基因转移临床核心单元-猫眼课题宝

基因转移临床核心单元

批准号：

7688331

负责人：

Paul E Monahan

金额：

$0.0万

依托单位：

UNIV OF NORTH CAROLINA CHAPEL HILL

依托单位国家：

美国

项目类别：

财政年份：

2009

资助国家：

美国

项目状态：

已结题

起止时间：

2009-04-01 至 2014-03-31

来源：

https://reporter.nih.gov/project-details/7688331

关键词：

Accident and Emergency department Address Adherence Adverse event Advertisements Advisory Committees Advocacy Amendment Animals Annual Reports Area Attention Authorization documentation Back Basic Science Benefits and Risks Bioethics Biological Biological Assay Biological Products Biology Biotechnology Canavan Disease Caring Case Report Form Cessation of life Charge Classification Clinical Clinical Investigator Clinical Protocols Clinical Research Clinical Research Protocols Clinical Trials Clinical Trials Data Monitoring Committees Clinical Trials Design Code Coercion Collaborations Collection Committee Members Communication Communities Competence Complement Complex Conflict (Psychology)Consent Consent Forms Consult Consultations Continuing Education Continuity of Patient Care Coupled Critiques Cyclic GMP Cystic Fibrosis Data Data Analyses Data Collection Data Quality Databases Development Disease Disease Vectors Doctor of Medicine Doctor of Philosophy Documentation Dose Duchenne muscular dystrophy Early identification Education Enrollment Ensure Epidemiologist Epidemiology Ethics European Evaluation Evaluation Research Evaluation Studies Event Exclusion Criteria Familiarity Fanconi&apos s Anemia Fellowship Florida Follow-Up Studies Forcible intercourse Frequencies Funding Future Gender Gene Delivery Gene Transfer Genes Genetic Genetic Recombination Goals Grant Guidelines Hand Head Health Health Professional Hemophilia A Hemostatic function Hospitals Human Human Resources Human Rights Human Virus Individual Infection Control Informed Consent Institutes Institution International Intervention Journals Knowledge Laboratories Life Liposomes Maintenance Master of Public Health Measures Medical Medicine Methods Minority Mission Modeling Modification Molecular Molecular Biology Monitor Monitoring Clinical Trials Nasal cavity National Heart, Lung, and Blood Institute Nature Notification Nursing Staff Office for Protection from Research Risks Oncogenic Outcome Pamphlets Participant Pathway interactions Patient Care Patient Recruitments Patient Selection Patients Peer Review Pennsylvania Performance Pharmaceutical Preparations Pharmacology Phase Phase I Clinical Trials Phase II Clinical Trials Phase III Clinical Trials Physicians Plasmids Play Population Population Study Preparation Principal Investigator Private Sector Procedures Process Processed Genes Progress Reports Protocols documentation Public Health Schools Reagent Recombinant DNA Recombinant DNA Research Recombinants Recommendation Records Recruitment Activity Registered nurse Registries Regulation Regulatory Pathway Relative (related person)Report (document)Reporting Research Research Design Research Ethics Research Ethics Committees Research Personnel Research Proposals Research Subjects Research Training Resolution Resources Review Committee Rights Risk Role Running Safety Schedule Science Scientist Screening procedure Series Serious Adverse Event Services Site Social Medicine Societies Source Specific qualifier value Speed Structure Study Subject Support Groups System Techniques Technology Testing Therapeutic Therapeutic Agents Therapeutic Studies Thrombosis Time TimeLine Tissues Toxic effect Toxicology Training Training Activity Training Programs Translating Translational Research Translations Travel Trypsin United States United States Food and Drug Administration United States National Institutes of Health Universities Update Viral Vector Virus Visit Voting Work World War II Writing adeno-associated viral vector authority base clinical application clinical care clinical efficacy clinical practice computerized data management design drug development experience follow-up gene replacement gene therapy gene therapy clinical trial gene transfer vector human subject improved institutional biosafety committee interest medical schools meetings member multidisciplinary novel patient safety pre-clinical preclinical study programs prospective protocol development research clinical testing research study response safety testing symposium tool training project vector virology volunteer working group

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中文摘要

翻译

北卡罗来纳大学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。这些试验包括12名受试者的剂量范围、安全性/有效性的Ad-CFTR的I期试验在鼻腔和随后的11名患者中，剂量范围、安全性/有效性I期脂质体-质粒鼻腔DMA试验(16例；17例)。在慢性阻塞性肺疾病中的这些试验得到了两项补充(逆转录病毒/高 Capacity ADV)治疗血友病的试验，以及另一项治疗范可尼贫血的试验。此外，北卡罗来纳大学的矢量核心和人类应用实验室已经生产出cGMP腺相关病毒载体适当的FDA治疗Canavan病和Duchenne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FDA的正式审计)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。安大略省大学的惨死宾夕法尼亚州的一名志愿者强调了“知情同意”这一话题。知情同意的指导方针美国国立卫生研究院在一系列标准的基础上建立了人类临床研究。然而，这些指南是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支持的一项研究在 UNC在知情同意(GAIL)的背景下审查基因治疗研究的感知益处亨德森，博士，丹·尼尔森，硕士，北卡罗来纳大学社会医学系)(19；20)。的办公室研究课题倡导成立于2001年。它的负责人是David Weber，M.D.，M.P.H.，Co- 生物医学IRB主席，由副主任玛丽·卡普，R.N.，B.S.N.协调确保GCRC协议中涉及的研究对象的安全性，GCRC涉及所有基因北卡罗来纳大学的传输协议。一个关键的职能是监督和教育，以避免误解或在临床试验同意过程中的错误陈述。在病毒载体的背景下进行基因治疗的感染控制也是一个重要的新伦理和功能问题。大多数用于基因转移的载体来自自然产生的人类病毒，人们非常担心这些载体可能会变得“复制能力强”和可能会与其他病毒发生传播/重组。到目前为止，还没有广泛可用的联邦或私人组织提出的指导感染控制的建议。韦伯博士研制出 UNC囊性纤维化中腺病毒基因转移研究的感染控制指南(16；21)。博士韦伯随后呼吁开发针对基因转移载体的感染控制策略，导致了第一次多学科会议对这种基因临床应用的建议转移(22；23)。北卡罗来纳州立大学临床核心小组由Paul Monahan医学博士领导，与执行 CF和基因治疗中心委员会确定应该转移到临床的载体在人体上进行测试。与预期的临床项目首席研究员合作，临床 CORE帮助制定计划，测试新药物的安全性以及生物和临床疗效用于基因转移的载体。这项评估包括在动物身上进行适当的临床前研究生物有效性和毒性。此外，临床核心小组在帮助未来研究人员开发了临床方案，以确定相关的终点基因转移效率和生成高质量的信息，以促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 GCRC和临床试验办公室(OCT)的研究课题倡导，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。这个临床核心小组还与OCT密切合作，通过复合体指导基因治疗临床试验制定必要的工具，如病例报告表和临床流程图项目，确保人类主体合规性，监测单个项目，并为UNC创建一个注册表基因治疗的患者。北卡罗来纳大学临床核心中心还与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人员提供功能培训。这 “动手”临床研究培训与基础科学实验室以及 GCRC和CAP近年来的奖学金产生了富有成效和独立的临床更多传统药理学领域的研究人员。在下一节中，我们将介绍北卡罗来纳大学CH提供的人力和机构资源满足这些关键任务。

英文摘要

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.

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