Safety and Efficacy of Deoxycytidine/Deoxythymidine Combination Therapy for POLG-Related Disorders: Clinical Trial
Abstract number :
2.481
Submission category :
4. Clinical Epilepsy / 4C. Clinical Treatments
Year :
2023
Submission ID :
1371
Source :
www.aesnet.org
Presentation date :
12/3/2023 12:00:00 AM
Published date :
Authors :
Presenting Author: Kenneth Myers, MD, PhD, FRCPC – Research Institute of the McGill University Health Centre
Saoussen Berrahmoune, PhD – Research Institute of the McGill University Health Centre; Daniela Buhas, MD – McGill University; Anthony Cheung, MD – McGill University; Christelle Dassi, PhD – Research Institute of the McGill University Health Centre; Ralf Eberhard, MD – McGill University; Heather Pekeles, MD, MSc – McGill University; Paula Waters, PhD, FCCMG – University of Sherbrooke
Rationale:
POLG-related disorders are a rare group of genetic conditions caused by biallelic mutations in the POLG gene. Patients have dysfunction of POLG, an enzyme involved in production of DNA in the mitochondria, the part of our cells responsible for energy generation. This leads to any or all of the following: seizures, progressive cognitive impairment, liver failure, weakness, hearing loss, and heart abnormalities. Onset is usually in childhood with death typically occurring within three months to 12 years of symptom onset. At present, there are no effective treatments for these conditions, but some in vitro and animal data suggests treatment with deoxynucleosides could have therapeutic benefit. This study aims to evaluate the safety and efficacy of the combination of enteral deoxycytidine and deoxythymidine (dC/dT) in treatment of patients with POLG-related disorders.
Methods: br>In November 2021, we began a phase II open-label trial using the combination of oral/enteral deoxycytidine and deoxythymidine to treat pediatric patients with POLG-related disorders and other mtDNA depletion diseases. Patients receive dC/dT in a 1:1 ratio for a two year treatment period. Our primary clinical outcome is Newcastle Mitochondrial Disease Scale (NMDS) score. Our primary biomarker is growth differentiation factor 15 (GDF-15), used to evaluate mitochondrial dysfunction. Secondary outcome measures include clinical evaluation, seizure diaries, electroencephalography, and a panel of blood and urine tests that evaluate mitochondrial and end organ function.
Results:
We have thus far initiated treatment in 11 patients with POLG-related disorders. Significant improvement in NMDS score has been seen at three month, six month, and twelve month timepoints (see attached table), which is a clear departure from the known natural history of this progressive, degenerative disease. Seizure frequency has remained stable or improved in all patients. There is also a trend of improvement in GDF-15, with some patients showing dramatic improvement (see attached figure), and the rest remaining at least stable. No significant adverse events have occurred that were attributed to the treatment.
Conclusions:
dC/dT therapy appears safe and possibly effective in the treatment of POLG-related disorders. Further research is necessary, including randomized controlled trials with long-term follow-up, in order to confirm efficacy and determine the impact on the long-term natural history of the disease.
Funding:
This study was supported by funding from the Liam Foundation, Savoy Foundation, Grand Défi Pierre Lavoie Foundation, and Fonds de Recherche du Québec – Santé.
Clinical Epilepsy