The goal of this application is to develop an effective gene therapy for ornithine transcarbamylase (OTC) deficiency. Studies begin with the development of an optimal AAV vector called the """"""""clinical candidate"""""""" in Project I. Additional studies will be performed in this project to evaluate potential immunologic barriers to successful liver directed gene therapy. The clinical candidate will be evaluated for safety and efficacy in OTC deficient mice and nonhuman primates in Project II. The molecular state of the vector genome and its potential oncogenicity will be studied in Project III. Cores for vector production, cell morphology, animal models, and administration will provide support to the projects. An External Scientific Advisory Committee and an Ethics Advisory Board will be convened to provide advice to the program leadership. At the completion of this four year program, the investigators hope to provide an AAV vector with preclinical data to support its translation into humans.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD057247-03
Application #
7802304
Study Section
Special Emphasis Panel (ZHD1-MRG-C (JW))
Program Officer
Oster-Granite, Mary Lou
Project Start
2008-04-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
3
Fiscal Year
2010
Total Cost
$998,305
Indirect Cost
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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
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
Wilson, James M; Shchelochkov, Oleg A; Gallagher, Renata C et al. (2012) Hepatocellular carcinoma in a research subject with ornithine transcarbamylase deficiency. Mol Genet Metab 105:263-5

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