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

基本信息

批准号：
10665798
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
项目类别：
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/10665798
关键词：
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 Dedications Development Disease Dose Duchenne muscular dystrophy Dystrophin Engraftment Ensure Etiology Exons FDA approved Family 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 Learning 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 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 Therapeutic Tissues Training Translations Transplantation Universities Validation Variant Work body system clinical trial implementation efficacy evaluation exon skipping experience falls first-in-human functional improvement improved induced pluripotent stem cell interdisciplinary treatment approach mRNA Precursor manufacture 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

项目摘要

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.

抽象的 Duchenne肌肉营养不良（DMD）的治疗景观已在批准后转化自2016年以来，FDA为该疾病的五种新化合物中的五种化合物中的四种。诱导肌营养不良蛋白前MRNA的外显子跳过的寡核苷酸，恢复了特定的阅读框致病变体的子集。这些进步是显着的，但是还有很多工作要做。大约三分之二的DMD群体具有致病性变异，这些变异不适合任何一个目前批准的反义寡核苷酸化合物。虽然DMD的预期寿命比以前有多学科治疗方法，大多数受影响的人在青春期，缩短了预期寿命。已经对基于细胞的细胞进行了广泛的研究在过去的几十年中，治疗方法包括一些人类的临床试验。我们的小组有对基于干细胞的方法进行临床前研究，这是有利的补充肌肉干细胞池并增强受损骨骼肌的长期再生。和我们的团队的最新临床前进步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类临床试验，首先是一个阶段 1评估肌内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会植入骨骼肌肉没有明显的安全问题。该计划赠款的目标是准备所需的最后一步启动该阶段1临床试验。在此计划期间要完成的任务包括成立研究团队并开始定期安排的团队会议；组成和临床研究方案的完善；单个站点手册的组成和完善符合NIAMS要求的程序（MOOP）；任命数据和安全监控董事会（DSMB）并建立一个用于数据和安全监控报告的模板；提交一个网站IRB 协议;制定一组新的IND提交所需的监管文件；和为实施1期临床试验的U01提案准备。到资金结束时时期，我们的目标是获得FDA和IRB的批准来启动这项研究。