CORE SUPPORT AS AN NGVL TOXICOLOGY CENTER

作为 NGVL 毒理学中心的核心支持

• 批准号: 6662561
• 负责人: JOHN G PAGE
• 金额: $ 19.24万
• 依托单位: SOUTHERN RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6662561
• 关键词: Adenoviridae; Animalia; cooperative study; gene delivery system; gene therapy; genetic disorder; microorganism toxicology; nonhuman therapy evaluation; polymerase chain reaction; transfection /expression vector; urinalysis

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.

单个基因的缺失或突变可能会导致特定的疾病。人类基因组测序已导致人们付出巨大努力来识别和分离与各种疾病（包括癌症、艾滋病、糖尿病和囊性纤维化）病因学相关的特定基因。在过去的十年中，已经开发了许多基因疗法，用正常的功能基因替代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第一个因基因疗法直接导致死亡的已知人。 NGVL 的成立是为了支持安全有效的基因疗法的开发。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（例如静脉推注剂量）和剂量方案旨在用于人体的初始 I 期和 II 期临床试验。南方研究所 (SRI) 在开展临床前毒理学研究方面拥有多年经验，以支持在人体临床试验开始之前向美国食品和药物管理局提交的 IND 申请。本提案的研究设计和方法部分列出了过去 5 年在 SRI 进行的用于支持 IND 申请的研究列表。该申请介绍了 SRI 的设施和专业知识，这些设施和专业知识将为 NGVL 作为毒理学中心提供特殊的资源。此申请寻求支持以在 SRI 建立 NGVL 毒理学承租人。这些资金将用于帮助 NGVL 和 SRI 之间的互动，包括为各个 NGVL 赞助商设计和准备协议。一旦协议最终确定，SRI 将开发进行研究和准备最终报告的费用。研究费用将根据具体情况进行计算；进行这些研究的费用尚未包含在 SRI 建立 NGVL 毒理学中心所需的资金中。包括阿拉巴马大学伯明翰分校 (UAB) 基因治疗中心在内的许多机构均表示有兴趣利用 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在 J 部分找到。此外，UAB 的一些教员已同意通过担任无偿顾问的方式向 SRI 的 NGVL 毒理学中心提供进一步支持；这些人的承诺书可以在 K 部分“顾问”中找到。