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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD057247-06
Application #
8474803
Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Oster-Granite, Mary Lou
Project Start
2008-04-01
Project End
2017-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
6
Fiscal Year
2013
Total Cost
$1,068,145
Indirect Cost
$297,897
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Wang, Lili; Wang, Huan; Bell, Peter et al. (2012) Hepatic gene transfer in neonatal mice by adeno-associated virus serotype 8 vector. Hum Gene Ther 23:533-9
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

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