Affiliation:
1. Institute for Human Gene Therapy and Departments of Medicine and Molecular and Cellular Engineering, University of Pennsylvania Health System, and The Wistar Institute, Philadelphia, Pennsylvania 19104
Abstract
ABSTRACT
Immune responses to vector-corrected cells have limited the application of gene therapy for treatment of chronic disorders such as inherited deficiency states. We have found that recombinant adeno-associated virus (AAV) efficiently transduces muscle fibers in vivo without activation of cellular and humoral immunity to neoantigenic transgene products such as β-galactosidase, which differs from the experience with recombinant adenovirus, where vibrant T-cell responses to the transgene product destroy the targeted muscle fibers. T cells activated following intramuscular administration of adenovirus expressing
lacZ
(Ad
lacZ
) can destroy AAV
lacZ
-transduced muscle fibers, indicating a prior state of immunologic nonresponsiveness in the context of AAV gene therapy. Adoptive transfer of dendritic cells infected with Ad
lacZ
leads to immune mediated elimination of AAV
lacZ
-transduced muscle fibers. AAV
lacZ
-transduced antigen-presenting cells fail to demonstrate β-galactosidase activity and are unable to elicit transgene immunity in adoptive transfer experiments. These studies indicate that vector-mediated transduction of dendritic cells is necessary for cellular immune responses to muscle gene therapy, a step which AAV avoids, providing a useful biological niche for its use in gene therapy.
Publisher
American Society for Microbiology
Subject
Virology,Insect Science,Immunology,Microbiology
Cited by
408 articles.
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