Antisense antiviral compound and method for treating picornavirus infection

• US 8,329,668 B2
• Filed: 09/08/2006
• Issued: 12/11/2012
• Est. Priority Date: 09/08/2005
• Status: Expired due to Fees

• Current Assignee: Avi Biopharma, Inc.
• Original Assignee: Avi Biopharma, Inc.
• Inventors: Stein, David A., Iversen, Patrick L., Weller, Dwight D., Rijnbrand, Cornelis A.
• Primary Examiner(s): SHIN, DANA H
• Application Number:
  US11/518,058
• Publication Number:
  US 20070129323A1
• Time in Patent Office: 2,286 Days
• Field of Search: 536/24.5, 514/44, 424/436
• 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 2770/32311 Enterovirus
• CPC Class Codes: C12N 2770/32711 Rhinovirus

Abstract

The invention provides antisense antiviral compounds and methods of their use and production in inhibition of growth of viruses of the Picornaviridae family and in the treatment of a viral infection. The compounds are particularly useful in the treatment of Enterovirus and/or Rhinovirus infection in a mammal. The antisense antiviral compounds are substantially uncharged, including partially positively charged, 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 32 nucleotide region of the viral 5′ untranslated region identified by SEQ ID NO:4.

Claims

1. A method of treating an Enterovirus or Rhinovirus infection in a mammalian subject, comprising:

administering to the mammalian subject, a therapeutically effective amount of an antisense conjugate comprising;

an antisense oligonucleotide composed of between 20 and 40 morpholino subunits linked by phosphorous-containing intersubunit linkages which join a morpholino nitrogen of one subunit to a 5′

exocyclic carbon of an adjacent subunit, and having a targeting sequence of at least 20 contiguous bases that are complementary to SEQ ID NO;

4, and

an arginine-rich carrier peptide conjugated to the antisense oligonucleotide, wherein the carrier peptide has the sequence of SEQ ID NO;

16.

2. The method of claim 1, wherein the antisense conjugate forms a heteroduplex with at least 20 contiguous bases of SEQ ID NO:

4, wherein the heteroduplex has a Tm of dissociation of at least 45°

C.

3. The method of claim 1, wherein the intersubunit linkages are uncharged.

4. The method of claim 1, wherein at least 2 and no more than half of the total number of intersubunit linkages of the antisense oligonucleotide are positively charged at physiological pH.

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

6. The method of claim 1, wherein the antisense oligonucleotide comprises at least 20 contiguous bases contained in SEQ ID NO:

6.

7. The method of claim 6, wherein the antisense oligonucleotide sequence is selected from the group consisting of SEQ ID NOS:

7, 8, 12 and 13.

8. The method of claim 1, further comprising administering an anti-viral composition to the mammalian subject.

9. The method of claim 1, wherein said administering is effective to reduce cardiopathology in a mammal infected with coxsackievirus B3.

10. The method of claim 1, wherein at least 2 and no more than half of the total number of intersubunit linkages of the antisense oligonucleotide contain a 1-piperazino group.