Emerging therapeutic candidates for rare maternally inherited mitochondrial diseases with shared etiologies

项目摘要/摘要 该UG3/UH3提案是对RFA-TR-20-031篮子药物靶向共享药物临床试验的回应 多种罕见疾病的分子病因。拟议的研究集中在两种极稀有的母体上 遗传性线粒体疾病MELAS(线粒体脑病、乳酸酸中毒、卒中样发作) 和LHON-Plus(Leber遗传性视神经病变-Plus)。这两种疾病都在 罕见病临床研究网络。患者无法获得有效的治疗干预， 导致严重的残疾、发病率和过早死亡。这些疾病造成的破坏 强调了解决这一未得到满足的医疗需求和开发新的候选治疗方法的紧迫性。 然而，它们极其罕见的流行使得招募累积数量的MELAS和LHON- 加上临床试验的病人。因此，拟议的篮子临床试验设计将结合这两种超罕见的 为不同的患者群体提供其可行性的概念证明。 MELAS和LHON-Plus患者表现出不同和重叠的临床神经学和非神经学 症状。它们是由一种母系遗传的致病变异引起的，这种变异导致氧化缺陷 线粒体ATP合成的磷酸化途径。这两种疾病都有相同的分子 复合体I缺乏的病因，导致ATP缺乏和慢性能量缺乏。 我们设计了一种新的双管齐下的药物表观基因组学策略来增加MELAS和 LHON-Plus患者。我们使用体外患者来源的成纤维细胞进行的临床前研究表明 我们的先导化合物促进MELAS和LHON-Plus患者线粒体恢复的可行性 成纤维细胞。拟议的多PI研究结合了乔治·华盛顿大学的跨学科优势 大学医学与健康科学学院和国家儿童医学中心，一个参考网站 北美线粒体疾病联合会。这一合作伙伴关系由NIH临床和 翻译科学奖UL1计划为拟议的研究提供了强有力的基础设施。 目标1(UG3阶段)侧重于翻译MELAS和LHON-Plus研究并提交IND 给FDA的协议。AIM 2(UH3阶段)重点是MELAS和LHON-Plus的篮子临床试验，以：1) 提供概念验证，证明篮子设计可应用于不同的超罕见疾病；2)推动 我们的先导化合物的安全性和药代动力学/药效学的数据集 患者比传统临床试验环境中的患者更多；以及3)收集结果和实用信息 优化未来篮子临床试验设计。 我们的创新设计在于将篮子临床试验的概念应用于多种疾病，而不仅仅是 共同的分子靶点，但也针对具有相似体外成纤维细胞对丁酸盐反应的组 以提高我们在极罕见疾病人群中评估我们的治疗药物的能力。

Project Summary/Abstract This UG3/UH3 proposal is in response to RFA-TR-20-031-Basket Clinical Trials of Drugs targeting Shared Molecular Etiologies in Multiple Rare Diseases. The proposed studies focus on two ultra-rare maternally inherited mitochondrial diseases MELAS (mitochondrial encephalopathy, lactic acidosis, stroke-like episodes) and LHON-Plus (Leber’s hereditary optic neuropathy-Plus). Both diseases are among those studied by the Rare Diseases Clinical Research Network. Patients do not have access to effective therapeutic intervention, resulting in significant disability, morbidity, and premature death. The devastation wrought by these diseases underscores the urgency to address this unmet medical need and develop novel therapeutic candidates. However, their ultra-rare prevalence makes it challenging to recruit an accrued number of MELAS and LHON- Plus patients to clinical trials. Thus, the proposed basket clinical trial design will combine these two ultra-rare populations to provide proof-of-concept of its feasibility for divergent patient populations. MELAS and LHON-Plus patients exhibit divergent and overlapping clinical neurological and non-neurological symptoms. They are caused by a maternally inherited pathogenic variant that results in a defective oxidative phosphorylation pathway responsible for mitochondrial ATP synthesis. Both diseases share the molecular etiology of Complex I deficiency, causing ATP deficiency and chronic energy deficit. We designed a novel two-pronged pharmaco-epigenomic strategy to increase ATP output in MELAS and LHON-Plus patients. Our pre-clinical studies using ex-vivo patient-derived fibroblasts demonstrate the feasibility of our lead compound to promote mitochondrial recovery in MELAS and LHON-Plus patient’s fibroblasts. The proposed multi-PI studies combines the cross-disciplinary strengths of the George Washington University School of Medicine and Health Sciences and Children’s National Medical Center, a referring site for the North American Mitochondrial Disease Consortium. This partnership is funded by an NIH Clinical and Translational Science Award UL1 Program providing a robust infrastructure for the proposed studies. Aim 1 (UG3 phase) focuses on translational MELAS and LHON-Plus studies and submission of an IND protocol to the FDA. Aim 2 (UH3 phase)focuses on a basket clinical trial with MELAS and LHON-Plus to: 1) provide proof-of-concept that the basket design can be applied to divergent ultra-rare diseases; 2) advance the dataset for safety and pharmacokinetics/pharmacodynamics of our lead compound for a larger number of patients than in a conventional clinical trial setting; and 3) gather outcomes and practical information for optimizing the design of future basket clinical trial. Our innovative design lies in applying the concept of basket clinical trial not only to multiple diseases with a common molecular target, but also to groups with similar ex-vivo fibroblasts response to butyrate across these diseases to improve our ability to evaluate our therapeutic drug in ultra-rare disease populations.