Abstract

The Animal Models Core will provide technical support to Projects I, II and III to allow for the evaluation of various in vivo strategies for adeno-associated virus-based gene therapy for ornithine transcarbamylase deficiency (OTCD). The Gene Therapy Program at the University of Pennsylvania has extensive experience with the in vivo characterization of vectors in various murine models of OTCD. In the context of this P01 application, the Animal Models Core will provide full support at all levels of the in vivo gene transfer studies including study design;animal acquisition;breeding of OTC and FRG mice, management of in-life phase of studies including organization of the study, technical support for procedures and harvesting of samples;and necropsy. The Core will maintain four colonies that include the spf[ash], spf, OTC-KO and FRG mice to support the experimental needs of Projects I, II and III.

Public Health Relevance

The Animal Models Core is pivotal to the success of this POI. The Core will expand and maintain the spf, spf[ash], OTC and FRG mouse colonies that are critical for the experiments of all three projects of this program The Core has the technical expertise to perform all animal-related experiments that have been designed to address the barriers to effective gene transfer in humans in an effort to bring AAVS to the clinic.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD057247-07
Application #
8652994
Study Section
Pediatrics Subcommittee (CHHD)
Project Start
Project End
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
7
Fiscal Year
2014
Total Cost
$103,402
Indirect Cost
$38,775

  Institution

Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104

  Publications

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

Showing the most recent 10 out of 26 publications