Adenovirus-Mediated Transfer of the CFTR Gene to Lung of Nonhuman Primates: Biological Efficacy Study

Abstract

We have evaluated the biological efficacy of E1-deleted adenoviruses in baboons for lung-directed gene therapy of cystic fibrosis (CF). The experimental design attempted to simulate a phase I clinical trial with animals receiving a single dose of virus to an isolated pulmonary segment. A total of 14 animals divided into four groups, each of which received escalating doses of virus, were used. Individual animals were necropsied 4 and 21 days after gene transfer and tissues were carefully surveyed for gene expression. Expression of the transgene was localized primarily to the area into which it was infused; the efficiency of recombinant gene expression and the abundance of transgene sequences were proportional to dose and both diminished with time. Transgene expression was found predominantly in alveolar cells with patches of expression in the proximal and distal airway. Analysis of adenoviral protein expression within transgene-expressing cells revealed infrequent expression of the E2a gene and no detectable expression of late genes (i.e., fiber protein). These results suggest that recombinant adenovirus can be used to transfer genes efficiently to the lung of nonhuman primates and that therapeutic strategies of cystic fibrosis may require repetitive administration with current vectors. Recombinant adenoviruses hold tremendous promise for gene therapies of lung disease in cystic fibrosis (CF). An evaluation of the feasibility and safety of this technology in nonhuman primates is critical in the design of clinical protocols. In a series of two papers, Wilson and colleagues describe an extensive study in baboons designed to evaluate the feasibility and safety of direct instillation of CF transmembrane conductance regulator (CFTR)-expressing adenoviruses into the airway. This paper by Engelhardt et al., addresses the biological efficacy of E1-deleted adenoviruses for gene therapy of CF lung disease.