A new therapy based on RNA interference (RNAi) successfully reduces respiratory syncytial virus (RSV) infection in humans. The study, published free online in PNAS, demonstrates that therapeutic RNAi-based drugs are clinically effective, and suggests that similar ‘silencing’ therapies could be useful against other respiratory pathogens.
RSV is an RNA virus that infects the lungs to cause respiratory tract infections—especially in the lower respiratory tract. RSV infection can be severe in immunocompromised patients, the elderly and young children; in the US alone, the virus has a ten times higher mortality rate in young children than the influenza virus and is the most common cause of infant hospitalisation. No vaccine for RSV exists, and the only approved drug treatment, ribavirin, has limited use and effectiveness. Current treatment strategies for RSV infection are only supportive—namely oxygen and fluids until the infection naturally resolves. Previous work has shown that a small interfering RNA (siRNA) drug—called ALN-RSV01—effectively silences a RSV protein that is critical for virus replication, and has a considerable antiviral effect in a mouse model of RSV infection. Evidence for the clinical effectiveness of siRNA drugs to treat disease in humans is, however, lacking.
DeVincenzo and colleagues tested whether ALN-RSV01 was an effective antiviral drug in adult, human volunteers who were infected with wild-type RSV. The investigators enrolled 88 healthy participants into a double-blind, placebo-controlled trial. They randomly assigned the volunteers to receive a nasal spray containing either ALN-RSV01 or saline as a placebo control. This nasal spray was administered 2 days prior to, and 3 days after, inoculation with RSV. They found that treatment with the siRNA nasal spray decreased the number of people infected with RSV by 38%, with the greatest reduction in people’s symptoms between 4–7 days after RSV inoculation. This antiviral effect was not related to the concentration of proinflammatory cytokines (such as tumor necrosis factor and interferon α) in the nose or whether the participants had pre-existing antibodies against RSV. Furthermore, the scientists showed that intranasal ALN-RSV01 was well tolerated and safe to use in humans.
DeVincenzo et al. argue that their findings represent a “significant advance in the development of human therapies…[and] a definitive demonstration in humans of an RNAi effect using a synthetic siRNA.” More clinical trials are needed to determine whether intranasal ALN-RSV01 can reduce RSV infection in children and adults that are naturally infected by the virus, and to determine the optimal dose and frequency for ALN-RSV01 administration that produces the best antiviral effect and clinical outcome. The results from this study also demonstrate a “broader potential” for “locally delivered siRNAs as unique anti-infective drugs against other respiratory pathogens.”
DeVincenzo, J., Lambkin-Williams, R., Wilkinson, T., Cehelsky, J., Nochur, S., Walsh, E., Meyers, R., Gollob, J., & Vaishnaw, A. (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 DOI: 10.1073/pnas.0912186107