CLINICAL STUDIES OF MITOCHONDRIAL DISEASE

Beth Israel Deaconess Medical Center, Boston MA

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Abstract

DESCRIPTION (Adapted from The Applicant's Abstract): Mitochondrial diseases have protean clinical manifestations, including the nervous system and eye. We identified a novel mitochondrial disease, Sensory Ataxic Neuropathy, Dysarthria, and Ophthalmoplegia (SANDO), which is associated with multiple mitochondrial DNA (mtDNA) deletions. Sensory ataxia is prominent in two other neurologic diseases, Friedreich's ataxia and ataxia with vitamin E deficiency, caused by neuronal oxidative stress. Leber's hereditary optic neuropathy (LHON) was the first disease to be associated with mtDNA point mutations. There have been tremendous diagnostic advances in LHON, but little therapeutic progress. Three primary LHON-associated mtDNA mutations account for the majority of LHON cases. Tobacco and alcohol act as interacting epigenetic factors in LHON. Cybrids are cytoplasmic hybrid cell lines, formed by the fusion of the same recipient nucleus with different donor mutant mitochondria, that are cellular models of mtDNA-mediated disease. Oxidative stress is a critical cellular imbalance between prooxidant species and antioxidant defenses. The hypothesis to be tested is that disruption of mitochondrial energy production (via mtDNA point mutations or multiple deletions) renders neurons more sensitive to oxidative stress and is a unifying feature of LHON and SANDO. We propose studies with the following specific aims: 1. To develop an in vitro cybrid cellular therapeutic model of LHON to facilitate the testing of novel therapeutic hypotheses and guide future rational therapy; 2. To define the epigenetic risk factors that interact with LHON-associated mtDNA mutations. Clinical epidemiology (retrospective & prospective) studies of our extensive population of molecularly-confirmed LHON patients will be performed; 3.To perform preventive and therapeutic clinical trials in molecularly-confirmed LHON patients and their at-risk maternal relatives; 4. To refine and expand the molecularly-proven SANDO clinical phenotype. The ultimate goal of this patient-oriented research, is to advance the prevention and treatment of LHON, SANDO, and other mitochondrial diseases.