This is an application from the University of Pennsylvania and the Children's National MedicalCenter to renew funding of an existing P01 entitled "Gene Therapy of Urea Cycle Disorders." We achieved the primary objectives of the current 4 year cycle of this P01. A Clinical Candidate vector was established: AAVS expressing a codon-optimized cDNA for ornithine transcarbamylase (OTC) from the liver-specific TBG promoter. In close consultation with our Ethics Advisory Board, it was decided to initially evaluate the Clinical Candidate in a phase I clinical trial in infants with late onset but severe OTC deficiency (OTCD). We will be using mechanisms to fund the clinical trial separate from this P01 competing renewal. In the conduct of our preclinical studies, we identified several issues that should be addressed before considering clinical trials in those with severe OTCD who present with life-threatening episodes of hyperammonemia as neonates. High level gene transfer in newborn mice and monkeys is acheivable, however, it diminishes to low levels due to dilution in the setting of the developing newborn liver. We also have concerns about T cell responses to some neonatal onset subjects since they may have null alleles that fail to delete T cells reactive to the normal version of OTC. Finally, some newborns will have pre-existing immunity to AAVS due to passive transfer of maternal antibodies. Project I will address issues related to T cell responses to transgene-encoded OTC and will attempt to engineer the vector genome to allow for replication when the target cell population is proliferating. Project II will evaluate novel pharmacologic interventions that could augment the efficacy of gene therapy that is less than curative. Project III will engineer the AAVS capsid to escape some level of pre-existing neutralizing antibodies. These Projects will be supported by Core laboratories that specialize in Vector, Cell Morphology and Animal Models. The deliverable at the end of the renewal application is a second generation Clinical Candidate which, in the setting of adjuvant pharmacologic therapy, is suitable for evaluation in humans with neonatal onset OTCD.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
Project #
Application #
Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Oster-Granite, Mary Lou
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
Schools of Medicine
United States
Zip Code
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
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
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
Wang, L; Wang, H; Morizono, H et al. (2012) Sustained correction of OTC deficiency in spf(?ash) mice using optimized self-complementary AAV2/8 vectors. Gene Ther 19:404-10
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
Wang, Lili; Morizono, Hiroki; Lin, Jianping et al. (2012) Preclinical evaluation of a clinical candidate AAV8 vector for ornithine transcarbamylase (OTC) deficiency reveals functional enzyme from each persisting vector genome. Mol Genet Metab 105:203-11
Wang, Lili; Bell, Peter; Lin, Jianping et al. (2011) AAV8-mediated hepatic gene transfer in infant rhesus monkeys (Macaca mulatta). Mol Ther 19:2012-20
Bell, Peter; Wang, Lili; Gao, Guangping et al. (2011) Inverse zonation of hepatocyte transduction with AAV vectors between mice and non-human primates. Mol Genet Metab 104:395-403
Wang, Lili; Calcedo, Roberto; Bell, Peter et al. (2011) Impact of pre-existing immunity on gene transfer to nonhuman primate liver with adeno-associated virus 8 vectors. Hum Gene Ther 22:1389-401

Showing the most recent 10 out of 19 publications