GNAQ targeted dsRNA compositions and methods for inhibiting expression
The invention relates to a double-stranded ribonucleic acid (dsRNA) targeting a G-alpha q subunit (GNAQ) of a heterotrimeric G gene, and methods of using the dsRNA to inhibit expression of GNAQ.
1. An isolated double-stranded ribonucleic acid (dsRNA) for inhibiting expression of a G-alpha q subunit (GNAQ) of a heterotrimeric G gene, comprising a sense strand and an antisense strand, wherein the antisense strand is complementary to at least 15 contiguous nucleotides of SEQ ID NO:1409, and wherein each strand is 15-30 nucleotides in length.
2. The dsRNA of claim 1 , comprising a modification that causes the dsRNA to have increased stability in a biological sample.
3. The dsRNA of claim 1 , comprising at least one modified nucleotide.
4. The dsRNA of claim 3 , wherein said modified nucleotide is selected from the group of: a 2′-O-methyl modified nucleotide, a nucleotide comprising a 5′-phosphorothioate group, a terminal nucleotide linked to a cholesteryl derivative or dodecanoic acid bisdecylamide group, a 2′-deoxy-2′-fluoro modified nucleotide, a 2′-deoxy-modified nucleotide, a locked nucleotide, an abasic nucleotide, a 2′-amino-modified nucleotide, a 2′-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, and a non-natural base comprising nucleotide.
5. The dsRNA of claim 3 , comprising at least one 2′-O-methyl modified nucleotide and at least one 2′-fluoro modified nucleotide.
6. The dsRNA of claim 1 , further comprising a ligand.
7. The dsRNA of claim 1 , further comprising a ligand conjugated to the 3′-end of the sense strand of the dsRNA.
8. A composition for inhibiting expression of a GNAQ gene comprising the dsRNA of claim 1 and pharmaceutical formulation.
9. The composition of claim 8 , wherein the pharmaceutical formulation is a lipid formulation.
10. The composition of claim 8 , wherein the pharmaceutical formulation is a (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl 4-(dimethylamino)butanoate (MC3) comprising formulation.
11. An isolated cell containing the dsRNA of claim 1 .
12. A vector comprising a nucleotide sequence that encodes at least one strand of the dsRNA of claim 1 .
13. The dsRNA of claim 1 , wherein said dsRNA, upon contact with a cell expressing said GNAQ, inhibits expression of said GNAQ gene by at least 40% compared to a cell not so contacted.
14. The dsRNA of claim 1 , wherein the dsRNA has an IC50 of less than 10 pM.
15. The dsRNA of claim 1 , wherein the sense strand comprises SEQ II) NO:1409 and the antisense strand comprises SEQ ID NO:1410, and wherein each strand is 19-30 nucleotides in length.
16. The dsRNA of claim 1 , wherein the sense strand consists of the nucleotide sequence of SEQ ID NO:1409 and the antisense strand consists of the nucleotide sequences of SEQ ID NO 1410.
17. The dsRNA of claim 1 , wherein the sense strand consists of SEQ ID NO 1567 (cAcAAAGAuAAGAcuuGuudTdT) and the antisense strand consists of SEQ ID NO:1568 (AAcAAGUCUuAUCUUUGUGdTdT), wherein each strand includes 2′-O-methyl ribonucleotides as indicated by a lower case letter “c” and “u”, and wherein each strand includes 2′-deoxythymidine as indicated by a “dT”.
18. The dsRNA of claim 15 , comprising at least one modified nucleotide.
19. The dsRNA of claim 18 , comprising at least one 2′-O-methyl modified nucleotide and at least one 2′-fluoro modified nucleotide.
20. The dsRNA of claim 16 , comprising at least one modified nucleotide.