A Phase I Study of Aerosolized Administration of tgAAVCF to Cystic Fibrosis Subjects with Mild Lung Disease

囊性纤维化 医学 遗传增强 不利影响 囊性纤维化跨膜传导调节器 载体(分子生物学) 气溶胶化 内科学 腺相关病毒 免疫学 胃肠病学 药理学 生物 基因 麻醉 遗传学 吸入 重组DNA
作者
Moira L. Aitken,Richard B. Moss,David A. Waltz,Mark Dovey,Mark R. Tonelli,Sharon McNamara,Ronald L. Gibson,Bonnie W. Ramsey,Barrie J. Carter,Thomas C. Reynolds
出处
期刊:Human Gene Therapy [Mary Ann Liebert]
卷期号:12 (15): 1907-1916 被引量:231
标识
DOI:10.1089/104303401753153956
摘要

Cystic fibrosis (CF) is one of the most common autosomal recessive disorders in North America, leading to significant morbidity and early mortality. The defect in the cystic fibrosis transmembrane conductance regulator protein (CFTR) function can be corrected in vitro by gene replacement with a wild-type gene. A Phase I, single administration, dose escalation trial was designed and executed to assess safety and delivery of tgAAVCF, an adeno-associated virus (AAV) vector encoding the human CFTR cDNA, by nebulization to the lungs of CF subjects. Four cohorts of three subjects each were administered increasing doses of the study agent, beginning with 1010 DNase-resistant particles (DRP) and escalating in log increments up to 1013 DRP. Sequential bronchoscopies were performed to gather analytical samples throughout the study. All 12 subjects completed the study. There were a total of 242 adverse events (AEs), six of which were defined as serious and three of which were defined as possibly being related to the study drug. A clear dose-response relationship was observed in vector gene transfer. A maximum of 0.6 and 0.1 vector copies per brushed cell were observed 14 days and 30 days, respectively, following nebulization of 1013 DRP tgAAVCF, and this declined to nearly undetectable levels by day 90. Vector gene transfer was evenly distributed throughout the fourth airway generation following single-dose administration. RNA-specific PCR did not detect vector-derived mRNA. This Phase I trial shows that aerosolized tgAAVCF is safe and widely delivered to the proximal airways of CF subjects by nebulization.
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