Deoxycytidine and Deoxythymidine Treatment for Thymidine Kinase 2 Deficiency
We previously reported that molecular bypass therapy using oral administration of the TK2 products, dCMP and dTMP, in our mouse model of TK2 deficiency (Tk2 H126N knock‐in [Tk2–/–] mice)6 delays onset of molecular and biochemical abnormalities, ameliorates the symptoms, and prolongs the life span of the animals by 2‐ to 3‐fold.7 We also observed that after administration, dCMP and dTMP were rapidly catabolized to dC and dT, suggesting that nucleosides, rather than nucleotides, are the major active therapeutic agents. Thus, we hypothesize that the increase of the nucleoside substrates enhances residual activity of TK1, TK2, or both, leading to correction of dNTP pool imbalances. Furthermore, dCMP+dTMP treatment increased levels of deoxyuridine in liver, indicating deamination of dC.
To further enhance this therapy, in this study, we have assessed two different approaches. First, because we have hypothesized that nucleosides are the active therapeutic compounds, we have tested the effects of oral dC+dT on the Tk2 H126N knock‐in mouse model. Second, we have assessed the effects of coadministration of tetrahydrouridine (THU), an inhibitor of the cytidine deaminase, with dCMP+dTMP to attempt to increase levels of dC. We have observed that oral dC+dT prolongs the life span of mutant animals by restoring mtDNA copy number and respiratory chain enzyme (RCE) activities and levels. In contrast, addition of THU unexpectedly reduces the life span of animals comparing to oral dCMP+dTMP therapy alone. These results reveal a novel nucleoside substrate enhancement therapy, which significantly ameliorates Tk2 deficiency in our mouse model.