Antisense antiviral compound and method for treating influenza viral infection

Abstract

The invention provides antisense antiviral compounds and methods of their use and production in inhibition of growth of viruses of the Orthomyxoviridae family and in the treatment of a viral infection. The compounds are particularly useful in the treatment of influenza virus infection in a mammal. The antisense antiviral compounds are substantially uncharged, including partially positively charged, morpholino oligonucleotides having 1) a nuclease resistant backbone, 2) 12-40 nucleotide bases, and 3) a targeting sequence of at least 12 bases in length that hybridizes to a target region selected from the following: a) the 5′ or 3′ terminal 25 bases of the negative sense viral RNA segment of Influenzavirus A, Influenzavirus B and Influenzavirus C; b) the terminal 25 bases of the 3′ terminus of the positive sense cRNA and; and c) the 50 bases surrounding the AUG start codon of an influenza viral mRNA.

Description

[0001] This is a continuation-in-part of U.S. patent application Ser. No. 11 / 259,434, filed Oct. 25, 2005, which claims the benefit of priority to U.S. Provisional Application No. 60 / 622,077, filed Oct. 26, 2004. Both applications are incorporated herein by reference.FIELD OF THE INVENTION [0002] The invention relates to antisense oligonucleotide compounds for use in treating an influenza virus infection and antiviral treatment methods employing the compounds. REFERENCES [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] Blommers, M. J., U. Pieles, et al. (1994). “An approach to the structure determination of nucleic acid analogues hybridized to RNA. NMR studies of a duplex between 2′-OMe RNA and an oligonucleotide containing a single amide backbone modification.”Nucleic Acids Res 22(20): 4187-94. [0005] Bonham, M. A., S. Brown, et al. (1995). “...

AI Technical Summary

Problems solved by technology

Influenza viruses have been a major cause of human mortality and morbidity throughout recorded history.

Epidemics vary widely in severity but occur at regular intervals and always cause significant mortality and morbidity, most frequently in the elderly population.

Furthermore, vaccination does not provide protection against unexpected strains, such as the H5 and H7 avian influenza outbreaks in Hong Kong in 1997 and Europe and Southeast Asia in 2003 and 2004.

Current anti-influenza drugs are limited in their capacity to provide protection and therapeutic effect (Cox and Subbarao 1999; Cox and Subbarao 2000).

This provides a considerable species barrier between birds and humans which is not easily overcome.

None, however, have been completely successful, particularly on a long-term basis.

Thus, a long-term vaccination approach has failed, due to the emergence of new subtypes (antigenic “shift”).

This high degree of variation explains why specific immunity developed against a particular influenza virus does not establish protection against new variants.

However, migratory birds can carry the bird flu to infect domestic chickens, ducks and turkeys causing illness and even death.

Avian flu does not easily infect humans but when human exposure is more frequent, such as contact with domestic birds, human infections occur.

Unfortunately, the H5N1 virus is resistant to both amantadine and rimantidine.

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