Expression of human alpha1-antitrypsin in mice and dogs following AAV6 vector-mediated gene transfer to the lungs.

Publication Type:

Journal Article


Molecular therapy : the journal of the American Society of Gene Therapy, Volume 18, Issue 6, p.1165-72 (2010)


2010, alpha 1-Antitrypsin, alpha 1-Antitrypsin Deficiency, Animals, Bronchoalveolar Lavage Fluid, Center-Authored Paper, Clinical Research Division, Comparative Medicine Core Facility, Dependovirus, DNA, Complementary, Dogs, Enzyme-Linked Immunosorbent Assay, Experimental Histopathology Core Facility, Gene Therapy, Gene Transfer Techniques, Genetic Vectors, Genomics Core Facility, Humans, lung, MICE, Shared Resources


We evaluated the potential of lung-directed gene therapy for alpha1-antitrypsin (AAT) deficiency using an adeno-associated virus type 6 (AAV6) vector containing a human AAT (hAAT) complementary DNA (cDNA) delivered to the lungs of mice and dogs. The results in normal and immune-deficient mice showed that hAAT concentrations were much higher in lung fluid than in plasma, and therapeutic levels were obtained even in normal mice. However, in normal mice an immune response against the vector and/or transgene limited long-term gene expression. An AAV6 vector expressing a marker protein verified that AAV6 vectors efficiently transduced lung cells in dogs. Delivery of AAV6-hAAT resulted in low levels of hAAT in dog serum but therapeutic levels in the lung that persisted for at least 58 days to 4 months in three immunosuppressed dogs. Expression in the serum was not detectable after 45 days in one nonimmune suppressed dog. A lymphoproliferative response to AAV capsid but not to hAAT was detected even after immunosuppression. These results in mice and dogs show the feasibility of expression of therapeutic levels of AAT in the lungs after AAV vector delivery, and advocate for approaches to prevent cellular immune responses to AAV capsid proteins for persistence of gene expression in humans.