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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
1P01HD080642-01
Application #
8741702
Study Section
Developmental Biology Subcommittee (CHHD)
Program Officer
Krotoski, Danuta
Project Start
2014-09-30
Project End
2019-05-31
Budget Start
2014-09-30
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Neurology
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10032
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Barca, E; Musumeci, O; Montagnese, F et al. (2016) Cerebellar ataxia and severe muscle CoQ10 deficiency in a patient with a novel mutation in ADCK3. Clin Genet 90:156-60
Torres-Torronteras, Javier; Cabrera-Pérez, Raquel; Barba, Ignasi et al. (2016) Long-Term Restoration of Thymidine Phosphorylase Function and Nucleoside Homeostasis Using Hematopoietic Gene Therapy in a Murine Model of Mitochondrial Neurogastrointestinal Encephalomyopathy. Hum Gene Ther 27:656-67
Fryer, Robert H; Bain, Jennifer M; De Vivo, Darryl C (2016) Mitochondrial Encephalomyopathy Lactic Acidosis and Stroke-Like Episodes (MELAS): A Case Report and Critical Reappraisal of Treatment Options. Pediatr Neurol 56:59-61
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Barca, Emanuele; Tang, Maoxue; Kleiner, Giulio et al. (2016) CoQ10 Deficiency Is Not a Common Finding in GLUT1 Deficiency Syndrome. JIMD Rep 29:47-52
Sadat, Roa; Barca, Emanuele; Masand, Ruchi et al. (2016) Functional cellular analyses reveal energy metabolism defect and mitochondrial DNA depletion in a case of mitochondrial aconitase deficiency. Mol Genet Metab 118:28-34
Varma, Hemant; Faust, Phyllis L; Iglesias, Alejandro D et al. (2016) Whole exome sequencing identifies a homozygous POLG2 missense variant in an infant with fulminant hepatic failure and mitochondrial DNA depletion. Eur J Med Genet 59:540-5

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