RNA Interference Therapy in Lung Transplant Patients Infected with Respiratory Syncytial Virus
RNA Interference Therapy in Lung Transplant Patients Infected with Respiratory Syncytial Virus
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DOI：
10.1164/rccm.201003-0422oc
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发表时间：
2011-02-15
影响因子：
24.7
通讯作者：
Glanville, Allan R.
中科院分区：
文献类型：
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作者：
Zamora, Martin R.;Budev, Marie;Glanville, Allan R.
基本原理：呼吸道合胞病毒（RSV）引起的下呼吸道感染与肺移植（LTX）受者闭塞性细支气管炎综合征的发生相关。ALN-RSV 01是一种靶向RSV复制的小干扰RNA，目的：研究ALN-RSV 01治疗RSV感染的安全性和有效性。允许患者接受RSV标准治疗。每天给予雾化ALN-RSV 01（0.6 mg/kg）或安慰剂，持续3天。通过定量逆转录聚合酶链反应对连续鼻拭子进行病毒载量测定。患者每天填写两次症状评分卡。在第90天记录肺功能，包括新发或进行性闭塞性细支气管炎综合征的发生率。测量和主要结果：我们招募了24名患者（ALN-RSV 01，n = 16;安慰剂，n = 8）;随机化按利巴韦林使用分层。ALN-RSV 01耐受性良好，没有药物相关的严重不良事件或吸入后肺功能紊乱。两组之间病毒载量和症状发作至首次给药时间的基线差异混淆了病毒指标的解释。接受ALN-RSV 01的受试者的平均每日症状评分较低，平均累积每日总症状评分显著较低（114.7 +/- 63.13 vs. 189.3 +/- 99.59，P = 0.035）。在第90天，与安慰剂相比，ALN-RSV 01接受者新发或进行性闭塞性细支气管炎综合征的发生率显著降低（6.3% vs. 50%，P = 0.027）。结论：ALN-RSV 01是安全的，可能对RSV感染的LTX患者的长期同种异体移植物功能有有益影响。在www.clinicaltrials.gov注册的临床试验（NCT 00658086）。
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 (NCT 00658086).