A phase I study of adenovirus-mediated transfer of the human cystic fibrosis transmembrane conductance regulator gene to a lung segment of individuals with cystic fibrosis

A third-generation adenoviral vector containing recombinant human cystic fi brosis transmembrane conductance regulator (CFTR) gene was delivered by bro nchoscope in escalating doses to the conducting airway of 11 volunteers wit h cystic fibrosis, Assessments of dose-limiting:toxicity (DLT), efficiency of gene transfer, and cell-mediated and humoral immune responses to vector administration were performed. DLT, manifest by flulike symptoms and transi ent radiographic infiltrates,was seen at 2.1 x 10(11) total viral particles . A highly specific assay for gene transfer was developed using in, situ hy bridization with an oligoprobe against unique vector sequence. Detectable g ene transfer was observed in harvested bronchial epithelial cells (<1%) 4 d ays after vector instillation, which diminished to undetectable levels by d ay 43. Adenovirus-specific cell-mediated T-cells were induced in most subje cts, although only mild increases in systemic humoral immune response were observed. These results demonstrate that gene transfer: to epithelium of th e lower respiratory tract can be achieved in humans with adenoviral vectors but that efficiency is low and of short duration in the native CF airway.