CORE SUPPORT AS AN NGVL TOXICOLOGY CENTER

单个基因的缺失或突变可能导致特定的疾病。人类基因组测序已经带来了巨大的努力，以识别和分离与各种疾病的病因有关的特定基因，包括癌症、艾滋病、糖尿病和囊性纤维化。在过去的十年中，已经开发了一些基因疗法，用正常的功能基因代替有缺陷或缺失的基因。虽然基因疗法在治疗和/或治愈各种疾病方面具有巨大潜力，但它并非没有风险，1999年一名青少年成为该国已知的第一个直接因基因疗法而死亡的人就证明了这一点。NGVL的建立是为了支持安全有效的基因疗法的发展。与传统疗法一样，基因疗法的安全性必须在人体初步临床试验之前确定。这些临床前毒理学评估通常在啮齿动物（例如，大鼠、小鼠）和非啮齿动物（例如，狗、食蟹猴）中进行，使用相同的载体（例如，腺病毒）、剂量途径（例如，静脉注射剂量）以及用于人类初始I期和I期临床试验的剂量计划。南方研究所（SRI）在开展临床前毒理学研究方面有多年的经验，以支持在人体临床试验开始之前提交给美国食品和药物管理局的IND申请。本提案的研究设计和方法部分列出了过去5年中在SRI进行并用于支持IND应用的研究清单。该申请介绍了SRI的设施和专业知识，将为NGVL作为毒理学中心提供特殊资源。本申请寻求在SRI建立NGVL毒理学中心的支持。这些资金将用于帮助NGVL和SRI之间的互动，包括为各种NGVL赞助商设计和准备协议。一旦协议最终确定，SRI将制定进行研究和编写最后报告的费用。研究将按个案计算费用；进行这些研究的费用并未包括在为在SRI建立NGVL毒理学中心所申请的资金中。许多机构，包括阿拉巴马大学伯明翰分校的基因治疗中心（UAB），已经表示有兴趣使用SRI的NGVL毒理学中心对其基因治疗产品进行临床前毒理学研究；这些机构的支持信可以在j部分找到。此外，UAB的一些教师已经同意以无偿顾问的身份向SRI的NGVL毒理学中心提供进一步的支持；这些个人的承诺书可在K部分“顾问”中找到。

Deletion or mutation of a single gene may result in a specific disease. Sequencing of the human genome has led to huge efforts to identify and isolate specific genes involved in the etiology of various diseases, including cancer, AIDS, diabetes, and cystic fibrosis. During the past decade, a number of gene therapies have been developed to replace defective or deleted genes with normal, functional genes. While gene therapy holds great potential for the treatment and/or cure of various diseases, it is not without risk, as demonstrated in 1999 when a teenager became the first known person in the country to die as a direct result of gene therapy. The NGVL was established to support development of safe and effective gene therapies. As with conventional therapeutics, the safety of the gene therapies must be established prior to initial clinical trials in humans. These preclinical toxicology evaluations are typically conducted in rodents (e.g., rats, mice) and nonrodents (e.g., dogs, Cynomolgus monkeys), using the same vectors (e.g., adenovirus), dose route (e.g., intravenous bolus dose), and dose schedule intended for use in the initial Phase I and Phase Il clinical trials in humans. Southern Research Institute (SRI) has many years of experience in conducting preclinical toxicology studies in support of IND applications that were submitted to the U.S. Food and Drug Administration prior to initiation of human clinical trials. A list of studies conducted at SRI and used to support IND applications in the past 5 years is presented in the Research Design and Methods section of this proposal. This application presents a description of the facilities and expertise available at SRI that will provide an exceptional resource to the NGVL as a Toxicology Center. This application seeks support to establish an NGVL Toxicology renter at SRI. The funds will be used to aid interaction between the NGVL and SRI, including design and preparation of protocols for various NGVL sponsors. As soon as the protocols are finalized, SRI will develop costs to conduct the study and to prepare a final report. Studies will be costed on a case-by-case basis; costs for conducting those studies have not been included in the funds requested for establishing the NGVL Toxicology Center at SRI. A number of institutions, including the Gene Therapy Center at the University of Alabama at Birmingham (UAB), have indicated an interest in using the NGVL Toxicology Center at SRI to conduct preclinical toxicology studies of their gene therapy products; letters of support from these institutions can be found in Section J. In addition, a number of the faculty at UAB have agreed to provide further support to the NGVL Toxicology Center at SRI by acting as unpaid consultants; letters of commitment from these individuals can be found in Section K, Consultants.