ANTISENSE ANTIVIRAL COMPOUNDS AND METHODS FOR TREATING A FILOVIRUS INFECTION

• US 20090186847A1
• Filed: 03/11/2009
• Published: 07/23/2009
• Est. Priority Date: 11/01/2004
• Status: Active Grant

• Current Assignee: Sarepta Therapeutics, Inc., United States Army Medical Research and Materiel Command
• Original Assignee: United States Army Medical Research and Materiel Command
• Inventors: Bavari, Sina, Iversen, Patrick L., Weller, Dwight D., Stein, David A.
• Granted Patent: US 8,030,291 B2
• Time in Patent Office: Days
• US Class Current: 514/44.R
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: C12N 15/1131 against viruses
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/31 of the backbone
• CPC Class Codes: C12N 2310/32 of the sugar
• CPC Class Codes: C12N 2310/3513 Protein; Peptide

Abstract

The invention provides antisense antiviral compounds and methods of their use and production in inhibition of growth of viruses of the Filoviridae family, and in the treatment of a viral infection. The compounds and methods relate to the treatment of viral infections in mammals including primates by Ebola and Marburg viruses. The antisense antiviral compounds are morpholino oligonucleotides having: a) a nuclease resistant backbone, b) 15-40 nucleotide bases, and c) a targeting sequence of at least 15 bases in length that hybridizes to a target region selected from the following: i) the Ebola virus AUG start site region of VP24; ii) the Ebola virus AUG start site region of VP35; iii) the Marburg virus AUG start site region of VP24; or iv) the Marburg virus AUG start site region of NP.

Claims

1. A method of treating Ebola virus infection in a subject, comprising:

administering to a subject a therapeutically effective amount of an antiviral composition of an antisense oligomer, wherein the oligomer comprises;

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, wherein at least 2 and no more than half of the total number of intersubunit linkages are positively charged at physiological pH; and

a targeting sequence which forms a heteroduplex with a target sequence of the AUG start-site region of a positive-strand mRNA for Ebola viral protein 24 (VP24);

wherein the antisense oligomer inhibits virus production.

2. The method of claim 1, wherein the targeting sequence forms a heteroduplex with the AUG start-site region defined by SEQ ID NO:

2.

3. The method of claim 2, wherein the targeting sequence is complementary to at least 12 contiguous bases of the sequence of SEQ ID NO:

2.

4. The method of claim 2, wherein the oligomer has between 12-40 subunits.

5. The method of claim 2, wherein the heteroduplex has a Tm of dissociation of at least 45°

C.

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

8. The method of claim 1, wherein the Ebola virus is viral strain ebola Zaire.

9. The method of claim 1, which further includes administering to the subject a therapeutically effective amount of an antiviral composition of an antisense oligomer having the same structure recited in claim 1, but targeting sequence which forms a heteroduplex with a target sequence of the AUG start-site region of a positive-strand mRNA for Ebola viral protein 35 (VP35).

10. The method of claim 9, wherein the Ebola viral protein 35 targeting sequence forms a heteroduplex with the AUG start-site region defined by SEQ ID NO:

1.

11. The method of claim 2, wherein the Ebola viral protein 35 targeting sequence is complementary to at least 12 contiguous bases of the sequence of SEQ ID NO:

1.