RNA interference therapy in lung transplant patients infected with respiratory syncytial virus.
BACKGROUND
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.


OBJECTIVE
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.


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 (NCT 00658086).
Zamora
Martin R
MR
Department of Medicine, University of Colorado at Denver Health Sciences Center, Aurora, Colorado, USA. marty.zamora@uchsc.edu
Budev
Marie
M
Rolfe
Mark
M
Gottlieb
Jens
J
Humar
Atul
A
Devincenzo
John
J
Vaishnaw
Akshay
A
Cehelsky
Jeffrey
J
Albert
Gary
G
Nochur
Sara
S
Gollob
Jared A
JA
Glanville
Allan R
AR
D000280:Administration, Inhalation; D000293:Adolescent; D000998:Antiviral Agents / Q000627:therapeutic use*; D001989:Bronchiolitis Obliterans / Q000150:complications / Q000517:prevention & control; D002097:C-Reactive Protein / Q000187:drug effects; D016207:Cytokines / Q000097:blood / Q000187:drug effects; D004311:Double-Blind Method; D005500:Follow-Up Studies; D006801:Humans; D016040:Lung Transplantation; D034622:RNA Interference / Q000187:drug effects*; D034741:RNA, Small Interfering / Q000627:therapeutic use*; D012129:Respiratory Function Tests; D018357:Respiratory Syncytial Virus Infections / Q000097:blood / Q000150:complications / Q000628:therapy*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013577:Syndrome; D016896:Treatment Outcome; D055815:Young Adult
D000998:Antiviral Agents; D016207:Cytokines; D034741:RNA, Small Interfering; D002097:C-Reactive Protein