Abstract Details

POLG-related disorders are caused by pathogenic variants in POLG, encoding DNA polymerase γ (POLG). This enzyme is responsible for mtDNA replication and proof-reading; with enzyme dysfunction, there may be an increased rate of mtDNA mutations and reduction in total mtDNA. As a result, patients with POLG-related disorders may have a range of clinical manifestations, including epilepsy, encephalopathy, neuropathy, myopathy, ataxia, eye movement abnormalities, liver dysfunction, lactic acidosis, renal dysfunction, hearing loss, pancreatitis. There are presently no effective treatments for POLG-related disorders.

Evaluate the safety and efficacy of the combination of enteral deoxycytidine and deoxythymidine (dC/dT) in treatment of patients with POLG-related disorders involving depletion of mitochondrial DNA (mtDNA).

Phase II, single-centre, open-label trial of dC/dT for people with POLG-related disorders and other mtDNA depletion disease. Inclusion criteria are: pathogenic variant in POLG or other gene associated with mitochondrial DNA depletion, neurological dysfunction, capable of taking liquid orally or via nasogastric/gastrostomy tube.

Patients receive dC/dT in a 1:1 ratio, given enterally, divided in 3 doses/day, titrated to 400 mg/kg/day, for a 2-year treatment period. Patients are evaluated at baseline, 1-month, 2-month, 3-month, and 6-month, 12-month, 18-month, and 24-month timepoints. Outcome measures include: Newcastle Pediatric Mitochondrial Disease Scale (NPMDS), EEG, seizure diary, liver function tests, kidney function tests, CK, lactate, and growth differentiation factor 15 (GDF-15). The latter is a marker of severity of mitochondrial dysfunction.

We have 6-month treatment data for 11 patients, including 8 with POLG-related disorders. No significant adverse events attributed to the treatment. All POLG patients had improved or stable NPMDS scores. All caregivers of POLG patients reported clinical improvement, including cognition, alertness, and energy level. Serum GDF-15 has either remained stable or decreased; in some POLG patients, the response has been dramatic.

dC/dT therapy appears safe and effective in treatment of POLG-related disorders involving mtDNA depletion.