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A Pharmaco-Epigenomic Intervention for the Mitochondrial Disorder MELAS

针对线粒体疾病的药物表观基因组干预 MELAS

基本信息

批准号：
8891656
负责人：
Anne Eliane CHIARAMELLO
金额：
$ 40.84万
依托单位：
GEORGE WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-15 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8891656
关键词：
ATP Synthesis Pathway Affect American Bioenergetics Biogenesis Biopsy Butyrates Bypass Case Study Cells Cessation of life Child Childhood Chronic Clinical Clinical Research Collaborations Complex Confocal Microscopy Data Diffuse Disease Disease Progression Encephalopathies Energy Metabolism Ensure Exposure to Fatty Acids Fibroblasts Future Gene Expression Genes Histone Deacetylase Inhibitor Impaired cognition Individual Inherited Intervention Investigational New Drug Application Lactic Acidosis Leucine-Specific tRNA Life Lung diseases Mediating Medical center Membrane Potentials Metabolic Microarray Analysis Mission Mitochondria Mitochondrial DNA Mitochondrial Diseases Mutation Myopathy NADH dehydrogenase (ubiquinone)National Institute of Neurological Disorders and Stroke Neurodegenerative Disorders Neurologist Neurons Nuclear Organ failure Output Oxidative Phosphorylation Palliative Care Pathogenesis Pathway interactions Patients Phenotype Population Production Property Public Health Rare Diseases Recovery Recruitment Activity Regulation Reporting Research Residual state Respiration Disorders Seizures Seminal Skin Sodium Butyrate Staging Stroke Symptoms System Testing Therapeutic Translating Translational Research Tubular formation Up-Regulation Volatile Fatty Acids base bench to bedside disability driving force drug development early childhood effective therapy epigenomics fatty acid oxidation genome-wide innovation mitochondrial dysfunction mitochondrial genome mitochondrial membrane mutant novel nuclear reprogramming outcome forecast oxidation pediatrician pre-clinical premature prevent public health relevance respiratory sound tributyrin

项目摘要

DESCRIPTION (provided by applicant): The most common mitochondrial respiratory disorder is MELAS (Mitochondrial Encephalopathy Lactic Acidosis with Stroke-like Episodes), an incurable progressive neurodegenerative disease with early childhood onset. This orphan disease causes heterogeneous clinical symptoms, such as encephalopathy, seizures, stroke-like episodes, cognitive impairment, chronic lactic acidosis, and myopathy. Most MELAS patients harbor a maternally inherited mutation (A3243G) in the mitochondrial-encoded tRNALeu/UUR gene, which affects the oxidative phosphorylation (OXPHOS) system responsible for ATP synthesis. In MELAS cells, the multi-copy mitochondrial genome population is heterogeneous, with variable ratios of mutant mtDNAs and wild type (WT) mtDNAs, a state known as heteroplasmy. Individuals with the MELAS mutation become symptomatic only when the mutant load exceeds a certain threshold of heteroplasmy. Currently, no therapeutic options are available to prevent the progression of the disease, resulting in significant disability, a poo prognosis, and premature death. Our proposed novel pharmacological approach uses butyrates to promote nuclear and mitochondrial metabolic reprogramming by boosting mitochondrial biogenesis and maximizing residual ATP output. Using primary fibroblasts derived from a skin biopsy of two MELAS patients, we performed an Affymetrix-based genome-wide microarray analysis that revealed enrichment of pathways for mitochondrial biogenesis and bioenergetics upon exposure to butyrates. From live cell confocal microscopy, we found that butyrates restored the mitochondrial mass and the pool of bioenergetically competent mitochondria in MELAS fibroblasts. In healthy neuronal cells, we found that butyrates induced mitochondrial biogenesis via expression of essential nuclear-encoded regulators and augmented the pool of bioenergetic mitochondria and ATP levels. Thus, our collective preliminary data validate our pharmaco-epigenomic approach and establish proof-of-principle for the proposed studies. We hypothesize that butyrates can augment the functional mitochondrial mass in skin fibroblasts from 20 MELAS patients. Fibroblasts from this number of patients, each with different nuclear backgrounds and heteroplasmic loads, will ensure the findings extend beyond a case study into a statistically sound and broadly applicable report. We will test whether butyrates: (Aim 1) induce favorable mitochondrial biogenesis, thereby shifting heteroplasmy toward healthy mitochondria; and (Aim 2) maximize ATP output via optimization of OXPHOS activity and a metabolic shift toward fatty acid beta oxidation. We anticipate identifying the most promising butyrate candidate for alleviating the symptoms of the MELAS disease. The proposed study will set the stage for future clinical studies with the Children's National Medical Center and the North American Mitochondrial Disease Consortium, in concordance with the PAR-13-023 issued by the NINDS Office of Translational Research for R21 exploratory projects.