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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 107; no. 19; pp. 8800 - 8805
• Main Authors: DeVincenzo, John, Lambkin-Williams, Robert, Wilkinson, Tom, Cehelsky, Jeffrey, Nochur, Sara, Walsh, Edward, Meyers, Rachel, Gollob, Jared, Vaishnaw, Akshay
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 11.05.2010; National Acad Sciences
• Subjects: Adolescent; Adult; Antiviral Agents - metabolism; Antivirals; Biological Sciences; Cytokines; Double-Blind Method; Human respiratory syncytial virus; Humans; Immune system; Infections; Inoculation; Kaplan-Meier Estimate; Logistic Models; Medical research; Middle Aged; Mitochondria; Placebos; Proteins; Respiratory syncytial virus; Respiratory Syncytial Virus Infections - genetics; Respiratory Syncytial Virus Infections - therapy; Respiratory Syncytial Virus Infections - virology; Respiratory Syncytial Virus, Human - genetics; Respiratory syncytial viruses; Ribonucleic acid; RNA; RNA Interference; RNA, Small Interfering - genetics; Small interfering RNA; Symptoms; Treatment Outcome; Viral load; Viruses; Young Adult
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0912186107

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.