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A randomized, double-blind, placebo-controlled study of an RNAi-based therapy directed against respiratory syncytial virus

DeVincenzo, John, Lambkin-Williams, Robert, Wilkinson, Tom M.A., Cehelsky, Jeffrey, Nochur, Sara, Walsh, Edward, Meyers, Rachel, Gollob, Jared and Vaishnaw, Akshay (2010) A randomized, double-blind, placebo-controlled study of an RNAi-based therapy directed against respiratory syncytial virus Proceedings of the National Academy of Sciences, 107, (19), pp. 8800-8805. (doi:10.1073/pnas.0912186107).

Record type: Article


RNA interference (RNAi) is a natural mechanism regulating protein expression that is mediated by small interfering RNAs (siRNA). Harnessing RNAi has potential to treat human disease; however, clinical evidence for the effectiveness of this therapeutic approach is lacking. ALN-RSV01 is an siRNA directed against the mRNA of the respiratory syncytial virus (RSV) nucleocapsid (N) protein and has substantial antiviral activity in a murine model of RSV infection. We tested the antiviral activity of ALN-RSV01 in adults experimentally infected with wild-type RSV. Eighty-eight healthy subjects were enrolled into a randomized, double-blind, placebo-controlled trial. A nasal spray of ALN-RSV01 or saline placebo was administered daily for 2 days before and for 3 days after RSV inoculation. RSV was measured serially in nasal washes using several different viral assays. Intranasal ALN-RSV01 was well tolerated, exhibiting a safety profile similar to saline placebo. The proportion of culture-defined RSV infections was 71.4 and 44.2% in placebo and ALN-RSV01 recipients, respectively (P = 0.009), representing a 38% decrease in the number of infected and a 95% increase in the number of uninfected subjects. The acquisition of infection over time was significantly lower in ALN-RSV01 recipients (P = 0.007 and P = 0.03, viral culture and PCR, respectively). Multiple logistic regression analysis showed that the ALN-RSV01 antiviral effect was independent of other factors, including preexisting RSV antibody and intranasal proinflammatory cytokine concentrations. ALN-RSV01 has significant antiviral activity against human RSV infection, thus establishing a unique proof-of-concept for an RNAi therapeutic in humans and providing the basis for further evaluation in naturally infected children and adults.

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Published date: 11 May 2010
Organisations: Infection Inflammation & Immunity


Local EPrints ID: 153393
ISSN: 0027-8424
PURE UUID: c50b1a2e-a771-4c33-99d2-a444ae8844e0

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Date deposited: 19 May 2010 15:44
Last modified: 18 Jul 2017 12:51

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Author: John DeVincenzo
Author: Robert Lambkin-Williams
Author: Jeffrey Cehelsky
Author: Sara Nochur
Author: Edward Walsh
Author: Rachel Meyers
Author: Jared Gollob
Author: Akshay Vaishnaw

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