ANTISENSE ANTIVIRAL COMPOUND AND METHOD FOR TREATING ARENAVIRUS INFECTION

• US 20100063133A1
• Filed: 08/25/2009
• Published: 03/11/2010
• Est. Priority Date: 03/07/2006
• Status: Active Grant

• Current Assignee: Sarepta Therapeutics, Inc.
• Original Assignee: Benjamin Neuman, David A. Stein, Michael Buchmeier, Patrick L. Iversen
• Inventors: Neuman, Benjamin, Buchmeier, Michael, Iversen, Patrick L., Stein, David A.
• Granted Patent: US 7,855,283 B2
• Time in Patent Office: Days
• US Class Current: 514/44.A
• CPC Class Codes: C12N 15/1131 against viruses
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/3145 with the nitrogen in 3' or 5'-position
• CPC Class Codes: C12N 2310/3233 Morpholino-type ring
• CPC Class Codes: C12N 2310/3513 Protein; Peptide
• CPC Class Codes: C12N 2760/10011 Arenaviridae

Abstract

The invention provides antisense antiviral compounds and methods of their use and production in inhibition of growth of viruses of the Arenaviridae family and in the treatment of a viral infection. The compounds are particularly useful in the treatment of Arenavirus infection in a mammal. The antisense antiviral compounds are substantially uncharged morpholino oligonucleotides have a sequence of 12-40 subunits, including at least 12 subunits having a targeting sequence that is complementary to a region associated with viral RNA sequences within a 19 nucleotide region of the 5′-terminal regions of the viral RNA, viral complementary RNA and/or mRNA identified by SEQ ID NO:1.

Claims

1-17. -17. (canceled)

18. A method of inhibiting viral infection in mammalian cells by an Arenavirus in the Arenaviridae family, comprising

(a) exposing the cells to an antisense oligonucleotide compound capable of uptake by mammalian host cells, wherein the antisense oligonucleotide compound is comprised of morpholino subunits and phosphorous-containing intersubunit linkages having the following structure (I):

19. The method of claim 18, wherein X is dimethylamino for the phosphorous-containing intersubunit linkages which are uncharged at physiological pH.

20. The method of claim 18, wherein at least 80% of the phosphorous-containing intersubunit linkages are uncharged at physiological pH.

21. The method of claim 18, wherein about one phosphorous-containing intersubunit linkage is charged at physiological pH per every five phosphorous-containing intersubunit linkages which are uncharged at physiological pH.

22. The method of claim 18, wherein two of the phosphorous-containing intersubunit linkages are charged at physiological pH.

23. The method of claim 18, wherein the antisense oligonucleotide compound contains between 14-24 base-pairing moieties.

24. The method of claim 23, wherein the antisense oligonucleotide compound contains 20 base-pairing moieties.

25. The method of claim 18, wherein the antisense oligonucleotide compound comprises a targeting sequence of 19 contiguous base-pairing moieties complementary to SEQ ID NO:

1.

26. The method of claim 18, wherein the antisense oligonucleotide compound comprises a polyethyleneglycol moiety for enhancing the solubility of the antisense oligonucleotide compound.

27. The method of claim 18, for use in treating a mammalian subject infected by an Arenavirus in the Arenaviridae family, wherein said exposing includes administering to the subject, a pharmaceutically effective amount of the antisense oligonucleotide compound, and which further includes continuing said administering until a significant reduction in viral infection or the symptoms thereof is observed.

28. The method of claim 27, further comprising administering a second anti-viral compound to the subject.

29. The method of claim 18, for use in treating a mammalian subject at risk of infection by an Arenavirus in the Arenaviridae family, wherein said exposing includes administering to the subject, an amount of the oligonucleotide compound effective to inhibit infection of subject host cells by the virus.

30. An antisense oligonucleotide compound comprised of morpholino subunits and phosphorous-containing intersubunit linkages having the following structure (I):

31. The antisense oligonucleotide compound of claim 30, wherein X is dimethylamino for the phosphorous-containing intersubunit linkages which are uncharged at physiological pH.

32. The antisense oligonucleotide compound of claim 30, wherein at least 80% of the phosphorous-containing intersubunit linkages are uncharged at physiological pH.

33. The antisense oligonucleotide compound of claim 30, wherein about one phosphorous-containing intersubunit linkage is charged at physiological pH per every five phosphorous-containing intersubunit linkages which are uncharged at physiological pH.

34. The antisense oligonucleotide compound of claim 30, wherein two of the phosphorous-containing intersubunit linkages are charged at physiological pH.

35. The antisense oligonucleotide compound of claim 30, wherein the antisense oligonucleotide compound contains between 14-24 base-pairing moieties.

36. The antisense oligonucleotide compound of claim 30, wherein the antisense oligonucleotide compound comprises a targeting sequence of 19 contiguous base-pairing moieties complementary to SEQ ID NO:

1.

37. The antisense oligonucleotide compound of claim 30, wherein the antisense oligonucleotide compound comprises a polyethyleneglycol moiety for enhancing the solubility of the antisense oligonucleotide compound.