The Pathology Core of the University of Florida Gene Therapy Center was formed to assist investigators participating in gene therapy projects aimed at reversing and preventing genetic and metabolic disasters. These diseases have included cystic fibrosis, alpha-1-antitrypsin deficiency, and type 1 diabetes. Specifically, the Pathology Core supports these investigators by performing histopathological analyses that characterize the host's cell/tissue response to agents proposed for or actively used in clinical trials based on gene therapy. This program project proposes to study gene therapy applications for acyl-CoA dehydrogenase (ACD) and acid alpha-glucosidase (GAA) deficiencies and lentivirus transgene delivery. The goals of the Pathology Core will be accomplished by performance of four specific aims: 1) Determine the tissue compartments of virus engraftment in host tissues; 2) Determine the toxicity of treatment protocols to endogenous host tissues; 3) Determine the potential beneficial effects of transgene expression on liver and muscle pathology in rodent models of metabolic disease (ACD and GAA deficiencies); and 4) Determine the biodistribution of rAAV and lentiviral vectors. Such studies are vital in order to evaluate whether gene therapy successfully transduces a particular population or proportion of cells and to determine the extent to which gene therapy induces inflammatory responses against vector capsid proteins and transgene products. Centralization of the morphologic studies, and especially the histopathology/toxicology program, enables rigorous assessment of whether host toxicity develops as a result of these treatment algorithms. Efficiency of analyses for immunolocalization of transgenes and biodistribution studies also is maximized through the use of the Pathology Core. Specific examples of vector based systems to which these services will be provided include the rAAV-ACDs and lacZ transgene expression in murine models. In addition to providing a critical element for assurance of safety, the Pathology Core should provide information that will enhance the feasibility and efficacy of gene delivery trials.
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