Assessment of F/HN-pseudotyped Lentivirus as a Clinically Relevant Vector For Lung Gene Therapy

Rational Our ongoing efforts to improve pulmonary gene transfer thereby enabling gene therapy for the treatment of lung diseases such as cystic fibrosis (CF) has led to the development of a lentiviral vector (SIV) pseudotyped with the Sendai virus envelope proteins F and HN.

Objectives Here, we begin to place this vector onto a translational pathway to the clinic, by addressing some key milestones that have to be achieved.

Main results These include: (1) a single dose produces lung expression for the life-time of the mouse (approximately 2 years), (2) only brief contact time is needed to achieve transduction, (3) repeated daily administration leads to a dose-related increase in gene expression, (4) repeated monthly administration to mouse lower airways is feasible without loss of gene expression, (5) there is no evidence of chronic toxicity during a 2 year study period, (6) F/HN-SIV transduction generates persistent gene expression in human differentiated airway cultures, and human lung slices and transduces freshly obtained primary human airway epithelial cells.

Conclusions The data support F/HN-pseudotyped SIV as a promising vector for pulmonary gene therapy for a number of diseases including CF and we are now undertaking the necessary refinements to progress this vector into clinical trials.