GENE TRANSFER OF THE CYSTIC FIBROSIS TRANSMEMBRANE REGULATOR

点击翻译按钮获取中文摘要

The host immune response and low vector efficiency are key impediments to effective cystic fibrosis transmembrane conductance regulator (CFTR) gene transfer by adenoviral and liposomal vectors, respectively. Adeno- associated virus mediated transduction of CFTR (AAV-CTR) is an attractive potential gene therapeutic agent for CF patients because of long-term expression and low pathogenicity in animal studies. AAV-CFTR was used in a phase I dose-escalation study to transfer CFTR cDNA into respiratory epithelial cells in the maxillary sinus of 10 CF patients. The maxillary sinuses are attractive for evaluating new treatments of CF because they have the same ion transport systems and microbiology as the lower respiratory tract and allow localized delivery of known concentrations of agents directly to human respiratory epithelial cells. Dose dependent gene transfer, assayed by semi-quantitative PCR, was observed at doses of greater that 1 X 10e4 replication units (RU) AAV- CFTR. At 1 X 10e5 RU AAV-CFTR, gene transfer was observed in the range of 0.1-1 vector copy per cell in biopsies obtained two weeks after treatment. Persistence was observed for up to 10 weeks. Functional restoration of the sinus transepithelial potential differences (TEPD) was observed. Dose-dependent hyperpolarization was observed in response to low chloride and isoproterenol. At 5 X 10e4 and 1 X10e5 RU AAV-CFTR, hyperpolarizations of 6.9 (+/-) 3.7 and 10.8 (+/-) 4.7 mV (mean (+/-) s.d., respectively, were observed. In contrast to adenoviral vectors, little or no immune response or inflammation was observed, even after repeat dosing. The results of this phase I study suggest that AAV-CFTR administration to the maxillary sinus results in successful, dose-dependent gene transfer to the maxillary sinus with partial correction of sinus TEFP and little or no host immune response. Based on these results, a phase II, double-blind, placebo-controlled, within-subjects study on the effect of AAV-CFTR at a dose of 1 X 10e5 RU on the clinical recurrence of sinusitis is planned. This represents the first opportunity to study the effects of CFTR gene transfer on a clinical endpoint.