Assessment of F/HN-Pseudotyped Lentivirus as a Clinically Relevant Vector for Lung Gene Therapy
File(s)
Author(s)
Type
Journal Article
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.
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.
Date Issued
2012-11-01
Date Acceptance
2012-08-21
Citation
American Journal of Respiratory and Critical Care Medicine, 2012, 186 (9), pp.846-856
ISSN
1535-4970
Publisher
American Thoracic Society
Start Page
846
End Page
856
Journal / Book Title
American Journal of Respiratory and Critical Care Medicine
Volume
186
Issue
9
Copyright Statement
© 2012 by the American Thoracic Society
Subjects
Science & Technology
Life Sciences & Biomedicine
Critical Care Medicine
Respiratory System
General & Internal Medicine
CRITICAL CARE MEDICINE
RESPIRATORY SYSTEM
lentivirus
cystic fibrosis
gene therapy
lung
gene transfer
CYSTIC-FIBROSIS
SENDAI-VIRUS
MOUSE AIRWAYS
EXPRESSION
EPITHELIUM
IMMUNODEFICIENCY
ENVELOPES
PROGRESS
Publication Status
Published