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.