COMPOSITIONS AND METHODS FOR THE TREATMENT OF INFLUENZA INFECTION

Abstract

The invention provides compositions of oligonucleotides targeted at influenza genes and at host animal genes involved in response to influenza infection. In some embodiments, the oligonucleotides are modified. In some embodiments, the compositions contain one, or more than one, oligonucleotide. The invention also provides methods and kits using the compositions of the invention for the treatment and prevention of influenza.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

FIG. 1 is a schematic representation of a virus illustrating the location of genes targeted by the compositions of the invention.

FIG. 2 is a graphical representation of inhibition of bird flu replication in CEF cells by treatment with microRNA targeting 10 different regions of viral genes compared with controls.

FIG. 3 is a graphical representation of survival in groups of chickens treated with a composition of multiple RNA oligonucleotides directed against NSI, mock treatment, or control and infected with H5N1 influenza virus.

FIG. 4 is a graph depicting the survival of groups of mice treated with RNA oligonucleotides or saline after infection with H5N1 influenza virus.

Claims

1. A composition suitable for administration to an animal comprising at least one modified oligonucleotide containing 7 to 75 contiguous ribose groups linked by achiral 5′ to 3′ internucleoside phosphate linkages, wherein said at least one modified oligonucleotide is complementary to a region of a gene selected from the group consisting of influenza viral genes and animal host genes involved in response to influenza infection.

2. The composition of claim 1 wherein said region of said gene is chosen from the group consisting of the 5′ UTR region, translational start site, the 3′ UTR, translational termination site and transcription start site.

3. The composition of claim 1 wherein said at least one modified oligonucleotide is chosen from SEQ ID NOS: 1-110.

2. The composition of claim 1 wherein said at least one modified oligonucleotide has a Tm of about 75-115° C. at a concentration of 1 mM and a length of 10 to 26 bases, or a Tm of about 40° C. to 85° C. at a concentration of 1 pM and a length of 10 to 26 bases.

3. The composition of claim 1 wherein said at least one modified oligonucleotides are ribonucleotides and deoxyribonucleotides.

4. The composition of claim 1 further comprises a plurality of modified oligonucleotides.

5. The composition of claim 1 wherein said animal comprises an avian species.

6. The composition of claim 1 wherein said animal is a mammal.

7. The composition of claim 1 wherein said animal is a human.

8. The composition of claim 4 wherein a 2′ substituent on said ribose groups comprises hydrogen, methoxy, propoxy, ethyloxymethoxy, fluorine, chlorine, bromine and iodine.

9. The composition of claim 1 wherein said modified oligonucleotide comprises 3′ and 5′ end-modifications.

10. The composition of claim 1 wherein said modified oligonucleotide comprises 3′ and 5′ end-blocking groups.

11. The composition of claim 1 wherein said modified oligonucleotides are antisense oligonucleotides.

12. The composition of claim 1 wherein said animal host genes comprise genes regulating inflammation and genes regulating apoptosis.

13. The composition of claim 1 wherein said influenza genes comprise PA, PB1, PB2, HA, M, NP, NA and NS1.

14. The composition of claim 1 wherein said animal host gene comprises Fas, Fas-L, TACE, TNF-R1, TNF-α, Caspase-3, Rantes. IL-1b, IL-18, P38 MARK, CXCL-1, and IP-10.

15. The composition of claim 4 wherein said plurality of oligonucleotides comprises: more than one oligonucleotide targeted to a first gene selected from the group of influenza viral genes and animal host genes involved in response to influenza infection complementary to the 5′ UTR region, translational start site, the 3′ UTR, and translational termination site of said first gene; and,optionally at least one oligonucleotide targeted to a different gene selected from the group of influenza viral genes and animal host genes related to influenza infection complementary to the 5′ UTR region, translational start site, the 3′ UTR, translational termination site and transcription start site of said second gene.

16. The composition of claim 15 wherein said plurality of oligonucleotides are SEQ ID NO: 20, SEQ ID NO: 111, and SEQ ID NO: 112.

17. The composition of claim 15 wherein said plurality of oligonucleotides are SEQ ID NO: 21, SEQ ID NO: 113, and SEQ ID NO: 114.

18. A method of treating an animal suffering from influenza infection comprising: administering a composition to an animal comprising:at least one modified oligonucleotide containing 7 to 75 contiguous ribose groups linked by achiral 5′ to 3′ internucleoside phosphate linkages, wherein said at least one modified oligonucleotide is complementary to a region of a gene selected from the group comprising influenza viral genes and animal host genes involved in response to influenza infection; and,an excipient.

19. The method of claim 18 further wherein said composition comprises a plurality of modified oligonucleotides.

20. The method of claim 19 further wherein said plurality of oligonucleotides comprises: more than one oligonucleotide targeted to a first gene selected from the group of influenza viral genes and animal host genes involved in response to influenza infection complementary to the 5′ UTR region, translational start site, the 3′ UTR, and translational termination site of said first gene; and,optionally at least one oligonucleotide targeted to a different gene selected from the group of influenza viral genes and animal host genes related to influenza infection complementary to the 5′ UTR region, translational start site, the 3′ UTR, translational termination site and transcription start site of said second gene.

21. The method of claim 18 wherein said influenza genes comprise PA, PB1, PB2, HA, M, NP, NA and NS1.

22. The method of claim 18 wherein said animal host gene comprises Fas, Fas-L, TACE, TNF-R1, TNF-α, Caspase-3, Rantes. IL-1b, IL-18, P38 MARK, CXCL-1, and IP-10.