OF DISCUSSION: This is a new application requesting four years of support to identify and evaluate the efficacy and safety of a new adeno-associated virus (AAV) expression vector for treatment of the urea cycle disorder ornithine transcarbamylase deficiency. The three component research projects aim to identify immune barriers to AAV gene therapy, perform preclinical studies of selected clinical candidate in mouse models and nonhuman primates, and evaluate liver gene transfer and its oncogenic potential. An administrative core, a vector service, a morphology resource, and an animal models facility coordinate these projects. The overall effort represents a collaborative effort between University of Pennsylvania and Children?s National Medical Center. This is a highly meritorious program by leading investigators who have dedicated their careers to the clinical gene therapy of urea cycle disorders. The proposed approach is systematic and comprehensive, and addresses basic and fundamental questions related to the safe and efficient gene delivery to the liver. The research projects are tightly focused and interrelated as well as interdependent on each other. The core facilities provide important and competent services that help to synergize the individual research efforts. Although some reservations were noted about specific experimental approach, there is confidence that the investigative team would develop considerable insight into some of the most fundamental problems related to the use of AAV for liver gene therapy. As such, this application is recommended for further consideration as requested with high level of enthusiasm.
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