MITOCHONDRIAL ENCEPHALOMYOPATHIES: APPROACHES TO TREATMENT

DESCRIPTION (provided by applicant): Mitochondrial Encephalomyopathies: Approaches to Treatment. Mitochondrial encephalomyopathies are a heavy public health burden and therapy is woefully inadequate. We are proposing therapy-directed studies for disorders associated with mitochondrial DNA (mtDNA) point mutations, especially mitochondrial encephalomyopathy, lactic acidosis, and stroke like episodes (MELAS-3243), and for mendelian disorders, including the mtDNA depletion due to TK2 deficiency and coenzyme Q10 (CoQ10) deficiencies. In Project # I, Dr. Darryl De Vivo, P.I. will continue to characterize the natural history of MELAS, correlating clinical course in probands and carriers with cerebral and muscle biomarkers assessed by MRSI and 31P- NMR. He will seek new biomarkers by applying metabolomics (collaboration with Dr. Vamsi Mootha, Harvard University and MIT, Boston, MA). Project #2 (Dr. Eric A. Schon, P.I.) will concentrate on pharmacological approaches to mtDNA-related disorders by evaluating the effectiveness of compounds affecting heteroplasmic shifting or functional rescuing through modulation of mitophagy and quality control. Project # 3 (Dr. Michio Hirano, P.I.) will use pharmacological and gene therapy of thymidine kinase 2 (TK2) deficiency in mice that faithfully recapitulate the human disease. A molecular bypass therapy is showing promising preliminary results, with amelioration of the abnormal phenotype and extension of the lifespan not only in mice but also in a few human subjects. In TK2 knock-in mice he also plans to test gene therapy using adeno- associated virus (AAV) vectors to deliver human TK2 and restore enzymatic activity. In Project # 4 (Dr. Catarina Quinzii, PI), Dr. Quinzii will test genetic and pharmacologic therapies for CoQ10 deficiency in vitro through ADCK3 overexpression and exposure to analogs of 4-hydroxybenzoic acid, a precursor required for CoQ10 biosynthesis. She also proposes to compare efficacies of oral and intrathecal administration of CoQ10 and idebenone in preventing or delaying the molecular and biochemical abnormalities, and the clinical onset of the disease in the Pdss2kd/kd and in the newly available Coq9X/X mutant mice Core Unit A (the Administrative Core) (Dr. Salvatore DiMauro, Director; Dr.Michio Hirano, Co-Director) will provide direction, administration, and external consultation. Core Unit B (the Technical Core) (Dr. Ali Naini, Director) will provide technical service (tissue culture), diagnostc tools (histochemistry, biochemistry, molecular genetics), and manage shared equipment for the project as a whole.