RT Journal Article
T1 Deoxycytidine and Deoxythymidine Treatment for Thymidine Kinase 2 Deficiency.
A1 Lopez-Gomez, Carlos
A1 Levy, Rebecca J
A1 Sanchez-Quintero, Maria J
A1 Juanola-Falgarona, Martí
A1 Barca, Emanuele
A1 Garcia-Diaz, Beatriz
A1 Tadesse, Saba
A1 Garone, Caterina
A1 Hirano, Michio
K1 Mitochondrial Diseases
K1 Tetrahydrouridine
K1 Thymidine
K1 Thymidine Kinase
AB Thymidine kinase 2 (TK2), a critical enzyme in the mitochondrial pyrimidine salvage pathway, is essential for mitochondrial DNA (mtDNA) maintenance. Mutations in the nuclear gene, TK2, cause TK2 deficiency, which manifests predominantly in children as myopathy with mtDNA depletion. Molecular bypass therapy with the TK2 products, deoxycytidine monophosphate (dCMP) and deoxythymidine monophosphate (dTMP), prolongs the life span of Tk2-deficient (Tk2-/- ) mice by 2- to 3-fold. Because we observed rapid catabolism 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. To test these hypotheses, we assessed two therapies in Tk2-/- mice: (1) dT+dC and (2) coadministration of the deaminase inhibitor, tetrahydrouridine (THU), with dTMP+dCMP. We observed that dC+dT delayed disease onset, prolonged life span of Tk2-deficient mice and restored mtDNA copy number as well as respiratory chain enzyme activities and levels. In contrast, dCMP+dTMP+THU therapy decreased life span of Tk2-/- animals compared to dCMP+dTMP. Our studies demonstrate that deoxynucleoside substrate enhancement is a novel therapy, which may ameliorate TK2 deficiency in patients. Ann Neurol 2017;81:641-652.
PB Wiley
YR 2017
FD 2017-03-09
LK http://hdl.handle.net/10668/10975
UL http://hdl.handle.net/10668/10975
LA en
NO Lopez-Gomez C, Levy RJ, Sanchez-Quintero MJ, Juanola-Falgarona M, Barca E, Garcia-Diaz B, et al. Deoxycytidine and Deoxythymidine Treatment for Thymidine Kinase 2 Deficiency. Ann Neurol. 2017 May;81(5):641-652
DS RISalud
RD Apr 7, 2025