title: Expression of human alpha1-antitrypsin in mice and dogs following AAV6 vector-mediated gene transfer to the lungs.
abstract: 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.
authors.affiliation: Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA.
authors.forename: Christine L
authors.initials: CL
authors.lastname: Halbert
authors.forename: David K
authors.initials: DK
authors.lastname: Madtes
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Vaughan
authors.forename: Zejing
authors.initials: Z
authors.lastname: Wang
authors.forename: Rainer
authors.initials: R
authors.lastname: Storb
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Tapscott
authors.forename: A Dusty
authors.initials: AD
authors.lastname: Miller
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D018076:DNA, Complementary; D000229:Dependovirus / Q000235:genetics*; D004285:Dogs; D004797:Enzyme-Linked Immunosorbent Assay; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D008168:Lung / Q000378:metabolism*; D051379:Mice; D000515:alpha 1-Antitrypsin / Q000235:genetics*; D019896:alpha 1-Antitrypsin Deficiency / Q000628:therapy
chemical_list: D018076:DNA, Complementary; D000515:alpha 1-Antitrypsin