Antisense antiviral compounds and methods for treating a filovirus infection

• US 8,524,684 B2
• Filed: 05/11/2012
• Issued: 09/03/2013
• Est. Priority Date: 08/09/2010
• Status: Active Grant

• Current Assignee: Avi Biopharma, Inc.
• Original Assignee: Avi Biopharma, Inc.
• Inventors: Iversen, Patrick L., Weller, Dwight D.
• Primary Examiner(s): GIBBS, TERRA C
• Application Number:
  US13/469,892
• Publication Number:
  US 20130011420A1
• Time in Patent Office: 480 Days
• Field of Search: 536/24.5, 514/44
• US Class Current: 514/44.A
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 31/713 Double-stranded nucleic acids or oligonucleotides
• 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: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 15/1131 against viruses
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/3233 Morpholino-type ring

Abstract

The present invention provides antisense antiviral compounds, compositions, and methods of their use and production, mainly for inhibiting the replication of viruses of the Filoviridae family, including Ebola and Marburg viruses. The compounds, compositions, and methods also relate to the treatment of viral infections in mammals including primates by Ebola and Marburg viruses. The antisense antiviral compounds include phosphorodiamidate morpholino oligonucleotides (PMOplus) having a nuclease resistant backbone, about 15-40 nucleotide bases, at least two but typically no more than half piperazine-containing intersubunit linkages, and a targeting sequence that is targeted against the AUG start site region of Ebola virus VP35, Ebola virus VP24, Marburg virus VP24, or Marburg virus NP, including combinations and mixtures thereof.

Claims

1. An antisense oligonucleotide compound comprising morpholino subunits linked by phosphorous-containing intersubunit linkages, the intersubunit linkages joining a 3′

morpholino nitrogen of one subunit to a 5′

exocyclic carbon of an adjacent subunit in accordance with the following structure;

2. The antisense oligonucleotide compound of claim 1, wherein each X is independently —

N(CH₃)₂ or 1-piperazino.

3. The antisense oligonucleotide compound of claim 1, wherein the antisense oligonucleotide compound comprises a sequence having at least 95% sequence homology to the sequence set forth in SEQ ID NO:

79.

4. The antisense oligonucleotide compound of claim 1, wherein the antisense oligonucleotide compound consists of the sequence set forth in SEQ ID NO:

79.

5. A Pharmaceutical composition comprising an antisense oligonucleotide compound and a physiologically acceptable carrier, wherein the oligonucleotide compound comprises morpholino subunits linked by phosphorous-containing intersubunit linkages, the intersubunit linkages joining a 3′

morpholino nitrogen of one subunit to a 5′

exocyclic carbon of an adjacent subunit in accordance with the following structure;

6. The pharmaceutical composition of claim 5, wherein each X is independently —

N(CH₃)₂ or 1-piperazino.

7. The pharmaceutical composition of claim 5, wherein the antisense oligonucleotide compound comprises a sequence having at least 95% sequence homology to the sequence set forth in SEQ ID NO:

79.

8. The pharmaceutical composition of claim 5, wherein the antisense oligonucleotide compound consists of the sequence set forth in SEQ ID NO:

79.

9. A method for treating a Marburg infection in a mammalian host, the method comprising administering a therapeutically effective amount of the composition of claim 5 to the host.

10. The method of claim 9, wherein each X is independently —

N(CH₃)₂ or 1-piperazino.

11. The method of claim 9, wherein the antisense oligonucleotide compound comprises a sequence having at least 95% sequence homology to the sequence set forth in SEQ ID NO:

79.

12. The method of claim 9, wherein the antisense oligonucleotide compound consists of the sequence set forth in SEQ ID NO:

79.

13. A method of vaccinating a mammalian subject against Marburg virus, the method comprising administering a therapeutically effective amount of the composition of claim 5 to the subject.

14. The method of claim 13, wherein each X is independently —

N(CH₃)₂ or 1-piperazino.

15. The method of claim 13, wherein the antisense oligonucleotide compound comprises a sequence having at least 95% sequence homology to the sequence set forth in SEQ ID NO:

79.

16. The method of claim 13, wherein the antisense oligonucleotide compound consists of the sequence set forth in SEQ ID NO:

79.