RNAI THERAPEUTIC FOR RESPIRATORY VIRUS INFECTION

• US 20100144843A1
• Filed: 02/12/2010
• Published: 06/10/2010
• Est. Priority Date: 04/08/2005
• Status: Abandoned Application

• Current Assignee: Mdrna Inc. (Adhera Therapeutics, Inc.)
• Original Assignee: Mdrna Inc. (Adhera Therapeutics, Inc.)
• Inventors: McSwiggen, James Anthony, Ge, Qing
• Application Number:
  US12/705,463
• Publication Number:
  US 20100144843A1
• Time in Patent Office: Days
• US Class Current: 514/44.A
• CPC Class Codes: C12N 15/1131 against viruses
• CPC Class Codes: C12N 2310/14 interfering N.A.

Abstract

Double stranded siRNA molecules for combatting a respiratory virus, wherein the strands of an siRNA molecule may be from about 15 to about 60 nucleotides, and uses thereof. One strand of an siRNA molecule can be a nucleic acid sequence identical to a conserved site, or a variant thereof, within the nucleic acid sequence of the respiratory virus.

Claims

1. A double-stranded ribonucleic acid (dsRNA) molecule that decreases expression of a respiratory virus gene by RNA interference, wherein the dsRNA molecule has a double-stranded region of from about 15 to about 60 base pairs, the dsRNA molecule comprising:

a. a first strand comprising from about 15 to about 60 nucleotides having a region of at least 15 contiguous nucleotides that are 100% complementary to a nucleic acid sequence of the respiratory virus gene, wherein the region of at least 15 contiguous nucleotides is present in a homologous gene of the virus in at least about 70% of the respiratory virus variants (strains) containing the homologous gene, except for no more than three (3) nucleotide mismatches among the region of at least 15 contiguous nucleotides; and

b. a second strand comprising from about 15 to about 60 nucleotides that is at least 70% complementary to the first strand.

2. The dsRNA molecule of claim 1, wherein the double-stranded region is from about 15 to about 40 base pairs, the dsRNA molecule comprising:

a. a first strand comprising from about 15 to about 40 nucleotides having a region of at least 19 contiguous nucleotides that are 100% complementary to a nucleic acid sequence of the respiratory virus gene, wherein the region of at least 19 contiguous nucleotides is present in a homologous gene of the virus in at least about 84% of the respiratory virus variants (strains) containing the homologous gene, except for no more than three (3) nucleotide mismatches among the region of at least 19 contiguous nucleotides; and

b. a second strand comprising from about 15 to about 40 nucleotides that is at least 70% complementary to the first strand.

3. The dsRNA molecule of claim 1, wherein the double-stranded region is from about 15 to about 40 base pairs, the dsRNA molecule comprising:

a. a first strand comprising from about 15 to about 40 nucleotides having a region of at least 25 contiguous nucleotides that are 100% complementary to a nucleic acid sequence of the respiratory virus gene, wherein the region of at least 25 contiguous nucleotides is present in a homologous gene of the virus in at least about 88% of the respiratory virus variants (strains) containing the homologous gene, except for no more than three (3) nucleotide mismatches among the region of at least 25 contiguous nucleotides; and

b. a second strand comprising from about 15 to about 40 nucleotides that is at least 70% complementary to the first strand.

4. The dsRNA molecule of claim 1, wherein the double-stranded region is from about 15 to about 60 base pairs, the dsRNA molecule comprising:

a. a first strand comprising from about 15 to about 60 nucleotides having a region of at least 15 contiguous nucleotides that are 100% complementary to a nucleic acid sequence of the respiratory virus gene, wherein the region of at least 15 contiguous nucleotides is present in a homologous gene of the virus in at least about 88% of the respiratory virus variants (strains) containing the homologous gene, except for no more than one (1) nucleotide mismatch among the region of at least 15 contiguous nucleotides; and

b. a second strand comprising from about 15 to about 60 nucleotides that is at least 70% complementary to the first strand.

5. The dsRNA molecule of claim 1, wherein the dsRNA molecule is an siRNA or an shRNA.

6. The dsRNA molecule of claim 1, wherein the dsRNA molecule has a 3′

overhang.

7. The dsRNA molecule of claim 1, wherein the dsRNA molecule has a 3′

overhang containing a deoxythymidine (dT).

8. The dsRNA molecule of claim 1, wherein the respiratory virus is influenza A virus.

9. The dsRNA molecule of claim 1, wherein the dsRNA molecule is an shRNA further comprising a hairpin loop structure.

10. The dsRNA molecule of claim 1, wherein the dsRNA molecule is an shRNA further comprising a hairpin loop structure having from 4 to 11 nucleotides.

11. The dsRNA molecule of claim 1, wherein the dsRNA molecule decreases expression of a respiratory virus gene by at least about 25% by RNA interference in a mammalian cell.

20. A composition comprising a dsRNA according to claim 1 and a delivery agent.

21. A composition comprising two or more dsRNAs according to claim 1, wherein the genes are from two or more strains of the same viral species.

22. A method of preventing or treating a viral infection in a subject comprising administering an effective amount of a therapeutic dsRNA molecule according to claim 1.

23. The method of claim 22, wherein the virus is influenza A.

24. The method of claim 22, wherein the dsRNA is administered to the subject at a dosage of from about 0.1 mg/kg to about 20 mg/kg of body weight.

25. The method of claim 22, wherein the administration is intranasal, inhalation, oral, or intravenous.

12. A double-stranded ribonucleic acid (dsRNA) molecule that decreases expression of a respiratory virus gene by RNA interference, wherein the dsRNA molecule has a double-stranded region of from about 15 to about 60 base pairs, the dsRNA molecule comprising:

a. a first strand comprising from about 15 to about 60 nucleotides having a region of at least 15 contiguous nucleotides that are 100% complementary to a nucleic acid sequence of the respiratory virus gene selected from the group consisting of SEQ ID NOS. 1-16949, wherein the region of at least 15 contiguous nucleotides is present in a homologous gene of the virus in at least about 70% of the respiratory virus variants (strains) containing the homologous gene, except for no more than three (3) nucleotide mismatches among the region of at least 15 contiguous nucleotides; and

b. a second strand comprising from about 15 to about 60 nucleotides that is at least 70% complementary to the first strand.

13. The dsRNA molecule of claim 12, wherein the dsRNA molecule is an siRNA or an shRNA.

14. The dsRNA molecule of claim 12, wherein the dsRNA molecule has a 3′

overhang.

15. The dsRNA molecule of claim 12, wherein the dsRNA molecule has a 3′

overhang containing a deoxythymidine (dT).

16. The dsRNA molecule of claim 12, wherein the respiratory virus is influenza A virus.

17. The dsRNA molecule of claim 12, wherein the dsRNA molecule is an shRNA further comprising a hairpin loop structure.

18. The dsRNA molecule of claim 12, wherein the dsRNA molecule is an shRNA further comprising a hairpin loop structure having from 4 to 11 nucleotides.

19. The dsRNA molecule of claim 12, wherein the dsRNA molecule decreases expression of a respiratory virus gene by at least about 25% by RNA interference in a mammalian cell.