title: A randomized, double-blind, placebo-controlled study of an RNAi-based therapy directed against respiratory syncytial virus.
abstract: 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.
authors.affiliation: Department of Pediatrics, University of Tennessee School of Medicine, Memphis, TN 38103, USA.
authors.forename: John
authors.initials: J
authors.lastname: DeVincenzo
authors.forename: Robert
authors.initials: R
authors.lastname: Lambkin-Williams
authors.forename: Tom
authors.initials: T
authors.lastname: Wilkinson
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Cehelsky
authors.forename: Sara
authors.initials: S
authors.lastname: Nochur
authors.forename: Edward
authors.initials: E
authors.lastname: Walsh
authors.forename: Rachel
authors.initials: R
authors.lastname: Meyers
authors.forename: Jared
authors.initials: J
authors.lastname: Gollob
authors.forename: Akshay
authors.initials: A
authors.lastname: Vaishnaw
mesh_terms: D000293:Adolescent; D000328:Adult; D000998:Antiviral Agents / Q000378:metabolism; D004311:Double-Blind Method; D006801:Humans; D053208:Kaplan-Meier Estimate; D016015:Logistic Models; D008875:Middle Aged; D010919:Placebos; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D018357:Respiratory Syncytial Virus Infections / Q000235:genetics / Q000628:therapy* / Q000821:virology*; D018113:Respiratory Syncytial Virus, Human / Q000235:genetics*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D010919:Placebos; D034741:RNA, Small Interfering