Rnai modulation of scap and therapeutic uses thereof

Abstract

The invention relates to a double-stranded ribonucleic acid (dsRNA) for inhibiting the expression of a SCAP gene (Human SCAP gene), comprising an antisense strand having a nucleotide sequence which is less that 30 nucleotides in length, generally 19-25 nucleotides in length, and which is substantially complementary to at least a part of a SCAP gene. The invention also relates to a pharmaceutical composition comprising the dsRNA together with a pharmaceutically acceptable carrier; methods for treating diseases caused by Human SCAP expression and the expression of a SCAP gene using the pharmaceutical composition; and methods for inhibiting the expression of a SCAP gene in a cell.

We claim: 
     
         1 . A double-stranded ribonucleic acid (dsRNA) for inhibiting the expression of a SCAP gene in a cell, wherein said dsRNA comprises at least two sequences that are complementary to each other and wherein a sense strand comprises a first sequence and an antisense strand comprises a second sequence comprising a region of complementarity which is substantially complementary to at least a part of a mRNA encoding a SCAP gene, and wherein said region of complementarity is less than 30 nucleotides in length and wherein said dsRNA, upon contact with a cell expressing said SCAP, inhibits expression of said SCAP gene by at least 20%. 
     
     
         2 . The dsRNA of  claim 1 , wherein said SCAP gene is a human SCAP gene, and preferably a  Homo sapiens  SCAP gene. 
     
     
         3 . The dsRNA of  claim 1 , wherein said at least 20% inhibition of expression of a SCAP gene is effected in primary hamster hepatocytes. 
     
     
         4 . The dsRNA of  claim 1 , wherein said first sequence and said second sequence are selected from even and uneven numbers of the group consisting of SEQ ID NO:1-48 respectively. 
     
     
         5 . The dsRNA of  claim 1 , wherein the dsRNA is chosen from the group of AD-9505, AD-9498, AD-9512, AD-9490, AD-9495, AD-9503, AD-9494, AD-9500, AD-9492, AD-9499, AD-9496, AD-9510, AD-9511, AD-9491, AD-9506, AD-9508, AD-9502, AD-9504, AD-9507, AD-9493, AD-9501, AD-9497, AD-9509 and AD-9513. 
     
     
         6 . The dsRNA of  claim 1 , wherein said dsRNA comprises at least one modified nucleotide. 
     
     
         7 . The dsRNA of  claim 6 , wherein said modified nucleotide is chosen from the group of: a 2′-O-methyl modified nucleotide, a nucleotide comprising a 5′-phosphorothioate group, and a terminal nucleotide linked to a cholesteryl derivative or dodecanoic acid bisdecylamide group. 
     
     
         8 . The dsRNA of  claim 6 , wherein said modified nucleotide is 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. 
     
     
         9 . The dsRNA of  claim 6 , wherein said first sequence and said second sequence are selected from even and uneven numbers of the group consisting of SEQ ID NO:1-48 respectively. 
     
     
         10 . A cell comprising the dsRNA of  claim 1 . 
     
     
         11 . A pharmaceutical composition for inhibiting the expression of a SCAP gene in an organism, comprising a dsRNA and a pharmaceutically acceptable carrier, wherein the dsRNA comprises at least two sequences that are complementary to each other and wherein a sense strand comprises a first sequence and an antisense strand comprises a second sequence comprising a region of complementarity which is substantially complementary to at least a part of a mRNA encoding SCAP, and wherein said region of complementarity is less than 30 nucleotides in length and wherein said dsRNA, upon contact with a cell expressing said Human SCAP, inhibits expression of said  Homo sapiens  SCAP gene by at least 20%. 
     
     
         12 . The pharmaceutical composition of  claim 11 , wherein said SCAP gene is a human SCAP gene, and preferably a  Homo sapiens  SCAP gene. 
     
     
         13 . The pharmaceutical composition of  claim 11 , wherein said at least 20% inhibition of expression of a SCAP gene is effected in primary hamster hepatocytes. 
     
     
         14 . The pharmaceutical composition of  claim 11 , wherein said first sequence and said second sequence are selected from even and uneven numbers of the group consisting of SEQ NO:1-48, respectively. 
     
     
         15 . The pharmaceutical composition of  claim 11 , wherein the dsRNA is chosen from the group of AD-9505, AD-9498, AD-9512, AD-9490, AD-9495, AD-9503, AD-9494, AD-9500, AD-9492, AD-9499, AD-9496, AD-9510, AD-9511, AD-9491, AD-9506, AD-9508, AD-9502, AD-9504, AD-9507, AD-9493, AD-9501, AD-9497, AD-9509 and AD-9513. 
     
     
         16 . A method for inhibiting the expression of a SCAP gene in a cell, the method comprising:
 (a) introducing into the cell a double-stranded ribonucleic acid (dsRNA), wherein the dsRNA comprises at least two sequences that are complementary to each other and wherein a sense strand comprises a first sequence and an antisense strand comprises a second sequence comprising a region of complementarity which is substantially complementary to at least a part of a mRNA encoding SCAP, and wherein said region of complementarity is less than 30 nucleotides in length and wherein said dsRNA, upon contact with a cell expressing said SCAP gene, inhibits expression of said SCAP gene by at least 20%; and   (b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of a SCAP gene, thereby inhibiting expression of a SCAP gene in the cell.   
     
     
         17 . The method of  claim 16 , wherein the gene is a human SCAP gene, and preferably a  Homo sapiens  SCAP gene. 
     
     
         18 . A method of treating, preventing or managing pathological processes mediated by SCAP expression comprising administering to a patient in need of such treatment, prevention or management a therapeutically or prophylactically effective amount of a dsRNA, wherein the dsRNA comprises at least two sequences that are complementary to each other and wherein a sense strand comprises a first sequence and an antisense strand comprises a second sequence comprising a region of complementarity which is substantially complementary to at least a part of an mRNA encoding SCAP, and wherein said region of complementarity is less than 30 nucleotides in length and wherein said dsRNA, upon contact with a cell expressing said SCAP gene, inhibits expression of said SCAP gene by at least 20%. 
     
     
         19 . The method of  claim 18 , wherein the patient suffers from non-alcoholic liver disease, fatty liver, hyperlipemia, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia and/or hypertriglyceridemia, atherosclerosis, pancreatitis, non-insulin dependent diabetes mellitus (NIDDM), coronary heart disease, obesity, metabolic syndrome, peripheral arterial disease, and cerebrovascular disease 
     
     
         20 . A vector for inhibiting the expression of a SCAP gene in a cell, said vector comprising a regulatory sequence operably linked to a nucleotide sequence that encodes at least one strand of a dsRNA, wherein one of the strands of said dsRNA is substantially complementary to at least a part of a mRNA encoding SCAP and wherein said dsRNA is less than 30 base pairs in length and wherein said dsRNA, upon contact with a cell expressing said SCAP gene, inhibits the expression of said SCAP gene by at least 20%. 
     
     
         21 . A cell comprising the vector of  claim 20 .