Antisense antiviral compounds and methods for treating a filovirus infection

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 substantially uncharged 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 AUG start site region of VP35, as exemplified by antisense compounds SEQ ID NO:21-26, ii) the AUG start site region of VP24, as exemplified by antisense compound SEQ ID NO:34, iii) the region 85 to 65 base pairs upstream of the AUG start site of VP24, as exemplified by SEQ ID NO:39, iv) the AUG start site region of polymerase L, as exemplified by antisense compound SEQ ID NO: 17, and v) combinations of (i), (ii), (iii), and / or (iv).

Description

[0001] This application claims priority to U.S. provisional Patent Application No. 60 / 671,694 filed Apr. 14, 2005, and U.S. provisional Patent Application No. 60 / 624,277 filed Nov. 1, 2004, which are both incorporated herein in their entirety by reference.FIELD OF THE INVENTION [0002] This invention relates to antisense oligonucleotide compounds for use in treating an infection by a virus of the Filoviridae family and antiviral treatment methods employing the compounds. More specifically, it relates to treatment methods and compounds for treating viral infections in mammals including primates by Ebola and Marburg viruses. [0003] Agrawal, S., S. H. Mayrand, et al. (1990). “Site-specific excision from RNA by RNase H and mixed-phosphate-backbone oligodeoxynucleotides.”Proc Natl Acad Sci USA 87(4): 1401-5. [0004] Arora, V. and P. L. Iversen (2001). “Redirection of drug metabolism using antisense technology.”Curr Opin Mol Ther 3(3): 249-57. [0005] Blommers, M. J., U. Pieles, et al. (1994...

AI Technical Summary

Benefits of technology

[0062] The antisense compound(s) in the composition preferably target(s) at least 18, more preferably, at least 20 target base pairs.

[0063] In another aspect, the invention includes a method of treating an Ebola or Marburg virus infection in a mammalian host, by administering to the host, a therapeutically effective amount of a composition of the type described above. The method includes, in exemplary embodiments, administering a

Problems solved by technology

In general, no effective antiviral therapies are available to treat an infection by any of these viruses.

Although they cause only a few hundred deaths worldwide each year, filoviruses are considered a significant world health threat and have many of the characteristics commonly associated with biological weapons since they can be grown in large quantities, can be fairly stable, are highly infectious as an aerosol, and are exceptionally deadly (Borio, Inglesby et al.

The development of an effective therapeutic for Ebola virus has been hindered by a lack of reagents and a clear understanding of filovirus pathogenesis, disparity between animal models, and both the difficulty and danger of working with Ebola virus in biosafety level (BSL)-4 conditions (Geisbert and Hensley 2004; Burnett, Henchal et al.

Host-directed therapeutics alone have not proven to be a sufficiently efficacious therapeutic approach.

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