Expanded Access Deoxynucleoside Therapy for Thymidine Kinase 2 (TK2) Deficiency

Thymidine kinase 2 (TK2) is required for synthesis of pyrimidine deoxynucleoside triphosphate building blocks for mitochondrial DNA (mtDNA) synthesis. Autosomal recessive TK2 mutations cause depletion and multiple deletions of mtDNA that manifest predominantly as a myopathy usually beginning in childhood and progressing relentlessly. Based upon our pre-clinical studies in a Tk2 H126N knockin mouse model demonstrated efficacy of deoxynucleoside monophosphate and deoxynucleoside therapies, we have administered these treatments to 30 patients internationally on an expanded access basis. In a retrospective analysis of 16 genetically confirmed TK2 deficient patients who had received treatment for at least one year, we observed stabilization or improvements of clinical functions. In the subgroup of 5 patients with early onset and severe disease, survival and motor functions improved significantly compared to historical untreated patients. In the 11 childhood- and adult-onset patients, all clinical measures stabilized or improved. We observed increases in the 6-minute walk test. Three of 8 patients who were non- ambulatory at baseline gained ability to walk on therapy; 4 of 5 patients who required enteric nutrition were able to discontinue feeding tube use; and 2 of 10 patients who required mechanical ventilation became able to breathe independently. The only side-effect observed in 8 of the 16 patients was dose-dependent diarrhea, which did not require withdrawal of treatment. While our preliminary data on safety and efficacy of expanded access deoxynucleoside therapy in TK2d patients are very promising, there are potential concerns about long-term safety and efficacy of deoxynucleoside therapy that warrant further investigation in this proposed open-label expanded access multi-center NAMDC study involving three sites.