The National Gene Vector Laboratory (NGVL) Toxicology Center at the University of Florida (UF) will facilitate efficient, cost-effective, and rigorous preclinical testing of gene therapy vectors, with a special emphasis on recombinant adeno-associated virus (rAAV) vectors. Investigators and staff of the center have experience in production of preclinical grade rAAV and with formal preclinical toxicology testing in rodents and non-human primates. The vector core facility at the Powell Gene Therapy Center (PGTC) has extensive experience in the production of preclinical grade rAAV for investigators throughout the U.S. and abroad, with rigorous quality control (QC) standards. The center has previously been awarded a subcontract from the NGVL to produce a batch of rAAV to serve as a national reference standard stock for calibrating titer and other QC assays. Our group has performed rabbit and non-human primate studies that supported the successful completion of phase I trials of rAAV in cystic fibrosis patients. The center has also performed a rodent toxicology study in support of a phase I trial of rAAV expressing the alpha 1-antitrypsin (AAT) gene vector, and a key study of the potential risk for carcinogenesis after IV injection in neonatal mice. OF has taken the lead in sharing those preclinical data with the NGVL by depositing data in the rAAV drug master file (DMF). The development of centralized core facilities for vector production, animal toxicology, pathology, and biostatistics/bioinformatics has allowed these procedures to proceed more efficiently. The PGTC now proposes to function as a Toxicology Center for the NGVL in the context of the following aims:
Aim I . To provide preclinical vector toxicology testing and biodistribution studies using real-time PCR. All classes of vector could be handled under this aim;
Aim 2. To perform immune response assays, tissue processing, immunohistochemistry, and expert histopathologic assessment in a centralized pathology/immunology core;
Aim 3. To provide biostatistical consultation and informatics/database support for preclinical toxicology studies;
Aim 4. To put in place a regulatory framework intended to ensure consistent data quality and facilitate rapid communication of adverse toxicology results. In summary, the proposed of Toxicology Center will provide the resources, scientific expertise and experience to support rodent, non-human primate and large animal toxicology, histopathologic analysis, biostatistical.support, informatics support, and regulatory oversight for preclinical studies of all classes of gene therapy vectors. These services will be offered in an open flexible, collaborative, and interactive manner, and in compliance with the Terms of Cooperation of the NGVL.
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