Method for treating enterovirus or rhinovirus infection using antisense antiviral compounds

• US 8,524,676 B2
• Filed: 09/08/2006
• Issued: 09/03/2013
• Est. Priority Date: 09/08/2005
• Status: Expired due to Fees

• Current Assignee: Sarepta Therapeutics, Inc.
• Original Assignee: Sarepta Therapeutics, Inc.
• Inventors: Stein, David A., Bestwick, Richard K., Iversen, Patrick L., Weller, Dwight D.
• Primary Examiner(s): SHIN, DANA H
• Application Number:
  US11/517,757
• Publication Number:
  US 20070066556A1
• Time in Patent Office: 2,552 Days
• Field of Search: 514/44, 514/81, 536/24.5, 435/5, 435/6, 435/7.1, 435/91.2, 435/320.1, 530/327
• US Class Current: 514/44.A
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: C12N 15/1131 against viruses
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/314 Phosphoramidates
• CPC Class Codes: C12N 2310/3233 Morpholino-type ring
• CPC Class Codes: C12N 2770/32311 Enterovirus
• CPC Class Codes: C12N 2770/32711 Rhinovirus
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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, 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:7.

Claims

1. A method of treating viral infection of mammalian cells by an Enterovirus or Rhinovirus, comprising exposing host cells to an effective amount of an antiviral compound that comprises a morpholino antisense oligonucleotide of between 15 and 25 morpholino subunits having a substantially uncharged, nuclease-resistant backbone containing phosphorodiamidate intersubunit linkages joining a morpholino nitrogen of one subunit to a 5′

exocyclic carbon of an adjacent subunit, wherein the morpholino antisense oligonucleotide comprises a targeting sequence of at least 15 nucleotide bases complementary to SEQ ID NO;

7 and, conjugated to the morpholino antisense oligonucleotide, an arginine-rich polypeptide effective to promote uptake of the antiviral compound into the host cells, wherein the arginine-rich polypeptide has the sequence of SEQ ID NO;

15.

2. The method of claim 1, wherein the morpholino antisense oligonucleotide forms a heteroduplex with its target sequence, wherein the heteroduplex has a T_m of at least 45°

C.

3. The method of claim 1, wherein the morpholino antisense oligonucleotide contains an intersubunit linkages in accordance with the structure:

4. The method of claim 1, wherein the morpholino antisense oligonucleotide contains an intersubunit linkages in accordance with the structure:

5. The method of claim 1, wherein the oligonucleotide has at least 15 nucleotide bases contained in SEQ ID NO:

10.

6. The method of claim 5, wherein the oligonucleotide is selected from the group consisting of SEQ ID NOS:

11, 12, and 13.

7. The method of claim 1, wherein the exposing is by administering to a subject a therapeutically effective amount of the antiviral compound.

8. The method of claim 7, further comprising administering a second antiviral compound to the subject.