Compositions and methods for the treatment of influenza infection
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.
1. A method of treating an animal suffering from an influenza infection comprising nasally or orally administering to said animal a composition comprising:
at least one modified antisense oligonucleotide containing about 12 to about 26 contiguous ribose groups linked by achiral 5′ to 3′ internucleoside phosphodiester linkages, wherein
a) at least one ribose group of said at least one modified antisense oligonucleotide has a modified 2′ substituent, wherein said 2′ substituent is selected from the group consisting of methoxy, propoxy, methoxy-ethoxy, fluorine, chlorine, bromine, and iodine,
b) the 3′ end of said at least one modified antisense oligonucleotide is end-blocked with an alkyl or an alcohol group,
c) said at least one modified antisense oligonucleotide is complementary to a region of an influenza virus gene that encodes a NS1 protein,
d) said antisense oligonucleotide inhibits gene expression by blocking translation of mRNA; and,
an excipient.
2. The method of claim 1 , wherein said composition comprises a plurality of modified oligonucleotides.
3. The method of claim 2 , wherein said plurality of oligonucleotides comprises:
more than one oligonucleotide targeted to a first influenza viral gene, wherein each of said more than one oligonucleotide targeted to a first influenza viral gene is independently complementary to the 5′ UTR region, translational start site, the 3′ UTR, or translational termination site of said first influenza viral gene; and,
at least one oligonucleotide targeted to a second influenza viral gene, wherein each of said at least one oligonucleotide targeted to a second influenza viral gene is independently complementary to the 5′ UTR region, translational start site, the 3′ UTR, translational termination site or transcription start site of said second influenza viral gene.
4. The method of claim 1 , wherein at least one modified oligonucleotide comprises SEQ ID NO: 21.
5. The method of claim 1 , wherein said 2′ substituent is selected from the group consisting of methoxy, propoxy, and methoxy-ethoxy.
6. The method of claim 1 , wherein said 3′ end is end-blocked with a butanol.
7. The method of claim 1 , wherein said animal is human.
8. The method of claim 1 , wherein each ribose group of said at least one modified oligonucleotide comprises said modified 2′ substituent.
9. The method of claim 8 , wherein said 2′ substituent of each said ribose group is methoxy, propoxy, or methoxy-ethoxy.
10. The method of claim 2 , wherein each of said plurality of oligonucleotides is an antisense oligonucleotide.
11. The method of claim 3 , wherein each of said more than one oligonucleotides targeted to said first influenza viral gene is an antisense oligonucleotide.
12. The method of claim 3 , wherein each of said at least one oligonucleotides targeted to said second influenza viral gene is an antisense oligonucleotide.
13. The method of claim 3 , wherein said more than one oligonucleotide targeted to said first influenza viral gene comprises a combination of oligonucleotides complementary to the 5′ UTR region, translational start site, the 3′ UTR, and translational termination site of said first influenza viral gene.
14. The method of claim 3 , wherein said at least one oligonucleotide targeted to said second influenza viral gene comprises a combination of oligonucleotides complementary to the 5′ UTR region, translational start site, the 3′ UTR, translational termination site and transcription start site of said second influenza viral gene.
15. The method of claim 1 , wherein said at least one modified antisense oligonucleotide is a single modified antisense oligonucleotide, such that said composition comprises one modified antisense oligonucleotide.
16. The method of claim 15 , wherein said single modified antisense oligonucleotide contains about 12 to about 26 contiguous ribose groups linked by achiral 5′ to 3′ internucleoside phosphodiester linkages, and wherein
a) each ribose group of said single modified antisense oligonucleotide comprises a 2′-O-methyl substitution,
b) the 3′ end of said single modified antisense oligonucleotide comprises a butanol end-bocking group, and
c) said single modified antisense oligonucleotide is complementary to a region of a H5N1 influenza virus gene that encodes a NS1 protein.
17. The method of claim 16 , wherein said single modified antisense oligonucleotide comprises nucleotides having the sequence of SEQ ID NO. 4, 5, 6, 7, 14, 20, 21, 111, 112, 113, or 114.
18. The method of claim 16 , wherein said single modified antisense oligonucleotide comprises nucleotides having the sequence of SEQ ID NO. 15, 16, 17, 18, 19, or 21.