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

杜氏肌营养不良症细胞疗法一期临床试验的基础

• 批准号: 10517066
• 负责人: PETER B. KANG
• 金额: $ 20.46万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10517066
• 关键词: Address; Adolescence; Adrenal Cortex Hormones; Adverse event; Affect; Aftercare; Allogenic; Antisense Oligonucleotides; Appointment; Cell Therapy; Cells; Cellular Structures; Certification; Childhood; Clinical Research; Clinical Trials; Clinical Trials Data Monitoring Committees; Clinical Trials Design; Consent Forms; Data; Development; Disease; Dose; Duchenne muscular dystrophy; Dystrophin; Ensure; Etiology; Exons; FDA approved; Family Physicians; Foundations; Funding; Genetic; Goals; Good Clinical Practice; Grant; Guidelines; Histologic; Human; Individual; Inherited; Institutional Review Boards; International; Intramuscular; Intramuscular Injections; Investigation; Investigational Drugs; Investigational New Drug Application; Laboratories; Life Expectancy; Link; Manuals; Measures; Minnesota; Molecular; Monitor; Mus; Muscle satellite cell; Myopathy; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Natural regeneration; Neurologist; Neuromuscular Diseases; Nursing Research; Participant; Pathogenicity; Patients; Phase; Phase I Clinical Trials; Phase I/II Trial; Physicians; Population; Preparation; Principal Investigator; Procedures; Process; Proteins; Protocols documentation; Quality Control; Quality of life; RNA Splicing; Reading Frames; Reporting; Research; Research Design; Risk; Route; Safety; Sample Size; Schedule; Scientist; Site; Skeletal Muscle; System; Therapeutic; Tissues; Training; Transplantation; Universities; Validation; Variant; Work; base; clinical trial implementation; efficacy evaluation; exon skipping; experience; falls; first-in-human; functional improvement; improved; induced pluripotent stem cell; interdisciplinary treatment approach; mRNA Precursor; meetings; multidisciplinary; muscle degeneration; muscle regeneration; neuromuscular; novel therapeutic intervention; novel therapeutics; patient prognosis; phase 1 testing; phase I trial; physical therapist; pre-clinical; preclinical study; precursor cell; progenitor; research clinical testing; research study; safety assessment; safety testing; stem cell based approach; stem cell therapy; stem cells; symposium; therapeutic development

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.

摘要 Duchenne肌营养不良症（DMD）的治疗前景随着批准而改变 自2016年以来，FDA已经批准了五种用于这种疾病的新化合物。五种化合物中有四种是反义的 诱导肌营养不良蛋白前体mRNA的外显子跳跃的寡核苷酸，恢复特异性肌营养不良蛋白前体mRNA的阅读框架， 致病性变体的子集。这些进展是显著的，但仍有许多工作要做。 大约三分之二的DMD人群具有致病性变异体，这些变异体不适合任何一种基因。 目前批准的反义寡核苷酸化合物。虽然DMD的预期寿命比 以往任何时候都与多学科治疗方法，大多数受影响的人仍然失去了amphalomyelia期间， 青春期和预期寿命缩短。已经有广泛的研究基于细胞的 在过去的几十年里，包括一些人类临床试验，我们集团 进行了基于干细胞的方法的临床前研究，这是有利的，因为有可能 补充肌肉干细胞库并增强受损骨骼肌的长期再生。与 我们团队最近的临床前进展专注于诱导多能干细胞（iPSC）衍生的肌源性 前体细胞，时机适合一组新的人体临床试验，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衍生的肌源性前体细胞将植入骨骼肌中， 而没有显著的安全问题。这项规划补助金的目标是准备所需的最后步骤， 启动第一阶段临床试验在这一规划期间要完成的任务包括 成立研究小组，并开始定期举行小组会议; 完善临床研究方案;编写和完善单个研究中心操作手册 符合NIAMS要求的程序（MOOP）;任命数据和安全监测 委员会（DSMB），并建立数据和安全性监测报告模板;提交单个研究中心IRB 方案;制定向FDA提交新IND所需的一整套监管文件;以及 为实施I期临床试验编制U 01提案。在资助结束时， 在此期间，我们的目标是获得FDA和IRB的批准以启动本研究。