschleiβheim, Germany). Double stranded RNA was generated by mixing an equimolar solution of complementary strands in annealing buffer (20 mM sodium phosphate, pH 6.8; 100 mM sodium chloride), heated in a water bath at 85-90° C. for 3 minutes and cooled to room temperature over a period of 3-4 hours. The annealed RNA solution was stored at −20° C. until use. 
     For the synthesis of 3′-cholesterol-conjugated siRNAs (herein referred to as -Chol-3), an appropriately modified solid support is used for RNA synthesis. The modified solid support is prepared as follows: 
     Diethyl-2-azabutane-1,4-dicarboxylate AA 
     
       
         
         
             
             
         
       
     
     A 4.7 M aqueous solution of sodium hydroxide (50 mL) is added into a stirred, ice-cooled solution of ethyl glycinate hydrochloride (32.19 g, 0.23 mole) in water (50 mL). Then, ethyl acrylate (23.1 g, 0.23 mole) is added and the mixture is stirred at room temperature until completion of the reaction is ascertained by TLC. After 19 h the solution is partitioned with dichloromethane (3×100 mL). The organic layer is dried with anhydrous sodium sulfate, filtered and evaporated. The residue is distilled to afford AA (28.8 g, 61%). 
     3-{Ethoxycarbonylmethyl-[6-(9H-fluoren-9-ylmethoxycarbonyl-amino)-hexanoyl]-amino}-propionic acid ethyl ester AB 
     
       
         
         
             
             
         
       
     
     Fmoc-6-amino-hexanoic acid (9.12 g, 25.83 mmol) is dissolved in dichloromethane (50 mL) and cooled with ice. Diisopropylcarbodiimde (3.25 g, 3.99 mL, 25.83 mmol) is added to the solution at 0° C. It is then followed by the addition of Diethyl-azabutane-1,4-dicarboxylate (5 g, 24.6 mmol) and dimethylamino pyridine (0.305 g, 2.5 mmol). The solution is brought to room temperature and stirred further for 6 h. Completion of the reaction is ascertained by TLC. The reaction mixture is concentrated under vacuum and ethyl acetate is added to precipitate diisopropyl urea. The suspension is filtered. The filtrate is washed with 5% aqueous hydrochloric acid, 5% sodium bicarbonate and water. The combined organic layer is dried over sodium sulfate and concentrated to give the crude product which is purified by column chromatography (50% EtOAC/Hexanes) to yield 11.87 g (88%) of AB. 
     3-[(6-Amino-hexanoyl)-ethoxycarbonylmethyl-amino]-propionic acid ethyl ester AC 
     
       
         
         
             
             
         
       
     
     3-{Ethoxycarbonylmethyl-[6-(9H-fluoren-9-ylmethoxycarbonylamino)-hexanoyl]-amino}-propionic acid ethyl ester AB (11.5 g, 21.3 mmol) is dissolved in 20% piperidine in dimethylformamide at 0° C. The solution is continued stirring for 1 h. The reaction mixture is concentrated under vacuum, water is added to the residue, and the product is extracted with ethyl acetate. The crude product is purified by conversion into its hydrochloride salt. 
     3-({6-[17-(1,5-Dimethyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yloxycarbonylamino]-hexanoyl}ethoxycarbonylmethyl-amino)-propionic acid ethyl ester AD 
     
       
         
         
             
             
         
       
     
     The hydrochloride salt of 3-[(6-Amino-hexanoyl)-ethoxycarbonylmethyl-amino]-propionic acid ethyl ester AC (4.7 g, 14.8 mmol) is taken up in dichloromethane. The suspension is cooled to 0° C. on ice. To the suspension diisopropylethylamine (3.87 g, 5.2 mL, 30 mmol) is added. To the resulting solution cholesteryl chloroformate (6.675 g, 14.8 mmol) is added. The reaction mixture is stirred overnight. The reaction mixture is diluted with dichloromethane and washed with 10% hydrochloric acid. The product is purified by flash chromatography (10.3 g, 92%). 
     1-{6-[17-(1,5-Dimethyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yloxycarbonylamino]-hexanoyl}-4-oxo-pyrrolidine-3-carboxylic acid ethyl ester AE 
     
       
         
         
             
             
         
       
     
     Potassium t-but oxide (1.1 g, 9.8 mmol) is slurred in 30 mL of dry toluene. The mixture is cooled to 0° C. on ice and 5 g (6.6 mmol) of diester AD is added slowly with stirring within 20 mins. The temperature is kept below 5° C. during the addition. The stirring is continued for 30 mins at 0° C. and 1 mL of glacial acetic acid is added, immediately followed by 4 g of NaH 2 PO 4 .H 2 O in 40 mL of water The resultant mixture is extracted twice with 100 mL of dichloromethane each and the combined organic extracts are washed twice with 10 mL of phosphate buffer each, dried, and evaporated to dryness. The residue is dissolved in 60 mL of toluene, cooled to 0° C. and extracted with three 50 mL portions of cold pH 9.5 carbonate buffer. The aqueous extracts are adjusted to pH 3 with phosphoric acid, and extracted with five 40 mL portions of chloroform which are combined, dried and evaporated to dryness. The residue is purified by column chromatography using 25% ethylacetate/hexane to afford 1.9 g of b-ketoester (39%). 
     [6-(3-Hydroxy-4-hydroxymethyl-pyrrolidin-1-yl)-6-oxo-hexyl]-carbamic acid 17-(1,5-dimethyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl ester AF 
     
       
         
         
             
             
         
       
     
     Methanol (2 mL) is added dropwise over a period of 1 h to a refluxing mixture of b-ketoester AE (1.5 g, 2.2 mmol) and sodium borohydride (0.226 g, 6 mmol) in tetrahydrofuran (10 mL). Stirring is continued at reflux temperature for 1 h. After cooling to room temperature, 1 N HCl (12.5 mL) is added, the mixture is extracted with ethylacetate (3×40 mL). The combined ethylacetate layer is dried over anhydrous sodium sulfate and concentrated under vacuum to yield the product which is purified by column chromatography (10% MeOH/CHCl 3 ) (89%). 
     (6-{3-[Bis-(4-methoxy-phenyl)-phenyl-methoxymethyl]-4-hydroxy-pyrrolidin-1-yl}-6-oxo-hexyl)-carbamic acid 17-(1,5-dimethyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl ester AG 
     
       
         
         
             
             
         
       
     
     Diol AF (1.25 gm 1.994 mmol) is dried by evaporating with pyridine (2×5 mL) in vacuo. Anhydrous pyridine (10 mL) and 4,4′-dimethoxytritylchloride (0.724 g, 2.13 mmol) are added with stirring. The reaction is carried out at room temperature overnight. The reaction is quenched by the addition of methanol. The reaction mixture is concentrated under vacuum and to the residue dichloromethane (50 mL) is added. The organic layer is washed with 1M aqueous sodium bicarbonate. The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated. The residual pyridine is removed by evaporating with toluene. The crude product is purified by column chromatography (2% MeOH/Chloroform, Rf=0.5 in 5% MeOH/CHCl 3 ) (1.75 g, 95%). 
     Succinic acid mono-(4-[bis-(4-methoxy-phenyl)-phenyl-methoxymethyl]-1-{6-[17-(1,5-dimethyl-hexyl)-10,13-dimethyl2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H cyclopenta[a]phenanthren-3-yloxycarbonylamino]-hexanoyl}-pyrrolidin-3-yl)ester AH 
     
       
         
         
             
             
         
       
     
     Compound AG (1.0 g, 1.05 mmol) is mixed with succinic anhydride (0.150 g, 1.5 mmol) and DMAP (0.073 g, 0.6 mmol) and dried in a vacuum at 40° C. overnight. The mixture is dissolved in anhydrous dichloroethane (3 mL), triethylamine (0.318 g, 0.440 mL, 3.15 mmol) is added and the solution is stirred at room temperature under argon atmosphere for 16 h. It is then diluted with dichloromethane (40 mL) and washed with ice cold aqueous citric acid (5 wt %, 30 mL) and water (2×20 mL). The organic phase is dried over anhydrous sodium sulfate and concentrated to dryness. The residue is used as such for the next step. 
     Cholesterol derivatised CPG AI 
     
       
         
         
             
             
         
       
     
     Succinate AH (0.254 g, 0.242 mmol) is dissolved in a mixture of dichloromethane/acetonitrile (3:2, 3 mL). To that solution DMAP (0.0296 g, 0.242 mmol) in acetonitrile (1.25 mL), 2,2′-Dithio-bis(5-nitropyridine) (0.075 g, 0.242 mmol) in acetonitrile/dichloroethane (3:1, 1.25 mL) are added successively. To the resulting solution triphenylphosphine (0.064 g, 0.242 mmol) in acetonitrile (0.6 ml) is added. The reaction mixture turned bright orange in color. The solution is agitated briefly using a wrist-action shaker (5 mins). Long chain alkyl amine-CPG (LCAA-CPG) (1.5 g, 61 mM) is added. The suspension is agitated for 2 h. The CPG is filtered through a sintered funnel and washed with acetonitrile, dichloromethane and ether successively. Unreacted amino groups are masked using acetic anhydride/pyridine. The achieved loading of the CPG is measured by taking UV measurement (37 mM/g). 
     The synthesis of siRNAs bearing a 5′-12-dodecanoic acid bisdecylamide group (herein referred to as “5′-C32-”) or a 5′-cholesteryl derivative group (herein referred to as “5′-Chol-”) is performed as described in WO 2004/065601, except that, for the cholesteryl derivative, the oxidation step is performed using the Beaucage reagent in order to introduce a phosphorothioate linkage at the 5′-end of the nucleic acid oligomer. 
     Nucleic acid sequences are represented below using standard nomenclature, and specifically 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′-3′-phosphodiester bonds. 
               
            
           
           
               
               
               
            
               
                   
                 Abbreviation 
                 Nucleotide(s) 
               
               
                   
                   
               
               
                   
                 A 
                 adenosine 
               
               
                   
                 C 
                 cytidine 
               
               
                   
                 G 
                 guanosine 
               
               
                   
                 T 
                 thymidine 
               
               
                   
                 U 
                 uridine 
               
               
                   
                 N 
                 any nucleotide (G, A, C, T or U) 
               
               
                   
                 a 
                 2′-O-methyladenosine 
               
               
                   
                 c 
                 2′-O-methylcytidine 
               
               
                   
                 g 
                 2′-O-methylguanosine 
               
               
                   
                 u 
                 2′-O-methyluridine 
               
               
                   
                 dT 
                 2′-deoxythymidine 
               
               
                   
                 s 
                 phosphorothioate linkage 
               
               
                   
                   
               
            
           
         
       
     
     Example 2 
     MIG12 siRNA Design 
     Transcripts 
     siRNAs targeting MIG-12 were designed and synthesized. The design used transcript NM — 001098791.1 (SEQ ID NO:1299,  FIG. 1 ) from the NCBI Refseq collection. 
     siRNA duplexes were designed with 100% identity to the MIG12 gene. 
     A total of 140 sense and 140 antisense human MIG12 derived siRNA oligos were synthesized and formed into duplexes. The oligos are presented in Tables 2, 3 and 4 (human MIG12). 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Sense and antisense strand sequences of human MIG12 dsRNAs 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 position of 5′ 
                   
                   
                   
                   
               
               
                   
                 base on 
                   
                   
                   
                   
               
               
                 Strand ID 
                 transcript 
                   
                   
                   
                   
               
               
                 (S = sense; 
                 (NM_001098791.1, 
                   
                 SEQ 
                 Sequence with 3′ dinucleotide  
                 SEQ 
               
               
                 AS = antisense) 
                 SEQ ID NO: 1299) 
                 Sequence (5′ to 3′) 
                 ID NO: 
                 overhang (5′ to 3′) 
                 ID NO: 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 S 
                 355 
                 AUGGCGUUAAAGAGCGAGU 
                 1 
                 AUGGCGUUAAAGAGCGAGUNN 
                 313 
               
               
                   
               
               
                 AS 
                 373 
                 ACUCGCUCUUUAACGCCAU 
                 2 
                 ACUCGCUCUUUAACGCCAUNN 
                 314 
               
               
                   
               
               
                 S 
                 352 
                 GCGUUAAAGAGCGAGUGCU 
                 3 
                 GCGUUAAAGAGCGAGUGCUNN 
                 315 
               
               
                   
               
               
                 AS 
                 370 
                 AGCACUCGCUCUUUAACGC 
                 4 
                 AGCACUCGCUCUUUAACGCNN 
                 316 
               
               
                   
               
               
                 S 
                 1442 
                 UGUGCGCUUAUCACAAUGG 
                 5 
                 UGUGCGCUUAUCACAAUGGNN 
                 317 
               
               
                   
               
               
                 AS 
                 1460 
                 CCAUUGUGAUAAGCGCACA 
                 6 
                 CCAUUGUGAUAAGCGCACANN 
                 318 
               
               
                   
               
               
                 S 
                 1441 
                 GUGCGCUUAUCACAAUGGA 
                 7 
                 GUGCGCUUAUCACAAUGGANN 
                 319 
               
               
                   
               
               
                 AS 
                 1459 
                 UCCAUUGUGAUAAGCGCAC 
                 8 
                 UCCAUUGUGAUAAGCGCACNN 
                 320 
               
               
                   
               
               
                 S 
                 356 
                 CAUGGCGUUAAAGAGCGAG 
                 9 
                 CAUGGCGUUAAAGAGCGAGNN 
                 321 
               
               
                   
               
               
                 AS 
                 374 
                 CUCGCUCUUUAACGCCAUG 
                 10 
                 CUCGCUCUUUAACGCCAUGNN 
                 322 
               
               
                   
               
               
                 S 
                 353 
                 GGCGUUAAAGAGCGAGUGC 
                 11 
                 GGCGUUAAAGAGCGAGUGCNN 
                 323 
               
               
                   
               
               
                 AS 
                 371 
                 GCACUCGCUCUUUAACGCC 
                 12 
                 GCACUCGCUCUUUAACGCCNN 
                 324 
               
               
                   
               
               
                 S 
                 580 
                 AGCACGUAGUGGCUGUACA 
                 13 
                 AGCACGUAGUGGCUGUACANN 
                 325 
               
               
                   
               
               
                 AS 
                 598 
                 UGUACAGCCACUACGUGCU 
                 14 
                 UGUACAGCCACUACGUGCUNN 
                 326 
               
               
                   
               
               
                 S 
                 1440 
                 UGCGCUUAUCACAAUGGAA 
                 15 
                 UGCGCUUAUCACAAUGGAANN 
                 327 
               
               
                   
               
               
                 AS 
                 1458 
                 UUCCAUUGUGAUAAGCGCA 
                 16 
                 UUCCAUUGUGAUAAGCGCANN 
                 328 
               
               
                   
               
               
                 S 
                 367 
                 AUGAAGCGAUUCAUGGCGU 
                 17 
                 AUGAAGCGAUUCAUGGCGUNN 
                 329 
               
               
                   
               
               
                 AS 
                 385 
                 ACGCCAUGAAUCGCUUCAU 
                 18 
                 ACGCCAUGAAUCGCUUCAUNN 
                 330 
               
               
                   
               
               
                 S 
                 368 
                 AAUGAAGCGAUUCAUGGCG 
                 19 
                 AAUGAAGCGAUUCAUGGCGNN 
                 331 
               
               
                   
               
               
                 AS 
                 386 
                 CGCCAUGAAUCGCUUCAUU 
                 20 
                 CGCCAUGAAUCGCUUCAUUNN 
                 332 
               
               
                   
               
               
                 S 
                 1443 
                 UUGUGCGCUUAUCACAAUG 
                 21 
                 UUGUGCGCUUAUCACAAUGNN 
                 333 
               
               
                   
               
               
                 AS 
                 1461 
                 CAUUGUGAUAAGCGCACAA 
                 22 
                 CAUUGUGAUAAGCGCACAANN 
                 334 
               
               
                   
               
               
                 S 
                 357 
                 UCAUGGCGUUAAAGAGCGA 
                 23 
                 UCAUGGCGUUAAAGAGCGANN 
                 335 
               
               
                   
               
               
                 AS 
                 375 
                 UCGCUCUUUAACGCCAUGA 
                 24 
                 UCGCUCUUUAACGCCAUGANN 
                 336 
               
               
                   
               
               
                 S 
                 321 
                 UGUCGCAGAUUUGCAUCAU 
                 25 
                 UGUCGCAGAUUUGCAUCAUNN 
                 337 
               
               
                   
               
               
                 AS 
                 339 
                 AUGAUGCAAAUCUGCGACA 
                 26 
                 AUGAUGCAAAUCUGCGACANN 
                 338 
               
               
                   
               
               
                 S 
                 351 
                 CGUUAAAGAGCGAGUGCUU 
                 27 
                 CGUUAAAGAGCGAGUGCUUNN 
                 339 
               
               
                   
               
               
                 AS 
                 369 
                 AAGCACUCGCUCUUUAACG 
                 28 
                 AAGCACUCGCUCUUUAACGNN 
                 340 
               
               
                   
               
               
                 S 
                 1771 
                 AGAAUAUAGUCUACAUCUG 
                 29 
                 AGAAUAUAGUCUACAUCUGNN 
                 341 
               
               
                   
               
               
                 AS 
                 1789 
                 CAGAUGUAGACUAUAUUCU 
                 30 
                 CAGAUGUAGACUAUAUUCUNN 
                 342 
               
               
                   
               
               
                 S 
                 1773 
                 UUAGAAUAUAGUCUACAUC 
                 31 
                 UUAGAAUAUAGUCUACAUCNN 
                 343 
               
               
                   
               
               
                 AS 
                 1791 
                 GAUGUAGACUAUAUUCUAA 
                 32 
                 GAUGUAGACUAUAUUCUAANN 
                 344 
               
               
                   
               
               
                 S 
                 1501 
                 UACAGUGUAACAGAAAAUC 
                 33 
                 UACAGUGUAACAGAAAAUCNN 
                 345 
               
               
                   
               
               
                 AS 
                 1519 
                 GAUUUUCUGUUACACUGUA 
                 34 
                 GAUUUUCUGUUACACUGUANN 
                 346 
               
               
                   
               
               
                 S 
                 1765 
                 UAGUCUACAUCUGGAUUAA 
                 35 
                 UAGUCUACAUCUGGAUUAANN 
                 347 
               
               
                   
               
               
                 AS 
                 1783 
                 UUAAUCCAGAUGUAGACUA 
                 36 
                 UUAAUCCAGAUGUAGACUANN 
                 348 
               
               
                   
               
               
                 S 
                 478 
                 CUGCCGCCUACCUCCACGC 
                 37 
                 CUGCCGCCUACCUCCACGCNN 
                 349 
               
               
                   
               
               
                 AS 
                 496 
                 GCGUGGAGGUAGGCGGCAG 
                 38 
                 GCGUGGAGGUAGGCGGCAGNN 
                 350 
               
               
                   
               
               
                 S 
                 764 
                 CAGCCCGCGCAGGUGGUAG 
                 39 
                 CAGCCCGCGCAGGUGGUAGNN 
                 351 
               
               
                   
               
               
                 AS 
                 782 
                 CUACCACCUGCGCGGGCUG 
                 40 
                 CUACCACCUGCGCGGGCUGNN 
                 352 
               
               
                   
               
               
                 S 
                 348 
                 UAAAGAGCGAGUGCUUCUG 
                 41 
                 UAAAGAGCGAGUGCUUCUGNN 
                 353 
               
               
                   
               
               
                 AS 
                 366 
                 CAGAAGCACUCGCUCUUUA 
                 42 
                 CAGAAGCACUCGCUCUUUANN 
                 354 
               
               
                   
               
               
                 S 
                 349 
                 UUAAAGAGCGAGUGCUUCU 
                 43 
                 UUAAAGAGCGAGUGCUUCUNN 
                 355 
               
               
                   
               
               
                 AS 
                 367 
                 AGAAGCACUCGCUCUUUAA 
                 44 
                 AGAAGCACUCGCUCUUUAANN 
                 356 
               
               
                   
               
               
                 S 
                 354 
                 UGGCGUUAAAGAGCGAGUG 
                 45 
                 UGGCGUUAAAGAGCGAGUGNN 
                 357 
               
               
                   
               
               
                 AS 
                 372 
                 CACUCGCUCUUUAACGCCA 
                 46 
                 CACUCGCUCUUUAACGCCANN 
                 358 
               
               
                   
               
               
                 S 
                 1772 
                 UAGAAUAUAGUCUACAUCU 
                 47 
                 UAGAAUAUAGUCUACAUCUNN 
                 359 
               
               
                   
               
               
                 AS 
                 1790 
                 AGAUGUAGACUAUAUUCUA 
                 48 
                 AGAUGUAGACUAUAUUCUANN 
                 360 
               
               
                   
               
               
                 S 
                 1357 
                 GAAAUAGUGCAAACAGGAA 
                 49 
                 GAAAUAGUGCAAACAGGAANN 
                 361 
               
               
                   
               
               
                 AS 
                 1375 
                 UUCCUGUUUGCACUAUUUC 
                 50 
                 UUCCUGUUUGCACUAUUUCNN 
                 362 
               
               
                   
               
               
                 S 
                 396 
                 CCGUCUGGUCCAUGUUGUU 
                 51 
                 CCGUCUGGUCCAUGUUGUUNN 
                 363 
               
               
                   
               
               
                 AS 
                 414 
                 AACAACAUGGACCAGACGG 
                 52 
                 AACAACAUGGACCAGACGGNN 
                 364 
               
               
                   
               
               
                 S 
                 358 
                 UUCAUGGCGUUAAAGAGCG 
                 53 
                 UUCAUGGCGUUAAAGAGCGNN 
                 365 
               
               
                   
               
               
                 AS 
                 376 
                 CGCUCUUUAACGCCAUGAA 
                 54 
                 CGCUCUUUAACGCCAUGAANN 
                 366 
               
               
                   
               
               
                 S 
                 350 
                 GUUAAAGAGCGAGUGCUUC 
                 55 
                 GUUAAAGAGCGAGUGCUUCNN 
                 367 
               
               
                   
               
               
                 AS 
                 368 
                 GAAGCACUCGCUCUUUAAC 
                 56 
                 GAAGCACUCGCUCUUUAACNN 
                 368 
               
               
                   
               
               
                 S 
                 832 
                 CCGAUCUCCUGCUUGUAUC 
                 57 
                 CCGAUCUCCUGCUUGUAUCNN 
                 369 
               
               
                   
               
               
                 AS 
                 850 
                 GAUACAAGCAGGAGAUCGG 
                 58 
                 GAUACAAGCAGGAGAUCGGNN 
                 370 
               
               
                   
               
               
                 S 
                 1485 
                 AUCAUUAAUAAAGUAGUAC 
                 59 
                 AUCAUUAAUAAAGUAGUACNN 
                 371 
               
               
                   
               
               
                 AS 
                 1503 
                 GUACUACUUUAUUAAUGAU 
                 60 
                 GUACUACUUUAUUAAUGAUNN 
                 372 
               
               
                   
               
               
                 S 
                 345 
                 AGAGCGAGUGCUUCUGGUU 
                 61 
                 AGAGCGAGUGCUUCUGGUUNN 
                 373 
               
               
                   
               
               
                 AS 
                 363 
                 AACCAGAAGCACUCGCUCU 
                 62 
                 AACCAGAAGCACUCGCUCUNN 
                 374 
               
               
                   
               
               
                 S 
                 833 
                 GCCGAUCUCCUGCUUGUAU 
                 63 
                 GCCGAUCUCCUGCUUGUAUNN 
                 375 
               
               
                   
               
               
                 AS 
                 851 
                 AUACAAGCAGGAGAUCGGC 
                 64 
                 AUACAAGCAGGAGAUCGGCNN 
                 376 
               
               
                   
               
               
                 S 
                 1359 
                 AAGAAAUAGUGCAAACAGG 
                 65 
                 AAGAAAUAGUGCAAACAGGNN 
                 377 
               
               
                   
               
               
                 AS 
                 1377 
                 CCUGUUUGCACUAUUUCUU 
                 66 
                 CCUGUUUGCACUAUUUCUUNN 
                 378 
               
               
                   
               
               
                 S 
                 765 
                 GCAGCCCGCGCAGGUGGUA 
                 67 
                 GCAGCCCGCGCAGGUGGUANN 
                 379 
               
               
                   
               
               
                 AS 
                 783 
                 UACCACCUGCGCGGGCUGC 
                 68 
                 UACCACCUGCGCGGGCUGCNN 
                 380 
               
               
                   
               
               
                 S 
                 479 
                 ACUGCCGCCUACCUCCACG 
                 69 
                 ACUGCCGCCUACCUCCACGNN 
                 381 
               
               
                   
               
               
                 AS 
                 497 
                 CGUGGAGGUAGGCGGCAGU 
                 70 
                 CGUGGAGGUAGGCGGCAGUNN 
                 382 
               
               
                   
               
               
                 S 
                 1358 
                 AGAAAUAGUGCAAACAGGA 
                 71 
                 AGAAAUAGUGCAAACAGGANN 
                 383 
               
               
                   
               
               
                 AS 
                 1376 
                 UCCUGUUUGCACUAUUUCU 
                 72 
                 UCCUGUUUGCACUAUUUCUNN 
                 384 
               
               
                   
               
               
                 S 
                 1483 
                 CAUUAAUAAAGUAGUACCG 
                 73 
                 CAUUAAUAAAGUAGUACCGNN 
                 385 
               
               
                   
               
               
                 AS 
                 1501 
                 CGGUACUACUUUAUUAAUG 
                 74 
                 CGGUACUACUUUAUUAAUGNN 
                 386 
               
               
                   
               
               
                 S 
                 1775 
                 UUUUAGAAUAUAGUCUACA 
                 75 
                 UUUUAGAAUAUAGUCUACANN 
                 387 
               
               
                   
               
               
                 AS 
                 1793 
                 UGUAGACUAUAUUCUAAAA 
                 76 
                 UGUAGACUAUAUUCUAAAANN 
                 388 
               
               
                   
               
               
                 S 
                 858 
                 CGCCUCAGUGGCCCCAAUU 
                 77 
                 CGCCUCAGUGGCCCCAAUUNN 
                 389 
               
               
                   
               
               
                 AS 
                 876 
                 AAUUGGGGCCACUGAGGCG 
                 78 
                 AAUUGGGGCCACUGAGGCGNN 
                 390 
               
               
                   
               
               
                 S 
                 369 
                 CAAUGAAGCGAUUCAUGGC 
                 79 
                 CAAUGAAGCGAUUCAUGGCNN 
                 391 
               
               
                   
               
               
                 AS 
                 387 
                 GCCAUGAAUCGCUUCAUUG 
                 80 
                 GCCAUGAAUCGCUUCAUUGNN 
                 392 
               
               
                   
               
               
                 S 
                 362 
                 GCGAUUCAUGGCGUUAAAG 
                 81 
                 GCGAUUCAUGGCGUUAAAGNN 
                 393 
               
               
                   
               
               
                 AS 
                 380 
                 CUUUAACGCCAUGAAUCGC 
                 82 
                 CUUUAACGCCAUGAAUCGCNN 
                 394 
               
               
                   
               
               
                 S 
                 1770 
                 GAAUAUAGUCUACAUCUGG 
                 83 
                 GAAUAUAGUCUACAUCUGGNN 
                 395 
               
               
                   
               
               
                 AS 
                 1788 
                 CCAGAUGUAGACUAUAUUC 
                 84 
                 CCAGAUGUAGACUAUAUUCNN 
                 396 
               
               
                   
               
               
                 S 
                 1766 
                 AUAGUCUACAUCUGGAUUA 
                 85 
                 AUAGUCUACAUCUGGAUUANN 
                 397 
               
               
                   
               
               
                 AS 
                 1784 
                 UAAUCCAGAUGUAGACUAU 
                 86 
                 UAAUCCAGAUGUAGACUAUNN 
                 398 
               
               
                   
               
               
                 S 
                 395 
                 CGUCUGGUCCAUGUUGUUC 
                 87 
                 CGUCUGGUCCAUGUUGUUCNN 
                 399 
               
               
                   
               
               
                 AS 
                 413 
                 GAACAACAUGGACCAGACG 
                 88 
                 GAACAACAUGGACCAGACGNN 
                 400 
               
               
                   
               
               
                 S 
                 1491 
                 CAGAAAAUCAUUAAUAAAG 
                 89 
                 CAGAAAAUCAUUAAUAAAGNN 
                 401 
               
               
                   
               
               
                 AS 
                 1509 
                 CUUUAUUAAUGAUUUUCUG 
                 90 
                 CUUUAUUAAUGAUUUUCUGNN 
                 402 
               
               
                   
               
               
                 S 
                 370 
                 CCAAUGAAGCGAUUCAUGG 
                 91 
                 CCAAUGAAGCGAUUCAUGGNN 
                 403 
               
               
                   
               
               
                 AS 
                 388 
                 CCAUGAAUCGCUUCAUUGG 
                 92 
                 CCAUGAAUCGCUUCAUUGGNN 
                 404 
               
               
                   
               
               
                 S 
                 576 
                 CGUAGUGGCUGUACAUGUC 
                 93 
                 CGUAGUGGCUGUACAUGUCNN 
                 405 
               
               
                   
               
               
                 AS 
                 594 
                 GACAUGUACAGCCACUACG 
                 94 
                 GACAUGUACAGCCACUACGNN 
                 406 
               
               
                   
               
               
                 S 
                 1484 
                 UCAUUAAUAAAGUAGUACC 
                 95 
                 UCAUUAAUAAAGUAGUACCNN 
                 407 
               
               
                   
               
               
                 AS 
                 1502 
                 GGUACUACUUUAUUAAUGA 
                 96 
                 GGUACUACUUUAUUAAUGANN 
                 408 
               
               
                   
               
               
                 S 
                 1490 
                 AGAAAAUCAUUAAUAAAGU 
                 97 
                 AGAAAAUCAUUAAUAAAGUNN 
                 409 
               
               
                   
               
               
                 AS 
                 1508 
                 ACUUUAUUAAUGAUUUUCU 
                 98 
                 ACUUUAUUAAUGAUUUUCUNN 
                 410 
               
               
                   
               
               
                 S 
                 578 
                 CACGUAGUGGCUGUACAUG 
                 99 
                 CACGUAGUGGCUGUACAUGNN 
                 411 
               
               
                   
               
               
                 AS 
                 596 
                 CAUGUACAGCCACUACGUG 
                 100 
                 CAUGUACAGCCACUACGUGNN 
                 412 
               
               
                   
               
               
                 S 
                 1767 
                 UAUAGUCUACAUCUGGAUU 
                 101 
                 UAUAGUCUACAUCUGGAUUNN 
                 413 
               
               
                   
               
               
                 AS 
                 1785 
                 AAUCCAGAUGUAGACUAUA 
                 102 
                 AAUCCAGAUGUAGACUAUANN 
                 414 
               
               
                   
               
               
                 S 
                 1351 
                 GUGCAAACAGGAAAACUGA 
                 103 
                 GUGCAAACAGGAAAACUGANN 
                 415 
               
               
                   
               
               
                 AS 
                 1369 
                 UCAGUUUUCCUGUUUGCAC 
                 104 
                 UCAGUUUUCCUGUUUGCACNN 
                 416 
               
               
                   
               
               
                 S 
                 408 
                 UGGGCACCAUCACCGUCUG 
                 105 
                 UGGGCACCAUCACCGUCUGNN 
                 417 
               
               
                   
               
               
                 AS 
                 426 
                 CAGACGGUGAUGGUGCCCA 
                 106 
                 CAGACGGUGAUGGUGCCCANN 
                 418 
               
               
                   
               
               
                 S 
                 577 
                 ACGUAGUGGCUGUACAUGU 
                 107 
                 ACGUAGUGGCUGUACAUGUNN 
                 419 
               
               
                   
               
               
                 AS 
                 595 
                 ACAUGUACAGCCACUACGU 
                 108 
                 ACAUGUACAGCCACUACGUNN 
                 420 
               
               
                   
               
               
                 S 
                 1498 
                 AGUGUAACAGAAAAUCAUU 
                 109 
                 AGUGUAACAGAAAAUCAUUNN 
                 421 
               
               
                   
               
               
                 AS 
                 1516 
                 AAUGAUUUUCUGUUACACU 
                 110 
                 AAUGAUUUUCUGUUACACUNN 
                 422 
               
               
                   
               
               
                 S 
                 1437 
                 GCUUAUCACAAUGGAAUCG 
                 111 
                 GCUUAUCACAAUGGAAUCGNN 
                 423 
               
               
                   
               
               
                 AS 
                 1455 
                 CGAUUCCAUUGUGAUAAGC 
                 112 
                 CGAUUCCAUUGUGAUAAGCNN 
                 424 
               
               
                   
               
               
                 S 
                 347 
                 AAAGAGCGAGUGCUUCUGG 
                 113 
                 AAAGAGCGAGUGCUUCUGGNN 
                 425 
               
               
                   
               
               
                 AS 
                 365 
                 CCAGAAGCACUCGCUCUUU 
                 114 
                 CCAGAAGCACUCGCUCUUUNN 
                 426 
               
               
                   
               
               
                 S 
                 1438 
                 CGCUUAUCACAAUGGAAUC 
                 115 
                 CGCUUAUCACAAUGGAAUCNN 
                 427 
               
               
                   
               
               
                 AS 
                 1456 
                 GAUUCCAUUGUGAUAAGCG 
                 116 
                 GAUUCCAUUGUGAUAAGCGNN 
                 428 
               
               
                   
               
               
                 S 
                 346 
                 AAGAGCGAGUGCUUCUGGU 
                 117 
                 AAGAGCGAGUGCUUCUGGUNN 
                 429 
               
               
                   
               
               
                 AS 
                 364 
                 ACCAGAAGCACUCGCUCUU 
                 118 
                 ACCAGAAGCACUCGCUCUUNN 
                 430 
               
               
                   
               
               
                 S 
                 753 
                 GGUGGUAGUGGAACUGCUG 
                 119 
                 GGUGGUAGUGGAACUGCUGNN 
                 431 
               
               
                   
               
               
                 AS 
                 771 
                 CAGCAGUUCCACUACCACC 
                 120 
                 CAGCAGUUCCACUACCACCNN 
                 432 
               
               
                   
               
               
                 S 
                 361 
                 CGAUUCAUGGCGUUAAAGA 
                 121 
                 CGAUUCAUGGCGUUAAAGANN 
                 433 
               
               
                   
               
               
                 AS 
                 379 
                 UCUUUAACGCCAUGAAUCG 
                 122 
                 UCUUUAACGCCAUGAAUCGNN 
                 434 
               
               
                   
               
               
                 S 
                 360 
                 GAUUCAUGGCGUUAAAGAG 
                 123 
                 GAUUCAUGGCGUUAAAGAGNN 
                 435 
               
               
                   
               
               
                 AS 
                 378 
                 CUCUUUAACGCCAUGAAUC 
                 124 
                 CUCUUUAACGCCAUGAAUCNN 
                 436 
               
               
                   
               
               
                 S 
                 760 
                 CCGCGCAGGUGGUAGUGGA 
                 125 
                 CCGCGCAGGUGGUAGUGGANN 
                 437 
               
               
                   
               
               
                 AS 
                 778 
                 UCCACUACCACCUGCGCGG 
                 126 
                 UCCACUACCACCUGCGCGGNN 
                 438 
               
               
                   
               
               
                 S 
                 1355 
                 AAUAGUGCAAACAGGAAAA 
                 127 
                 AAUAGUGCAAACAGGAAAANN 
                 439 
               
               
                   
               
               
                 AS 
                 1373 
                 UUUUCCUGUUUGCACUAUU 
                 128 
                 UUUUCCUGUUUGCACUAUUNN 
                 440 
               
               
                   
               
               
                 S 
                 1356 
                 AAAUAGUGCAAACAGGAAA 
                 129 
                 AAAUAGUGCAAACAGGAAANN 
                 441 
               
               
                   
               
               
                 AS 
                 1374 
                 UUUCCUGUUUGCACUAUUU 
                 130 
                 UUUCCUGUUUGCACUAUUUNN 
                 442 
               
               
                   
               
               
                 S 
                 1366 
                 UUACAAAAAGAAAUAGUGC 
                 131 
                 UUACAAAAAGAAAUAGUGCNN 
                 443 
               
               
                   
               
               
                 AS 
                 1384 
                 GCACUAUUUCUUUUUGUAA 
                 132 
                 GCACUAUUUCUUUUUGUAANN 
                 444 
               
               
                   
               
               
                 S 
                 574 
                 UAGUGGCUGUACAUGUCCC 
                 133 
                 UAGUGGCUGUACAUGUCCCNN 
                 445 
               
               
                   
               
               
                 AS 
                 592 
                 GGGACAUGUACAGCCACUA 
                 134 
                 GGGACAUGUACAGCCACUANN 
                 446 
               
               
                   
               
               
                 S 
                 1368 
                 UGUUACAAAAAGAAAUAGU 
                 135 
                 UGUUACAAAAAGAAAUAGUNN 
                 447 
               
               
                   
               
               
                 AS 
                 1386 
                 ACUAUUUCUUUUUGUAACA 
                 136 
                 ACUAUUUCUUUUUGUAACANN 
                 448 
               
               
                   
               
               
                 S 
                 575 
                 GUAGUGGCUGUACAUGUCC 
                 137 
                 GUAGUGGCUGUACAUGUCCNN 
                 449 
               
               
                   
               
               
                 AS 
                 593 
                 GGACAUGUACAGCCACUAC 
                 138 
                 GGACAUGUACAGCCACUACNN 
                 450 
               
               
                   
               
               
                 S 
                 1774 
                 UUUAGAAUAUAGUCUACAU 
                 139 
                 UUUAGAAUAUAGUCUACAUNN 
                 451 
               
               
                   
               
               
                 AS 
                 1792 
                 AUGUAGACUAUAUUCUAAA 
                 140 
                 AUGUAGACUAUAUUCUAAANN 
                 452 
               
               
                   
               
               
                 S 
                 763 
                 AGCCCGCGCAGGUGGUAGU 
                 141 
                 AGCCCGCGCAGGUGGUAGUNN 
                 453 
               
               
                   
               
               
                 AS 
                 781 
                 ACUACCACCUGCGCGGGCU 
                 142 
                 ACUACCACCUGCGCGGGCUNN 
                 454 
               
               
                   
               
               
                 S 
                 480 
                 CACUGCCGCCUACCUCCAC 
                 143 
                 CACUGCCGCCUACCUCCACNN 
                 455 
               
               
                   
               
               
                 AS 
                 498 
                 GUGGAGGUAGGCGGCAGUG 
                 144 
                 GUGGAGGUAGGCGGCAGUGNN 
                 456 
               
               
                   
               
               
                 S 
                 1764 
                 AGUCUACAUCUGGAUUAAA 
                 145 
                 AGUCUACAUCUGGAUUAAANN 
                 457 
               
               
                   
               
               
                 AS 
                 1782 
                 UUUAAUCCAGAUGUAGACU 
                 146 
                 UUUAAUCCAGAUGUAGACUNN 
                 458 
               
               
                   
               
               
                 S 
                 758 
                 GCGCAGGUGGUAGUGGAAC 
                 147 
                 GCGCAGGUGGUAGUGGAACNN 
                 459 
               
               
                   
               
               
                 AS 
                 776 
                 GUUCCACUACCACCUGCGC 
                 148 
                 GUUCCACUACCACCUGCGCNN 
                 460 
               
               
                   
               
               
                 S 
                 766 
                 UGCAGCCCGCGCAGGUGGU 
                 149 
                 UGCAGCCCGCGCAGGUGGUNN 
                 461 
               
               
                   
               
               
                 AS 
                 784 
                 ACCACCUGCGCGGGCUGCA 
                 150 
                 ACCACCUGCGCGGGCUGCANN 
                 462 
               
               
                   
               
               
                 S 
                 755 
                 CAGGUGGUAGUGGAACUGC 
                 151 
                 CAGGUGGUAGUGGAACUGCNN 
                 463 
               
               
                   
               
               
                 AS 
                 773 
                 GCAGUUCCACUACCACCUG 
                 152 
                 GCAGUUCCACUACCACCUGNN 
                 464 
               
               
                   
               
               
                 S 
                 407 
                 GGGCACCAUCACCGUCUGG 
                 153 
                 GGGCACCAUCACCGUCUGGNN 
                 465 
               
               
                   
               
               
                 AS 
                 425 
                 CCAGACGGUGAUGGUGCCC 
                 154 
                 CCAGACGGUGAUGGUGCCCNN 
                 466 
               
               
                   
               
               
                 S 
                 1489 
                 GAAAAUCAUUAAUAAAGUA 
                 155 
                 GAAAAUCAUUAAUAAAGUANN 
                 467 
               
               
                   
               
               
                 AS 
                 1507 
                 UACUUUAUUAAUGAUUUUC 
                 156 
                 UACUUUAUUAAUGAUUUUCNN 
                 468 
               
               
                   
               
               
                 S 
                 409 
                 CUGGGCACCAUCACCGUCU 
                 157 
                 CUGGGCACCAUCACCGUCUNN 
                 469 
               
               
                   
               
               
                 AS 
                 427 
                 AGACGGUGAUGGUGCCCAG 
                 158 
                 AGACGGUGAUGGUGCCCAGNN 
                 470 
               
               
                   
               
               
                 S 
                 754 
                 AGGUGGUAGUGGAACUGCU 
                 159 
                 AGGUGGUAGUGGAACUGCUNN 
                 471 
               
               
                   
               
               
                 AS 
                 772 
                 AGCAGUUCCACUACCACCU 
                 160 
                 AGCAGUUCCACUACCACCUNN 
                 472 
               
               
                   
               
               
                 S 
                 404 
                 CACCAUCACCGUCUGGUCC 
                 161 
                 CACCAUCACCGUCUGGUCCNN 
                 473 
               
               
                   
               
               
                 AS 
                 422 
                 GGACCAGACGGUGAUGGUG 
                 162 
                 GGACCAGACGGUGAUGGUGNN 
                 474 
               
               
                   
               
               
                 S 
                 1486 
                 AAUCAUUAAUAAAGUAGUA 
                 163 
                 AAUCAUUAAUAAAGUAGUANN 
                 475 
               
               
                   
               
               
                 AS 
                 1504 
                 UACUACUUUAUUAAUGAUU 
                 164 
                 UACUACUUUAUUAAUGAUUNN 
                 476 
               
               
                   
               
               
                 S 
                 1762 
                 UCUACAUCUGGAUUAAAAA 
                 165 
                 UCUACAUCUGGAUUAAAAANN 
                 477 
               
               
                   
               
               
                 AS 
                 1780 
                 UUUUUAAUCCAGAUGUAGA 
                 166 
                 UUUUUAAUCCAGAUGUAGANN 
                 478 
               
               
                   
               
               
                 S 
                 1361 
                 AAAAGAAAUAGUGCAAACA 
                 167 
                 AAAAGAAAUAGUGCAAACANN 
                 479 
               
               
                   
               
               
                 AS 
                 1379 
                 UGUUUGCACUAUUUCUUUU 
                 168 
                 UGUUUGCACUAUUUCUUUUNN 
                 480 
               
               
                   
               
               
                 S 
                 1492 
                 ACAGAAAAUCAUUAAUAAA 
                 169 
                 ACAGAAAAUCAUUAAUAAANN 
                 481 
               
               
                   
               
               
                 AS 
                 1510 
                 UUUAUUAAUGAUUUUCUGU 
                 170 
                 UUUAUUAAUGAUUUUCUGUNN 
                 482 
               
               
                   
               
               
                 S 
                 759 
                 CGCGCAGGUGGUAGUGGAA 
                 171 
                 CGCGCAGGUGGUAGUGGAANN 
                 483 
               
               
                   
               
               
                 AS 
                 777 
                 UUCCACUACCACCUGCGCG 
                 172 
                 UUCCACUACCACCUGCGCGNN 
                 484 
               
               
                   
               
               
                 S 
                 1439 
                 GCGCUUAUCACAAUGGAAU 
                 173 
                 GCGCUUAUCACAAUGGAAUNN 
                 485 
               
               
                   
               
               
                 AS 
                 1457 
                 AUUCCAUUGUGAUAAGCGC 
                 174 
                 AUUCCAUUGUGAUAAGCGCNN 
                 486 
               
               
                   
               
               
                 S 
                 834 
                 AGCCGAUCUCCUGCUUGUA 
                 175 
                 AGCCGAUCUCCUGCUUGUANN 
                 487 
               
               
                   
               
               
                 AS 
                 852 
                 UACAAGCAGGAGAUCGGCU 
                 176 
                 UACAAGCAGGAGAUCGGCUNN 
                 488 
               
               
                   
               
               
                 S 
                 397 
                 ACCGUCUGGUCCAUGUUGU 
                 177 
                 ACCGUCUGGUCCAUGUUGUNN 
                 489 
               
               
                   
               
               
                 AS 
                 415 
                 ACAACAUGGACCAGACGGU 
                 178 
                 ACAACAUGGACCAGACGGUNN 
                 490 
               
               
                   
               
               
                 S 
                 1496 
                 UGUAACAGAAAAUCAUUAA 
                 179 
                 UGUAACAGAAAAUCAUUAANN 
                 491 
               
               
                   
               
               
                 AS 
                 1514 
                 UUAAUGAUUUUCUGUUACA 
                 180 
                 UUAAUGAUUUUCUGUUACANN 
                 492 
               
               
                   
               
               
                 S 
                 762 
                 GCCCGCGCAGGUGGUAGUG 
                 181 
                 GCCCGCGCAGGUGGUAGUGNN 
                 493 
               
               
                   
               
               
                 AS 
                 780 
                 CACUACCACCUGCGCGGGC 
                 182 
                 CACUACCACCUGCGCGGGCNN 
                 494 
               
               
                   
               
               
                 S 
                 836 
                 GAAGCCGAUCUCCUGCUUG 
                 183 
                 GAAGCCGAUCUCCUGCUUGNN 
                 495 
               
               
                   
               
               
                 AS 
                 854 
                 CAAGCAGGAGAUCGGCUUC 
                 184 
                 CAAGCAGGAGAUCGGCUUCNN 
                 496 
               
               
                   
               
               
                 S 
                 1353 
                 UAGUGCAAACAGGAAAACU 
                 185 
                 UAGUGCAAACAGGAAAACUNN 
                 497 
               
               
                   
               
               
                 AS 
                 1371 
                 AGUUUUCCUGUUUGCACUA 
                 186 
                 AGUUUUCCUGUUUGCACUANN 
                 498 
               
               
                   
               
               
                 S 
                 1497 
                 GUGUAACAGAAAAUCAUUA 
                 187 
                 GUGUAACAGAAAAUCAUUANN 
                 499 
               
               
                   
               
               
                 AS 
                 1515 
                 UAAUGAUUUUCUGUUACAC 
                 188 
                 UAAUGAUUUUCUGUUACACNN 
                 500 
               
               
                   
               
               
                 S 
                 322 
                 GUGUCGCAGAUUUGCAUCA 
                 189 
                 GUGUCGCAGAUUUGCAUCANN 
                 501 
               
               
                   
               
               
                 AS 
                 340 
                 UGAUGCAAAUCUGCGACAC 
                 190 
                 UGAUGCAAAUCUGCGACACNN 
                 502 
               
               
                   
               
               
                 S 
                 359 
                 AUUCAUGGCGUUAAAGAGC 
                 191 
                 AUUCAUGGCGUUAAAGAGCNN 
                 503 
               
               
                   
               
               
                 AS 
                 377 
                 GCUCUUUAACGCCAUGAAU 
                 192 
                 GCUCUUUAACGCCAUGAAUNN 
                 504 
               
               
                   
               
               
                 S 
                 401 
                 CAUCACCGUCUGGUCCAUG 
                 193 
                 CAUCACCGUCUGGUCCAUGNN 
                 505 
               
               
                   
               
               
                 AS 
                 419 
                 CAUGGACCAGACGGUGAUG 
                 194 
                 CAUGGACCAGACGGUGAUGNN 
                 506 
               
               
                   
               
               
                 S 
                 402 
                 CCAUCACCGUCUGGUCCAU 
                 195 
                 CCAUCACCGUCUGGUCCAUNN 
                 507 
               
               
                   
               
               
                 AS 
                 420 
                 AUGGACCAGACGGUGAUGG 
                 196 
                 AUGGACCAGACGGUGAUGGNN 
                 508 
               
               
                   
               
               
                 S 
                 1487 
                 AAAUCAUUAAUAAAGUAGU 
                 197 
                 AAAUCAUUAAUAAAGUAGUNN 
                 509 
               
               
                   
               
               
                 AS 
                 1505 
                 ACUACUUUAUUAAUGAUUU 
                 198 
                 ACUACUUUAUUAAUGAUUUNN 
                 510 
               
               
                   
               
               
                 S 
                 1364 
                 ACAAAAAGAAAUAGUGCAA 
                 199 
                 ACAAAAAGAAAUAGUGCAANN 
                 511 
               
               
                   
               
               
                 AS 
                 1382 
                 UUGCACUAUUUCUUUUUGU 
                 200 
                 UUGCACUAUUUCUUUUUGUNN 
                 512 
               
               
                   
               
               
                 S 
                 835 
                 AAGCCGAUCUCCUGCUUGU 
                 201 
                 AAGCCGAUCUCCUGCUUGUNN 
                 513 
               
               
                   
               
               
                 AS 
                 853 
                 ACAAGCAGGAGAUCGGCUU 
                 202 
                 ACAAGCAGGAGAUCGGCUUNN 
                 514 
               
               
                   
               
               
                 S 
                 1776 
                 UUUUUAGAAUAUAGUCUAC 
                 203 
                 UUUUUAGAAUAUAGUCUACNN 
                 515 
               
               
                   
               
               
                 AS 
                 1794 
                 GUAGACUAUAUUCUAAAAA 
                 204 
                 GUAGACUAUAUUCUAAAAANN 
                 516 
               
               
                   
               
               
                 S 
                 756 
                 GCAGGUGGUAGUGGAACUG 
                 205 
                 GCAGGUGGUAGUGGAACUGNN 
                 517 
               
               
                   
               
               
                 AS 
                 774 
                 CAGUUCCACUACCACCUGC 
                 206 
                 CAGUUCCACUACCACCUGCNN 
                 518 
               
               
                   
               
               
                 S 
                 371 
                 GCCAAUGAAGCGAUUCAUG 
                 207 
                 GCCAAUGAAGCGAUUCAUGNN 
                 519 
               
               
                   
               
               
                 AS 
                 389 
                 CAUGAAUCGCUUCAUUGGC 
                 208 
                 CAUGAAUCGCUUCAUUGGCNN 
                 520 
               
               
                   
               
               
                 S 
                 406 
                 GGCACCAUCACCGUCUGGU 
                 209 
                 GGCACCAUCACCGUCUGGUNN 
                 521 
               
               
                   
               
               
                 AS 
                 424 
                 ACCAGACGGUGAUGGUGCC 
                 210 
                 ACCAGACGGUGAUGGUGCCNN 
                 522 
               
               
                   
               
               
                 S 
                 757 
                 CGCAGGUGGUAGUGGAACU 
                 211 
                 CGCAGGUGGUAGUGGAACUNN 
                 523 
               
               
                   
               
               
                 AS 
                 775 
                 AGUUCCACUACCACCUGCG 
                 212 
                 AGUUCCACUACCACCUGCGNN 
                 524 
               
               
                   
               
               
                 S 
                 1365 
                 UACAAAAAGAAAUAGUGCA 
                 213 
                 UACAAAAAGAAAUAGUGCANN 
                 525 
               
               
                   
               
               
                 AS 
                 1383 
                 UGCACUAUUUCUUUUUGUA 
                 214 
                 UGCACUAUUUCUUUUUGUANN 
                 526 
               
               
                   
               
               
                 S 
                 481 
                 CCACUGCCGCCUACCUCCA 
                 215 
                 CCACUGCCGCCUACCUCCANN 
                 527 
               
               
                   
               
               
                 AS 
                 499 
                 UGGAGGUAGGCGGCAGUGG 
                 216 
                 UGGAGGUAGGCGGCAGUGGNN 
                 528 
               
               
                   
               
               
                 S 
                 1761 
                 CUACAUCUGGAUUAAAAAA 
                 217 
                 CUACAUCUGGAUUAAAAAANN 
                 529 
               
               
                   
               
               
                 AS 
                 1779 
                 UUUUUUAAUCCAGAUGUAG 
                 218 
                 UUUUUUAAUCCAGAUGUAGNN 
                 530 
               
               
                   
               
               
                 S 
                 1777 
                 UUUUUUAGAAUAUAGUCUA 
                 219 
                 UUUUUUAGAAUAUAGUCUANN 
                 531 
               
               
                   
               
               
                 AS 
                 1795 
                 UAGACUAUAUUCUAAAAAA 
                 220 
                 UAGACUAUAUUCUAAAAAANN 
                 532 
               
               
                   
               
               
                 S 
                 1769 
                 AAUAUAGUCUACAUCUGGA 
                 221 
                 AAUAUAGUCUACAUCUGGANN 
                 533 
               
               
                   
               
               
                 AS 
                 1787 
                 UCCAGAUGUAGACUAUAUU 
                 222 
                 UCCAGAUGUAGACUAUAUUNN 
                 534 
               
               
                   
               
               
                 S 
                 398 
                 CACCGUCUGGUCCAUGUUG 
                 223 
                 CACCGUCUGGUCCAUGUUGNN 
                 535 
               
               
                   
               
               
                 AS 
                 416 
                 CAACAUGGACCAGACGGUG 
                 224 
                 CAACAUGGACCAGACGGUGNN 
                 536 
               
               
                   
               
               
                 S 
                 1149 
                 GAAAGGCACAGGCUGAAUG 
                 225 
                 GAAAGGCACAGGCUGAAUGNN 
                 537 
               
               
                   
               
               
                 AS 
                 1167 
                 CAUUCAGCCUGUGCCUUUC 
                 226 
                 CAUUCAGCCUGUGCCUUUCNN 
                 538 
               
               
                   
               
               
                 S 
                 1354 
                 AUAGUGCAAACAGGAAAAC 
                 227 
                 AUAGUGCAAACAGGAAAACNN 
                 539 
               
               
                   
               
               
                 AS 
                 1372 
                 GUUUUCCUGUUUGCACUAU 
                 228 
                 GUUUUCCUGUUUGCACUAUNN 
                 540 
               
               
                   
               
               
                 S 
                 502 
                 GUGCGCUCCUCCAGGCAGC 
                 229 
                 GUGCGCUCCUCCAGGCAGCNN 
                 541 
               
               
                   
               
               
                 AS 
                 520 
                 GCUGCCUGGAGGAGCGCAC 
                 230 
                 GCUGCCUGGAGGAGCGCACNN 
                 542 
               
               
                   
               
               
                 S 
                 831 
                 CGAUCUCCUGCUUGUAUCU 
                 231 
                 CGAUCUCCUGCUUGUAUCUNN 
                 543 
               
               
                   
               
               
                 AS 
                 849 
                 AGAUACAAGCAGGAGAUCG 
                 232 
                 AGAUACAAGCAGGAGAUCGNN 
                 544 
               
               
                   
               
               
                 S 
                 405 
                 GCACCAUCACCGUCUGGUC 
                 233 
                 GCACCAUCACCGUCUGGUCNN 
                 545 
               
               
                   
               
               
                 AS 
                 423 
                 GACCAGACGGUGAUGGUGC 
                 234 
                 GACCAGACGGUGAUGGUGCNN 
                 546 
               
               
                   
               
               
                 S 
                 579 
                 GCACGUAGUGGCUGUACAU 
                 235 
                 GCACGUAGUGGCUGUACAUNN 
                 547 
               
               
                   
               
               
                 AS 
                 597 
                 AUGUACAGCCACUACGUGC 
                 236 
                 AUGUACAGCCACUACGUGCNN 
                 548 
               
               
                   
               
               
                 S 
                 1779 
                 UAUUUUUUAGAAUAUAGUC 
                 237 
                 UAUUUUUUAGAAUAUAGUCNN 
                 549 
               
               
                   
               
               
                 AS 
                 1797 
                 GACUAUAUUCUAAAAAAUA 
                 238 
                 GACUAUAUUCUAAAAAAUANN 
                 550 
               
               
                   
               
               
                 S 
                 1360 
                 AAAGAAAUAGUGCAAACAG 
                 239 
                 AAAGAAAUAGUGCAAACAGNN 
                 551 
               
               
                   
               
               
                 AS 
                 1378 
                 CUGUUUGCACUAUUUCUUU 
                 240 
                 CUGUUUGCACUAUUUCUUUNN 
                 552 
               
               
                   
               
               
                 S 
                 363 
                 AGCGAUUCAUGGCGUUAAA 
                 241 
                 AGCGAUUCAUGGCGUUAAANN 
                 553 
               
               
                   
               
               
                 AS 
                 381 
                 UUUAACGCCAUGAAUCGCU 
                 242 
                 UUUAACGCCAUGAAUCGCUNN 
                 554 
               
               
                   
               
               
                 S 
                 1780 
                 UUAUUUUUUAGAAUAUAGU 
                 243 
                 UUAUUUUUUAGAAUAUAGUNN 
                 555 
               
               
                   
               
               
                 AS 
                 1798 
                 ACUAUAUUCUAAAAAAUAA 
                 244 
                 ACUAUAUUCUAAAAAAUAANN 
                 556 
               
               
                   
               
               
                 S 
                 573 
                 AGUGGCUGUACAUGUCCCG 
                 245 
                 AGUGGCUGUACAUGUCCCGNN 
                 557 
               
               
                   
               
               
                 AS 
                 591 
                 CGGGACAUGUACAGCCACU 
                 246 
                 CGGGACAUGUACAGCCACUNN 
                 558 
               
               
                   
               
               
                 S 
                 364 
                 AAGCGAUUCAUGGCGUUAA 
                 247 
                 AAGCGAUUCAUGGCGUUAANN 
                 559 
               
               
                   
               
               
                 AS 
                 382 
                 UUAACGCCAUGAAUCGCUU 
                 248 
                 UUAACGCCAUGAAUCGCUUNN 
                 560 
               
               
                   
               
               
                 S 
                 372 
                 CGCCAAUGAAGCGAUUCAU 
                 249 
                 CGCCAAUGAAGCGAUUCAUNN 
                 561 
               
               
                   
               
               
                 AS 
                 390 
                 AUGAAUCGCUUCAUUGGCG 
                 250 
                 AUGAAUCGCUUCAUUGGCGNN 
                 562 
               
               
                   
               
               
                 S 
                 1499 
                 CAGUGUAACAGAAAAUCAU 
                 251 
                 CAGUGUAACAGAAAAUCAUNN 
                 563 
               
               
                   
               
               
                 AS 
                 1517 
                 AUGAUUUUCUGUUACACUG 
                 252 
                 AUGAUUUUCUGUUACACUGNN 
                 564 
               
               
                   
               
               
                 S 
                 1768 
                 AUAUAGUCUACAUCUGGAU 
                 253 
                 AUAUAGUCUACAUCUGGAUNN 
                 565 
               
               
                   
               
               
                 AS 
                 1786 
                 AUCCAGAUGUAGACUAUAU 
                 254 
                 AUCCAGAUGUAGACUAUAUNN 
                 566 
               
               
                   
               
               
                 S 
                 482 
                 GCCACUGCCGCCUACCUCC 
                 255 
                 GCCACUGCCGCCUACCUCCNN 
                 567 
               
               
                   
               
               
                 AS 
                 500 
                 GGAGGUAGGCGGCAGUGGC 
                 256 
                 GGAGGUAGGCGGCAGUGGCNN 
                 568 
               
               
                   
               
               
                 S 
                 394 
                 GUCUGGUCCAUGUUGUUCA 
                 257 
                 GUCUGGUCCAUGUUGUUCANN 
                 569 
               
               
                   
               
               
                 AS 
                 412 
                 UGAACAACAUGGACCAGAC 
                 258 
                 UGAACAACAUGGACCAGACNN 
                 570 
               
               
                   
               
               
                 S 
                 1781 
                 UUUAUUUUUUAGAAUAUAG 
                 259 
                 UUUAUUUUUUAGAAUAUAGNN 
                 571 
               
               
                   
               
               
                 AS 
                 1799 
                 CUAUAUUCUAAAAAAUAAA 
                 260 
                 CUAUAUUCUAAAAAAUAAANN 
                 572 
               
               
                   
               
               
                 S 
                 365 
                 GAAGCGAUUCAUGGCGUUA 
                 261 
                 GAAGCGAUUCAUGGCGUUANN 
                 573 
               
               
                   
               
               
                 AS 
                 383 
                 UAACGCCAUGAAUCGCUUC 
                 262 
                 UAACGCCAUGAAUCGCUUCNN 
                 574 
               
               
                   
               
               
                 S 
                 1362 
                 AAAAAGAAAUAGUGCAAAC 
                 263 
                 AAAAAGAAAUAGUGCAAACNN 
                 575 
               
               
                   
               
               
                 AS 
                 1380 
                 GUUUGCACUAUUUCUUUUU 
                 264 
                 GUUUGCACUAUUUCUUUUUNN 
                 576 
               
               
                   
               
               
                 S 
                 503 
                 CGUGCGCUCCUCCAGGCAG 
                 265 
                 CGUGCGCUCCUCCAGGCAGNN 
                 577 
               
               
                   
               
               
                 AS 
                 521 
                 CUGCCUGGAGGAGCGCACG 
                 266 
                 CUGCCUGGAGGAGCGCACGNN 
                 578 
               
               
                   
               
               
                 S 
                 1367 
                 GUUACAAAAAGAAAUAGUG 
                 267 
                 GUUACAAAAAGAAAUAGUGNN 
                 579 
               
               
                   
               
               
                 AS 
                 1385 
                 CACUAUUUCUUUUUGUAAC 
                 268 
                 CACUAUUUCUUUUUGUAACNN 
                 580 
               
               
                   
               
               
                 S 
                 1763 
                 GUCUACAUCUGGAUUAAAA 
                 269 
                 GUCUACAUCUGGAUUAAAANN 
                 581 
               
               
                   
               
               
                 AS 
                 1781 
                 UUUUAAUCCAGAUGUAGAC 
                 270 
                 UUUUAAUCCAGAUGUAGACNN 
                 582 
               
               
                   
               
               
                 S 
                 1778 
                 AUUUUUUAGAAUAUAGUCU 
                 271 
                 AUUUUUUAGAAUAUAGUCUNN 
                 583 
               
               
                   
               
               
                 AS 
                 1796 
                 AGACUAUAUUCUAAAAAAU 
                 272 
                 AGACUAUAUUCUAAAAAAUNN 
                 584 
               
               
                   
               
               
                 S 
                 366 
                 UGAAGCGAUUCAUGGCGUU 
                 273 
                 UGAAGCGAUUCAUGGCGUUNN 
                 585 
               
               
                   
               
               
                 AS 
                 38 
                 AACGCCAUGAAUCGCUUCA 
                 274 
                 AACGCCAUGAAUCGCUUCANN 
                 586 
               
               
                   
               
               
                 S 
                 1352 
                 AGUGCAAACAGGAAAACUG 
                 275 
                 AGUGCAAACAGGAAAACUGNN 
                 587 
               
               
                   
               
               
                 AS 
                 1370 
                 CAGUUUUCCUGUUUGCACU 
                 276 
                 CAGUUUUCCUGUUUGCACUNN 
                 588 
               
               
                   
               
               
                 S 
                 761 
                 CCCGCGCAGGUGGUAGUGG 
                 277 
                 CCCGCGCAGGUGGUAGUGGNN 
                 589 
               
               
                   
               
               
                 AS 
                 779 
                 CCACUACCACCUGCGCGGG 
                 278 
                 CCACUACCACCUGCGCGGGNN 
                 590 
               
               
                   
               
               
                 S 
                 1493 
                 AACAGAAAAUCAUUAAUAA 
                 279 
                 AACAGAAAAUCAUUAAUAANN 
                 591 
               
               
                   
               
               
                 AS 
                 1511 
                 UUAUUAAUGAUUUUCUGUU 
                 280 
                 UUAUUAAUGAUUUUCUGUUNN 
                 592 
               
               
                   
               
               
                 S 
                 399 
                 UCACCGUCUGGUCCAUGUU 
                 281 
                 UCACCGUCUGGUCCAUGUUNN 
                 593 
               
               
                   
               
               
                 AS 
                 417 
                 AACAUGGACCAGACGGUGA 
                 282 
                 AACAUGGACCAGACGGUGANN 
                 594 
               
               
                   
               
               
                 S 
                 400 
                 AUCACCGUCUGGUCCAUGU 
                 283 
                 AUCACCGUCUGGUCCAUGUNN 
                 595 
               
               
                   
               
               
                 AS 
                 418 
                 ACAUGGACCAGACGGUGAU 
                 284 
                 ACAUGGACCAGACGGUGAUNN 
                 596 
               
               
                   
               
               
                 S 
                 393 
                 UCUGGUCCAUGUUGUUCAC 
                 285 
                 UCUGGUCCAUGUUGUUCACNN 
                 597 
               
               
                   
               
               
                 AS 
                 411 
                 GUGAACAACAUGGACCAGA 
                 286 
                 GUGAACAACAUGGACCAGANN 
                 598 
               
               
                   
               
               
                 S 
                 767 
                 GUGCAGCCCGCGCAGGUGG 
                 287 
                 GUGCAGCCCGCGCAGGUGGNN 
                 599 
               
               
                   
               
               
                 AS 
                 785 
                 CCACCUGCGCGGGCUGCAC 
                 288 
                 CCACCUGCGCGGGCUGCACNN 
                 600 
               
               
                   
               
               
                 S 
                 403 
                 ACCAUCACCGUCUGGUCCA 
                 289 
                 ACCAUCACCGUCUGGUCCANN 
                 601 
               
               
                   
               
               
                 AS 
                 421 
                 UGGACCAGACGGUGAUGGU 
                 290 
                 UGGACCAGACGGUGAUGGUNN 
                 602 
               
               
                   
               
               
                 S 
                 768 
                 UGUGCAGCCCGCGCAGGUG 
                 291 
                 UGUGCAGCCCGCGCAGGUGNN 
                 603 
               
               
                   
               
               
                 AS 
                 786 
                 CACCUGCGCGGGCUGCACA 
                 292 
                 CACCUGCGCGGGCUGCACANN 
                 604 
               
               
                   
               
               
                 S 
                 1500 
                 ACAGUGUAACAGAAAAUCA 
                 293 
                 ACAGUGUAACAGAAAAUCANN 
                 605 
               
               
                   
               
               
                 AS 
                 1518 
                 UGAUUUUCUGUUACACUGU 
                 294 
                 UGAUUUUCUGUUACACUGUNN 
                 606 
               
               
                   
               
               
                 S 
                 1495 
                 GUAACAGAAAAUCAUUAAU 
                 295 
                 GUAACAGAAAAUCAUUAAUNN 
                 607 
               
               
                   
               
               
                 AS 
                 1513 
                 AUUAAUGAUUUUCUGUUAC 
                 296 
                 AUUAAUGAUUUUCUGUUACNN 
                 608 
               
               
                   
               
               
                 S 
                 1760 
                 UACAUCUGGAUUAAAAAAA 
                 297 
                 UACAUCUGGAUUAAAAAAANN 
                 609 
               
               
                   
               
               
                 AS 
                 1778 
                 UUUUUUUAAUCCAGAUGUA 
                 298 
                 UUUUUUUAAUCCAGAUGUANN 
                 610 
               
               
                   
               
               
                 S 
                 1782 
                 UUUUAUUUUUUAGAAUAUA 
                 299 
                 UUUUAUUUUUUAGAAUAUANN 
                 611 
               
               
                   
               
               
                 AS 
                 1800 
                 UAUAUUCUAAAAAAUAAAA 
                 300 
                 UAUAUUCUAAAAAAUAAAANN 
                 612 
               
               
                   
               
               
                 S 
                 1488 
                 AAAAUCAUUAAUAAAGUAG 
                 301 
                 AAAAUCAUUAAUAAAGUAGNN 
                 613 
               
               
                   
               
               
                 AS 
                 1506 
                 CUACUUUAUUAAUGAUUUU 
                 302 
                 CUACUUUAUUAAUGAUUUUNN 
                 614 
               
               
                   
               
               
                 S 
                 769 
                 GUGUGCAGCCCGCGCAGGU 
                 303 
                 GUGUGCAGCCCGCGCAGGUNN 
                 615 
               
               
                   
               
               
                 AS 
                 787 
                 ACCUGCGCGGGCUGCACAC 
                 304 
                 ACCUGCGCGGGCUGCACACNN 
                 616 
               
               
                   
               
               
                 S 
                 373 
                 GCGCCAAUGAAGCGAUUCA 
                 305 
                 GCGCCAAUGAAGCGAUUCANN 
                 617 
               
               
                   
               
               
                 AS 
                 391 
                 UGAAUCGCUUCAUUGGCGC 
                 306 
                 UGAAUCGCUUCAUUGGCGCNN 
                 618 
               
               
                   
               
               
                 S 
                 1363 
                 CAAAAAGAAAUAGUGCAAA 
                 307 
                 CAAAAAGAAAUAGUGCAAANN 
                 619 
               
               
                   
               
               
                 AS 
                 1381 
                 UUUGCACUAUUUCUUUUUG 
                 308 
                 UUUGCACUAUUUCUUUUUGNN 
                 620 
               
               
                   
               
               
                 S 
                 1494 
                 UAACAGAAAAUCAUUAAUA 
                 309 
                 UAACAGAAAAUCAUUAAUANN 
                 621 
               
               
                   
               
               
                 AS 
                 1512 
                 UAUUAAUGAUUUUCUGUUA 
                 310 
                 UAUUAAUGAUUUUCUGUUANN 
                 622 
               
               
                   
               
               
                 S 
                 1748 
                 AAAAAAAGUUUUAAAUAAA 
                 311 
                 AAAAAAAGUUUUAAAUAAANN 
                 623 
               
               
                   
               
               
                 AS 
                 1766 
                 UUUAUUUAAAACUUUUUUU 
                 312 
                 UUUAUUUAAAACUUUUUUUNN 
                 624 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 3  
               
             
            
               
                   
               
               
                 Sense and antisense strand sequences of human MIG12 dsRNAs 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 position of  
                   
                   
                   
                   
               
               
                 Strand ID 
                 5′ base on 
                 Sequence with 
                   
                 Sequence with 
                   
               
               
                 (S = sense; 
                 transcript 
                 3′deoxythimidine  
                 SEQ 
                 3′deoxythimidine overhang 
                 SEQ 
               
               
                 AS = anti- 
                 (NM_001098791.1, 
                 overhang (phosphodiester 
                 ID 
                 (phosphorothioate 
                 ID 
               
               
                 sense) 
                 SEQ ID NO: 1299) 
                 linkage) (5′ to 3′) 
                 NO: 
                 linkage)(5′ to 3′) 
                 NO: 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 S 
                 355 
                 AUGGCGUUAAAGAGCGAGUdTdT 
                 625 
                 AUGGCGUUAAAGAGCGAGUdTsdT 
                 937 
               
               
                   
               
               
                 AS 
                 373 
                 ACUCGCUCUUUAACGCCAUdTdT 
                 626 
                 ACUCGCUCUUUAACGCCAUdTsdT 
                 938 
               
               
                   
               
               
                 S 
                 352 
                 GCGUUAAAGAGCGAGUGCUdTdT 
                 627 
                 GCGUUAAAGAGCGAGUGCUdTsdT 
                 939 
               
               
                   
               
               
                 AS 
                 370 
                 AGCACUCGCUCUUUAACGCdTdT 
                 628 
                 AGCACUCGCUCUUUAACGCdTsdT 
                 940 
               
               
                   
               
               
                 S 
                 1442 
                 UGUGCGCUUAUCACAAUGGdTdT 
                 629 
                 UGUGCGCUUAUCACAAUGGdTsdT 
                 941 
               
               
                   
               
               
                 AS 
                 1460 
                 CCAUUGUGAUAAGCGCACAdTdT 
                 630 
                 CCAUUGUGAUAAGCGCACAdTsdT 
                 942 
               
               
                   
               
               
                 S 
                 1441 
                 GUGCGCUUAUCACAAUGGAdTdT 
                 631 
                 GUGCGCUUAUCACAAUGGAdTsdT 
                 943 
               
               
                   
               
               
                 AS 
                 1459 
                 UCCAUUGUGAUAAGCGCACdTdT 
                 632 
                 UCCAUUGUGAUAAGCGCACdTsdT 
                 944 
               
               
                   
               
               
                 S 
                 356 
                 CAUGGCGUUAAAGAGCGAGdTdT 
                 633 
                 CAUGGCGUUAAAGAGCGAGdTsdT 
                 945 
               
               
                   
               
               
                 AS 
                 374 
                 CUCGCUCUUUAACGCCAUGdTdT 
                 634 
                 CUCGCUCUUUAACGCCAUGdTsdT 
                 946 
               
               
                   
               
               
                 S 
                 353 
                 GGCGUUAAAGAGCGAGUGCdTdT 
                 635 
                 GGCGUUAAAGAGCGAGUGCdTsdT 
                 947 
               
               
                   
               
               
                 AS 
                 371 
                 GCACUCGCUCUUUAACGCCdTdT 
                 636 
                 GCACUCGCUCUUUAACGCCdTsdT 
                 948 
               
               
                   
               
               
                 S 
                 580 
                 AGCACGUAGUGGCUGUACAdTdT 
                 637 
                 AGCACGUAGUGGCUGUACAdTsdT 
                 949 
               
               
                   
               
               
                 AS 
                 598 
                 UGUACAGCCACUACGUGCUdTdT 
                 638 
                 UGUACAGCCACUACGUGCUdTsdT 
                 950 
               
               
                   
               
               
                 S 
                 1440 
                 UGCGCUUAUCACAAUGGAAdTdT 
                 639 
                 UGCGCUUAUCACAAUGGAAdTsdT 
                 951 
               
               
                   
               
               
                 AS 
                 1458 
                 UUCCAUUGUGAUAAGCGCAdTdT 
                 640 
                 UUCCAUUGUGAUAAGCGCAdTsdT 
                 952 
               
               
                   
               
               
                 S 
                 367 
                 AUGAAGCGAUUCAUGGCGUdTdT 
                 641 
                 AUGAAGCGAUUCAUGGCGUdTsdT 
                 953 
               
               
                   
               
               
                 AS 
                 385 
                 ACGCCAUGAAUCGCUUCAUdTdT 
                 642 
                 ACGCCAUGAAUCGCUUCAUdTsdT 
                 954 
               
               
                   
               
               
                 S 
                 368 
                 AAUGAAGCGAUUCAUGGCGdTdT 
                 643 
                 AAUGAAGCGAUUCAUGGCGdTsdT 
                 955 
               
               
                   
               
               
                 AS 
                 386 
                 CGCCAUGAAUCGCUUCAUUdTdT 
                 644 
                 CGCCAUGAAUCGCUUCAUUdTsdT 
                 956 
               
               
                   
               
               
                 S 
                 1443 
                 UUGUGCGCUUAUCACAAUGdTdT 
                 645 
                 UUGUGCGCUUAUCACAAUGdTsdT 
                 957 
               
               
                   
               
               
                 AS 
                 1461 
                 CAUUGUGAUAAGCGCACAAdTdT 
                 646 
                 CAUUGUGAUAAGCGCACAAdTsdT 
                 958 
               
               
                   
               
               
                 S 
                 357 
                 UCAUGGCGUUAAAGAGCGAdTdT 
                 647 
                 UCAUGGCGUUAAAGAGCGAdTsdT 
                 959 
               
               
                   
               
               
                 AS 
                 375 
                 UCGCUCUUUAACGCCAUGAdTdT 
                 648 
                 UCGCUCUUUAACGCCAUGAdTsdT 
                 960 
               
               
                   
               
               
                 S 
                 321 
                 UGUCGCAGAUUUGCAUCAUdTdT 
                 649 
                 UGUCGCAGAUUUGCAUCAUdTsdT 
                 961 
               
               
                   
               
               
                 AS 
                 339 
                 AUGAUGCAAAUCUGCGACAdTdT 
                 650 
                 AUGAUGCAAAUCUGCGACAdTsdT 
                 962 
               
               
                   
               
               
                 S 
                 351 
                 CGUUAAAGAGCGAGUGCUUdTdT 
                 651 
                 CGUUAAAGAGCGAGUGCUUdTsdT 
                 963 
               
               
                   
               
               
                 AS 
                 369 
                 AAGCACUCGCUCUUUAACGdTdT 
                 652 
                 AAGCACUCGCUCUUUAACGdTsdT 
                 964 
               
               
                   
               
               
                 S 
                 1771 
                 AGAAUAUAGUCUACAUCUGdTdT 
                 653 
                 AGAAUAUAGUCUACAUCUGdTsdT 
                 965 
               
               
                   
               
               
                 AS 
                 1789 
                 CAGAUGUAGACUAUAUUCUdTdT 
                 654 
                 CAGAUGUAGACUAUAUUCUdTsdT 
                 966 
               
               
                   
               
               
                 S 
                 1773 
                 UUAGAAUAUAGUCUACAUCdTdT 
                 655 
                 UUAGAAUAUAGUCUACAUCdTsdT 
                 967 
               
               
                   
               
               
                 AS 
                 1791 
                 GAUGUAGACUAUAUUCUAAdTdT 
                 656 
                 GAUGUAGACUAUAUUCUAAdTsdT 
                 968 
               
               
                   
               
               
                 S 
                 1501 
                 UACAGUGUAACAGAAAAUCdTdT 
                 657 
                 UACAGUGUAACAGAAAAUCdTsdT 
                 969 
               
               
                   
               
               
                 AS 
                 1519 
                 GAUUUUCUGUUACACUGUAdTdT 
                 658 
                 GAUUUUCUGUUACACUGUAdTsdT 
                 970 
               
               
                   
               
               
                 S 
                 1765 
                 UAGUCUACAUCUGGAUUAAdTdT 
                 659 
                 UAGUCUACAUCUGGAUUAAdTsdT 
                 971 
               
               
                   
               
               
                 AS 
                 1783 
                 UUAAUCCAGAUGUAGACUAdTdT 
                 660 
                 UUAAUCCAGAUGUAGACUAdTsdT 
                 972 
               
               
                   
               
               
                 S 
                 478 
                 CUGCCGCCUACCUCCACGCdTdT 
                 661 
                 CUGCCGCCUACCUCCACGCdTsdT 
                 973 
               
               
                   
               
               
                 AS 
                 496 
                 GCGUGGAGGUAGGCGGCAGdTdT 
                 662 
                 GCGUGGAGGUAGGCGGCAGdTsdT 
                 974 
               
               
                   
               
               
                 S 
                 764 
                 CAGCCCGCGCAGGUGGUAGdTdT 
                 663 
                 CAGCCCGCGCAGGUGGUAGdTsdT 
                 975 
               
               
                   
               
               
                 AS 
                 782 
                 CUACCACCUGCGCGGGCUGdTdT 
                 664 
                 CUACCACCUGCGCGGGCUGdTsdT 
                 976 
               
               
                   
               
               
                 S 
                 348 
                 UAAAGAGCGAGUGCUUCUGdTdT 
                 665 
                 UAAAGAGCGAGUGCUUCUGdTsdT 
                 977 
               
               
                   
               
               
                 AS 
                 366 
                 CAGAAGCACUCGCUCUUUAdTdT 
                 666 
                 CAGAAGCACUCGCUCUUUAdTsdT 
                 978 
               
               
                   
               
               
                 S 
                 349 
                 UUAAAGAGCGAGUGCUUCUdTdT 
                 667 
                 UUAAAGAGCGAGUGCUUCUdTsdT 
                 979 
               
               
                   
               
               
                 AS 
                 367 
                 AGAAGCACUCGCUCUUUAAdTdT 
                 668 
                 AGAAGCACUCGCUCUUUAAdTsdT 
                 980 
               
               
                   
               
               
                 S 
                 354 
                 UGGCGUUAAAGAGCGAGUGdTdT 
                 669 
                 UGGCGUUAAAGAGCGAGUGdTsdT 
                 981 
               
               
                   
               
               
                 AS 
                 372 
                 CACUCGCUCUUUAACGCCAdTdT 
                 670 
                 CACUCGCUCUUUAACGCCAdTsdT 
                 982 
               
               
                   
               
               
                 S 
                 1772 
                 UAGAAUAUAGUCUACAUCUdTdT 
                 671 
                 UAGAAUAUAGUCUACAUCUdTsdT 
                 983 
               
               
                   
               
               
                 AS 
                 1790 
                 AGAUGUAGACUAUAUUCUAdTdT 
                 672 
                 AGAUGUAGACUAUAUUCUAdTsdT 
                 984 
               
               
                   
               
               
                 S 
                 1357 
                 GAAAUAGUGCAAACAGGAAdTdT 
                 673 
                 GAAAUAGUGCAAACAGGAAdTsdT 
                 985 
               
               
                   
               
               
                 AS 
                 1375 
                 UUCCUGUUUGCACUAUUUCdTdT 
                 674 
                 UUCCUGUUUGCACUAUUUCdTsdT 
                 986 
               
               
                   
               
               
                 S 
                 396 
                 CCGUCUGGUCCAUGUUGUUdTdT 
                 675 
                 CCGUCUGGUCCAUGUUGUUdTsdT 
                 987 
               
               
                   
               
               
                 AS 
                 414 
                 AACAACAUGGACCAGACGGdTdT 
                 676 
                 AACAACAUGGACCAGACGGdTsdT 
                 988 
               
               
                   
               
               
                 S 
                 358 
                 UUCAUGGCGUUAAAGAGCGdTdT 
                 677 
                 UUCAUGGCGUUAAAGAGCGdTsdT 
                 989 
               
               
                   
               
               
                 AS 
                 376 
                 CGCUCUUUAACGCCAUGAAdTdT 
                 678 
                 CGCUCUUUAACGCCAUGAAdTsdT 
                 990 
               
               
                   
               
               
                 S 
                 350 
                 GUUAAAGAGCGAGUGCUUCdTdT 
                 679 
                 GUUAAAGAGCGAGUGCUUCdTsdT 
                 991 
               
               
                   
               
               
                 AS 
                 368 
                 GAAGCACUCGCUCUUUAACdTdT 
                 680 
                 GAAGCACUCGCUCUUUAACdTsdT 
                 992 
               
               
                   
               
               
                 S 
                 832 
                 CCGAUCUCCUGCUUGUAUCdTdT 
                 681 
                 CCGAUCUCCUGCUUGUAUCdTsdT 
                 993 
               
               
                   
               
               
                 AS 
                 850 
                 GAUACAAGCAGGAGAUCGGdTdT 
                 682 
                 GAUACAAGCAGGAGAUCGGdTsdT 
                 994 
               
               
                   
               
               
                 S 
                 1485 
                 AUCAUUAAUAAAGUAGUACdTdT 
                 683 
                 AUCAUUAAUAAAGUAGUACdTsdT 
                 995 
               
               
                   
               
               
                 AS 
                 1503 
                 GUACUACUUUAUUAAUGAUdTdT 
                 684 
                 GUACUACUUUAUUAAUGAUdTsdT 
                 996 
               
               
                   
               
               
                 S 
                 345 
                 AGAGCGAGUGCUUCUGGUUdTdT 
                 685 
                 AGAGCGAGUGCUUCUGGUUdTsdT 
                 997 
               
               
                   
               
               
                 AS 
                 363 
                 AACCAGAAGCACUCGCUCUdTdT 
                 686 
                 AACCAGAAGCACUCGCUCUdTsdT 
                 998 
               
               
                   
               
               
                 S 
                 833 
                 GCCGAUCUCCUGCUUGUAUdTdT 
                 687 
                 GCCGAUCUCCUGCUUGUAUdTsdT 
                 999 
               
               
                   
               
               
                 AS 
                 851 
                 AUACAAGCAGGAGAUCGGCdTdT 
                 688 
                 AUACAAGCAGGAGAUCGGCdTsdT 
                 1000 
               
               
                   
               
               
                 S 
                 1359 
                 AAGAAAUAGUGCAAACAGGdTdT 
                 689 
                 AAGAAAUAGUGCAAACAGGdTsdT 
                 1001 
               
               
                   
               
               
                 AS 
                 1377 
                 CCUGUUUGCACUAUUUCUUdTdT 
                 690 
                 CCUGUUUGCACUAUUUCUUdTsdT 
                 1002 
               
               
                   
               
               
                 S 
                 765 
                 GCAGCCCGCGCAGGUGGUAdTdT 
                 691 
                 GCAGCCCGCGCAGGUGGUAdTsdT 
                 1003 
               
               
                   
               
               
                 AS 
                 783 
                 UACCACCUGCGCGGGCUGCdTdT 
                 692 
                 UACCACCUGCGCGGGCUGCdTsdT 
                 1004 
               
               
                   
               
               
                 S 
                 479 
                 ACUGCCGCCUACCUCCACGdTdT 
                 693 
                 ACUGCCGCCUACCUCCACGdTsdT 
                 1005 
               
               
                   
               
               
                 AS 
                 497 
                 CGUGGAGGUAGGCGGCAGUdTdT 
                 694 
                 CGUGGAGGUAGGCGGCAGUdTsdT 
                 1006 
               
               
                   
               
               
                 S 
                 1358 
                 AGAAAUAGUGCAAACAGGAdTdT 
                 695 
                 AGAAAUAGUGCAAACAGGAdTsdT 
                 1007 
               
               
                   
               
               
                 AS 
                 1376 
                 UCCUGUUUGCACUAUUUCUdTdT 
                 696 
                 UCCUGUUUGCACUAUUUCUdTsdT 
                 1008 
               
               
                   
               
               
                 S 
                 1483 
                 CAUUAAUAAAGUAGUACCGdTdT 
                 697 
                 CAUUAAUAAAGUAGUACCGdTsdT 
                 1009 
               
               
                   
               
               
                 AS 
                 1501 
                 CGGUACUACUUUAUUAAUGdTdT 
                 698 
                 CGGUACUACUUUAUUAAUGdTsdT 
                 1010 
               
               
                   
               
               
                 S 
                 1775 
                 UUUUAGAAUAUAGUCUACAdTdT 
                 699 
                 UUUUAGAAUAUAGUCUACAdTsdT 
                 1011 
               
               
                   
               
               
                 AS 
                 1793 
                 UGUAGACUAUAUUCUAAAAdTdT 
                 700 
                 UGUAGACUAUAUUCUAAAAdTsdT 
                 1012 
               
               
                   
               
               
                 S 
                 858 
                 CGCCUCAGUGGCCCCAAUUdTdT 
                 701 
                 CGCCUCAGUGGCCCCAAUUdTsdT 
                 1013 
               
               
                   
               
               
                 AS 
                 876 
                 AAUUGGGGCCACUGAGGCGdTdT 
                 702 
                 AAUUGGGGCCACUGAGGCGdTsdT 
                 1014 
               
               
                   
               
               
                 S 
                 369 
                 CAAUGAAGCGAUUCAUGGCdTdT 
                 703 
                 CAAUGAAGCGAUUCAUGGCdTsdT 
                 1015 
               
               
                   
               
               
                 AS 
                 387 
                 GCCAUGAAUCGCUUCAUUGdTdT 
                 704 
                 GCCAUGAAUCGCUUCAUUGdTsdT 
                 1016 
               
               
                   
               
               
                 S 
                 362 
                 GCGAUUCAUGGCGUUAAAGdTdT 
                 705 
                 GCGAUUCAUGGCGUUAAAGdTsdT 
                 1017 
               
               
                   
               
               
                 AS 
                 380 
                 CUUUAACGCCAUGAAUCGCdTdT 
                 706 
                 CUUUAACGCCAUGAAUCGCdTsdT 
                 1018 
               
               
                   
               
               
                 S 
                 1770 
                 GAAUAUAGUCUACAUCUGGdTdT 
                 707 
                 GAAUAUAGUCUACAUCUGGdTsdT 
                 1019 
               
               
                   
               
               
                 AS 
                 1788 
                 CCAGAUGUAGACUAUAUUCdTdT 
                 708 
                 CCAGAUGUAGACUAUAUUCdTsdT 
                 1020 
               
               
                   
               
               
                 S 
                 1766 
                 AUAGUCUACAUCUGGAUUAdTdT 
                 709 
                 AUAGUCUACAUCUGGAUUAdTsdT 
                 1021 
               
               
                   
               
               
                 AS 
                 1784 
                 UAAUCCAGAUGUAGACUAUdTdT 
                 710 
                 UAAUCCAGAUGUAGACUAUdTsdT 
                 1022 
               
               
                   
               
               
                 S 
                 395 
                 CGUCUGGUCCAUGUUGUUCdTdT 
                 711 
                 CGUCUGGUCCAUGUUGUUCdTsdT 
                 1023 
               
               
                   
               
               
                 AS 
                 413 
                 GAACAACAUGGACCAGACGdTdT 
                 712 
                 GAACAACAUGGACCAGACGdTsdT 
                 1024 
               
               
                   
               
               
                 S 
                 1491 
                 CAGAAAAUCAUUAAUAAAGdTdT 
                 713 
                 CAGAAAAUCAUUAAUAAAGdTsdT 
                 1025 
               
               
                   
               
               
                 AS 
                 1509 
                 CUUUAUUAAUGAUUUUCUGdTdT 
                 714 
                 CUUUAUUAAUGAUUUUCUGdTsdT 
                 1026 
               
               
                   
               
               
                 S 
                 370 
                 CCAAUGAAGCGAUUCAUGGdTdT 
                 715 
                 CCAAUGAAGCGAUUCAUGGdTsdT 
                 1027 
               
               
                   
               
               
                 AS 
                 388 
                 CCAUGAAUCGCUUCAUUGGdTdT 
                 716 
                 CCAUGAAUCGCUUCAUUGGdTsdT 
                 1028 
               
               
                   
               
               
                 S 
                 576 
                 CGUAGUGGCUGUACAUGUCdTdT 
                 717 
                 CGUAGUGGCUGUACAUGUCdTsdT 
                 1029 
               
               
                   
               
               
                 AS 
                 594 
                 GACAUGUACAGCCACUACGdTdT 
                 718 
                 GACAUGUACAGCCACUACGdTsdT 
                 1030 
               
               
                   
               
               
                 S 
                 1484 
                 UCAUUAAUAAAGUAGUACCdTdT 
                 719 
                 UCAUUAAUAAAGUAGUACCdTsdT 
                 1031 
               
               
                   
               
               
                 AS 
                 1502 
                 GGUACUACUUUAUUAAUGAdTdT 
                 720 
                 GGUACUACUUUAUUAAUGAdTsdT 
                 1032 
               
               
                   
               
               
                 S 
                 1490 
                 AGAAAAUCAUUAAUAAAGUdTdT 
                 721 
                 AGAAAAUCAUUAAUAAAGUdTsdT 
                 1033 
               
               
                   
               
               
                 AS 
                 1508 
                 ACUUUAUUAAUGAUUUUCUdTdT 
                 722 
                 ACUUUAUUAAUGAUUUUCUdTsdT 
                 1034 
               
               
                   
               
               
                 S 
                 578 
                 CACGUAGUGGCUGUACAUGdTdT 
                 723 
                 CACGUAGUGGCUGUACAUGdTsdT 
                 1035 
               
               
                   
               
               
                 AS 
                 596 
                 CAUGUACAGCCACUACGUGdTdT 
                 724 
                 CAUGUACAGCCACUACGUGdTsdT 
                 1036 
               
               
                   
               
               
                 S 
                 1767 
                 UAUAGUCUACAUCUGGAUUdTdT 
                 725 
                 UAUAGUCUACAUCUGGAUUdTsdT 
                 1037 
               
               
                   
               
               
                 AS 
                 1785 
                 AAUCCAGAUGUAGACUAUAdTdT 
                 726 
                 AAUCCAGAUGUAGACUAUAdTsdT 
                 1038 
               
               
                   
               
               
                 S 
                 1351 
                 GUGCAAACAGGAAAACUGAdTdT 
                 727 
                 GUGCAAACAGGAAAACUGAdTsdT 
                 1039 
               
               
                   
               
               
                 AS 
                 1369 
                 UCAGUUUUCCUGUUUGCACdTdT 
                 728 
                 UCAGUUUUCCUGUUUGCACdTsdT 
                 1040 
               
               
                   
               
               
                 S 
                 408 
                 UGGGCACCAUCACCGUCUGdTdT 
                 729 
                 UGGGCACCAUCACCGUCUGdTsdT 
                 1041 
               
               
                   
               
               
                 AS 
                 426 
                 CAGACGGUGAUGGUGCCCAdTdT 
                 730 
                 CAGACGGUGAUGGUGCCCAdTsdT 
                 1042 
               
               
                   
               
               
                 S 
                 577 
                 ACGUAGUGGCUGUACAUGUdTdT 
                 731 
                 ACGUAGUGGCUGUACAUGUdTsdT 
                 1043 
               
               
                   
               
               
                 AS 
                 595 
                 ACAUGUACAGCCACUACGUdTdT 
                 732 
                 ACAUGUACAGCCACUACGUdTsdT 
                 1044 
               
               
                   
               
               
                 S 
                 1498 
                 AGUGUAACAGAAAAUCAUUdTdT 
                 733 
                 AGUGUAACAGAAAAUCAUUdTsdT 
                 1045 
               
               
                   
               
               
                 AS 
                 1516 
                 AAUGAUUUUCUGUUACACUdTdT 
                 734 
                 AAUGAUUUUCUGUUACACUdTsdT 
                 1046 
               
               
                   
               
               
                 S 
                 1437 
                 GCUUAUCACAAUGGAAUCGdTdT 
                 735 
                 GCUUAUCACAAUGGAAUCGdTsdT 
                 1047 
               
               
                   
               
               
                 AS 
                 1455 
                 CGAUUCCAUUGUGAUAAGCdTdT 
                 736 
                 CGAUUCCAUUGUGAUAAGCdTsdT 
                 1048 
               
               
                   
               
               
                 S 
                 347 
                 AAAGAGCGAGUGCUUCUGGdTdT 
                 737 
                 AAAGAGCGAGUGCUUCUGGdTsdT 
                 1049 
               
               
                   
               
               
                 AS 
                 365 
                 CCAGAAGCACUCGCUCUUUdTdT 
                 738 
                 CCAGAAGCACUCGCUCUUUdTsdT 
                 1050 
               
               
                   
               
               
                 S 
                 1438 
                 CGCUUAUCACAAUGGAAUCdTdT 
                 739 
                 CGCUUAUCACAAUGGAAUCdTsdT 
                 1051 
               
               
                   
               
               
                 AS 
                 1456 
                 GAUUCCAUUGUGAUAAGCGdTdT 
                 740 
                 GAUUCCAUUGUGAUAAGCGdTsdT 
                 1052 
               
               
                   
               
               
                 S 
                 346 
                 AAGAGCGAGUGCUUCUGGUdTdT 
                 741 
                 AAGAGCGAGUGCUUCUGGUdTsdT 
                 1053 
               
               
                   
               
               
                 AS 
                 364 
                 ACCAGAAGCACUCGCUCUUdTdT 
                 742 
                 ACCAGAAGCACUCGCUCUUdTsdT 
                 1054 
               
               
                   
               
               
                 S 
                 753 
                 GGUGGUAGUGGAACUGCUGdTdT 
                 743 
                 GGUGGUAGUGGAACUGCUGdTsdT 
                 1055 
               
               
                   
               
               
                 AS 
                 771 
                 CAGCAGUUCCACUACCACCdTdT 
                 744 
                 CAGCAGUUCCACUACCACCdTsdT 
                 1056 
               
               
                   
               
               
                 S 
                 361 
                 CGAUUCAUGGCGUUAAAGAdTdT 
                 745 
                 CGAUUCAUGGCGUUAAAGAdTsdT 
                 1057 
               
               
                   
               
               
                 AS 
                 379 
                 UCUUUAACGCCAUGAAUCGdTdT 
                 746 
                 UCUUUAACGCCAUGAAUCGdTsdT 
                 1058 
               
               
                   
               
               
                 S 
                 360 
                 GAUUCAUGGCGUUAAAGAGdTdT 
                 747 
                 GAUUCAUGGCGUUAAAGAGdTsdT 
                 1059 
               
               
                   
               
               
                 AS 
                 378 
                 CUCUUUAACGCCAUGAAUCdTdT 
                 748 
                 CUCUUUAACGCCAUGAAUCdTsdT 
                 1060 
               
               
                   
               
               
                 S 
                 760 
                 CCGCGCAGGUGGUAGUGGAdTdT  
                 749 
                 CCGCGCAGGUGGUAGUGGAdTsdT 
                 1061 
               
               
                   
               
               
                 AS 
                 778 
                 UCCACUACCACCUGCGCGGdTdT  
                 750 
                 UCCACUACCACCUGCGCGGdTsdT 
                 1062 
               
               
                   
               
               
                 S 
                 1355 
                 AAUAGUGCAAACAGGAAAAdTdT  
                 751 
                 AAUAGUGCAAACAGGAAAAdTsdT 
                 1063 
               
               
                   
               
               
                 AS 
                 1373 
                 UUUUCCUGUUUGCACUAUUdTdT  
                 752 
                 UUUUCCUGUUUGCACUAUUdTsdT 
                 1064 
               
               
                   
               
               
                 S 
                 1356 
                 AAAUAGUGCAAACAGGAAAdTdT  
                 753 
                 AAAUAGUGCAAACAGGAAAdTsdT 
                 1065 
               
               
                   
               
               
                 AS 
                 1374 
                 UUUCCUGUUUGCACUAUUUdTdT  
                 754 
                 UUUCCUGUUUGCACUAUUUdTsdT 
                 1066 
               
               
                   
               
               
                 S 
                 1366 
                 UUACAAAAAGAAAUAGUGCdTdT  
                 755 
                 UUACAAAAAGAAAUAGUGCdTsdT 
                 1067 
               
               
                   
               
               
                 AS 
                 1384 
                 GCACUAUUUCUUUUUGUAAdTdT  
                 756 
                 GCACUAUUUCUUUUUGUAAdTsdT 
                 1068 
               
               
                   
               
               
                 S 
                 574 
                 UAGUGGCUGUACAUGUCCCdTdT  
                 757 
                 UAGUGGCUGUACAUGUCCCdTsdT 
                 1069 
               
               
                   
               
               
                 AS 
                 592 
                 GGGACAUGUACAGCCACUAdTdT  
                 758 
                 GGGACAUGUACAGCCACUAdTsdT 
                 1070 
               
               
                   
               
               
                 S 
                 1368 
                 UGUUACAAAAAGAAAUAGUdTdT  
                 759 
                 UGUUACAAAAAGAAAUAGUdTsdT 
                 1071 
               
               
                   
               
               
                 AS 
                 1386 
                 ACUAUUUCUUUUUGUAACAdTdT 
                 760 
                 ACUAUUUCUUUUUGUAACAdTsdT 
                 1072 
               
               
                   
               
               
                 S 
                 575 
                 GUAGUGGCUGUACAUGUCCdTdT 
                 761 
                 GUAGUGGCUGUACAUGUCCdTsdT 
                 1073 
               
               
                   
               
               
                 AS 
                 593 
                 GGACAUGUACAGCCACUACdTdT 
                 762 
                 GGACAUGUACAGCCACUACdTsdT 
                 1074 
               
               
                   
               
               
                 S 
                 1774 
                 UUUAGAAUAUAGUCUACAUdTdT 
                 763 
                 UUUAGAAUAUAGUCUACAUdTsdT 
                 1075 
               
               
                   
               
               
                 AS 
                 1792 
                 AUGUAGACUAUAUUCUAAAdTdT 
                 764 
                 AUGUAGACUAUAUUCUAAAdTsdT 
                 1076 
               
               
                   
               
               
                 S 
                 763 
                 AGCCCGCGCAGGUGGUAGUdTdT 
                 765 
                 AGCCCGCGCAGGUGGUAGUdTsdT 
                 1077 
               
               
                   
               
               
                 AS 
                 781 
                 ACUACCACCUGCGCGGGCUdTdT 
                 766 
                 ACUACCACCUGCGCGGGCUdTsdT 
                 1078 
               
               
                   
               
               
                 S 
                 480 
                 CACUGCCGCCUACCUCCACdTdT 
                 767 
                 CACUGCCGCCUACCUCCACdTsdT 
                 1079 
               
               
                   
               
               
                 AS 
                 498 
                 GUGGAGGUAGGCGGCAGUGdTdT 
                 768 
                 GUGGAGGUAGGCGGCAGUGdTsdT 
                 1080 
               
               
                   
               
               
                 S 
                 1764 
                 AGUCUACAUCUGGAUUAAAdTdT 
                 769 
                 AGUCUACAUCUGGAUUAAAdTsdT 
                 1081 
               
               
                   
               
               
                 AS 
                 1782 
                 UUUAAUCCAGAUGUAGACUdTdT 
                 770 
                 UUUAAUCCAGAUGUAGACUdTsdT 
                 1082 
               
               
                   
               
               
                 S 
                 758 
                 GCGCAGGUGGUAGUGGAACdTdT 
                 771 
                 GCGCAGGUGGUAGUGGAACdTsdT 
                 1083 
               
               
                   
               
               
                 AS 
                 776 
                 GUUCCACUACCACCUGCGCdTdT 
                 772 
                 GUUCCACUACCACCUGCGCdTsdT 
                 1084 
               
               
                   
               
               
                 S 
                 766 
                 UGCAGCCCGCGCAGGUGGUdTdT 
                 773 
                 UGCAGCCCGCGCAGGUGGUdTsdT 
                 1085 
               
               
                   
               
               
                 AS 
                 784 
                 ACCACCUGCGCGGGCUGCAdTdT 
                 774 
                 ACCACCUGCGCGGGCUGCAdTsdT 
                 1086 
               
               
                   
               
               
                 S 
                 755 
                 CAGGUGGUAGUGGAACUGCdTdT 
                 775 
                 CAGGUGGUAGUGGAACUGCdTsdT 
                 1087 
               
               
                   
               
               
                 AS 
                 773 
                 GCAGUUCCACUACCACCUGdTdT 
                 776 
                 GCAGUUCCACUACCACCUGdTsdT 
                 1088 
               
               
                   
               
               
                 S 
                 407 
                 GGGCACCAUCACCGUCUGGdTdT 
                 777 
                 GGGCACCAUCACCGUCUGGdTsdT 
                 1089 
               
               
                   
               
               
                 AS 
                 425 
                 CCAGACGGUGAUGGUGCCCdTdT 
                 778 
                 CCAGACGGUGAUGGUGCCCdTsdT 
                 1090 
               
               
                   
               
               
                 S 
                 1489 
                 GAAAAUCAUUAAUAAAGUAdTdT 
                 779 
                 GAAAAUCAUUAAUAAAGUAdTsdT 
                 1091 
               
               
                   
               
               
                 AS 
                 1507 
                 UACUUUAUUAAUGAUUUUCdTdT 
                 780 
                 UACUUUAUUAAUGAUUUUCdTsdT 
                 1092 
               
               
                   
               
               
                 S 
                 409 
                 CUGGGCACCAUCACCGUCUdTdT 
                 781 
                 CUGGGCACCAUCACCGUCUdTsdT 
                 1093 
               
               
                   
               
               
                 AS 
                 427 
                 AGACGGUGAUGGUGCCCAGdTdT 
                 782 
                 AGACGGUGAUGGUGCCCAGdTsdT 
                 1094 
               
               
                   
               
               
                 S 
                 754 
                 AGGUGGUAGUGGAACUGCUdTdT 
                 783 
                 AGGUGGUAGUGGAACUGCUdTsdT 
                 1095 
               
               
                   
               
               
                 AS 
                 772 
                 AGCAGUUCCACUACCACCUdTdT 
                 784 
                 AGCAGUUCCACUACCACCUdTsdT 
                 1096 
               
               
                   
               
               
                 S 
                 404 
                 CACCAUCACCGUCUGGUCCdTdT 
                 785 
                 CACCAUCACCGUCUGGUCCdTsdT 
                 1097 
               
               
                   
               
               
                 AS 
                 422 
                 GGACCAGACGGUGAUGGUGdTdT 
                 786 
                 GGACCAGACGGUGAUGGUGdTsdT 
                 1098 
               
               
                   
               
               
                 S 
                 1486 
                 AAUCAUUAAUAAAGUAGUAdTdT 
                 787 
                 AAUCAUUAAUAAAGUAGUAdTsdT 
                 1099 
               
               
                   
               
               
                 AS 
                 1504 
                 UACUACUUUAUUAAUGAUUdTdT 
                 788 
                 UACUACUUUAUUAAUGAUUdTsdT 
                 1100 
               
               
                   
               
               
                 S 
                 1762 
                 UCUACAUCUGGAUUAAAAAdTdT 
                 789 
                 UCUACAUCUGGAUUAAAAAdTsdT 
                 1101 
               
               
                   
               
               
                 AS 
                 1780 
                 UUUUUAAUCCAGAUGUAGAdTdT 
                 790 
                 UUUUUAAUCCAGAUGUAGAdTsdT 
                 1102 
               
               
                   
               
               
                 S 
                 1361 
                 AAAAGAAAUAGUGCAAACAdTdT 
                 791 
                 AAAAGAAAUAGUGCAAACAdTsdT 
                 1103 
               
               
                   
               
               
                 AS 
                 1379 
                 UGUUUGCACUAUUUCUUUUdTdT 
                 792 
                 UGUUUGCACUAUUUCUUUUdTsdT 
                 1104 
               
               
                   
               
               
                 S 
                 1492 
                 ACAGAAAAUCAUUAAUAAAdTdT 
                 793 
                 ACAGAAAAUCAUUAAUAAAdTsdT  
                 1105 
               
               
                   
               
               
                 AS 
                 1510 
                 UUUAUUAAUGAUUUUCUGUdTdT 
                 794 
                 UUUAUUAAUGAUUUUCUGUdTsdT  
                 1106 
               
               
                   
               
               
                 S 
                 759 
                 CGCGCAGGUGGUAGUGGAAdTdT 
                 795 
                 CGCGCAGGUGGUAGUGGAAdTsdT  
                 1107 
               
               
                   
               
               
                 AS 
                 777 
                 UUCCACUACCACCUGCGCGdTdT 
                 796 
                 UUCCACUACCACCUGCGCGdTsdT  
                 1108 
               
               
                   
               
               
                 S 
                 1439 
                 GCGCUUAUCACAAUGGAAUdTdT 
                 797 
                 GCGCUUAUCACAAUGGAAUdTsdT  
                 1109 
               
               
                   
               
               
                 AS 
                 1457 
                 AUUCCAUUGUGAUAAGCGCdTdT 
                 798 
                 AUUCCAUUGUGAUAAGCGCdTsdT  
                 1110 
               
               
                   
               
               
                 S 
                 834 
                 AGCCGAUCUCCUGCUUGUAdTdT 
                 799 
                 AGCCGAUCUCCUGCUUGUAdTsdT  
                 1111 
               
               
                   
               
               
                 AS 
                 852 
                 UACAAGCAGGAGAUCGGCUdTdT 
                 800 
                 UACAAGCAGGAGAUCGGCUdTsdT  
                 1112 
               
               
                   
               
               
                 S 
                 397 
                 ACCGUCUGGUCCAUGUUGUdTdT 
                 801 
                 ACCGUCUGGUCCAUGUUGUdTsdT  
                 1113 
               
               
                   
               
               
                 AS 
                 415 
                 ACAACAUGGACCAGACGGUdTdT 
                 802 
                 ACAACAUGGACCAGACGGUdTsdT  
                 1114 
               
               
                   
               
               
                 S 
                 1496 
                 UGUAACAGAAAAUCAUUAAdTdT 
                 803 
                 UGUAACAGAAAAUCAUUAAdTsdT  
                 1115 
               
               
                   
               
               
                 AS 
                 1514 
                 UUAAUGAUUUUCUGUUACAdTdT 
                 804 
                 UUAAUGAUUUUCUGUUACAdTsdT  
                 1116 
               
               
                   
               
               
                 S 
                 762 
                 GCCCGCGCAGGUGGUAGUGdTdT 
                 805 
                 GCCCGCGCAGGUGGUAGUGdTsdT  
                 1117 
               
               
                   
               
               
                 AS 
                 780 
                 CACUACCACCUGCGCGGGCdTdT 
                 806 
                 CACUACCACCUGCGCGGGCdTsdT  
                 1118 
               
               
                   
               
               
                 S 
                 836 
                 GAAGCCGAUCUCCUGCUUGdTdT 
                 807 
                 GAAGCCGAUCUCCUGCUUGdTsdT  
                 1119 
               
               
                   
               
               
                 AS 
                 854 
                 CAAGCAGGAGAUCGGCUUCdTdT 
                 808 
                 CAAGCAGGAGAUCGGCUUCdTsdT  
                 1120 
               
               
                   
               
               
                 S 
                 1353 
                 UAGUGCAAACAGGAAAACUdTdT 
                 809 
                 UAGUGCAAACAGGAAAACUdTsdT  
                 1121 
               
               
                   
               
               
                 AS 
                 1371 
                 AGUUUUCCUGUUUGCACUAdTdT 
                 810 
                 AGUUUUCCUGUUUGCACUAdTsdT  
                 1122 
               
               
                   
               
               
                 S 
                 1497 
                 GUGUAACAGAAAAUCAUUAdTdT 
                 811 
                 GUGUAACAGAAAAUCAUUAdTsdT  
                 1123 
               
               
                   
               
               
                 AS 
                 1515 
                 UAAUGAUUUUCUGUUACACdTdT 
                 812 
                 UAAUGAUUUUCUGUUACACdTsdT  
                 1124 
               
               
                   
               
               
                 S 
                 322 
                 GUGUCGCAGAUUUGCAUCAdTdT 
                 813 
                 GUGUCGCAGAUUUGCAUCAdTsdT  
                 1125 
               
               
                   
               
               
                 AS 
                 340 
                 UGAUGCAAAUCUGCGACACdTdT 
                 814 
                 UGAUGCAAAUCUGCGACACdTsdT  
                 1126 
               
               
                   
               
               
                 S 
                 359 
                 AUUCAUGGCGUUAAAGAGCdTdT 
                 815 
                 AUUCAUGGCGUUAAAGAGCdTsdT  
                 1127 
               
               
                   
               
               
                 AS 
                 377 
                 GCUCUUUAACGCCAUGAAUdTdT 
                 816 
                 GCUCUUUAACGCCAUGAAUdTsdT  
                 1128 
               
               
                   
               
               
                 S 
                 401 
                 CAUCACCGUCUGGUCCAUGdTdT 
                 817 
                 CAUCACCGUCUGGUCCAUGdTsdT  
                 1129 
               
               
                   
               
               
                 AS 
                 419 
                 CAUGGACCAGACGGUGAUGdTdT 
                 818 
                 CAUGGACCAGACGGUGAUGdTsdT  
                 1130 
               
               
                   
               
               
                 S 
                 402 
                 CCAUCACCGUCUGGUCCAUdTdT 
                 819 
                 CCAUCACCGUCUGGUCCAUdTsdT  
                 1131 
               
               
                   
               
               
                 AS 
                 420 
                 AUGGACCAGACGGUGAUGGdTdT 
                 820 
                 AUGGACCAGACGGUGAUGGdTsdT  
                 1132 
               
               
                   
               
               
                 S 
                 1487 
                 AAAUCAUUAAUAAAGUAGUdTdT 
                 821 
                 AAAUCAUUAAUAAAGUAGUdTsdT  
                 1133 
               
               
                   
               
               
                 AS 
                 1505 
                 ACUACUUUAUUAAUGAUUUdTdT 
                 822 
                 ACUACUUUAUUAAUGAUUUdTsdT  
                 1134 
               
               
                   
               
               
                 S 
                 1364 
                 ACAAAAAGAAAUAGUGCAAdTdT 
                 823 
                 ACAAAAAGAAAUAGUGCAAdTsdT  
                 1135 
               
               
                   
               
               
                 AS 
                 1382 
                 UUGCACUAUUUCUUUUUGUdTdT 
                 824 
                 UUGCACUAUUUCUUUUUGUdTsdT  
                 1136 
               
               
                   
               
               
                 S 
                 835 
                 AAGCCGAUCUCCUGCUUGUdTdT 
                 825 
                 AAGCCGAUCUCCUGCUUGUdTsdT  
                 1137 
               
               
                   
               
               
                 AS 
                 853 
                 ACAAGCAGGAGAUCGGCUUdTdT 
                 826 
                 ACAAGCAGGAGAUCGGCUUdTsdT  
                 1138 
               
               
                   
               
               
                 S 
                 1776 
                 UUUUUAGAAUAUAGUCUACdTdT 
                 827 
                 UUUUUAGAAUAUAGUCUACdTsdT  
                 1139 
               
               
                   
               
               
                 AS 
                 1794 
                 GUAGACUAUAUUCUAAAAAdTdT 
                 828 
                 GUAGACUAUAUUCUAAAAAdTsdT  
                 1140 
               
               
                   
               
               
                 S 
                 756 
                 GCAGGUGGUAGUGGAACUGdTdT 
                 829 
                 GCAGGUGGUAGUGGAACUGdTsdT  
                 1141 
               
               
                   
               
               
                 AS 
                 774 
                 CAGUUCCACUACCACCUGCdTdT 
                 830 
                 CAGUUCCACUACCACCUGCdTsdT  
                 1142 
               
               
                   
               
               
                 S 
                 371 
                 GCCAAUGAAGCGAUUCAUGdTdT 
                 831 
                 GCCAAUGAAGCGAUUCAUGdTsdT  
                 1143 
               
               
                   
               
               
                 AS 
                 389 
                 CAUGAAUCGCUUCAUUGGCdTdT 
                 832 
                 CAUGAAUCGCUUCAUUGGCdTsdT  
                 1144 
               
               
                   
               
               
                 S 
                 406 
                 GGCACCAUCACCGUCUGGUdTdT 
                 833 
                 GGCACCAUCACCGUCUGGUdTsdT  
                 1145 
               
               
                   
               
               
                 AS 
                 424 
                 ACCAGACGGUGAUGGUGCCdTdT 
                 834 
                 ACCAGACGGUGAUGGUGCCdTsdT  
                 1146 
               
               
                   
               
               
                 S 
                 757 
                 CGCAGGUGGUAGUGGAACUdTdT 
                 835 
                 CGCAGGUGGUAGUGGAACUdTsdT  
                 1147 
               
               
                   
               
               
                 AS 
                 775 
                 AGUUCCACUACCACCUGCGdTdT 
                 836 
                 AGUUCCACUACCACCUGCGdTsdT  
                 1148 
               
               
                   
               
               
                 S 
                 1365 
                 UACAAAAAGAAAUAGUGCAdTdT 
                 837 
                 UACAAAAAGAAAUAGUGCAdTsdT  
                 1149 
               
               
                   
               
               
                 AS 
                 1383 
                 UGCACUAUUUCUUUUUGUAdTdT 
                 838 
                 UGCACUAUUUCUUUUUGUAdTsdT  
                 1150 
               
               
                   
               
               
                 S 
                 481 
                 CCACUGCCGCCUACCUCCAdTdT 
                 839 
                 CCACUGCCGCCUACCUCCAdTsdT  
                 1151 
               
               
                   
               
               
                 AS 
                 499 
                 UGGAGGUAGGCGGCAGUGGdTdT 
                 840 
                 UGGAGGUAGGCGGCAGUGGdTsdT  
                 1152 
               
               
                   
               
               
                 S 
                 1761 
                 CUACAUCUGGAUUAAAAAAdTdT 
                 841 
                 CUACAUCUGGAUUAAAAAAdTsdT  
                 1153 
               
               
                   
               
               
                 AS 
                 1779 
                 UUUUUUAAUCCAGAUGUAGdTdT 
                 842 
                 UUUUUUAAUCCAGAUGUAGdTsdT  
                 1154 
               
               
                   
               
               
                 S 
                 1777 
                 UUUUUUAGAAUAUAGUCUAdTdT 
                 843 
                 UUUUUUAGAAUAUAGUCUAdTsdT  
                 1155 
               
               
                   
               
               
                 AS 
                 1795 
                 UAGACUAUAUUCUAAAAAAdTdT 
                 844 
                 UAGACUAUAUUCUAAAAAAdTsdT  
                 1156 
               
               
                   
               
               
                 S 
                 1769 
                 AAUAUAGUCUACAUCUGGAdTdT 
                 845 
                 AAUAUAGUCUACAUCUGGAdTsdT  
                 1157 
               
               
                   
               
               
                 AS 
                 1787 
                 UCCAGAUGUAGACUAUAUUdTdT 
                 846 
                 UCCAGAUGUAGACUAUAUUdTsdT  
                 1158 
               
               
                   
               
               
                 S 
                 398 
                 CACCGUCUGGUCCAUGUUGdTdT 
                 847 
                 CACCGUCUGGUCCAUGUUGdTsdT  
                 1159 
               
               
                   
               
               
                 AS 
                 416 
                 CAACAUGGACCAGACGGUGdTdT 
                 848 
                 CAACAUGGACCAGACGGUGdTsdT  
                 1160 
               
               
                   
               
               
                 S 
                 1149 
                 GAAAGGCACAGGCUGAAUGdTdT 
                 849 
                 GAAAGGCACAGGCUGAAUGdTsdT  
                 1161 
               
               
                   
               
               
                 AS 
                 1167 
                 CAUUCAGCCUGUGCCUUUCdTdT 
                 850 
                 CAUUCAGCCUGUGCCUUUCdTsdT  
                 1162 
               
               
                   
               
               
                 S 
                 1354 
                 AUAGUGCAAACAGGAAAACdTdT 
                 851 
                 AUAGUGCAAACAGGAAAACdTsdT  
                 1163 
               
               
                   
               
               
                 AS 
                 1372 
                 GUUUUCCUGUUUGCACUAUdTdT 
                 852 
                 GUUUUCCUGUUUGCACUAUdTsdT  
                 1164 
               
               
                   
               
               
                 S 
                 502 
                 GUGCGCUCCUCCAGGCAGCdTdT 
                 853 
                 GUGCGCUCCUCCAGGCAGCdTsdT  
                 1165 
               
               
                   
               
               
                 AS 
                 520 
                 GCUGCCUGGAGGAGCGCACdTdT 
                 854 
                 GCUGCCUGGAGGAGCGCACdTsdT  
                 1166 
               
               
                   
               
               
                 S 
                 831 
                 CGAUCUCCUGCUUGUAUCUdTdT 
                 855 
                 CGAUCUCCUGCUUGUAUCUdTsdT  
                 1167 
               
               
                   
               
               
                 AS 
                 849 
                 AGAUACAAGCAGGAGAUCGdTdT 
                 856 
                 AGAUACAAGCAGGAGAUCGdTsdT  
                 1168 
               
               
                   
               
               
                 S 
                 405 
                 GCACCAUCACCGUCUGGUCdTdT 
                 857 
                 GCACCAUCACCGUCUGGUCdTsdT  
                 1169 
               
               
                   
               
               
                 AS 
                 423 
                 GACCAGACGGUGAUGGUGCdTdT 
                 858 
                 GACCAGACGGUGAUGGUGCdTsdT  
                 1170 
               
               
                   
               
               
                 S 
                 579 
                 GCACGUAGUGGCUGUACAUdTdT 
                 859 
                 GCACGUAGUGGCUGUACAUdTsdT  
                 1171 
               
               
                   
               
               
                 AS 
                 597 
                 AUGUACAGCCACUACGUGCdTdT 
                 860 
                 AUGUACAGCCACUACGUGCdTsdT  
                 1172 
               
               
                   
               
               
                 S 
                 1779 
                 UAUUUUUUAGAAUAUAGUCdTdT 
                 861 
                 UAUUUUUUAGAAUAUAGUCdTsdT  
                 1173 
               
               
                   
               
               
                 AS 
                 1797 
                 GACUAUAUUCUAAAAAAUAdTdT 
                 862 
                 GACUAUAUUCUAAAAAAUAdTsdT  
                 1174 
               
               
                   
               
               
                 S 
                 1360 
                 AAAGAAAUAGUGCAAACAGdTdT 
                 863 
                 AAAGAAAUAGUGCAAACAGdTsdT  
                 1175 
               
               
                   
               
               
                 AS 
                 1378 
                 CUGUUUGCACUAUUUCUUUdTdT 
                 864 
                 CUGUUUGCACUAUUUCUUUdTsdT  
                 1176 
               
               
                   
               
               
                 S 
                 363 
                 AGCGAUUCAUGGCGUUAAAdTdT 
                 865 
                 AGCGAUUCAUGGCGUUAAAdTsdT  
                 1177 
               
               
                   
               
               
                 AS 
                 381 
                 UUUAACGCCAUGAAUCGCUdTdT 
                 866 
                 UUUAACGCCAUGAAUCGCUdTsdT  
                 1178 
               
               
                   
               
               
                 S 
                 1780 
                 UUAUUUUUUAGAAUAUAGUdTdT 
                 867 
                 UUAUUUUUUAGAAUAUAGUdTsdT  
                 1179 
               
               
                   
               
               
                 AS 
                 1798 
                 ACUAUAUUCUAAAAAAUAAdTdT 
                 868 
                 ACUAUAUUCUAAAAAAUAAdTsdT 
                 1180 
               
               
                   
               
               
                 S 
                 573 
                 AGUGGCUGUACAUGUCCCGdTdT 
                 869 
                 AGUGGCUGUACAUGUCCCGdTsdT  
                 1181 
               
               
                   
               
               
                 AS 
                 591 
                 CGGGACAUGUACAGCCACUdTdT 
                 870 
                 CGGGACAUGUACAGCCACUdTsdT  
                 1182 
               
               
                   
               
               
                 S 
                 364 
                 AAGCGAUUCAUGGCGUUAAdTdT 
                 871 
                 AAGCGAUUCAUGGCGUUAAdTsdT  
                 1183 
               
               
                   
               
               
                 AS 
                 382 
                 UUAACGCCAUGAAUCGCUUdTdT 
                 872 
                 UUAACGCCAUGAAUCGCUUdTsdT  
                 1184 
               
               
                   
               
               
                 S 
                 372 
                 CGCCAAUGAAGCGAUUCAUdTdT 
                 873 
                 CGCCAAUGAAGCGAUUCAUdTsdT  
                 1185 
               
               
                   
               
               
                 AS 
                 390 
                 AUGAAUCGCUUCAUUGGCGdTdT 
                 874 
                 AUGAAUCGCUUCAUUGGCGdTsdT  
                 1186 
               
               
                   
               
               
                 S 
                 1499 
                 CAGUGUAACAGAAAAUCAUdTdT 
                 875 
                 CAGUGUAACAGAAAAUCAUdTsdT  
                 1187 
               
               
                   
               
               
                 AS 
                 1517 
                 AUGAUUUUCUGUUACACUGdTdT 
                 876 
                 AUGAUUUUCUGUUACACUGdTsdT  
                 1188 
               
               
                   
               
               
                 S 
                 1768 
                 AUAUAGUCUACAUCUGGAUdTdT 
                 877 
                 AUAUAGUCUACAUCUGGAUdTsdT  
                 1189 
               
               
                   
               
               
                 AS 
                 1786 
                 AUCCAGAUGUAGACUAUAUdTdT 
                 878 
                 AUCCAGAUGUAGACUAUAUdTsdT  
                 1190 
               
               
                   
               
               
                 S 
                 482 
                 GCCACUGCCGCCUACCUCCdTdT 
                 879 
                 GCCACUGCCGCCUACCUCCdTsdT  
                 1191 
               
               
                   
               
               
                 AS 
                 500 
                 GGAGGUAGGCGGCAGUGGCdTdT 
                 880 
                 GGAGGUAGGCGGCAGUGGCdTsdT  
                 1192 
               
               
                   
               
               
                 S 
                 394 
                 GUCUGGUCCAUGUUGUUCAdTdT 
                 881 
                 GUCUGGUCCAUGUUGUUCAdTsdT 
                 1193 
               
               
                   
               
               
                 AS 
                 412 
                 UGAACAACAUGGACCAGACdTdT 
                 882 
                 UGAACAACAUGGACCAGACdTsdT 
                 1194 
               
               
                   
               
               
                 S 
                 1781 
                 UUUAUUUUUUAGAAUAUAGdTdT 
                 883 
                 UUUAUUUUUUAGAAUAUAGdTsdT 
                 1195 
               
               
                   
               
               
                 AS 
                 1799 
                 CUAUAUUCUAAAAAAUAAAdTdT 
                 884 
                 CUAUAUUCUAAAAAAUAAAdTsdT 
                 1196 
               
               
                   
               
               
                 S 
                 365 
                 GAAGCGAUUCAUGGCGUUAdTdT 
                 885 
                 GAAGCGAUUCAUGGCGUUAdTsdT 
                 1197 
               
               
                   
               
               
                 AS 
                 383 
                 UAACGCCAUGAAUCGCUUCdTdT 
                 886 
                 UAACGCCAUGAAUCGCUUCdTsdT 
                 1198 
               
               
                   
               
               
                 S 
                 1362 
                 AAAAAGAAAUAGUGCAAACdTdT 
                 887 
                 AAAAAGAAAUAGUGCAAACdTsdT 
                 1199 
               
               
                   
               
               
                 AS 
                 1380 
                 GUUUGCACUAUUUCUUUUUdTdT 
                 888 
                 GUUUGCACUAUUUCUUUUUdTsdT 
                 1200 
               
               
                   
               
               
                 S 
                 503 
                 CGUGCGCUCCUCCAGGCAGdTdT 
                 889 
                 CGUGCGCUCCUCCAGGCAGdTsdT 
                 1201 
               
               
                   
               
               
                 AS 
                 521 
                 CUGCCUGGAGGAGCGCACGdTdT 
                 890 
                 CUGCCUGGAGGAGCGCACGdTsdT 
                 1202 
               
               
                   
               
               
                 S 
                 1367 
                 GUUACAAAAAGAAAUAGUGdTdT 
                 891 
                 GUUACAAAAAGAAAUAGUGdTsdT 
                 1203 
               
               
                   
               
               
                 AS 
                 1385 
                 CACUAUUUCUUUUUGUAACdTdT 
                 892 
                 CACUAUUUCUUUUUGUAACdTsdT 
                 1204 
               
               
                   
               
               
                 S 
                 1763 
                 GUCUACAUCUGGAUUAAAAdTdT 
                 893 
                 GUCUACAUCUGGAUUAAAAdTsdT 
                 1205 
               
               
                   
               
               
                 AS 
                 1781 
                 UUUUAAUCCAGAUGUAGACdTdT 
                 894 
                 UUUUAAUCCAGAUGUAGACdTsdT 
                 1206 
               
               
                   
               
               
                 S 
                 1778 
                 AUUUUUUAGAAUAUAGUCUdTdT 
                 895 
                 AUUUUUUAGAAUAUAGUCUdTsdT 
                 1207 
               
               
                   
               
               
                 AS 
                 1796 
                 AGACUAUAUUCUAAAAAAUdTdT 
                 896 
                 AGACUAUAUUCUAAAAAAUdTsdT 
                 1208 
               
               
                   
               
               
                 S 
                 366 
                 UGAAGCGAUUCAUGGCGUUdTdT 
                 897 
                 UGAAGCGAUUCAUGGCGUUdTsdT 
                 1209 
               
               
                   
               
               
                 AS 
                 38 
                 AACGCCAUGAAUCGCUUCAdTdT 
                 898 
                 AACGCCAUGAAUCGCUUCAdTsdT 
                 1210 
               
               
                   
               
               
                 S 
                 1352 
                 AGUGCAAACAGGAAAACUGdTdT 
                 899 
                 AGUGCAAACAGGAAAACUGdTsdT 
                 1211 
               
               
                   
               
               
                 AS 
                 1370 
                 CAGUUUUCCUGUUUGCACUdTdT 
                 900 
                 CAGUUUUCCUGUUUGCACUdTsdT 
                 1212 
               
               
                   
               
               
                 S 
                 761 
                 CCCGCGCAGGUGGUAGUGGdTdT 
                 901 
                 CCCGCGCAGGUGGUAGUGGdTsdT 
                 1213 
               
               
                   
               
               
                 AS 
                 779 
                 CCACUACCACCUGCGCGGGdTdT 
                 902 
                 CCACUACCACCUGCGCGGGdTsdT 
                 1214 
               
               
                   
               
               
                 S 
                 1493 
                 AACAGAAAAUCAUUAAUAAdTdT 
                 903 
                 AACAGAAAAUCAUUAAUAAdTsdT 
                 1215 
               
               
                   
               
               
                 AS 
                 1511 
                 UUAUUAAUGAUUUUCUGUUdTdT 
                 904 
                 UUAUUAAUGAUUUUCUGUUdTsdT 
                 1216 
               
               
                   
               
               
                 S 
                 399 
                 UCACCGUCUGGUCCAUGUUdTdT 
                 905 
                 UCACCGUCUGGUCCAUGUUdTsdT 
                 1217 
               
               
                   
               
               
                 AS 
                 417 
                 AACAUGGACCAGACGGUGAdTdT 
                 906 
                 AACAUGGACCAGACGGUGAdTsdT 
                 1218 
               
               
                   
               
               
                 S 
                 400 
                 AUCACCGUCUGGUCCAUGUdTdT 
                 907 
                 AUCACCGUCUGGUCCAUGUdTsdT 
                 1219 
               
               
                   
               
               
                 AS 
                 418 
                 ACAUGGACCAGACGGUGAUdTdT 
                 908 
                 ACAUGGACCAGACGGUGAUdTsdT 
                 1220 
               
               
                   
               
               
                 S 
                 393 
                 UCUGGUCCAUGUUGUUCACdTdT 
                 909 
                 UCUGGUCCAUGUUGUUCACdTsdT 
                 1221 
               
               
                   
               
               
                 AS 
                 411 
                 GUGAACAACAUGGACCAGAdTdT 
                 910 
                 GUGAACAACAUGGACCAGAdTsdT 
                 1222 
               
               
                   
               
               
                 S 
                 767 
                 GUGCAGCCCGCGCAGGUGGdTdT 
                 911 
                 GUGCAGCCCGCGCAGGUGGdTsdT 
                 1223 
               
               
                   
               
               
                 AS 
                 785 
                 CCACCUGCGCGGGCUGCACdTdT 
                 912 
                 CCACCUGCGCGGGCUGCACdTsdT 
                 1224 
               
               
                   
               
               
                 S 
                 403 
                 ACCAUCACCGUCUGGUCCAdTdT 
                 913 
                 ACCAUCACCGUCUGGUCCAdTsdT 
                 1225 
               
               
                   
               
               
                 AS 
                 421 
                 UGGACCAGACGGUGAUGGUdTdT 
                 914 
                 UGGACCAGACGGUGAUGGUdTsdT 
                 1226 
               
               
                   
               
               
                 S 
                 768 
                 UGUGCAGCCCGCGCAGGUGdTdT 
                 915 
                 UGUGCAGCCCGCGCAGGUGdTsdT 
                 1227 
               
               
                   
               
               
                 AS 
                 786 
                 CACCUGCGCGGGCUGCACAdTdT 
                 916 
                 CACCUGCGCGGGCUGCACAdTsdT 
                 1228 
               
               
                   
               
               
                 S 
                 1500 
                 ACAGUGUAACAGAAAAUCAdTdT 
                 917 
                 ACAGUGUAACAGAAAAUCAdTsdT 
                 1229 
               
               
                   
               
               
                 AS 
                 1518 
                 UGAUUUUCUGUUACACUGUdTdT 
                 918 
                 UGAUUUUCUGUUACACUGUdTsdT 
                 1230 
               
               
                   
               
               
                 S 
                 1495 
                 GUAACAGAAAAUCAUUAAUdTdT 
                 919 
                 GUAACAGAAAAUCAUUAAUdTsdT 
                 1231 
               
               
                   
               
               
                 AS 
                 1513 
                 AUUAAUGAUUUUCUGUUACdTdT 
                 920 
                 AUUAAUGAUUUUCUGUUACdTsdT 
                 1232 
               
               
                   
               
               
                 S 
                 1760 
                 UACAUCUGGAUUAAAAAAAdTdT 
                 921 
                 UACAUCUGGAUUAAAAAAAdTsdT 
                 1233 
               
               
                   
               
               
                 AS 
                 1778 
                 UUUUUUUAAUCCAGAUGUAdTdT 
                 922 
                 UUUUUUUAAUCCAGAUGUAdTsdT 
                 1234 
               
               
                   
               
               
                 S 
                 1782 
                 UUUUAUUUUUUAGAAUAUAdTdT 
                 923 
                 UUUUAUUUUUUAGAAUAUAdTsdT 
                 1235 
               
               
                   
               
               
                 AS 
                 1800 
                 UAUAUUCUAAAAAAUAAAAdTdT 
                 924 
                 UAUAUUCUAAAAAAUAAAAdTsdT 
                 1236 
               
               
                   
               
               
                 S 
                 1488 
                 AAAAUCAUUAAUAAAGUAGdTdT  
                 925 
                 AAAAUCAUUAAUAAAGUAGdTsdT 
                 1237 
               
               
                   
               
               
                 AS 
                 1506 
                 CUACUUUAUUAAUGAUUUUdTdT  
                 926 
                 CUACUUUAUUAAUGAUUUUdTsdT 
                 1238 
               
               
                   
               
               
                 S 
                 769 
                 GUGUGCAGCCCGCGCAGGUdTdT  
                 927 
                 GUGUGCAGCCCGCGCAGGUdTsdT 
                 1239 
               
               
                   
               
               
                 AS 
                 787 
                 ACCUGCGCGGGCUGCACACdTdT  
                 928 
                 ACCUGCGCGGGCUGCACACdTsdT 
                 1240 
               
               
                   
               
               
                 S 
                 373 
                 GCGCCAAUGAAGCGAUUCAdTdT  
                 929 
                 GCGCCAAUGAAGCGAUUCAdTsdT 
                 1241 
               
               
                   
               
               
                 AS 
                 391 
                 UGAAUCGCUUCAUUGGCGCdTdT  
                 930 
                 UGAAUCGCUUCAUUGGCGCdTsdT 
                 1242 
               
               
                   
               
               
                 S 
                 1363 
                 CAAAAAGAAAUAGUGCAAAdTdT  
                 931 
                 CAAAAAGAAAUAGUGCAAAdTsdT 
                 1243 
               
               
                   
               
               
                 AS 
                 1381 
                 UUUGCACUAUUUCUUUUUGdTdT  
                 932 
                 UUUGCACUAUUUCUUUUUGdTsdT 
                 1244 
               
               
                   
               
               
                 S 
                 1494 
                 UAACAGAAAAUCAUUAAUAdTdT  
                 933 
                 UAACAGAAAAUCAUUAAUAdTsdT 
                 1245 
               
               
                   
               
               
                 AS 
                 1512 
                 UAUUAAUGAUUUUCUGUUAdTdT  
                 934 
                 UAUUAAUGAUUUUCUGUUAdTsdT 
                 1246 
               
               
                   
               
               
                 S 
                 1748 
                 AAAAAAAGUUUUAAAUAAAdTdT  
                 935 
                 AAAAAAAGUUUUAAAUAAAdTsdT 
                 1247 
               
               
                   
               
               
                 AS 
                 1766 
                 UUUAUUUAAAACUUUUUUUdTdT  
                 936 
                 UUUAUUUAAAACUUUUUUUdTsdT 
                 1248 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 4  
               
             
            
               
                   
               
               
                 Chemically modified sense and antisense strand sequences 
               
               
                 of human MIG12 dsRNAs 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 Position of  
                   
                   
               
               
                 Strand ID 
                   
                 5′ base on 
                   
                   
               
               
                 (S = sense; 
                   
                 transcript 
                   
                 SEQ 
               
               
                 AS = anti- 
                 Oligo 
                 (NM_001098791.1, 
                   
                 ID 
               
               
                 sense) 
                 # 
                 SEQ ID NO: 1299) 
                 Sequence (5′ to 3′) 
                 NO: 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 S 
                 33656 
                 355 
                 AuGGcGuuAAAGAGcGAGudTsdT 
                 1249 
               
               
                   
               
               
                 AS 
                 33657 
                 373 
                 ACUCGCUCUUuAACGCcAUdTsdT 
                 1250 
               
               
                   
               
               
                 S 
                 33658 
                 352 
                 GcGuuAAAGAGcGAGuGcudTsdT 
                 1251 
               
               
                   
               
               
                 AS 
                 33659 
                 370 
                 AGcACUCGCUCUUuAACGCdTsdT 
                 1252 
               
               
                   
               
               
                 S 
                 33660 
                 1442 
                 uGuGcGcuuAucAcAAuGGdTsdT 
                 1253 
               
               
                   
               
               
                 AS 
                 33661 
                 1460 
                 CcAUUGUGAuAAGCGcAcAdTsdT 
                 1254 
               
               
                   
               
               
                 S 
                 33662 
                 1441 
                 GuGcGcuuAucAcAAuGGAdTsdT 
                 1255 
               
               
                   
               
               
                 AS 
                 33663 
                 1459 
                 UCcAUUGUGAuAAGCGcACdTsdT 
                 1256 
               
               
                   
               
               
                 S 
                 33664 
                 356 
                 cAuGGcGuuAAAGAGcGAGdTsdT 
                 1257 
               
               
                   
               
               
                 AS 
                 33665 
                 374 
                 CUCGCUCUUuAACGCcAUGdTsdT 
                 1258 
               
               
                   
               
               
                 S 
                 33666 
                 353 
                 GGcGuuAAAGAGcGAGuGcdTsdT 
                 1259 
               
               
                   
               
               
                 AS 
                 33667 
                 371 
                 GcACUCGCUCUUuAACGCCdTsdT 
                 1260 
               
               
                   
               
               
                 S 
                 33668 
                 580 
                 AGcAcGuAGuGGcuGuAcAdTsdT 
                 1261 
               
               
                   
               
               
                 AS 
                 33669 
                 598 
                 UGuAcAGCcACuACGUGCUdTsdT 
                 1262 
               
               
                   
               
               
                 S 
                 33670 
                 1440 
                 uGcGcuuAucAcAAuGGAAdTsdT 
                 1263 
               
               
                   
               
               
                 AS 
                 33671 
                 1458 
                 UUCcAUUGUGAuAAGCGcAdTsdT 
                 1264 
               
               
                   
               
               
                 S 
                 33672 
                 367 
                 AuGAAGcGAuucAuGGcGudTsdT 
                 1265 
               
               
                   
               
               
                 AS 
                 33673 
                 385 
                 ACGCcAUGAAUCGCUUcAUdTsdT 
                 1266 
               
               
                   
               
               
                 S 
                 33674 
                 368 
                 AAuGAAGcGAuucAuGGcGdTsdT 
                 1267 
               
               
                   
               
               
                 AS 
                 33675 
                 386 
                 CGCcAUGAAUCGCUUcAUUdTsdT 
                 1268 
               
               
                   
               
               
                 S 
                 33676 
                 1443 
                 uuGuGcGcuuAucAcAAuGdTsdT 
                 1269 
               
               
                   
               
               
                 AS 
                 33677 
                 1461 
                 cAUUGUGAuAAGCGcAcAAdTsdT 
                 1270 
               
               
                   
               
               
                 S 
                 33678 
                 357 
                 ucAuGGcGuuAAAGAGcGAdTsdT 
                 1271 
               
               
                   
               
               
                 AS 
                 33679 
                 375 
                 UCGCUCUUuAACGCcAUGAdTsdT 
                 1272 
               
               
                   
               
               
                 S 
                 33680 
                 321 
                 uGucGcAGAuuuGcAucAudTsdT 
                 1273 
               
               
                   
               
               
                 AS 
                 33681 
                 339 
                 AUGAUGcAAAUCUGCGAcAdTsdT 
                 1274 
               
               
                   
               
               
                 S 
                 33682 
                 351 
                 cGuuAAAGAGcGAGuGcuudTsdT 
                 1275 
               
               
                   
               
               
                 AS 
                 33683 
                 369 
                 AAGcACUCGCUCUUuAACGdTsdT 
                 1276 
               
               
                   
               
               
                 S 
                 33684 
                 1771 
                 AGAAuAuAGucuAcAucuGdTsdT 
                 1277 
               
               
                   
               
               
                 AS 
                 33685 
                 1789 
                 cAGAUGuAGACuAuAUUCUdTsdT 
                 1278 
               
               
                   
               
               
                 S 
                 33686 
                 1773 
                 uuAGAAuAuAGucuAcAucdTsdT 
                 1279 
               
               
                   
               
               
                 AS 
                 33687 
                 1791 
                 GAUGuAGACuAuAUUCuAAdTsdT 
                 1280 
               
               
                   
               
               
                 S 
                 33688 
                 1501 
                 uAcAGuGuAAcAGAAAAucdTsdT 
                 1281 
               
               
                   
               
               
                 AS 
                 33689 
                 1519 
                 GAUUUUCUGUuAcACUGuAdTsdT 
                 1282 
               
               
                   
               
               
                 S 
                 33690 
                 1765 
                 uAGucuAcAucuGGAuuAAdTsdT 
                 1283 
               
               
                   
               
               
                 AS 
                 33691 
                 1783 
                 UuAAUCcAGAUGuAGACuAdTsdT 
                 1284 
               
               
                   
               
               
                 S 
                 33692 
                 478 
                 cuGccGccuAccuccAcGcdTsdT 
                 1285 
               
               
                   
               
               
                 AS 
                 33693 
                 496 
                 GCGUGGAGGuAGGCGGcAGdTsdT 
                 1286 
               
               
                   
               
               
                 S 
                 33694 
                 764 
                 cAGcccGcGcAGGuGGuAGdTsdT 
                 1287 
               
               
                   
               
               
                 AS 
                 33695 
                 782 
                 CuACcACCUGCGCGGGCUGdTsdT 
                 1288 
               
               
                   
               
               
                 S 
                 33696 
                 348 
                 uAAAGAGcGAGuGcuucuGdTsdT 
                 1289 
               
               
                   
               
               
                 AS 
                 33697 
                 366 
                 cAGAAGcACUCGCUCUUuAdTsdT 
                 1290 
               
               
                   
               
               
                 S 
                 33698 
                 349 
                 uuAAAGAGcGAGuGcuucudTsdT 
                 1291 
               
               
                   
               
               
                 AS 
                 33699 
                 367 
                 AGAAGcACUCGCUCUUuAAdTsdT 
                 1292 
               
               
                   
               
               
                 S 
                 33700 
                 354 
                 uGGcGuuAAAGAGcGAGuGdTsdT 
                 1293 
               
               
                   
               
               
                 AS 
                 33701 
                 372 
                 cACUCGCUCUUuAACGCcAdTsdT 
                 1294 
               
               
                   
               
               
                 S 
                 33702 
                 1772 
                 uAGAAuAuAGucuAcAucudTsdT 
                 1295 
               
               
                   
               
               
                 AS 
                 33703 
                 1790 
                 AGAUGuAGACuAuAUUCuAdTsdT 
                 1296 
               
               
                   
               
               
                 S 
                 33704 
                 1357 
                 GAAAuAGuGcAAAcAGGAAdTsdT 
                 1297 
               
               
                   
               
               
                 AS 
                 33705 
                 1375 
                 UUCCUGUUUGcACuAUUUCdTsdT 
                 1298 
               
               
                   
               
            
           
         
       
     
     Synthesis of MIG12 Sequences 
     MIG12 sequences were synthesized on MerMade 192 synthesizer at 1 μmol scale. 
     For all the sequences in Table 4, ‘endolight’ chemistry was applied as detailed below. 
     All pyrimidines (cytosine and uridine) in the sense strand were replaced with corresponding 2′-O-Methyl bases (2′O-Methyl C and 2′-O-Methyl U)
         In the antisense strand, pyrimidines adjacent to (towards 5′ position) ribo A nucleoside were replaced with their corresponding 2-O-Methyl nucleosides   A two base dTsdT extension at 3′ end of both sense and anti sense sequences was introduced   The sequence file was converted to a text file to make it compatible for loading in the MerMade 192 synthesis software       

     The synthesis of MIG12 sequences used solid supported oligonucleotide synthesis using phosphoramidite chemistry 
     The synthesis of the above sequences was performed at 1 um scale in 96 well plates. The amidite solutions were prepared at 0.1M concentration and ethyl thio tetrazole (0.6M in Acetonitrile) was used as activator. 
     The synthesized sequences were cleaved and deprotected in 96 well plates, using methylamine in the first step and pyridine.3HF in the second step. The crude sequences thus obtained were precipitated using acetone: ethanol mix and the pellet were re-suspended in 0.5M sodium acetate buffer. Samples from each sequence were analyzed by LC-MS and the resulting mass data confirmed the identity of the sequences. A selected set of samples were also analyzed by IEX chromatography. 
     Next step in the process was purification. All sequences were purified on AKTA explorer purification system using Source 15Q column. A single peak corresponding to the full length sequence was collected in the eluent and was subsequently analyzed for purity by ion exchange chromatography. 
     The purified sequences were desalted on a Sephadex G25 column using AKTA purifier. The desalted MIG12 sequences were analyzed for concentration and purity. The single strands were then submitted for annealing. 
     Example 3 
     A human subject is treated with a dsRNA targeted to the MIG12 gene to inhibit expression of the MIG12 gene to treat a condition. 
     A subject in need of treatment is selected or identified. The subject could have, e.g., Opitz syndrome, or be susceptible to same. The subject could also have levels of Low Density Lipoprotein cholesterol (LDLc) at or above a minimum level, such greater than 130 mg/dL, 150 mg/dL, 200 mg/dL, 300 mg/dL, or 400 mg/dL. The subject can be selected, at least in part, on the basis of needing (as opposed to merely selecting a patient on the grounds of who happens to be in need of) LDL lowering, LDL lowering without lowering of HDL, ApoB lowering, or total cholesterol lowering without HDL lowering. 
     The identification of the subject can occur in a clinical setting, or elsewhere, e.g., in the subject&#39;s home through the subject&#39;s own use of a self-testing kit. 
     At time zero, a suitable first dose of an anti-MIG12 siRNA is administered to the subject. The dsRNA is formulated as described herein. After a period of time following the first dose, e.g., 7 days, 14 days, and 21 days, the subject&#39;s condition is evaluated, e.g., by measuring MIG12 levels or by measuring lowered LDLc levels, wherein said LDLc levels are lowered by at least 10%, e.g., by at least 15%, 20%, 25%, 30%, 40%, 50%, or 60%, or more. In another embodiment, the lowered LDLc level is maintained for at least 5, 10, 20, 30, or 40 days or longer. Other products of the successful siRNA-targeting of MIG12 mRNA can be evaluated, in addition to any other relevant criteria, e.g., an aspect of microtubule structure, function, or stability. The number and strength of doses are adjusted according to the subject&#39;s needs. 
     After treatment, the level of MIG12 siRNA is lowered relative to level existing prior to the treatment, or relative to the level measured in a similarly afflicted but untreated subject. 
     Other embodiments are in the claims.