PROJECT I - IMMUNE BARRIERS TO AAV GENE THERAPY The performance of novel AAV serotypes, with the use of the self complementing genome, has vastly improved the prospects of successful liver-directed in vivo gene therapy. Despite these encouraging data, a number of potential barriers remain, primarily focused on the immunologic biology of in vivo gene therapy. This project will systemically address the immunologic response to in vivo gene therapy of novel AAVs as a prerequisite to their considerations in clinical applications. The first specific aim will focus on the identification of a clinical candidate which is defined as the actual vector to be considered in the Phase 1 clinical trial. The two components of the vector that will be extensively studied and optimized are: 1) the capsid, evaluated for efficiency and stability of gene transfer, toxicity, transgene and capsid T cells, pre-existing immunity and biodistribution;and 2) the genome, evaluated for peak and onset of expression. The second specific aim will analyze the role of pre-existing T cells to AAV capsids in terms of the safety and efficacy of liver-directed gene transfer. The third specific aim will evaluate the role of the target organ in eliciting problematic immunologic responses, specifically focusing on activation of innate immunity or inflammation. These studies will focus on murine systems in establishing basic principles which are followed up selectively in nonhuman primates. The project will extensively use the Vector and Morphology Cores and will collaborate directly with Project II on the evaluation of vector efficacy in the OTC-deficient mouse model and with Project III by providing NHP tissue for molecular characterization. Lay description. A vector of use for the treatment of OTC deficiency called the clinical candidate will be created. Potential immunologic responses of the recipient to the vector will be studied.
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