Disseminating Curative Biological Therapies for Rare Pediatric Diseases

项目摘要/摘要 基因和细胞疗法，特别是对罕见疾病的治疗，需要复杂的针对特定产品的前 临床研究，昂贵的GMP制造，用于监测的独特实验室分析，以及非凡的 启动、执行和监督提供初步安全性评估的临床试验的监管管理 和药效。由于许多严重和危及生命的遗传病在儿科人群中很少见， 使用新兴的基因和细胞治疗方法，越来越多的这种疾病可能是可以治愈的，一个重要的 这些创新疗法和未来基因编辑方法转化的障碍是数量有限 拥有执行这些发展步骤和复杂监管措施的基础设施的机构 涉及生物制品和儿童早期人体研究的环境。这一点在 儿科罕见遗传性疾病，没有一个中心照顾足够数量的患者成功携带 进行强有力的前瞻性试验。这一组情况导致了严重的问题：1)从 由于漫长的搬迁，他们的工作和支持结构将参与以重要地点为中心的试验 离家很远；2)由于缺乏经济和社会条件，决定不参加试验 这些移位造成的结构；3)尽管有符合条件的患者，试验的收益仍然很慢。考虑到最近的 基因转移方法的早期成功和疾病遗传基础知识的扩展，这些 疾病专家可能越来越多地寻求新的治疗方法，他们缺乏对这种疾病的详细知识 涉及复杂的翻译途径。这些专家中的许多人都在研究/医疗中心，而这些研究/医疗中心 开发了昂贵的基础设施，以有效地将基因转移研究转移到临床，更不用说 开发一项多点临床试验，可能招募足够数量的受试者。第二个障碍是 这些高度监管的试验的高效翻译是导航多个监管机构所需的时间 结构，特别是由多个机构审查委员会(IRBs)进行的审查，这些委员会在 基因治疗试验的复杂性。我们建议建立一个具有独特专业知识的儿科中心网络。 以及基因疗法的翻译经验。我们的总体目标是支持多个领域的调查人员 CTSA将复杂的基因治疗更快地转化为研究人员发起的儿科临床早期阶段 适合转移到工业中的试验。参加U01的中心将处于有利地位， 申请临床试验资金，并与行业赞助商签订协议。传播学 治疗儿科罕见疾病的生物疗法合作联盟将提供关键服务 和专家建议，以提高全国基因疗法临床试验的登记人数。

Project Summary/Abstract Gene and cell therapies, especially for rare diseases, require complex product-specific development of pre- clinical studies, costly GMP manufacturing, unique laboratory assays for monitoring, and extraordinary regulatory management to initiate, perform and oversee clinical trials that provide initial assessments of safety and efficacy. Due to the rarity of many serious and life-threatening genetic diseases in the pediatric population, an increasing number of which may be curable using emerging gene and cell therapy approaches, a significant barrier to translation of these innovative therapies and future gene editing approaches is the limited number of institutions with infrastructure to carry out these developmental steps and the complex regulatory environment involving biologicals and early phase human studies in children. This is particularly true in pediatric rare genetic diseases where no one center cares for sufficient numbers of patients to successfully carry out robust prospective trials. This set of circumstances leads to significant problems: 1) families displaced from their jobs and support structures due to lengthy relocation to participate in trials centered at sites at significant distances from their homes; 2) decisions not to participate in trials due to the lack of financial and social structures created by these displacements; 3) slow accrual to trials in spite of eligible patients. Given the recent early successes of gene transfer methods and the expanding knowledge of the genetic basis of diseases, these novel therapeutic approaches may increasingly be sought by disease experts who lack detailed knowledge of the complex translational pathway involved. Many of these experts are in research/medical centers that have not developed the costly infrastructure to efficiently move the gene transfer research to the clinic, much less to develop a multi-site clinical trial likely to recruit adequate numbers of subjects. A second impediment to efficient translation of these highly regulated trials is the time required to navigate multiple regulatory structures, in particular, reviews by multiple Institutional Review Boards (IRBs) with little experience in the complexities of gene therapy trials. We propose to develop a network of pediatric centers with unique expertise and experience in translation of gene therapies. Our overall goal is to support investigators across multiple CTSAs to more rapidly translate complex gene therapies to early phase investigator-initiated pediatric clinical trials suitable for transfer to industry. The centers participating in this U01 would then be well positioned to apply for clinical trial funding and to enter into agreements with industry sponsors. The Disseminating Curative Biological Therapies for Rare Pediatric Diseases Collaborative Consortium will offer key services and expert advice in order to enhance enrollment on gene therapy clinical trials nationally.