RNAi modulation of SCAP and therapeutic uses thereof
View Patent ↗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.
1. A double-stranded ribonucleic acid (dsRNA), wherein said dsRNA comprises at least two sequences that are complementary to each other and wherein a sense strand comprises 15 or more contiguous bases of SEQ ID NO:17 and an antisense strand comprises 15 or more contiguous bases of SEQ ID NO:18, and wherein said dsRNA is less than 30 nucleotides in length.
2. The dsRNA of claim 1 , wherein said sense strand comprises 16, 17, 18 or 19 contiguous bases of SEQ ID NO:17, and said antisense strand comprises 16, 17, 18 or 19 contiguous bases of SEQ ID NO:18.
3. The dsRNA of claim 1 , wherein at least 20% inhibition of expression of a human SCAP gene is effected.
4. The dsRNA of claim 1 , wherein said said sense strand comprises SEQ ID NO:17 and said antisense strand comprises SEQ ID NO:18.
5. The dsRNA of claim 1 , wherein said sense strand consists of SEQ ID NO:17 and said antisense strand consists of SEQ ID NO:18.
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. A cell comprising the dsRNA of claim 1 .
10. A pharmaceutical composition comprising a double-stranded ribonucleic acid (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 15 or more contiguous bases of SEQ ID NO:17 and an antisense strand comprises 15 or more contiguous bases of SEQ ID NO:18, and wherein said dsRNA is less than 30 nucleotides in length.
11. The pharmaceutical composition of claim 10 , wherein said sense strand comprises 16, 17, 18 or 19 contiguous bases of SEQ ID NO:17, and said antisense strand comprises 16, 17, 18 or 19 contiguous bases of SEQ ID NO:18.
12. The pharmaceutical composition of claim 10 , wherein at least 20% inhibition of expression of a human SCAP gene is effected.
13. The pharmaceutical composition of claim 10 , wherein said said sense strand comprises SEQ ID NO:17 and said antisense strand comprises SEQ ID NO:18.
14. The pharmaceutical composition of claim 10 , wherein said sense strand consists of SEQ ID NO:17 and said antisense strand consists of SEQ ID NO:18.
15. A method for inhibiting the expression of a SCAP gene in a cell in vitro, 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 15 or more contiguous bases of SEQ ID NO:17 and an antisense strand comprises 15 or more contiguous bases of SEQ ID NO:18, and wherein said dsRNA is less than 30 nucleotides in length; 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.
16. The method of claim 15 , wherein the gene is a human SCAP gene, and preferably a Homo sapiens SCAP gene.
17. A vector comprising a regulatory sequence operably linked to a nucleotide sequence that encodes at least one strand of a dsRNA, wherein the nucleotide sequence encods 15 or more contiguous bases of either SEQ ID NO:17 or SEQ ID NO:18, and wherein said dsRNA is less than 30 base pairs in length.
18. A cell comprising the vector of claim 17 .