siRNA MICROBICIDES FOR PREVENTING AND TREATING DISEASES

• US 20090022783A1
• Filed: 06/05/2006
• Published: 01/22/2009
• Est. Priority Date: 06/03/2005
• Status: Active Grant

• Current Assignee: President and Fellows of Harvard College (Harvard Corporation), Immune Disease Institute, Inc.
• Original Assignee: President and Fellows of Harvard College (Harvard Corporation), Immune Disease Institute, Inc.
• Inventors: Palliser, Deborah, Lieberman, Judy, Knipe, David
• Granted Patent: US 7,943,589 B2
• Time in Patent Office: Days
• US Class Current: 424/450
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 31/22 for herpes viruses
• CPC Class Codes: C12N 15/1131 against viruses
• CPC Class Codes: C12N 15/1133 against herpetoviridae, e.g. HSV
• CPC Class Codes: C12N 2310/14 interfering N.A.

Abstract

The invention provides a microbicidal composition comprising at least one siRNA. The siRNA is an RNA duplex made of one or two molecules. A portion of the siRNA is identical to a target sequence in an essential gene of a virus. The virus may be a herpesvirus, for example, HSV-1 or HSV-2. Preferably, the herpesvirus is HSV-2. The microbicidal composition further comprises a pharmaceutically acceptable carrier. Also included in the invention are methods to prevent and treat viral infections by administration of the microbicidal composition. Preferably, the microbicidal composition is administered transmucosally.

Claims

1. A microbicidal composition comprising at least one siRNA, comprising a pharmaceutically acceptable carrier and the siRNA, wherein the siRNA comprises an RNA duplex comprised of one or two molecules, wherein a portion of the molecule comprises a nucleotide sequence having sufficient complementarity to a target sequence of about 15 to about 30 contiguous nucleotides in an RNA of a virus for the siRNA to direct cleavage of the RNA via RNA interference, wherein the virus is selected from the group consisting of picornaviruses, orthomyxoviruses, paramyxoviruses, coronaviruses, adenoviruses, hepadnaviruses, flaviviruses, retroviruses, papillomaviruses and herpesviruses, wherein the target sequence is in a gene essential for infectivity or replication of the virus.

2. The microbicidal composition of claim 1, wherein the pharmaceutically acceptable carrier comprises a lipofection reagent.

3. The microbicidal composition of claim 1, wherein the virus is a herpesvirus.

4. The microbicidal composition of claim 3, wherein the herpesvirus is HSV.

5. The microbicidal composition of claim 4, wherein the herpesvirus is HSV-1.

6. The microbicidal composition of claim 4, wherein the herpesvirus is HSV-2.

7. The microbicidal composition of claim 1, wherein the target sequence is in an essential HSV gene.

8. The microbicidal composition of claim 7, wherein the essential gene is selected from a group consisting of UL5, UL27 and UL29.

9. The microbicidal composition of claim 1, wherein the sense RNA strand comprises SEQ ID NO:

1, and the antisense strand comprises SEQ ID NO;

2.

10. The microbicidal composition of claim 1, wherein the sense RNA strand comprises SEQ ID NO:

3, and the antisense strand comprises SEQ ID NO;

4.

11. The microbicidal composition of claim 1, wherein the sense RNA strand comprises SEQ ID NO:

5, and the antisense strand comprises SEQ ID NO;

6.

12. The microbicidal composition of claim 1, wherein the sense RNA strand comprises SEQ ID NO:

7, and the antisense strand comprises SEQ ID NO;

8.

13. The microbicidal composition of claim 1, wherein the sense RNA strand comprises SEQ ID NO:

9, and the antisense strand comprises SEQ ID NO;

10.

14. The microbicidal composition of claim 1, wherein the sense RNA strand comprises SEQ ID NO:

11, and the antisense strand comprises SEQ ID NO;

12.

15. The microbicidal composition of claim 1, wherein the sense RNA strand comprises SEQ ID NO:

13, and the antisense strand comprises SEQ ID NO;

14.

16. A microbicidal delivery device, comprising the microbicidal composition of claim 1 and a physical vehicle.

17. The microbicidal delivery device or claim 16, wherein the physical vehicle is a contraceptive device.

18. The microbicidal delivery device of claim 16, wherein the physical vehicle is polyurethane foam.

19. The microbicidal delivery device of claim 16, wherein the physical vehicle is cellulose sulfate gel.

20. The microbicidal delivery device of claim 17, wherein the physical vehicle is a suppository.

21. A method of treating or preventing viral mediated disease, comprising administering to a cell an amount of the microbicide of claim 1.

22. The method of claim 21, wherein the cell is a human cell.

23. The method of claim 22, wherein the cell is located in a human subject.

24. The method of claim 23, wherein the cell is located in the genitalia, cervicovagina, rectum, oral cavity, lips, mouth, skin, or eyes of the subject.

25. The method of claim 21, wherein the pharmaceutically acceptable carrier further comprises a liposome.

26. The method of claim 21, wherein the pharmaceutically acceptable carrier further comprises a condensation agent.

27. The method of claim 26, wherein the condensation agent is a protamine.

28. The method of claim 21, wherein the pharmaceutically acceptable carrier further comprises a targeting agent.

29. The method of claim 21, wherein the siRNA is expressed from an vector.

30. The method of claim 21, wherein the microbicidal composition is administered by a topical administration.

31. The method of claim 30, wherein the topical composition is administration is cervicovaginal.

32. The method of claim 21, wherein the microbicidal composition is associated with a physical vehicle.

33. The method of claim 32, wherein the physical vehicle is a contraceptive device.

34. the method of claim 32, wherein the physical vehicle is selected from the group consisting of a polyurethane foam, a cellulose sulfate gel or a suppository.

35. The method of claim 21, wherein the microbicidal composition is administered by enteral administration.

36. The method of claim 21, wherein the microbicidal composition is administered by a parenteral administration.

37. The method of claim 21, wherein the microbicidal composition is administered in combination with a pharmaceutical agent for treating the viral disease, wherein the pharmaceutical agent is different from the siRNA and is selected from the group consisting of acyclovir, valacyclovir, famciclovir, penciclovir, vidarabine, ganciclovir, idoxuridine, foscarnet, trifluridine, levamisole, amlexanox, lidocaine, docosanol, tetracaine, diphenhydramine, hydroxyzine, aspirin or aspirin derivative, lysine or any combination thereof.