RNAi modulation of SCAP and therapeutic uses thereof
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) for inhibiting the expression of a human SCAP gene in a cell, wherein said dsRNA comprises a sense strand comprising SEQ ID NO:1 and an antisense strand comprising SEQ ID NO:2, and wherein said dsRNA is at least 15 nucleotides in length and less than 30 nucleotides in length.
2. The dsRNA of claim 1 , wherein said at least 20% inhibition of expression of a SCAP gene is effected in primary hamster hepatocytes.
3. The dsRNA of claim 1 , wherein said dsRNA comprises at least one modified nucleotide.
4. The dsRNA of claim 3 , 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.
5. The dsRNA of claim 3 , 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.
6. A cell comprising the dsRNA of claim 1 .
7. A pharmaceutical composition for inhibiting the expression of a human SCAP gene in an organism, comprising a dsRNA and a pharmaceutically acceptable carrier, wherein the dsRNA comprises a sense strand comprising SEQ ID NO:1 and an antisense strand comprising SEQ ID NO:2, and wherein said dsRNA is at least 15 nucleotides in length and less than 30 nucleotides in length.
8. The pharmaceutical composition of claim 7 , wherein said at least 20% inhibition of expression of a SCAP gene is effected in primary hamster hepatocytes.
9. A method for inhibiting the expression of a human SCAP gene in a cell, the method comprising: (a) introducing into the cell a double-stranded ribonucleic acid (dsRNA), wherein the dsRNA comprises a sense strand comprising SEQ ID NO:1 and an antisense strand comprising SEQ ID NO:2, and wherein said dsRNA is at least 15 nucleotides in length and less than 30 nucleotides in length; and (b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of a mRNA transcript of a human SCAP gene, thereby inhibiting expression of a human SCAP gene in the cell.
10. The method of claim 9 , wherein the human SCAP gene is a Homo sapiens SCAP gene.
11. A vector for inhibiting the expression of a human 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 a strand chosen from the group consisting of a strand comprising SEQ ID NO:1 and a strand comprising SEQ ID NO:2, and wherein said dsRNA is at least 15 nucleotides in length and less than 30 nucleotides in length.
12. A cell comprising the vector of claim 11 .