P17.19 Deoxypyrimidine monophosphates treatment for thymidine kinase 2 deficiency

Abstract

Autosomal recessive TK2 mutations have been associated with severe depletion of mitochondrial DNA (mtDNA) and devastating neuromuscular diseases in infants and children, and with mtDNA multiple deletions and progressive external ophthalmoplegia in adults. Similar to other mitochondrial disorders, only supportive treatments are available for TK2 deficiency. We generated a Tk2 H126N knock-in mouse model that manifests a phenotype strikingly similar to the human infantile encephalomyopathy. We demonstrated that lack of Tk2 activity cause nucleotide pools unbalance with severe reductions of deoxypyrimidine triphosphates (dTTP and dCTP) in brain and liver, leading to reduction of mtDNA copy number. To bypass Tk2 deficiency, we administered deoxypyrimidine monophosphates (dCMP + dTMP) to Tk2 knock-in mice by oral gavage from postnatal day 4, when mutant mice are biochemically affected but phenotypically normal. Assessment of 13-day old Tk2−/− mice treated with dCMP + dTMP 200 mg/kg/day each demonstrated that in mutant animals, the compounds: raise dCMP + dTMP concentrations; increase levels of mtDNA, augment quantity and activities of mitochondrial respiratory chain enzyme; and significantly prolong their lifespan (34 days with treatment vs 13 days untreated). A second trial of dCMP + dTMP at 400 mg/kg/day showed even greater phenotypic and biochemical improvements. No adverse effects were observed with both doses of dCMP + dTMP. Oral dCMP + dTMP supplementation is the first effective and safe treatment for TK2 deficiency in mice. This treatment can potentially be applied to patients.