Systemic Transplantation of MyoPAXon: IND Enabling Studies for the Treatment of DMD

MyoPAXon 的系统移植：治疗 DMD 的 IND 启用研究

• 批准号: 10822639
• 负责人: Michael Kyba
• 金额: $ 29.27万
• 依托单位: MYOGENICA INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-25 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10822639
• 关键词: 12 year old; 20 year old; Address; Adrenal Cortex Hormones; Affect; Allogenic; Animal Model; Animals; Biodistribution; Blood; Blood Vessels; Caring; Cell Therapy; Cells; Certification; Cessation of life; Clinic; Clinical; Clinical Research; Clinical Trials; Collaborations; Complement; Cyclic GMP; Data; Degenerative Disorder; Dependence; Dependovirus; Disease; Doctor of Philosophy; Dose; Drug Compounding; Drug Kinetics; Duchenne muscular dystrophy; Dystrophin; Engraftment; Evaluation; Failure; Femur; Foundations; Gene Mutation; Genes; Genetic Diseases; Goals; Health; Human; Immune; Immune response; Immunologic Deficiency Syndromes; Injections; Intramuscular; Intravenous; Investigational Drugs; Investigational New Drug Application; Link; Macaca fascicularis; Measurement; Mechanics; Mediating; Medical; Methods; Minnesota; Modeling; Mus; Muscle; Muscle Fibers; Muscle function; Muscle satellite cell; Muscular Atrophy; Muscular Dystrophies; Mutation; Myopathy; Natural regeneration; Organ; Outcome; Patients; Phase; Phase I/II Clinical Trial; Phenotype; Prednisone; Production; Research; Research Personnel; Route; Safety; Scientist; Skeletal Muscle; Small Business Technology Transfer Research; Teratoma; Testing; Therapeutic; Tissues; Toxic effect; Toxicology; Translating; Transplantation; Transplantation Immunology; Universities; Venous; Wheelchairs; comparative; cost; dystrophinopathy; efficacy evaluation; efficacy study; efficacy validation; exon skipping; experience; first-in-human; functional improvement; gene correction; gene therapy; human DNA; improved; induced pluripotent stem cell; male; mouse model; muscle regeneration; nonhuman primate; novel therapeutics; pre-clinical; preclinical study; progenitor; response; restoration; safety assessment; skeletal muscle wasting; stem cell expansion; stem cell therapy; stem cells

PROJECT SUMMARY Duchenne muscular dystrophy (DMD) is the most common type of muscular dystrophy, caused due to mutations in the dystrophin gene. DMD is characterized by progressive muscle wasting and overall loss of muscle function. DMD patients become wheel chair dependant by 12 years of age and the associated cardiorespiratory complications result in their early death around 20 years of age. Dystrophinopathies, which include DMD and the less severe phenotype Becker, are X-linked recessive disorders affecting primarily males, with 16,765 patients in the US. There is no cure for DMD and corticosteroids such as prednisone are used for symptomatic relief. Many emerging therapeutic approaches such as exon skipping, gene correction and adeno-associated virus (AAV) mediated gene therapy aim to increase dystrophin production but are restricted by the immune response, questionable efficacy, short term effect, high cost and are limited to certain mutations. Cell therapies have tremendous potential to treat degenerative conditions and genetic diseases. However, to date, production scalability, safety and efficacy of cell therapy have limited the clinical transition of cell therapies. Myogenica has developed MyoPAXon, a cGMP certified, induced pluripotent stem cell (iPSC) derived myogenic platform which regenerates skeletal muscle, leading to functional improvement. MyoPAXon not only replaces diseased muscle fibers with normal functional muscle fibers but also creates a muscle stem cell pool, enabling long-term muscle regeneration. Preclinical animal studies of intramuscular, intravascular and intra-arterial transplantation of MyoPAXon have shown significant engraftment and functional improvement. Myogenica has advanced intramuscular delivered MyoPAXon toward the clinic, with an IND expected in Q2 this year and first DMD patients to be treated later this year. As a next step, Myogenica seeks to develop systemically delivered MyoPAXon. The current STTR Fast track project, aimed at validating the efficacy and safety of systemic MyoPAXon delivery in preclinical animal models, will be carried out in collaboration with the University of Minnesota. Systemic MyoPAXon delivery will allow for the targeting of multiple skeletal muscles with a single injection, making it a compelling therapy for DMD patients and for a range of muscular dystrophies, since MyoPAXon’s mechanism is not mutation specific. During Phase I-Aim 1, we will select an optimal systemic delivery route (IV or IA) and conduct dose finding studies in immunodeficient NSG mice, assessing comparative engraftment. This will be followed by a preliminary safety assessment in Aim 2 where the presence of human cells in non-target tissues and organs of mice will be evaluated. In Phase II-Aim 1 will continue evaluating efficacy in the immune deficient, -NSGmdx4Cv mouse model for DMD, using the optimised dose and route determined in Phase I. During the Phase II-Aim 2, comprehensive GLP toxicology and pharmacokinetics will be performed on NSG mice which will be followed by safety and biodistribution evaluation in a Non-Human Primate (NHP) model. The results obtained from this STTR proposal will be leveraged in an Investigational New Drug (IND) application for clinical studies of systemic MyoPAXon.

项目摘要 Duchenne肌肉营养不良（DMD）是最常见的肌肉营养不良类型，是由于突变引起的 在肌营养不良的基因中。 DMD的特征是进行性肌肉浪费和肌肉功能的总体丧失。 DMD患者在12岁时成为依赖轮椅，并且相关心肺 并发症导致其早期死亡大约20岁。肌营养不良，其中包括DMD和 不太严重的表型贝克尔是影响原发性男性的X连锁隐性疾病，有16,765 美国的患者。无法治愈DMD，皮质类固醇（例如泼尼松）用于症状学 宽慰。许多新兴的治疗方法，例如外显子跳过，基因校正和腺相关 病毒（AAV）介导的基因疗法旨在增加肌营养不良蛋白的产生，但受到免疫的限制 响应，可疑的有效性，短期效应，高成本，并且仅限于某些突变。细胞疗法 具有治疗退化疾病和遗传疾病的巨大潜力。但是，迄今为止的生产 细胞疗法的可伸缩性，安全性和效率限制了细胞疗法的临床过渡。肌根源有 开发了Myopaxon，这是CGMP认证的，诱导的多能干细胞（IPSC）衍生的肌源性平台 再生骨骼肌，导致功能改善。 Myopaxon不仅取代患病的肌肉 具有正常功能肌纤维的纤维，但还会产生肌肉干细胞池，使长期肌肉能够 再生。临床前动物研究对肌内，血管内和动脉内移植的研究 Myopaxon显示出明显的植入和功能改进。肌根疗法已经进展 肌肉内将Myopaxon送往诊所，预计今年是第一季度的DMD患者 将于今年晚些时候接受治疗。下一步，肌根源试图开发系统地交付的肌肉发达。 当前的STTR快速轨道项目，旨在验证系统性Myopaxon的效率和安全性 将与明尼苏达大学合作进行临床前动物模型的交付。 全身性肌膜输送将允许用单个注射的多个骨骼肌靶向 自从Myopaxon的病毒以来 机理不是突变的。在I-AIM阶段1期间，我们将选择一条最佳的系统交付路线（IV 或IA）并在免疫缺陷的NSG小鼠中进行剂量查找研究，以评估比较植入。这 在AIM 2中将进行初步安全评估，其中人类细胞在非目标中的存在 将评估小鼠的组织和器官。在II阶段中，1将继续评估免疫的效率 DMD缺乏DMD的-NSGMDX4CV小鼠模型，使用在第1期中确定的优化剂量和路线 II-II-AIM 2，全面的GLP毒理学和药代动力学将在NSG小鼠上进行 随后将在非人类灵长类动物（NHP）模型中进行安全和生物分布评估。结果 从该STTR提案获得的临床申请（IND）将利用 全身性肌伴侣的研究。