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

项目摘要 杜氏肌营养不良症（DMD）是最常见的类型的肌营养不良症，由于突变引起的 在抗肌萎缩蛋白基因中。DMD的特征在于进行性肌肉萎缩和肌肉功能的整体丧失。 DMD患者在12岁时成为轮椅依赖者， 并发症导致他们在20岁左右过早死亡。肌营养不良症，包括DMD和 不太严重的表型贝克尔，是X连锁隐性疾病，主要影响男性，有16765 美国的病人。DMD无法治愈，皮质类固醇如泼尼松用于对症治疗。 救灾许多新兴的治疗方法，如外显子跳跃，基因校正和腺相关病毒治疗， 腺相关病毒（AAV）介导的基因治疗旨在增加肌营养不良蛋白的产生，但受到免疫缺陷的限制。 反应，可疑的功效，短期效果，高成本，并限于某些突变。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 细胞疗法的可扩展性、安全性和功效限制了细胞疗法的临床转变。Myogenica拥有 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， 再生骨骼肌，导致功能改善。MyoPAXon不仅可以替代患病的肌肉 纤维与正常功能的肌肉纤维，但也创造了一个肌肉干细胞池，使长期肌肉 再生肌内、血管内和动脉内移植的临床前动物研究 MyoPAXon显示出显著的植入和功能改善。Myogenica已经发展到 肌内注射MyoPAXon进入临床，预计今年第二季度将有IND， 今年晚些时候接受治疗。作为下一步，Myogenica寻求开发全身递送的MyoPAXon。的 当前STTR快速跟踪项目，旨在验证全身MyoPAXon的有效性和安全性 在临床前动物模型中的交付，将与明尼苏达大学合作进行。 全身MyoPAXon递送将允许通过单次注射靶向多个骨骼肌， 使其成为DMD患者和一系列肌营养不良症的引人注目的疗法， 机制不是突变特异性的。在阶段I-目标1期间，我们将选择最佳的全身给药途径（IV 或IA），并在免疫缺陷NSG小鼠中进行剂量探索研究，评估比较移植。这 随后将在目标2中进行初步安全性评估，其中在非靶细胞中存在人细胞， 评价小鼠的组织和器官。在II期-目标1中，将继续评估免疫治疗的疗效。 缺陷型，-NSGmdx 4Cv小鼠模型的DMD，使用在I期确定的优化剂量和途径。期间 II期-目标2，将对NSG小鼠进行全面的GLP毒理学和药代动力学研究， 随后将在非人灵长类动物（NHP）模型中进行安全性和生物分布评价。结果 从本STTR提案中获得的信息将在临床试验新药（IND）申请中使用， 全身性MyoPAXon的研究。

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.