Assessment of F/HN-Pseudotyped Lentivirus in a Clinically Relevant Vector for Lung Gene Therapy

Griesenbach U, Inoue M, Meng C, Farley R, Chan M, Newman NK, Brum A, Kerton A, Shoemark A, Boyd AC, Davies JC, Higgins T, Gill DR, Hyde SC, Innes JA, Porteous DJ, Hasegawa M, Alton EW

Pediatic Pulmonology, 47 S35 Abstract 206

The North American Cystic Fibrosis Conference, Orlando, 2012

Our ongoing efforts to improve pulmonary gene transfer for the treat- ment of lung diseases such as cystic fibrosis (CF) have led to the develop- ment of a lentiviral vector (SIV) pseudotyped with the Sendai virus envelope proteins F and HN (Kobayashi, J Virol, Mitomo. Mol Therapy 2010). Mov- ing novel therapies to the clinic requires that relevant evidence for both safe- ty and efficacy is gathered in appropriate models. Here, we begin to place this vector onto a translational pathway to the clinic and provide a body of supportive evidence for F/HN-pseudotyped SIV as a potential gene transfer agent for CF. These include: (1) a single dose produces lung expression for the lifetime of the mouse (approximately 2 years), (2) only brief contact time (seconds) is needed to achieve transduction, (3) repeated daily admin- istration 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) 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. The data support F/HN-SIV as a promising vector for pulmonary gene therapy for a number of diseases including CF and we are now undertaking the necessary refine- ments to progress this vector into clinical trials.