NGVL TOXICOLOGY LABORATORY

位于佛罗里达大学（UF）的国家基因载体实验室（NGVL）毒理学中心将促进基因治疗载体的高效、经济和严格的临床前测试，特别强调重组腺相关病毒（rAAV）载体。该中心的研究人员和工作人员具有生产临床前级rAAV的经验，并具有在啮齿动物和非人灵长类动物中进行正式临床前毒理学试验的经验。鲍威尔基因治疗中心（PGTC）的载体核心设施在为美国和国外的研究人员生产临床前级rAAV方面具有丰富的经验，具有严格的质量控制（QC）标准。该中心此前已获得NGVL的授权，生产一批rAAV，作为校准滴度和其他QC检测的国家参考标准储备。我们的小组已经进行了兔子和非人灵长类动物研究，支持在囊性纤维化患者中成功完成rAAV的I期试验。该中心还进行了啮齿动物毒理学研究，以支持表达α 1-抗胰蛋白酶（AAT）基因载体的rAAV的I期试验，以及新生小鼠静脉注射后致癌潜在风险的关键研究。OF通过将数据存入rAAV药物主文件（DMF）中，率先与NGVL共享这些临床前数据。为病媒生产、动物毒理学、病理学和生物统计学/生物信息学建立了集中的核心设施，使这些程序能够更有效地进行。PGTC现在提议在以下目标的背景下作为NGVL的毒理学中心：目标I。使用实时PCR提供临床前载体毒理学测试和生物分布研究。所有类别的向量都可以在这个目标下处理;目标2。在一个集中的病理学/免疫学核心中进行免疫应答测定、组织处理、免疫组织化学和专家组织病理学评估;目标3。为临床前毒理学研究提供生物统计咨询和信息学/数据库支持;目标4。建立一个监管框架，以确保一致的数据质量，并促进不良毒理学结果的快速交流。总之，拟成立的毒理学中心将提供资源、科学专业知识和经验，以支持啮齿动物、非人灵长类动物和大型动物毒理学、组织病理学分析、biostatistical.support、信息学支持以及所有类别基因治疗载体临床前研究的监管监督。这些服务将以开放、灵活、协作和互动的方式提供，并符合NGVL的合作条款。

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.