ESTABLISHMENT OF NGVL TOXICOLOGY LAB: RAAV VECTORS, CYSTIC FIBROSIS

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。描述（由申请人提供）：UF的NGVL毒理学中心将促进基因治疗载体的有效，具有成本效益和严格的临床前测试，特别强调重组AAV（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Vector Core设施在为美国和国外的研究人员生产临床前级rAAV方面拥有丰富的经验，并具有严格的质量控制（QC）标准。该中心此前已获得NGVL的分包合同，生产一批rAV，作为校准滴度和其他QC测定的国家参考标准储备液。该研究小组已经进行了兔子和非人灵长类动物的研究，支持rAAV在囊性纤维化患者中成功完成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IV注射后致癌潜在风险的关键研究。UF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1：使用实时聚合酶链反应（PCR）提供临床前载体毒理学测试和生物分布研究。所有类别的载体都可以在此目标下处理;目标2：在集中的病理学/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学咨询和信息学/数据库支持;以及目标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。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. DESCRIPTION (provided by applicant): The NGVL Toxicology Center at the UF will facilitate efficient, cost-effective, and rigorous preclinical testing of gene therapy vectors, with a special emphasis on recombinant AAV (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. The investigators'''' 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. UF 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 1: To provide preclinical vector toxicology testing and biodistribution studies using real-time polymerase chain reaction (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; and Aim 4: To put in place a regulatory framework intended to ensure consistent data quality and facilitate rapid communication of adverse toxicology results.