Gene Transfer Clinical Core Unit

基因转移临床核心单元

• 批准号: 7688331
• 负责人: Paul E Monahan
• 金额: --
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7688331
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The UNC Core clinical gene transfer group has had extensive experience with gene transfer clinical trials. These include for CF a 12 subject, dose-ranging, safety/efficacy Phase I trial of Ad-CFTR in the nasal cavity, and a subsequent 11 patient, dose-ranging, safety/efficacy Phase I liposomal-plasmid DMA trial in the nasal cavity (16; 17). These trials in CF have been complemented by two (retroviral/high capacity AdV) trials for hemophilia, and another trial for Fanconi's anemia. In addition, the UNC Vector Core and Human Applications Laboratory have produced cGMP adeno-associated virus vector for human clinical trials of Canavan's Disease and Duchenne Muscular Dystrophy with appropriate FDA (Office of Cellular Tissue and Gene Therapies, OCTGT) and NIH RAC oversight (14). Thus, we have experience with regulatory aspects (pre- and post-trial, including a formal FDA audit) as well as the practical performance of gene therapy trials. In addition, we have accrued 'special' experience. The tragic death of the University of Pennsylvania volunteer highlighted the topic of "informed consent". Guidelines for informed consent for human clinical research have been established by the NIH, based on a series of standards that evolved after World War II. However, these guidelines were reviewed and revised by a group from UNC in the context of "gene therapy", based on the premise that clinical studies involving gene transfer are different from other studies involving humans (18). Subsequently, an NIH-supported study was performed at UNC to examine the perceived benefit of gene therapy studies in the context of informed consent (Gail Henderson, Ph.D., Dan Nelson, MS, UNC Department of Social Medicine) (19;20). The Office of Research Subject Advocacy was established in 2001. It is headed by David Weber, M.D., M.P.H., Co- Chair of the Biomedical IRB, and coordinated by Associate Director Marie Rape, R.N., B.S.N. This office ensures the safety of research subjects involved in protocols in the GCRC, which is involved in all gene transfer protocols at UNC. A critical function is oversight and education to avoid misconceptions or misrepresentations during the clinical trial consent process. Infection control in the context of viral vectors for gene therapy is also an important new ethical and functional issue. Most of the vectors for gene transfer are derived from naturally-occurring human viruses, and there is great concern that these vectors might become "replication-competent" and spread/recombination with other viruses might occur. To date, there are no widely available recommendations from Federal or private organizations to guide infection control. Dr. Weber developed infection control guidelines for the UNC adenoviral gene transfer study in cystic fibrosis (16;21). Dr Weber subsequently called for the development of infection control strategies for gene transfer vectors, leading to the first multidisciplinary conference recommendations for such clinical application in gene transfer (22;23). The UNC Clinical Core group, headed by Paul Monahan, M.D., works with the Executive Committee of the CF and Gene Therapy Centers to identify vectors that should be moved toward clinical testing in humans. Working with the prospective Principal Investigators of clinical projects, the Clinical Core helps to devise plans for testing of the safety, as well as biological and clinical efficacy, of new vectors for gene transfer. This assessment includes appropriate pre-clinical studies in animals for biological efficacy and toxicity. In addition, the Clinical Core group is instrumental in helping prospective investigators develop clinical protocols that identify pertinent endpoints for gene transfer efficacy and generate information of high quality to advance knowledge about the vector and the disease of interest. The Clinical Core group works with the GCRC, the Gene Transfer Subcommittee and the Office of Research Subject Advocacy of the GCRC, and the Office of Clinical Trials (OCT) to ensure that clinical protocols are rigorously monitored and meet all regulatory, ethical, and infection control issues. The Clinical Core group also works closely with the OCT to guide gene therapy clinical trials through complex regulatory pathways, develop the necessary tools, e.g.; Case Report Forms and flow sheets for clinical projects, ensure human subject compliance, monitor individual projects, and create a registry for UNC gene therapy patients. The UNC Clinical Core also works collaboratively with the GCRC and the Office of Clinical Trials to provide functional training for clinical trial coordinators, GCRC staff, and clinical investigators. This 'hands-on' clinical research training parallels successful models in basic science laboratories as well as the GCRC and CAP fellowships of recent years that have produced productive and independent clinical investigators in more traditional pharmacology areas. In the next section we describe the human and institutional resources available at UNC CH to meet these critical tasks.

UNC核心临床基因转移小组在基因转移方面拥有丰富的经验 临床试验。其中包括针对 CF 的 Ad-CFTR 的 12 名受试者、剂量范围、安全性/有效性 I 期试验 在鼻腔中，以及随后的 11 名患者，剂量范围，安全性/有效性 I 期脂质体质粒 鼻腔 DMA 试验 (16; 17)。这些 CF 试验得到了两项（逆转录病毒/高 容量AdV）针对血友病的试验，以及另一项针对范科尼贫血的试验。此外，北卡罗来纳大学矢量 核心和人类应用实验室生产了cGMP腺相关病毒载体 与适当的 FDA 进行卡纳万氏病和杜氏肌营养不良症的人体临床试验 （细胞组织和基因治疗办公室，OCTGT）和 NIH RAC 监督 (14)。因此，我们有 监管方面的经验（试验前和试验后，包括正式的 FDA 审核）以及 基因治疗试验的实际表现。 此外，我们还积累了“特殊”的经验。大学的惨死 宾夕法尼亚州志愿者强调了“知情同意”的主题。知情同意指南 美国国立卫生研究院 (NIH) 根据一系列不断发展的标准建立了人类临床研究 第二次世界大战后。然而，这些指南由北卡罗来纳大学的一个小组在 “基因治疗”的背景，基于涉及基因转移的临床研究不同的前提 来自其他涉及人类的研究 (18)。随后，美国国立卫生研究院 (NIH) 支持的一项研究在 北卡罗来纳大学将在知情同意的情况下审查基因治疗研究的感知益处（盖尔 Henderson，博士，Dan Nelson，MS，北卡罗来纳大学社会医学系）（19;20）。办公室 研究主题倡导成立于 2001 年。由 David Weber 领导，医学博士、公共卫生硕士、联合 生物医学 IRB 主席，由副主任 Marie Rape（注册护士、BSN）负责协调这个办公室 确保 GCRC 协议中涉及的研究对象的安全，该协议涉及所有基因 UNC 的传输协议。一项关键职能是监督和教育，以避免误解或 临床试验同意过程中的虚假陈述。 用于基因治疗的病毒载体的感染控制也是一个重要的新伦理 和功能问题。大多数基因转移载体源自天然存在的人类 病毒，并且人们非常担心这些载体可能变得“具有复制能力”并且 可能会发生与其他病毒的传播/重组。迄今为止，还没有广泛可用的 联邦或私人组织指导感染控制的建议。韦伯博士开发了 北卡罗来纳大学囊性纤维化腺病毒基因转移研究感染控制指南 (16;21)。博士 韦伯随后呼吁制定基因转移载体的感染控制策略， 导致了第一个针对基因临床应用的多学科会议建议 转移（22；23）。 由医学博士 Paul Monahan 领导的北卡罗来纳大学临床核心小组与执行官合作 CF 和基因治疗中心委员会确定应走向临床的载体 在人体中进行测试。与临床项目的潜在首席研究员合作，临床 Core 帮助制定测试新药物的安全性以及生物学和临床功效的计划 用于基因转移的载体。该评估包括在动物中进行适当的临床前研究 生物功效和毒性。此外，临床核心小组有助于帮助未来的患者 研究人员制定临床方案，确定基因转移功效的相关终点，并 生成高质量的信息，以增进有关媒介和感兴趣的疾病的知识。 临床核心小组与 GCRC、基因转移小组委员会和办公室合作 GCRC 和临床试验办公室 (OCT) 的研究主题倡导，以确保临床 协议受到严格监控并满足所有监管、道德和感染控制问题。这 临床核心小组还与 OCT 密切合作，通过复杂的流程指导基因治疗临床试验 监管途径，开发必要的工具，例如；临床病例报告表和流程图 项目，确保人类受试者合规性，监控单个项目，并为 UNC 创建注册表 基因治疗患者。 北卡罗来纳大学临床核心还与 GCRC 和临床试验办公室合作 为临床试验协调员、GCRC 工作人员和临床研究者提供功能培训。这 “实践”临床研究培训与基础科学实验室的成功模型以及 近年来，GCRC 和 CAP 奖学金产生了富有成效的独立临床研究 更传统药理学领域的研究人员。 在下一节中，我们将描述 UNC CH 可用的人力和机构资源，以 完成这些关键任务。