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dc.contributor.authorGarone, Caterinaes_ES
dc.contributor.authorGarcía-Díaz, Beatrizes_ES
dc.contributor.authorEmmanuele, Valentinaes_ES
dc.contributor.authorLópez García, Luis Carloses_ES
dc.contributor.authorTadesse, Sabaes_ES
dc.contributor.authorAkman, Hasan O.es_ES
dc.contributor.authorTanji, Kurenaies_ES
dc.contributor.authorQuinzii, Catarina M.es_ES
dc.contributor.authorHirano, Michioes_ES
dc.date.accessioned2014-09-12T07:14:19Z
dc.date.available2014-09-12T07:14:19Z
dc.date.issued2014
dc.identifier.citationGarone, 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]es_ES
dc.identifier.issn1757-4676
dc.identifier.urihttp://hdl.handle.net/10481/32994
dc.description.abstractAutosomal 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.en_EN
dc.description.sponsorshipThis 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).en_EN
dc.language.isoenges_ES
dc.publisherWiley-Blackwelles_ES
dc.rightsCreative Commons Attribution-NonCommercial-NoDerivs 3.0 Licensees_ES
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/es_ES
dc.subjectDeoxycytidine Monophosphateen_EN
dc.subjectDeoxythymidine Monophosphateen_EN
dc.subjectEncephalomyopathyen_EN
dc.subjectTherapyen_EN
dc.subjectThymidine Kinaseen_EN
dc.titleDeoxypyrimidine monophosphate bypass therapy for thymidine kinase 2 deficiencyen_EN
dc.typeinfo:eu-repo/semantics/articleen_EN
dc.rights.accessRightsinfo:eu-repo/semantics/openAccessen_EN
dc.identifier.doi10.15252/emmm.201404092en_EN


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