The Molecular Pathology and Immunology Core of the University of Florida assists investigators participating in gene therapy projects aimed at reversing and/or preventing liver diseases, metabolic disorders, cystic fibrosis, alpha-1-antitrypsin (AAT) deficiency, and diabetes. Specifically, the Core supports these investigations by performing pathological and immunological analyses that characterize the host's immune system and cell/tissue responses to vectors and transgenes proposed for or currently used in experimental and preclinical studies. This goal will be accomplished by performance of three specific aims: 1) Determine the site(s) of viral vector and adult stem cell engraftment and toxicity in host tissues with respect to administration site, vector dose, and treatment duration. 2) Determine the potential beneficial effects of transgene expression in rodent models of 1-antitrypsin (AAT) deficiency, glycogen storage diseases, and other genetic and metabolic disorders. 3) Determine the immunogenicity of rAAV transgene products and capsid molecules administered to animals in studies investigating long-term therapeutic gene transfer and expression. Such studies are vital in order to evaluate whether rAAV therapy successfully ameliorates the pro-inflammatory environment within the site of administration and to determine the extent to which rAAV therapy induces acute inflammation or cytotoxicity or spreads hematogenously outside the site of administration. Centralization of the morphological studies, and standardization of the histopathological and toxicological determinants, enables rigorous assessment of host toxicity as a result of these treatment algorithms. Procedures include standard immunoassays, histopathology, histochemistry, immunohistochemistry, and FISH in mouse, rat, rabbit, primate, and cat models. In addition to providing a critical element for assurance of therapeutic safety, the Core should provide information that will enhance the feasibility and efficacy of gene delivery trials to the hepatocyte.
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