CORE SUPPORT AS AN NGVL TOXICOLOGY CENTER

作为 NGVL 毒理学中心的核心支持

• 批准号: 6530166
• 负责人: JOHN G PAGE
• 金额: $ 28.82万
• 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/6530166
• 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导致一种特定的疾病。人类基因组的测序导致了巨大的努力来识别和分离与各种疾病的病因学有关的特定基因，包括癌症、艾滋病、糖尿病和囊性纤维化。在过去的十年里，已经开发了许多基因疗法来用正常的、有功能的基因取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的潜力，但它也不是没有风险，正如1999年所证明的那样，当时一名青少年成为该国第一个已知的直接死于基因疗法的人。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类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)和拟用于人类初始I期和I期临床试验的剂量计划。南方研究院(SRI)在进行临床前毒理学研究以支持在启动人体临床试验之前提交给美国食品和药物管理局的IND申请方面拥有多年的经验。本提案的研究设计和方法部分列出了过去5年在SRI进行并用于支持IND申请的研究清单。本申请描述了SRI现有的设施和专业知识，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。本申请寻求支持在SRI建立NGVL毒理学租赁者。这笔资金将用于帮助NGVL和SRI之间的互动，包括为各种NGVL赞助商设计和编写议定书。一旦议定书最终敲定，SRI将制定进行研究和编写最后报告的费用。研究费用将按个案计算；开展这些研究的费用没有包括在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(UAB)的基因治疗中心，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；这些机构的支持函可在J部分找到。此外，UAB的一些教职员工已同意以无偿顾问的身份为SRI的NGVL毒理中心提供进一步支持；这些个人的承诺书可在K部分顾问中找到。