Assessment of F/HN-pseudotyped lentivirus as a clinically relevant vector for lung gene therapy.

Journal article

RATIONALE: 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 assessment of a lentiviral vector (simian immunodeficiency virus [SIV]) pseudotyped with the Sendai virus envelope proteins F and HN. OBJECTIVES: To place this vector onto a translational pathway to the clinic by addressing some key milestones that have to be achieved. METHODS: F/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 RESULTS: A 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. CONCLUSIONS: The 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.

Authors: Griesenbach, U; Inoue, M; Meng, C; Farley, R; Chan, M

• Publication status: Published
• Journal: American journal of respiratory and critical care medicine
• Volume: 186
• Issue: 9
• Pages: 846-856
• Publication date: 2012-11-01
• DOI: 10.1164/rccm.201206-1056oc
• EISSN: 1535-4970
• ISSN: 1073-449X
• Language: English
• Keywords: Genetic Therapy; Genetic Vectors; Simian immunodeficiency virus; Mice; Disease Models, Animal; Analysis of Variance; Female; Animals; Mice, Inbred C57BL; Lung; Gene Transfer Techniques; Cystic Fibrosis; Lentivirus; Humans