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Inhibition of respiratory viruses by nasally administered siRNA

Abstract

Respiratory syncytial virus (RSV) and parainfluenza virus (PIV) are two respiratory pathogens of paramount medical significance that exert high mortality. At present, there is no reliable vaccine or antiviral drug against either virus. Using an RNA interference (RNAi) approach, we show that individual as well as joint infection by RSV and PIV can be specifically prevented and inhibited by short interfering RNAs (siRNAs), instilled intranasally in the mouse, with or without transfection reagents. The degree of protection matched the antiviral activity of the siRNA in cell culture, allowing an avenue for quick screening of an efficacious siRNA. When targeting both viruses in a joint infection, excess of one siRNA moderated the inhibitory effect of the other, suggesting competition for the RNAi machinery. Our results suggest that, if properly designed, low dosages of inhaled siRNA might offer a fast, potent and easily administrable antiviral regimen against respiratory viral diseases in humans.

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Figure 1: Titration of antiviral siRNAs ex vivo.
Figure 2: Knockdown of viral antigens in siRNA-treated mouse lung without IFN activation.
Figure 3: Competitive viral inhibition at high siRNA concentration in dual infection by RSV and PIV.
Figure 4: Relief of lung pathology and reduction of an asthma marker in siRNA#1-treated mice.
Figure 5: Therapeutic effect of siRNA in RSV disease.

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Acknowledgements

We thank A. Gard for use of the immunofluorescence microscope, S. Moyer (University of Florida) for a fresh HPIV3 inoculum, S. Pfeffer and T. Tuschl (Rockefeller University, NY) for advice on small RNA isolation, M. Ramaswamy (University of Iowa) for information on RSV-IFN relationship, R. Meyers (Alnylam Pharmaceuticals, Cambridge) for critical comments, and T. Barik for figure preparation. This research was supported in part by a grant from National Eye Institute (EY013826) and a NRSA Fellowship (AI049682) from the National Institute of Allergy and Infectious Diseases (NIH). Preliminary results were presented in the Keystone Symposium on “siRNAs and miRNAs,” April 14–19, 2004, Keystone, Colorado, USA.

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Correspondence to Sailen Barik.

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Bitko, V., Musiyenko, A., Shulyayeva, O. et al. Inhibition of respiratory viruses by nasally administered siRNA. Nat Med 11, 50–55 (2005). https://doi.org/10.1038/nm1164

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