Antisense antiviral agent and method for treating ssRNA viral infection

• US 8,785,407 B2
• Filed: 05/10/2006
• Issued: 07/22/2014
• Est. Priority Date: 05/10/2006
• Status: Expired due to Fees

• Current Assignee: Sarepta Therapeutics, Inc.
• Original Assignee: Sarepta Therapeutics, Inc.
• Inventors: Stein, David A., Skilling, Douglas E., Iversen, Patrick L., Smith, Alvin W., Weller, Dwight D.
• Primary Examiner(s): ANGELL, JON E
• Application Number:
  US11/431,968
• Publication Number:
  US 20070265214A1
• Time in Patent Office: 2,995 Days
• Field of Search: 514/44.A
• US Class Current: 514/44.A
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate

Abstract

The invention provides antisense antiviral compounds and methods of their use in inhibition of growth of viruses of the picornavirus, calicivirus, togavirus and flavivirus families, as in treatment of a viral infection. The antisense antiviral compounds have morpholino subunits linked by uncharged phosphorodiamidate linkages interspersed with cationic phosphorodiamidate linkages.

Claims

1. A method of inhibiting infection by an HCV virus in a subject, comprising administering to the subject, a therapeutically effective amount of a morpholino oligonucleotide composed of 12 to 30 morpholino subunits that is substantially complementary to the target sequence set forth in SEQ ID NO:

37, wherein the oligonucleotide has a T_m, with respect to binding to the target sequence of greater than about 50°

C., and wherein the morpholino subunits are linked by uncharged phosphorodiamidate linkages interspersed with at least two and up to eight phosphorodiamidate linkages containing piperazine groups.

2. The method of claim 1, wherein said morpholino subunits are joined by phosphorodiamidate linkages, in accordance with the structure:

3. The method of claim 1, wherein the oligonucleotide is actively taken up by mammalian cells.

4. The method of claim 1, wherein the oligonucleotide is complementary to at least 8 contiguous bases of SEQ ID NO:

15.

5. The method of claim 1, wherein an arginine-rich peptide is linked covalently to the 5′

or 3′

end of the oligonucleotide.

6. The method of claim 5, wherein the arginine-rich peptide is about 8-16 amino acids.

7. The method of claim 5, wherein the arginine-rich peptide is selected from SEQ ID NOS:

41-43.

8. The method of claim 1, wherein the oligonucleotide is composed of 12 to 25 morpholino subunits.

9. The method of claim 8, wherein the oligonucleotide is complementary to at least 12 contiguous bases of SEQ ID NO:

37.

10. The method of claim 1, wherein the oligonucleotide is complementary to at least 15 contiguous bases of SEQ ID NO:

37.

11. The method of claim 1, wherein the oligonucleotide is composed of 15 to 22 subunits and is 100% complementary to SEQ ID NO:

37.

12. The method of claim 2, wherein X is alkyl amino of the form NR₂, where R is methyl, and where the phosphorodiamidate linkages containing piperazine groups are represented by the same structure, but where X is 1-piperazino.