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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目摘要/摘要该UG3/UH3建议是针对靶向共享药物的RFA-TR-20-031-篮子临床试验多种罕见疾病的分子病因。拟议的研究重点是两个超稀有的研究遗传性线粒体疾病Melas（线粒体脑病，乳酸酸中毒，类似于中风样发作）和Lhon-Plus（Leber的遗传性视神经神经病加）。两种疾病都是研究的稀有疾病临床研究网络。患者无法获得有效的治疗干预措施，导致严重的残疾，发病率和过早死亡。这些疾病造成了破坏强调了解决这种未满足的医疗需求并发展新型治疗候选者的紧迫性。但是，他们的超稀有流行率使得招募累积数量的Melas和Lhon- 加上临床试验的患者。这是拟议的篮子临床试验设计将结合这两个超稀有的种群提供了概念概念，以证明其对不同患者人群的可行性。 Melas和Lhon-Plus患者暴露了分歧和重叠的临床神经系统和非神经学症状。它们是由主要遗传的致病变异引起的，导致氧化有缺陷负责线粒体ATP合成的磷酸化途径。两种疾病共享分子复杂I缺乏的病因，导致ATP缺乏和慢性能量不足。我们设计了一种新型的两种两种药物 - 蒙科策略，以增加Melas和Melas的ATP输出 LHON-PLUS患者。我们使用前病人衍生的成纤维细胞进行的临床前研究证明了我们的铅化合物的可行性可促进Melas和Lhon-Plus患者的线粒体恢复成纤维细胞。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，一个推荐地点北美线粒体疾病财团。该伙伴关系由NIH临床和转化科学奖UL1计划为拟议的研究提供了强大的基础设施。 AIM 1（UG3阶段）着重于翻译Melas和Lhon-Plus研究以及提交IND FDA的协议。 AIM 2（UH3期）专注于Melas和Lhon-Plus的篮子临床试验：1）提供概念证明，可以将篮子设计应用于发散的超稀有疾病； 2）推进铅化合物的安全性和药代动力学/药效学数据集患者比在常规的临床试验环境中； 3）收集结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概念应用于多种疾病常见的分子靶标，但也针对具有相似的前体内成纤维细胞对丁酸酯的反应的组疾病以提高我们评估超稀有疾病人群中治疗药物的能力。