A phase I study of aerosolized administration of tgAAVCF to cystic fibrosis subjects with mild lung disease

Cystic fibrosis (CF) is one of the most common autosomal recessive disorder s in North America, leading to significant morbidity and early mortality. T he defect in the cystic fibrosis transmembrane conductance regulator protei n (CFTR) function can be corrected in vitro by gene replacement with a wild -type gene. A Phase I, single administration, dose escalation trial was des igned and executed to assess safety and delivery of tgAAVCF, an adeno-assoc iated virus (AAV) vector encoding the human CFTR cDNA, by nebulization to t he lungs of CF subjects. Four cohorts of three subjects each were administe red increasing doses of the study agent, beginning with 10(10) DNase-resist ant particles (DRP) and escalating in log increments up to 10(13) DRP. Sequ ential bronchoscopies were performed to gather analytical samples throughou t 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 wh ich 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 10(13) DRP tgAAVCF, and this decli ned to nearly undetectable levels by day 90. Vector gene transfer was evenl y 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 t o the proximal airways of CF subjects by nebulization.