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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
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Special Emphasis Panel (ZHD1)
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University of Pennsylvania
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Ashley, Scott N; Somanathan, Suryanarayan; Hinderer, Christian et al. (2017) Alternative Start Sites Downstream of Non-Sense Mutations Drive Antigen Presentation and Tolerance Induction to C-Terminal Epitopes. J Immunol 198:4581-4587
Wang, Lili; Bell, Peter; Morizono, Hiroki et al. (2017) AAV gene therapy corrects OTC deficiency and prevents liver fibrosis in aged OTC-knock out heterozygous mice. Mol Genet Metab 120:299-305
Yang, Yang; Wang, Lili; Bell, Peter et al. (2016) A dual AAV system enables the Cas9-mediated correction of a metabolic liver disease in newborn mice. Nat Biotechnol 34:334-8
Bell, Peter; Wang, Lili; Chen, Shu-Jen et al. (2016) Effects of Self-Complementarity, Codon Optimization, Transgene, and Dose on Liver Transduction with AAV8. Hum Gene Ther Methods 27:228-237
Wang, Lili; Bell, Peter; Somanathan, Suryanarayan et al. (2015) Comparative Study of Liver Gene Transfer With AAV Vectors Based on Natural and Engineered AAV Capsids. Mol Ther 23:1877-87
Bissig-Choisat, Beatrice; Wang, Lili; Legras, Xavier et al. (2015) Development and rescue of human familial hypercholesterolaemia in a xenograft mouse model. Nat Commun 6:7339
Mays, Lauren E; Wang, Lili; Lin, Jianping et al. (2014) AAV8 induces tolerance in murine muscle as a result of poor APC transduction, T cell exhaustion, and minimal MHCI upregulation on target cells. Mol Ther 22:28-41
Mikals, Kyle; Nam, Hyun-Joo; Van Vliet, Kim et al. (2014) The structure of AAVrh32.33, a novel gene delivery vector. J Struct Biol 186:308-17
Bryant, Laura M; Christopher, Devin M; Giles, April R et al. (2013) Lessons learned from the clinical development and market authorization of Glybera. Hum Gene Ther Clin Dev 24:55-64
Zhong, Li; Malani, Nirav; Li, Mengxin et al. (2013) Recombinant adeno-associated virus integration sites in murine liver after ornithine transcarbamylase gene correction. Hum Gene Ther 24:520-5

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