Compositions for treating respiratory viral infections and their use
Inventors
Tang, Qingquan • Lu, Patrick • Woodle, Martin • Zheng, Bojian
Assignees
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Publication Number
US-8691781-B2
Publication Date
2014-04-08
Expiration Date
Abstract
The invention provides siRNA compositions that interfere with viral replication in respiratory viral infections, including respiratory syncytial virus and avian influenza A, including the H5N1 strain. The invention further provides uses of the siRNA compositions to inhibit expression of viral genes in respiratory virus-infected cells, and to uses in the treatment of respiratory virus infections in a subject. Generally the invention provides polynucleotide that includes a first nucleotide sequence of 15 to 30 bases that targets the genome of a respiratory syncytial virus or an influenza A virus, a complement thereof, a double stranded polynucleotide or a hairpin polynucleotide. Additionally the invention provides vectors, cells and pharmaceutical compositions containing siRNA sequences.
Core Innovation
The invention provides isolated siRNA molecules selected from specific paired sequences defined by SEQ ID No. 258 and its complementary sequence, and by paired sequences consisting of SEQ ID No. 262 and its complementary sequence. The siRNA is directed to respiratory viral infections, including respiratory syncytial virus (RSV) and influenza A, and includes sequence sets listed in the patent tables by SEQ ID NOS.
The disclosed siRNA molecules and related polynucleotides include forms described as linear polynucleotide, hairpin polynucleotide, and double stranded polynucleotide, including optional 3'2 dinucleotide overhangs with examples such as dTdT. The patent explains that targeting induces RNA interference in which a RNA-induced silencing complex (RISC) cleaves viral genomic RNA, cRNA, and mRNA, thereby inhibiting viral gene expression.
The document further provides experimental results for influenza A H5N1 showing inhibition of virus production and intracellular viral RNA in cells, including MDCK cells, using siRNAs identified by sequence sets corresponding to NP and M2 genes. It also describes combinations of multiple siRNAs targeting different influenza genes and reports strong reductions in virus production and intracellular viral RNA at certain conditions described in the examples.
Claims Coverage
The independent claim covers an isolated siRNA molecule selected from specific paired sequence sets defined by two SEQ ID No. pairings (SEQ ID No. 258 with its complementary sequence, and SEQ ID No. 262 with its complementary sequence). The dependent claims further refine the sequence selection, structural features, and application/formulation aspects, including a 3'2 dinucleotide overhang and specific overhang composition, and extend to pharmaceutical composition carriers and inhibiting replication of an H5N1 avian Influenza A virus in infected cells.
Isolated siRNA from paired SEQ ID sequence sets
An isolated siRNA molecule selected from the group consisting of paired sequences consisting of SEQ ID No. 258 and its complementary sequence, and paired sequences consisting of SEQ ID No. 262 and its complementary sequence.
Additional paired siRNA sequence pair
A paired sequence set comprising SEQ ID No. 260 and its complementary sequence, SEQ ID No. 261.
3'2 dinucleotide overhang at both 3'2 ends
The siRNA molecule includes a dinucleotide overhang bound to the 3'2 end of both sequences.
dTdT dinucleotide overhang
The dinucleotide overhang is made of dTdT.
Pharmaceutical composition with specified carriers
A pharmaceutical composition in which the carrier is chosen from histidine-lysine co-polymer, PEGylated polyethyleneimine, glucose, DOTAP, or DOTAP/cholesterol.
Inhibiting H5N1 replication by contacting infected cells
A method of inhibiting replication of an H5N1 avian Influenza A virus in an infected cell by contacting the cell with the siRNA molecule of the claim.
Across the independent and dependent claims, the coverage is centered on isolated siRNA defined by specific paired sequence sets, with additional dependent refinements adding further paired sequences, a specified 3'2 dinucleotide overhang including dTdT, and extending to pharmaceutical compositions using enumerated carriers and to inhibiting replication of an H5N1 avian Influenza A virus in infected cells.
Stated Advantages
Inhibits viral gene expression via RNA interference mediated by RISC cleavage of viral genomic RNA, cRNA, and mRNA.
Reduces virus production and intracellular viral RNA for influenza A H5N1 in cells, as reported in examples.
Documented Applications
Inhibition of replication of an H5N1 avian Influenza A virus in an infected cell by contacting the cell with the siRNA molecule.
Use of siRNA compositions, including gene-targeting sets such as NP and M2, to show reduced virus production and reduced intracellular viral RNA in MDCK cells in the documented examples.
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