RT Journal Article
T1 Deoxypyrimidine monophosphate bypass therapy for thymidine kinase 2 deficiency
A1 Garone, Caterina
A1 Garcia Diaz, Beatriz
A1 Emmanuele, Valentina
A1 Lopez, Luis C
A1 Tadesse, Saba
A1 Akman, Hasan O
A1 Tanji, Kurenai
A1 Quinzii, Catarina M
A1 Hirano, Michio
K1 Patología mitocondrial
AB utosomal 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.
PB Wiley; BlackWell Publishing Ltd; Wiley-Blackwell
YR 2014
FD 2014
LK https://hdl.handle.net/10630/32319
UL https://hdl.handle.net/10630/32319
LA eng
NO Garone C, Garcia-Diaz B, Emmanuele V, Lopez LC, Tadesse S, Akman HO, Tanji K, Quinzii CM, Hirano M. Deoxypyrimidine monophosphate bypass therapy for thymidine kinase 2 deficiency. EMBO Mol Med. 2014 Aug;6(8):1016-27. doi: 10.15252/emmm.201404092. PMID: 24968719; PMCID: PMC4154130.
DS RIUMA. Repositorio Institucional de la Universidad de Málaga
RD 19 ene 2026