RT Journal Article
T1 Deoxycytidine and deoxythymidine treatment for thymidine kinase 2 deficiency.
A1 López-Gómez, Carlos
A1 Levy, Rebecca J
A1 Sánchez-Quintero, María José
A1 Juanola-Falgarona, Martí
A1 Barca, Emanuele
A1 Garcia Diaz, Beatriz
A1 Tadesse, Saba
A1 Garone, Caterina
A1 Hirano, Michio
K1 Patología mitocondrial - Tratamiento
K1 ADN mitocondrial
K1 Patología mitocondrial - Mutación
AB Objective—Thymidine kinase 2 (TK2), a critical enzyme in the mitochondrial pyrimidinesalvage pathway, is essential for mitochondrial DNA (mtDNA) maintenance. Mutations in thenuclear gene TK2 cause TK2 deficiency, which manifests predominantly in children as myopathywith mtDNA depletion. Molecular bypass therapy with the TK2 products, dCMP and dTMP,prolongs the lifespan of Tk2-deficient (Tk2-/-) mice by 2-3 fold. Because we observed rapidcatabolism of the deoxynucleoside monophosphates to deoxythymidine (dT) and deoxycytidine(dC), we hypothesized that: 1) deoxynucleosides might be the major active agents and 2)inhibition of deoxycytidine deamination might enhance dTMP+dCMP therapy.Methods—To test these hypotheses, we assessed two therapies in Tk2-/- mice: 1) dT+dC and 2)co-administration of the deaminase inhibitor, tetrahydrouridine (THU), with dTMP+dCMP.Results—We observed that dC+dT delayed disease onset, prolonged lifespan of Tk2-deficientmice, and restored mtDNA copy number as well as respiratory chain enzyme activities and levels.In contrast, dCMP+dTMP+THU therapy decreased lifespan of Tk2-/- animals compared to dCMP+dTMP.
PB Wiley
YR 2017
FD 2017
LK https://hdl.handle.net/10630/32329
UL https://hdl.handle.net/10630/32329
LA eng
NO Lopez-Gomez, C., Levy, R.J., Sanchez-Quintero, M.J., Juanola-Falgarona, M., Barca, E., Garcia-Diaz, B., Tadesse, S., Garone, C. and Hirano, M. (2017), Deoxycytidine and Deoxythymidine Treatment for Thymidine Kinase 2 Deficiency. Ann Neurol., 81: 641-652. https://doi.org/10.1002/ana.24922
NO Política de acceso abierto tomada de: https://v2.sherpa.ac.uk/id/publication/7599
DS RIUMA. Repositorio Institucional de la Universidad de Málaga
RD 4 mar 2026