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

项目概要/摘要 本UG 3/UH 3提案是对RFA-TR-20-031-靶向共享药物的篮子临床试验的回应 多种罕见疾病的分子病因学。拟议的研究集中在两个超罕见的母亲 遗传性线粒体疾病MELAS（线粒体脑病、乳酸性酸中毒、卒中样发作） 和LHON-Plus（Leber遗传性视神经病-Plus）。这两种疾病都是由 罕见疾病临床研究网络。患者无法获得有效的治疗干预， 导致严重残疾、发病和过早死亡。这些疾病造成的破坏 强调了解决这一未满足的医疗需求和开发新的治疗候选物的紧迫性。 然而，它们的超罕见患病率使得招募累积数量的MELAS和LHON具有挑战性， 加上临床试验的病人。因此，拟定的网篮临床试验设计将联合收割机结合这两种超罕见 以提供其对于不同患者人群的可行性的概念验证。 MELAS和LHON-Plus患者表现出不同和重叠的临床神经和非神经 症状它们是由母系遗传的致病性变异引起的，导致有缺陷的氧化 磷酸化途径负责线粒体ATP合成。这两种疾病的分子 复合物I缺乏症的病因，引起ATP缺乏症和慢性能量缺乏症。 我们设计了一种新的双管齐下的药物表观基因组策略来增加MELAS中的ATP输出， LHON-Plus患者。我们使用离体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的跨学科优势 大学医学与健康科学学院和儿童国家医学中心， 北美线粒体疾病联盟该合作伙伴关系由NIH临床和 转化科学奖UL 1计划为拟议的研究提供了强大的基础设施。 目标1（UG 3阶段）侧重于翻译MELAS和LHON-Plus研究以及IND的提交 FDA的协议。目标2（UH 3阶段）侧重于MELAS和LHON-Plus的篮临床试验，以：1） 提供概念验证，证明篮设计可应用于不同的超罕见疾病; 2）推进 我们的先导化合物的安全性和药代动力学/药效学数据集， 患者比在传统的临床试验设置;和3）收集结果和实用信息， 优化未来网篮临床试验的设计。 我们的创新设计在于将篮子临床试验的概念不仅应用于多种疾病， 共同的分子靶点，但也适用于对丁酸盐具有相似的离体成纤维细胞反应的组。 疾病，以提高我们在超罕见疾病人群中评估治疗药物的能力。

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.