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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要杜氏肌营养不良症 (DMD) 是最常见的肌营养不良症类型，由突变引起 DMD 的特征是进行性肌肉萎缩和肌肉功能的整体丧失。 DMD 患者在 12 岁时开始依赖轮椅，并导致相关的心肺疾病并发症导致他们在 20 岁左右过早死亡，其中包括 DMD 和肌营养不良症。不太严重的 Becker 表型是 X 连锁隐性遗传病，主要影响男性，有 16,765 在美国，DMD 患者无法治愈，只能使用泼尼松等皮质类固醇来治疗症状。许多新兴的治疗方法，如外显子跳跃、基因校正和腺相关疗法。病毒（AAV）介导的基因治疗旨在增加抗肌萎缩蛋白的产生，但受到免疫系统的限制反应快、功效可疑、短期效果、成本高且仅限于某些突变细胞疗法。具有治疗退行性疾病和遗传疾病的巨大潜力，但迄今为止，其生产仍存在。细胞疗法的可扩展性、安全性和有效性限制了细胞疗法的临床转变。开发了 MyoPAXon，这是一种经过 cGMP 认证的诱导多能干细胞 (iPSC) 衍生的生肌平台， MyoPAXon 可以再生骨骼肌，从而改善功能，不仅可以替代患病的肌肉。具有正常功能性肌纤维的纤维，还创建了肌肉干细胞库，使长期肌肉肌内、血管内和动脉内移植的临床前动物研究。 MyoPAXon 已显示出显着的植入和功能改善。肌内注射 MyoPAXon 进入临床，预计将于今年第二季度获得 IND，并迎来首批 DMD 患者下一步，Myogenica 寻求开发系统性递送的 MyoPAXon。目前的 STTR 快速通道项目，旨在验证系统性 MyoPAXon 的有效性和安全性临床前动物模型的交付将与明尼苏达大学合作进行。全身性 MyoPAXon 输送将允许通过单次注射靶向多个骨骼肌，自从 MyoPAXon 的机制不是突变特异性的。在 I-Aim 1 阶段，我们将选择最佳的全身递送途径（IV）。或IA）并在免疫缺陷的NSG小鼠中进行剂量探索研究，评估比较植入。随后将在目标 2 中进行初步安全评估，其中非目标细胞中存在人类细胞在 II 期目标 1 中，将继续评估小鼠的组织和器官的免疫功效。使用第一阶段确定的优化剂量和途径，建立 DMD 缺陷型 -NSGmdx4Cv 小鼠模型。 II 期目标 2，将在 NSG 小鼠上进行全面的 GLP 毒理学和药代动力学研究，随后将在非人类灵长类动物（NHP）模型中进行安全性和生物分布评估。从该 STTR 提案中获得的资金将用于临床研究新药 (IND) 申请系统性 MyoPAXon 的研究。