Foundations for a Phase 1 Clinical Trial ofCell-based Therapy for Duchenne Muscular Dystrophy

摘要 Duchenne肌营养不良症(DMD)的治疗格局随着批准而改变 自2016年以来，FDA发布了五种治疗这种疾病的新化合物。这五种化合物中有四种是反义的。 诱导dystrophin Pre-mRNA外显子跳跃的寡核苷酸，恢复特定基因的阅读框架 致病变异体的亚群。这些进展是了不起的，但仍有许多工作要做。 大约三分之二的DMD人群有致病变异，这些变异不符合任何 目前批准的反义寡核苷酸化合物。尽管DMD的预期寿命比 在以前的多学科治疗方法中，大多数受影响的人在治疗期间仍然失去行走能力 青春期，缩短了预期寿命。已经有了广泛的基于细胞的研究 过去几十年的治疗方法，包括一些人类临床试验。我们的团队已经 进行基于干细胞的方法的临床前研究，这是有利的，因为有可能 补充肌肉干细胞库，促进受损骨骼肌的长期再生。使用 我们团队在诱导多能干细胞(IPSC)来源的肌源性方面的最新临床前进展 前体细胞，时机适合于一套新的人类临床试验，第一项研究将是一个阶段 1评价肌肉注射的安全性和耐受性。基于广泛的成功移植 在小鼠的研究中，我们假设IPSC来源的肌源性前体细胞将植入骨骼肌 没有重大的安全问题。这项计划拨款的目标是准备所需的最后步骤 启动这一阶段的临床试验。在本规划期内要完成的任务包括 组建研究小组并开始定期安排小组会议；组成和 临床研究方案的改进；单一部位操作手册的组成和改进 符合NIAMS要求的程序(MOOP)；指定数据和安全监测 董事会(DSMB)并建立数据和安全监测报告模板；提交单一站点IRB 协议；制定向FDA提交新的IND所需的一整套管理文件；以及 准备一期临床试验实施的U01提案。到基金结束时 在此期间，我们的目标是获得FDA和IRB的批准来启动这项研究。

ABSTRACT The therapeutic landscape for Duchenne muscular dystrophy (DMD) has been transformed with the approval of five new compounds for this disease by the FDA since 2016. Four of the five compounds are antisense oligonucleotides that induce exon skipping of the dystrophin pre-mRNA, restoring the reading frame for specific subsets of pathogenic variants. These advances are remarkable, but much work remains to be done. Approximately two-thirds of the DMD population have pathogenic variants that are not amenable to any of the currently approved antisense oligonucleotide compounds. Though the life expectancy for DMD is longer than ever before with a multidisciplinary treatment approach, most affected individuals still lose ambulation during adolescence and have shortened life expectancies. There have been extensive investigations of cell-based therapeutic approaches over the past several decades, including some human clinical trials. Our group has pursued preclinical studies of a stem cell-based approach, which is advantageous due to the potential to replenish the muscle stem cell pool and enhance long term regeneration of damaged skeletal muscle. With recent preclinical advances by our team focusing on induced pluripotent stem cell (iPSC)-derived myogenic precursor cells, the timing is appropriate for a new set of human clinical trials, with the first study to be a Phase 1 evaluation of safety and tolerability of intramuscular injections. Based on extensive successful transplantation studies in mice, we hypothesize that iPSC-derived myogenic precursor cells will engraft in skeletal muscle without significant safety concerns. The goal of this planning grant is to prepare the final steps needed to initiate this Phase 1 clinical trial. The tasks to be completed during the course of this planning period include formation of the Study Team and commencement of regularly scheduled team meetings; composition and refinement of a clinical study protocol; composition and refinement of a single site manual of operating procedures (MOOP) that are compliant with NIAMS requirements; appointment of a data and safety monitoring board (DSMB) and establish a template for data and safety monitoring reports; submit a single site IRB protocol; develop a complete set of regulatory documents required for a new IND submission to the FDA; and preparation of a U01 proposal for the implementation of the Phase 1 clinical trial. By the end of the funding period, our goal is to have approval from the FDA and the IRB to initiate this study.