Oral deoxynucleoside for the treatment of thymidine kinase 2 deficiency (P3.195)

Objective: To test whether effects of dCMP+dTMP treatment are attributable to increased levels of dC+dT, we treated our TK2 mouse model with oral dC+dT.

Background: TK2 is a nuclear gene encoding the mitochondrial enzyme thymidine kinase 2 (TK2), which phosphorylates the nucleosides deoxycytidine (dC) and deoxythymidine (dT) to dCMP and dTMP. Mutations in this gene cause TK2 deficiency, which most frequently leads to mitochondrial DNA (mtDNA) depletion syndrome in infants and children, manifesting as severe reduction of mtDNA copy number in muscle leading to a rapidly progressive mitochondrial myopathy. To date, there is no approved disease-modifying therapy for TK2 deficiency. We have reported that molecular bypass therapy via oral administration of the TK2 products, dCMP and dTMP, to our mouse model of TK2 deficiency ameliorates the symptoms and prolongs the lifespan of the animals. Despite the clear benefits of this therapeutic strategy, we observed that after administration, dCMP and dTMP were rapidly converted to their respective nucleosides suggesting that dC and dT are the active therapeutic agents.

Design/Methods: .

Results: Both 260 and 520mg/kg/day of oral dC+dT prolonged the lifespans of TK2 mutant animals to durations comparable to those achieved using 200 and 400mg/kg/day of dCMP+dTMP. Both doses of deoxynucleosides were sufficient to partially restore mtDNA levels in brain and completely prevent mtDNA depletion in heart, liver, kidney, intestine and muscle at age 13 days. Activities and amounts of respiratory chain enzymes were also partially restored at 29 days. There were slightly higher levels of complexes I and IV in brain from mice treated with the 520mg dose of dC+dT, compared to those treated with 260mg, which likely accounts for the prolonged survival time observed with the higher dose.

Conclusions: Our results reveal a novel therapy for TK2 deficiency. Although not curative, this substrate enhancement therapy may delay or halt progression of this devastating disease.

Study Supported by: This work was supported by the NICHD

Disclosure: Dr. Lopez Gomez has nothing to disclose. Dr. Levy has nothing to disclose. Dr. Sanchez-Quintero has nothing to disclose. Dr. Juanola-Falgarona has nothing to disclose. Dr. Barca has nothing to disclose. Dr. Garcia-Diaz has nothing to disclose. Dr. Tadesse has nothing to disclose. Dr. Garone has nothing to disclose. Dr. Hirano has received (royalty or license fee or contractual rights) payments from MitoRainbow Therapeutics, Inc.