Deoxycytidine and Deoxythymidine Treatment for Thymidine Kinase 2 Deficiency.
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.


CONCLUSIONS
Our studies demonstrate that deoxynucleoside substrate enhancement is a novel therapy, which may ameliorate TK2 deficiency in patients. Ann Neurol 2017;81:641-652.
Department of Neurology, H. Houston Merritt Neuromuscular Research Center, Columbia University Medical Center, New York, NY.
Carlos
C
Lopez-Gomez
Department of Neurology, H. Houston Merritt Neuromuscular Research Center, Columbia University Medical Center, New York, NY.
Rebecca J
RJ
Levy
Department of Neurology, H. Houston Merritt Neuromuscular Research Center, Columbia University Medical Center, New York, NY.
Maria J
MJ
Sanchez-Quintero
Department of Neurology, H. Houston Merritt Neuromuscular Research Center, Columbia University Medical Center, New York, NY.
Martí
M
Juanola-Falgarona
Department of Neurology, H. Houston Merritt Neuromuscular Research Center, Columbia University Medical Center, New York, NY.|Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
Emanuele
E
Barca
Department of Neurology, H. Houston Merritt Neuromuscular Research Center, Columbia University Medical Center, New York, NY.|Unidad de Gestión Clínica de Neurociencias, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Spain.
Beatriz
B
Garcia-Diaz
Department of Neurology, H. Houston Merritt Neuromuscular Research Center, Columbia University Medical Center, New York, NY.
Saba
S
Tadesse
Department of Neurology, H. Houston Merritt Neuromuscular Research Center, Columbia University Medical Center, New York, NY.|MRC Mitochondrial Biology Unit, Cambridge University, Cambridge, United Kingdom.
Caterina
C
Garone
Department of Neurology, H. Houston Merritt Neuromuscular Research Center, Columbia University Medical Center, New York, NY.
Michio
M
Hirano
D000818:Animals; D000963:Antimetabolites / Q000008:administration & dosage / Q000494:pharmacology*; D004272:DNA, Mitochondrial / Q000187:drug effects; D003843:Deoxycytidine Monophosphate / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D008661:Metabolism, Inborn Errors / Q000188:drug therapy* / Q000201:enzymology; D051379:Mice; D008822:Mice, Transgenic; D028361:Mitochondrial Diseases / Q000188:drug therapy* / Q000201:enzymology; D013767:Tetrahydrouridine / Q000008:administration & dosage / Q000494:pharmacology*; D013936:Thymidine / Q000008:administration & dosage / Q000494:pharmacology*; D013937:Thymidine Kinase / Q000172:deficiency*
D000963:Antimetabolites; D004272:DNA, Mitochondrial; D003843:Deoxycytidine Monophosphate; D013767:Tetrahydrouridine; C105339:thymidine kinase 2; D013937:Thymidine Kinase; D013936:Thymidine