Deoxycytidine and Deoxythymidine Treatment for Thymidine Kinase 2 Deficiency

open9siThis work was supported by research grants from the lNIH (P01 HD32062) (M.H.), Muscular Dystrophy Association (M.H.), and the Associazione Malattie Metaboliche Congenite ereditarie (AMMeC) (C.G.), as well as by the Arturo Estopinan TK2 Research Fund (M.H.) and the Marriott Mitochondrial Disease Clinic Research Fund (MMDCRF) from the J. Willard and Alice S. Marriott Foundation (M.H.). M.H. also acknowledges support from NIH grants (R01 HD057543, and R01 HD056103 from NICHD) and the Office of Dietary Supplements, as well as U54 NS078059 from NINDS and NICHD.Objective: 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. Methods: 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. Results: 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. Interpretation: Our studies demonstrate that deoxynucleoside substrate enhancement is a novel therapy, which may ameliorate TK2 deficiency in patients. Ann Neurol 2017;81:641–652.openLopez-Gomez C.; Levy R.J.; Sanchez-Quintero M.J.; Juanola-Falgarona M.; Barca E.; Garcia-Diaz B.; Tadesse S.; Garone C.; Hirano M.Lopez-Gomez C.; Levy R.J.; Sanchez-Quintero M.J.; Juanola-Falgarona M.; Barca E.; Garcia-Diaz B.; Tadesse S.; Garone C.; Hirano M