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

具有共同病因的罕见母系遗传线粒体疾病的新兴治疗候选药物

• 批准号: 10702207
• 负责人: Anne Eliane CHIARAMELLO
• 金额: $ 95.71万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10702207
• 关键词: ATP Synthesis Pathway; Address; Adult; Affect; American; Animal Model; Animals; Biological Assay; Butyrates; Butyric Acids; Bypass; Cell model; Cessation of life; Child; Childhood; Chronic; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Clinical and Translational Science Awards; Complex; Data Set; Diffusion; Disease; Dose; Drug Kinetics; Enrollment; Etiology; Exhibits; FDA approved; Fibroblasts; Funding; Future; Gene Expression; HDAC4 gene; Health Sciences; Histone Acetylation; Histone Deacetylase Inhibitor; Individual; Infrastructure; Inherited; Lead; Leber' s Hereditary Optic Neuropathy; Lipase; MELAS Syndrome; Medical; Medical center; Metabolism; Mitochondria; Mitochondrial Diseases; Molecular; Molecular Target; Morbidity - disease rate; National Cancer Institute; Neurodegenerative Disorders; Neurologic; Nuclear; Outcome; Output; Oxidative Phosphorylation; Pathogenicity; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology Study; Phase; Population; Prevalence; Prodrugs; Property; Protocols documentation; Rare Diseases; Recovery; Research Personnel; Safety; Site; Sodium Butyrate; Symptoms; Testing; Therapeutic; Therapeutic Intervention; Toxic effect; United States National Institutes of Health; Universities; Variant; Volatile Fatty Acids; Washington; arm; clinical heterogeneity; clinical phenotype; cohort; design; disability; drug withdrawal; effective therapy; epigenomics; fatty acid oxidation; improved; innovation; medical schools; mitochondrial metabolism; novel; novel therapeutics; open label; participant enrollment; patient population; patient response; personalized medicine; pharmacokinetics and pharmacodynamics; pharmacologic; pre-Investigational New Drug meeting; pre-clinical; preclinical study; preclinical trial; premature; programs; recruit; respiratory; response; safety study; targeted therapy trials; therapeutic candidate; therapeutically effective; tributyrin

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.

项目概要/摘要 该 UG3/UH3 提案是对 RFA-TR-20-031-针对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。拟议的研究重点关注两种极其罕见的母体 遗传性线粒体疾病 MELAS（线粒体脑病、乳酸性酸中毒、中风样发作） 和 LHON-Plus（莱伯遗传性视神经病-Plus）。这两种疾病都在研究范围内 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并开发新的治疗候选药物的紧迫性。 然而，它们极其罕见的患病率使得招募一定数量的 MELAS 和 LHON 变得具有挑战性。 加上患者进行临床试验。因此，拟议的篮子临床试验设计将结合这两种极其罕见的药物 人群，为其针对不同患者人群的可行性提供概念验证。 MELAS 和 LHON-Plus 患者表现出不同且重叠的临床神经学和非神经学症状 症状。它们是由母系遗传的致病变异引起的，导致氧化缺陷 磷酸化途径负责线粒体 ATP 合成。这两种疾病具有相同的分子特征 复合物 I 缺乏的病因，导致 ATP 缺乏和慢性能量缺乏。 我们设计了一种新颖的双管齐下的药物表观基因组策略来增加 MELAS 和 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证明 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儿童国家医疗中心，一个转介网站 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 UL1 计划为拟议研究提供强大的基础设施。 目标 1（UG3 阶段）侧重于转化性 MELAS 和 LHON-Plus 研究以及 IND 的提交 FDA 协议。目标 2（UH3 阶段）重点关注 MELAS 和 LHON-Plus 的篮子临床试验：1) 提供概念证明，证明篮子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，涉及大量 患者比传统临床试验环境中的患者； 3) 收集成果和实用信息 优化未来篮子临床试验的设计。 我们的创新设计在于将篮子临床试验的理念不仅仅应用于多种疾病 共同的分子靶标，而且还针对具有相似的离体成纤维细胞对丁酸盐反应的群体 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。