title: Deoxypyrimidine monophosphate bypass therapy for thymidine kinase 2 deficiency.
abstract: Autosomal recessive mutations in the thymidine kinase 2 gene (TK2) cause mitochondrial DNA depletion, multiple deletions, or both due to loss of TK2 enzyme activity and ensuing unbalanced deoxynucleotide triphosphate (dNTP) pools. To bypass Tk2 deficiency, we administered deoxycytidine and deoxythymidine monophosphates (dCMP+dTMP) to the Tk2 H126N (Tk2(-/-)) knock-in mouse model from postnatal day 4, when mutant mice are phenotypically normal, but biochemically affected. Assessment of 13-day-old Tk2(-/-) mice treated with dCMP+dTMP 200 mg/kg/day each (Tk2(-/-200dCMP/) (dTMP)) demonstrated that in mutant animals, the compounds raise dTTP concentrations, increase levels of mtDNA, ameliorate defects of mitochondrial respiratory chain enzymes, and significantly prolong their lifespan (34 days with treatment versus 13 days untreated). A second trial of dCMP+dTMP each at 400 mg/kg/day showed even greater phenotypic and biochemical improvements. In conclusion, dCMP/dTMP supplementation is the first effective pharmacologic treatment for Tk2 deficiency.
authors: Department of Neurology, Columbia University Medical Center, New York, NY, USA Human Genetics Joint PhD Program, University of Bologna and Turin, Turin, Italy.
authors: Caterina
authors: C
authors: Garone
authors: Department of Neurology, Columbia University Medical Center, New York, NY, USA.
authors: Beatriz
authors: B
authors: Garcia-Diaz
authors: Department of Neurology, Columbia University Medical Center, New York, NY, USA Pediatric Clinic University of Genoa IRCCS G. Gaslini Institute, Genoa, Italy.
authors: Valentina
authors: V
authors: Emmanuele
authors: Instituto de Biotecnología, Centro de Investigación Biomédica, Universidad de Granada Parque Tecnológico de Ciencias de la Salud, Armilla, Spain.
authors: Luis C
authors: LC
authors: Lopez
authors: Department of Neurology, Columbia University Medical Center, New York, NY, USA.
authors: Saba
authors: S
authors: Tadesse
authors: Department of Neurology, Columbia University Medical Center, New York, NY, USA.
authors: Hasan O
authors: HO
authors: Akman
authors: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA.
authors: Kurenai
authors: K
authors: Tanji
authors: Department of Neurology, Columbia University Medical Center, New York, NY, USA.
authors: Catarina M
authors: CM
authors: Quinzii
authors: Department of Neurology, Columbia University Medical Center, New York, NY, USA mh29@columbia.edu.
authors: Michio
authors: M
authors: Hirano
mesh_terms: D000818:Animals; D003843:Deoxycytidine Monophosphate / Q000627:therapeutic use; D055879:Gene Knock-In Techniques; D051379:Mice; D028361:Mitochondrial Diseases / Q000188:drug therapy*; D016019:Survival Analysis; D013937:Thymidine Kinase / Q000172:deficiency*; D013938:Thymidine Monophosphate / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D003843:Deoxycytidine Monophosphate; D013938:Thymidine Monophosphate; C105339:thymidine kinase 2; D013937:Thymidine Kinase
keywords: deoxycytidine monophosphate; deoxythymidine monophosphate; encephalomyopathy; therapy; thymidine kinase