Investigating the safety and efficacy of deoxycytidine/deoxythymidine in mitochondrial DNA depletion disorders: phase 2 open-label trial.

Objective: Mitochondrial DNA depletion disorders are rare genetic disorders involving mitochondrial dysfunction. These diseases are genetically and clinically heterogeneous but share the common feature of progressively degenerative courses. At present, there are no approved treatments for mitochondrial DNA depletion disorders, though recent reports have suggested that treatment with deoxycytidine/deoxythymidine could be effective for subtypes caused by pathogenic variants in two specific genes, POLG and TK2. We investigated the therapeutic potential of deoxycytidine/deoxythymidine for people with mitochondrial DNA depletion disorders due to pathogenic variants in genes other than POLG and TK2.

Methods: We analyzed interim data from an open-label clinical trial of deoxycytidine/deoxythymidine for treatment of mitochondrial DNA depletion disorders, specifically examining disorders due to pathogenic variants in genes other than POLG and TK2. Outcome measures included Newcastle Mitochondrial Disease Scale score and serum growth differentiation factor 15, a mitochondrial function biomarker.

Results: Data were available from eight individuals having pathogenic variants in FBXL4, SUCLG1, SUCLA2, or RRM2B. Newcastle Mitochondrial Disease Scale score improved in all individuals except for one who withdrew before the first follow-up visit; group level analysis was significant at 1-month and 6-month timepoints. Five patients had elevated growth differentiation factor 15 at baseline; of these, levels improved in four, including three whose values normalized.

Conclusion: These data suggest deoxycytidine/deoxythymidine is a safe and therapeutically promising intervention for a broad range of mitochondrial DNA depletion disorders.