Laboratory of Immunology and Developmental Biology, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892; and Influenza Branch, Division of Viral and Rickettsial Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333

Communicated by Herman N. Eisen, Massachusetts Institute of Technology, Cambridge, MA, April 13, 2004 (received for review March 18, 2003)

Influenza virus infection is responsible for hundreds of thousands of deaths annually. Current vaccination strategies and antiviral drugs provide limited protection; therefore, new strategies are needed. RNA interference is an effective means of suppressing virus replication in vitro. Here we demonstrate that treatment with small interfering RNAs (siRNAs) specific for highly conserved regions of the nucleoprotein or acidic polymerase inhibits influenza A virus replication in vivo. Delivery of these siRNAs significantly reduced lung virus titers in infected mice and protected animals from lethal challenge. This protection was specific and not mediated by an antiviral IFN response. Moreover, influenza-specific siRNA treatment was broadly effective and protected animals against lethal challenge with highly pathogenic avian influenza A viruses of the H5 and H7 subtypes. These results indicate that RNA interference is promising for control of influenza virus infection, as well as other viral infections.

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Abbreviations: eID₅₀, egg 50% infective dose; i.n., intranasal(ly); NP, nucleoprotein; PA, acidic polymerase; RNAi, RNA interference; siRNA, small interfering RNA; TCID₅₀, tissue culture 50% infective dose.

To whom correspondence should be addressed at: Laboratory of Immunology and Developmental Biology, Division of Cellular and Gene Therapies, Office of Cellular, Tissue, and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, 1401 Rockville Pike, HFM-730, Rockville, MD 20852-1448. E-mail: epsteins@cber.fda.gov .