CORE SUPPORT AS AN NGVL TOXICOLOGY CENTER

作为 NGVL 毒理学中心的核心支持

• 批准号: 6424904
• 负责人: JOHN G PAGE
• 金额: $ 32.17万
• 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/6424904
• 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特定疾病。人类基因组的测序导致了巨大的努力，以鉴定和分离参与各种疾病的病因，包括癌症，艾滋病，糖尿病和囊性纤维化。在过去的十年中，已经开发了许多基因疗法，以用正常的功能基因代替有缺陷的基因或删除的基因。尽管基因疗法具有各种疾病的治疗和/或治愈的巨大潜力，但并非没有风险，正如1999年所证明的那样，当时一个少年成为该国第一个死亡的人死亡，这是基因治疗的直接结果。建立了NGVL以支持安全有效的基因疗法的开发。与常规治疗剂一样，必须在人类初始临床试验之前确定基因疗法的安全性。这些临床前毒理学评估通常是在啮齿动物（例如，大鼠，小鼠）和非产物（例如狗，cynomolgus猴子）中进行的，使用相同的载体（例如腺病毒），剂量途径（例如旨在在人类的初始I期和IL临床试验中使用。南方研究所（SRI）在进行临床前毒理学研究方面拥有多年的经验，以支持在开始人类临床试验之前提交给美国食品和药物管理局的IND应用。该提案的研究设计和方法部分介绍了在过去5年中在SRI进行的研究清单，并用于支持IND应用。该应用程序对SRI可用的设施和专业知识进行了描述，该设施和专业知识将为NGVL提供卓越的资源作为毒理学中心。该申请寻求支持在SRI建立NGVL毒理学租户。这些资金将用于帮助NGVL和SRI之间的相互作用，包括针对各种NGVL赞助商的协议设计和准备。一旦完成协议，SRI将开发成本以进行研究并准备最终报告。研究将按具体情况进行付费；进行这些研究的成本尚未纳入要求在SRI建立NGVL毒理学中心的资金中。许多机构，包括阿拉巴马大学伯明翰大学（UAB）的基因治疗中心，表明有兴趣使用SRI的NGVL毒理学中心对其基因治疗产物进行临床前毒理学研究；这些机构的支持信可以在J节中找到。此外，UAB的许多教师同意通过担任无偿顾问来对SRI的NGVL毒理学中心提供进一步的支持；这些人的承诺信可以在顾问K节中找到。