Compositions and methods for inhibiting viral replication
View Patent ↗The present invention relates to a double-stranded ribonucleic acid (dsRNA) having a nucleotide sequence which is less that 30 nucleotides in length and which is substantially identical to at least a part of a 3′-untranslated region (3′-UTR) of a (+) strand RNA virus, such as HCV, as well as pharmaceutical compositions comprising the dsRNA, together with a pharmaceutically acceptable carrier. The pharmaceutical compositions are useful for treating infections and diseases caused by the replication or activity of the (+) strand RNA virus, as well as methods for inhibiting viral replication.
1. A double-stranded ribonucleic acid (dsRNA) for inhibiting the replication of a (+) strand RNA virus, wherein the dsRNA comprises a sense RNA strand comprising a the nucleotide sequence of SEQ ID NO:4 and a complementary RNA strand comprising the nucleotide sequence of SEQ ID NO:5, and wherein the dsRNA is less than 30 base pairs in length.
2. The dsRNA of claim 1 , wherein the complementary nucleotide sequence is less than 25 nucleotides in length.
3. The dsRNA of claim 1 , wherein the complementary nucleotide sequence is 23 or 24 nucleotides in length.
4. The dsRNA of claim 1 , wherein the dsRNA comprises a blunt end.
5. The dsRNA of claim 1 , wherein the dsRNA comprises two blunt ends.
6. The dsRNA of claim 1 , wherein the complementary RNA strand and the sense RNA strand comprise a 3′-terminus and a 5′-terminus, and wherein at least one of said RNA strands comprises a nucleotide overhang of 1 to 3 nucleotides in length.
7. The dsRNA of claim 6 , wherein the nucleotide overhang is two nucleotides in length.
8. The dsRNA of claim 6 , wherein the nucleotide overhang is on the 3′-terminus of the complementary RNA strand.
9. The dsRNA of claim 6 , wherein the dsRNA further comprises a first end and a second end, wherein the first end comprises the 3′-terminus of the complementary RNA strand and the 5′-terminus of the sense RNA strand, and wherein the second end comprises the 5′-terminus of the complementary RNA strand and the 3′-terminus of the sense RNA strand, wherein the first end comprises a nucleotide overhang on the 3′-terminus of the complementary RNA strand, and wherein the second end is blunt.
10. The dsRNA of claim 9 , wherein the complementary RNA strand comprises a 2-nucleotide overhang at the 3′-terminus and wherein the second end of the dsRNA is blunt.
11. A pharmaceutical composition for inhibiting the replication of a (+) strand RNA virus in an organism, comprising a dsRNA and a pharmaceutically acceptable carrier, wherein the dsRNA comprises a sense RNA strand comprising the nucleotide sequence of SEQ ID NO:4 and a complementary RNA strand comprising the nucleotide sequence of SEQ ID NO:5, and wherein the dsRNA is less than 30 base pairs in length.
12. The pharmaceutical composition of claim 11 , wherein the complementary nucleotide sequence is less than 25 nucleotides in length.
13. The pharmaceutical compositions of claim 11 , wherein the complementary nucleotide sequence is 23 or 24 nucleotides in length.
14. The pharmaceutical composition of claim 11 , wherein the dsRNA comprises a blunt end.
15. The pharmaceutical composition of claim 11 , wherein the dsRNA comprises two blunt ends.
16. The pharmaceutical composition of claim 11 , wherein the complementary RNA strand and the sense RNA strand comprise a 3′-terminus and a 5′-terminus, and wherein at least one of said RNA strands comprise a nucleotide overhang of 1 to 3 nucleotides in length.
17. The pharmaceutical composition of claim 16 , wherein the nucleotide overhang is two nucleotides in length.
18. The pharmaceutical composition of claim 16 , wherein the nucleotide overhang is on the 3′-terminus of the complementary RNA strand.
19. The pharmaceutical composition of claim 16 , wherein the dsRNA further comprises a first end and a second end, wherein the first end comprises the 3 ′-terminus of the complementary RNA strand and the 5′-terminus of the sense RNA strand, and wherein the second end comprises the 5′-terminus of the complementary RNA strand and the 3′-terminus of the sense RNA strand, wherein the first end comprises a nucleotide overhang on the 3′-terminus of the complementary RNA strand, and wherein the second end is blunt.
20. The pharmaceutical composition of claim 19 , wherein the complementary RNA strand comprises a 2-nucleotide overhang at the 3′-terminus and wherein the second end of the dsRNA is blunt.
21. The pharmaceutical composition of claim 11 , wherein a dosage unit of dsRNA is less than 5 milligram (mg) of dsRNA per kg body weight of the mammal.
22. The pharmaceutical composition of claim 11 , wherein a dosage unit of dsRNA is in a range of 0.01 to 2.5 milligrams (mg), 0.1 to 200 micrograms (μg), 0.1 to 100 μg per kilogram body weight of the mammal.
23. The pharmaceutical composition of claim 11 , wherein a dosage unit of dsRNA is less than 25 μg per kilogram body weight of the mammal.
24. The pharmaceutical composition of claim 11 , wherein the pharmaceutically acceptable carrier is an aqueous solution.
25. The pharmaceutical composition of claim 24 , wherein the aqueous solution is phosphate buffered saline.
26. The pharmaceutical composition of claim 11 , wherein the pharmaceutically acceptable carrier comprises a micellar structure selected from the group consisting of a liposome, capsid, capsoid, polymeric nanocapsule, and polymeric microcapsule.
27. The pharmaceutical composition of claim 11 , which is formulated to be administered by inhalation, infusion, injection, or orally.
28. The pharmaceutical composition of claim 11 , which is formulated to be administered by intravenous or intraperitoneal injection.