Deoxynucleosides Pyrimidines as Treatment for Mitochondrial Depletion Syndrome

Description

Mitochondrial DNA (mtDNA) depletion syndromes (MDS) are a genetically and clinically heterogeneous group of autosomal recessive disorders that are characterized by a severe reduction in mtDNA content leading to impaired energy production in affected tissues and organs. MDS are due to defects in mtDNA maintenance caused by mutations in nuclear genes that function in either mitochondrial nucleotide synthesis. MDS are phenotypically heterogeneous and usually classified as myopathic, encephalomyopathic, hepatocerebral or neurogastrointestinal. No efficacious therapy is available for any of these disorders. Affected individuals should have a comprehensive evaluation to assess the degree of involvement of different systems. Treatment is directed mainly toward providing symptomatic management. No treatment for MDS. Clinical trials studies and in vitro/in vivo research studies showed that the enhancement of the salvage pathway by increasing the availability of deoxyribonucleosides needed for each specific genetic defect prevents mtDNA depletion. Early recognition and immediate therapy to restore mitochondrial function could potentially improve clinical course. Confirming the benefit of deoxynucleosides as a safe and potentially efficacious therapy, will lead to the availability of the first specific and effective treatment for Mitochondria Depletion Disorders. In this phase II Trial a mix of Deoxynucleosides Pyrimidine (Deoxycytidine dC and Deoxythymidine dT) will be used as early treatment of MDS. The dose used has been already used in other clinical trials, and appears to effective and well-tolerated. The subjects included are children (0-18Y), with positive MDS diagnosis and express mutations in one of the following genes: POLG, POLG2, C10orf2, RRM2B, MPV17, SUCLA2, SUCLG1, FBXL4, DTYMK. Subjects with MDS expressing neurological phenotypes dysfunction.

Interventions

• deoxycytidine and deoxythymidine (Combination product)
  The Investigational Product (IP) dC/dT100-400 will be administered orally every day (QD) and the dose is divided over trid or bid for the daily dose of 100 mg/kg from Day 1-7, 200 mg/kg from Day 8-14, 300 mg/kg from Day 15- 21 and 400 mg/kg from Day 22 to 1825. Doses was chosen according to the safety and efficacy doses used in the literature.

Eligibility criteria

Conditions

Locations

• Research InstituMcGill University Health Centre - Children Hospital of Montreal — Montreal, Quebec, Canada