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Abstract Details

Deoxycytidine/Deoxythymidine Combination Therapy Safety and Efficacy in Treatment of POLG-Related Disorders: Results After 6 Months of Treatment
Child Neurology and Developmental Neurology
ES1 - Emerging Science 1 (11:45 AM-11:51 AM)
006

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.

Authors/Disclosures
Ken Myers, MD, PhD (Montreal Children'S Hospital/McGill University Health Centre)
PRESENTER
The institution of Dr. Myers has received research support from Savoy Foundation. The institution of Dr. Myers has received research support from Fonds de Recherche de Santé Québec. The institution of Dr. Myers has received research support from Liam Foundation. The institution of Dr. Myers has received research support from Grand Défi Pierre Lavoie Foundation. The institution of Dr. Myers has received research support from Epilepsy Canada. The institution of Dr. Myers has received research support from Pediatric Research Foundation.
Saoussen Berrahmoune, Sr., PhD (Research Institute of McGill University Health Centre) Dr. Berrahmoune has nothing to disclose.
Heather Pekeles, MD Dr. Pekeles has nothing to disclose.
Christelle Dassi, PhD (Research Institute of the McGill University Health Centre) Dr. Dassi has nothing to disclose.
Ralf Eberhard, MD,PhD Dr. Eberhard has received research support from Montreal Children's Hospital Foundation, Hoppenheim Fellowship Endowment Fund.
Daniela Buhas, MD (MUHC) The institution of Dr. Buhas has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Horizon. Dr. Buhas has received personal compensation in the range of $500-$4,999 for serving as a consultant with INESS.