• Uta Griesenbach, Makoto Inoue, Cuixiang Meng, Raymond Farley, Mario Chan, Nikki K Newman, Andrea Brum, Jun You, Angela Kerton, Amelia Shoemark, A Christopher Boyd, Jane C Davies, Tracy E Higgins, Deborah R Gill, Stephen C Hyde, J Alastair Innes, David J Porteous, Mamoru Hasegawa, and Eric W F W Alton.
• Department of Gene Therapy, Imperial College at the National Heart and Lung Institute, Manresa Road, London, UK.
• Am. J. Respir. Crit. Care Med. 2012 Nov 1; 186 (9): 846856846-56.

RationaleOngoing 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 assessment of a lentiviral vector (simian immunodeficiency virus [SIV]) pseudotyped with the Sendai virus envelope proteins F and HN.ObjectivesTo place this vector onto a translational pathway to the clinic by addressing some key milestones that have to be achieved.MethodsF/HN-SIV transduction efficiency, duration of expression, and toxicity were assessed in mice. In addition, F/HN-SIV was assessed in differentiated human air-liquid interface cultures, primary human nasal epithelial cells, and human and sheep lung slices.Measurements And Main ResultsA single dose produces lung expression for the lifetime of the mouse (~2 yr). Only brief contact time is needed to achieve transduction. Repeated daily administration leads to a dose-related increase in gene expression. Repeated monthly administration to mouse lower airways is feasible without loss of gene expression. There is no evidence of chronic toxicity during a 2-year study period. F/HN-SIV leads to persistent gene expression in human differentiated airway cultures and human lung slices and transduces freshly obtained primary human airway epithelial cells.ConclusionsThe data support F/HN-pseudotyped SIV as a promising vector for pulmonary gene therapy for several diseases including CF. We are now undertaking the necessary refinements to progress this vector into clinical trials.

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