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Please use this identifier to cite or link to this item: http://hdl.handle.net/10481/32994

Title: Deoxypyrimidine monophosphate bypass therapy for thymidine kinase 2 deficiency
Authors: Garone, Caterina
García-Díaz, Beatriz
Emmanuele, Valentina
López García, Luis Carlos
Tadesse, Saba
Akman, Hasan O.
Tanji, Kurenai
Quinzii, Catarina M.
Hirano, Michio
Issue Date: 2014
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.
Sponsorship: This work was supported by research grants from the Muscular Dystrophy Association (MH) and the Associazione Malattie Metaboliche Congenite ereditarie (AMMeC) (CG) as well as by the Arturo Estopinan TK2 Research Fund (MH and CG) and the Marriott Mitochondrial Disease Clinic Research Fund (MMDCRF) (MH). MH acknowledges support from NIH grants (P01 HD32062, R01 HD057543, and R01 HD056103 from NICHD) and the Office of Dietary Supplements, as well as U54 NS078059 from NINDS and NICHD. LCL acknowledges support from CEIBioTic‐University of Granada, RYC‐2011‐07643, and RETICEF (Spain).
Publisher: Wiley-Blackwell
Keywords: Deoxycytidine Monophosphate
Deoxythymidine Monophosphate
Encephalomyopathy
Therapy
Thymidine Kinase
URI: http://hdl.handle.net/10481/32994
ISSN: 1757-4676
Rights : Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License
Citation: Garone, C.; et al. Deoxypyrimidine monophosphate bypass therapy for thymidine kinase 2 deficiency. EMBO Molecular Medicine, 6(8): 1016-1027 (2014). [http://hdl.handle.net/10481/32994]
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