Use of nucleoside therapy for mitochondrial DNA depletion/deletion syndrome (MDDS)

Today, a new paper by Hirano et al. has been published into the use of nucleoside therapy for mitochondrial DNA depletion/deletion syndrome (MDDS).

The full article can be read here.

On November 3, 2025, the U.S. Food and Drug Administration (FDA) approved deoxycytidine/deoxythymidine (dC/dT) pyrimidine nucleoside therapy for clinical use in thymidine kinase 2 deficiency (TK2d), an ultra-rare autosomal recessive mitochondrial disease affecting patients with symptomatic onset at or before 12 years of age [1]. The European Commission subsequently granted marketing authorization on March 26, 2026 [2]. These approvals were based upon evidence from a pivotal phase 2 clinical trial, two retrospective multicenter chart reviews, and an expanded access program [3,4]. In matched-pair analyses of 82 treated and 93 untreated external control patients with disease onset at ≤12 years of age, nucleoside therapy was associated with a 92–94% reduction in the risk of death from time of treatment initiation [4]. Furthermore, among treated patients who had previously lost one or more motor milestones, 30 of 40 regained at least one milestone, including the ability to sit, stand, walk, or run [4]. These remarkable therapeutic advances have naturally stimulated interest in evaluating nucleoside therapy for other forms of mitochondrial DNA depletion/deletion syndrome (MDDS).

In this context, three exploratory studies have examined the use of dC/dT therapy in patients with non-TK2d MDDS, including POLG-related disease and other genetically heterogeneous disorders [5–7]. These reports include a 6-month interim analysis of an open-label study in POLG-related disease published in eClinicalMedicine [6], a heterogeneous MDDS cohort reported in the Journal of Neurology [5], and a longer-term follow-up study of the POLG cohort published in Neurotherapeutics [7]. Collectively, these investigations represent important early efforts to explore whether the clinical success observed in TK2d may extend to other disorders of mitochondrial DNA maintenance. Because those studies involve small, uncontrolled, and clinically heterogeneous cohorts, the findings should be interpreted as preliminary. In our view, the available evidence engenders several important questions regarding biological rationale, preclinical data, study design, and interpretation of efficacy that should be addressed as the field moves toward a definitive clinical evaluation.