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.

项目总结 Duchenne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 在营养不良蛋白基因中。DMD的特征是进行性肌肉萎缩和肌肉功能的全面丧失。 DMD患者在12岁时成为轮椅依赖者，并与相关的心肺疾病 并发症导致他们在20岁左右过早死亡。营养不良症，包括DMD和 不太严重的Becker表型是X连锁隐性疾病，主要影响男性，有16,765人 在美国的病人。DMD无法治愈，强的松等皮质类固醇可用于治疗症状 如释重负。许多新兴的治疗方法，如外显子跳过、基因纠正和腺相关 病毒(AAV)介导的基因治疗旨在增加dystrophin的产生，但受到免疫的限制 应答性差，疗效可疑，短期效果差，费用高，仅限于某些突变。细胞疗法 在治疗退行性疾病和遗传性疾病方面具有巨大的潜力。然而，到目前为止，生产 细胞治疗的可扩展性、安全性和有效性限制了细胞治疗的临床过渡。Mygenica有 开发了MyoPAXon，一种经cGMP认证的诱导多能干细胞(IPSC)来源的肌源性平台 再生骨骼肌，改善功能。MyoPAXon不仅可以替代患病的肌肉 纤维具有正常的肌肉纤维功能，但也创造了肌肉干细胞池，使肌肉能够长期存在 再生。肌内、血管内和动脉内移植的临床前动物研究 MyoPAXon显示出显著的植入性和功能改善。Mygenica已取得进展 肌肉注射MyoPAXon进入临床，预计今年第二季度将出现IND，并首次出现DMD患者 将在今年晚些时候接受治疗。作为下一步，Mygenica寻求开发系统递送的MyoPAXon。这个 目前的STTR快速通道项目，旨在验证全身MyoPAXon的有效性和安全性 临床前动物模型的分娩将与明尼苏达大学合作进行。 全身注射MyoPAXon将允许通过一次注射靶向多个骨骼肌， 使其成为DMD患者和一系列肌肉营养不良的令人信服的治疗方法，因为MyoPAXon的 机制不是突变所特有的。在第一阶段-目标1期间，我们将选择最优的系统交付路线(IV 或IA)，并在免疫缺陷的NSG小鼠中进行剂量发现研究，评估比较植入。这 之后将在目标2中进行初步安全评估，其中非目标中存在人类细胞 对小鼠的组织和器官进行评估。在第二阶段-AIM 1将继续评估免疫效果 -NSGmdx4Cv缺陷型DMD小鼠模型，采用第一阶段确定的最佳剂量和路线。 第二阶段-目标2，全面的GLP毒理学和药代动力学将在NSG小鼠身上进行， 之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。结果是 从这项STTR提案中获得的信息将被用于临床研究新药(IND)申请 系统性MyoPAXon的研究。