Journal Article

RNA Interference Therapy in Lung Transplant Patients Infected with Respiratory Syncytial Virus

Cehelsky, Jeffrey, Budev, Marie, Gottlieb, Jens, DeVincenzo, John, Albert, Gary, Zamora, Martin R., Vaishnaw, Akshay, Glanville, Allan R., Humar, Atul, Nochur, Sara, Gollob, Jared A., Rolfe, Mark

2011

Overview

Abstract Rationale Lower respiratory tract infections due to respiratory syncytial virus (RSV) are associated with development of bronchiolitis obliterans syndrome in lung transplant (LTX) recipients. ALN-RSV01 is a small interfering RNA targeting RSV replication. Objectives To determine the safety and explore the efficacy of ALN-RSV01 in RSV infection. Methods We performed a randomized, double-blind, placebo-controlled trial in LTX recipients with RSV respiratory tract infection. Patients were permitted to receive standard of care for RSV. Aerosolized ALN-RSV01 (0.6 mg/kg) or placebo was administered daily for 3 days. Viral load was determined by quantitative reverse transcriptase–polymerase chain reaction on serial nasal swabs. Patients completed symptom score cards twice daily. Lung function, including the incidence of new-onset or progressive bronchiolitis obliterans syndrome, was recorded at Day 90. Measurements and Main Results We enrolled 24 patients (ALN-RSV01, n = 16; placebo, n = 8); randomization was stratified by ribavirin use. ALN-RSV01 was well tolerated, with no drug-related serious adverse events or post-inhalation perturbations in lung function. Interpretation of viral measures was confounded by baseline differences between the two groups in viral load and time from symptom onset to first dose. Mean daily symptom scores were lower in subjects receiving ALN-RSV01, and the mean cumulative daily total symptom score was significantly lower with ALN-RSV01 (114.7 ± 63.13 vs. 189.3 ± 99.59, P = 0.035). At Day 90, incidence of new or progressive bronchiolitis obliterans syndrome was significantly reduced in ALN-RSV01 recipients compared with placebo (6.3% vs. 50%, P = 0.027). Conclusions ALN-RSV01 was safe and may have beneficial effects on long-term allograft function in LTX patients infected with RSV. Clinical trial registered with www.clinicaltrials.gov (NCT00658086).

• Publisher: Oxford University Press,American Thoracic Society
• Subject: Administration, Inhalation / Adolescent / Adults / Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy / Antiviral Agents - therapeutic use / Biological and medical sciences / Bronchiolitis Obliterans - complications / Bronchiolitis Obliterans - prevention & control / C-Reactive Protein - drug effects / Cytokines - blood / Cytokines - drug effects / Double-Blind Method / Drug dosages / Emergency and intensive respiratory care / Follow-Up Studies / Humans / Infections / Intensive care medicine / Lung Transplantation / Lung transplants / Medical sciences / Patients / Polymerase chain reaction / Respiratory Function Tests / Respiratory syncytial virus / Respiratory Syncytial Virus Infections - blood / Respiratory Syncytial Virus Infections - complications / Respiratory Syncytial Virus Infections - therapy / Reverse Transcriptase Polymerase Chain Reaction / RNA Interference - drug effects / RNA, Small Interfering - therapeutic use / Steroids / Syndrome / Treatment Outcome / Young Adult