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ABSTRACT: 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.
SUBMITTER: Griesenbach U
PROVIDER: S-EPMC3530223 | biostudies-literature | 2012 Nov
REPOSITORIES: biostudies-literature
American journal of respiratory and critical care medicine 20120906 9
<h4>Rationale</h4>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.<h4>Objectives</h4>To place this vector onto a translational pathway to the clinic by addressing some key milestones that have to be achieved.<h4>Methods</h4>F/HN-SIV transduction efficie ...[more]