DeVincenzo John, Cehelsky Jeffrey E, Alvarez Rene, Elbashir Sayda, Harborth Jens, Toudjarska Iva, Nechev Lubomir, Murugaiah Veeravagu, Van Vliet Andre, Vaishnaw Akshay K, Meyers Rachel
Department of Pediatrics, University of Tennessee Health Science Center, 50 North Dunlap, Memphis, TN 38103, USA.
Antiviral Res. 2008 Mar;77(3):225-31. doi: 10.1016/j.antiviral.2007.11.009. Epub 2007 Dec 26.
Small interfering RNAs (siRNAs) work through RNA interference (RNAi), the natural RNA inhibitory pathway, to down-regulate protein production by inhibiting targeted mRNA in a sequence-specific manner. ALN-RSV01 is an siRNA directed against the mRNA encoding the N-protein of respiratory syncytial virus (RSV) that exhibits specific in vitro and in vivo anti-RSV activity. The results of two safety and tolerability studies with ALN-RSV01 involving 101 healthy adults (65 active, 36 placebo, single- and multiple dose, observer-blind, randomized dose-escalation) are described. Intranasal administration of ALN-RSV01 was well tolerated over a dose range up through 150mg as a single dose and for five daily doses. Adverse events were similar in frequency and severity to placebo (normal saline) and were transient, mild to moderate, with no dose-dependent trend. The frequency or severity of adverse events did not increase with increasing ALN-RSV01 exposure. All subjects completed all treatments and assessments with no early withdrawals or serious adverse events. Physical examinations, vital signs, ECGs and laboratory tests were normal. Systemic bioavailability of ALN-RSV01 was minimal. ALN-RSV01 appears safe and well tolerated when delivered intranasally and is a promising therapeutic candidate for further clinical development.
小干扰RNA(siRNA)通过RNA干扰(RNAi)发挥作用,RNAi是一种天然的RNA抑制途径,通过以序列特异性方式抑制靶向mRNA来下调蛋白质生成。ALN-RSV01是一种针对呼吸道合胞病毒(RSV)N蛋白编码mRNA的siRNA,在体外和体内均表现出特异性抗RSV活性。本文描述了两项关于ALN-RSV01的安全性和耐受性研究结果,涉及101名健康成年人(65名接受活性药物,36名接受安慰剂,单剂量和多剂量,观察者盲法,随机剂量递增)。鼻内给予ALN-RSV01,在高达150mg的单剂量和每日五次剂量的范围内耐受性良好。不良事件在频率和严重程度上与安慰剂(生理盐水)相似,且为短暂性,轻度至中度,无剂量依赖性趋势。不良事件的频率或严重程度并未随着ALN-RSV01暴露量的增加而增加。所有受试者均完成了所有治疗和评估,无提前退出或严重不良事件。体格检查、生命体征、心电图和实验室检查均正常。ALN-RSV01的全身生物利用度极低。鼻内给药时,ALN-RSV01似乎安全且耐受性良好,是进一步临床开发中一个有前景的治疗候选药物。