Deoxynucleoside Therapy for Mitochondrial Disease

(dC-dT-MDS Trial)

Overseen by Kenneth Alexis MD Myers, MD PhD FRCPC

Age: < 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: McGill University Health Centre/Research Institute of the McGill University Health Centre

Disqualifiers: Chronic severe diarrhea, others

No Placebo Group

Prior Safety Data

Approved in 1 Jurisdiction

Trial Summary

What is the purpose of this trial?

This trial tests a treatment using specific DNA building blocks to help children with a severe genetic disorder that affects energy production in their cells. The goal is to see if this treatment can improve their condition by restoring the function of their mitochondria.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug Deoxycytidine and Deoxythymidine for mitochondrial disease?

Research suggests that deoxyribonucleosides like deoxycytidine can prevent the reduction of mitochondrial DNA in certain conditions, which may help in mitochondrial DNA depletion syndrome, a type of mitochondrial disease. ^{1 2 3 4 5}

How is the drug Deoxycytidine and Deoxythymidine unique for treating mitochondrial disease?

This drug is unique because it directly supplements the building blocks needed for mitochondrial DNA replication, addressing the root cause of mitochondrial DNA depletion syndrome, whereas other treatments do not target this specific mechanism. ^{2 6 7 8 9}

Research Team

Kenneth Alexis MD Myers, MD PhD FRCPC

Principal Investigator

RI-MUHC, Children Hospital of Montreal (MUHC), McGill University

Eligibility Criteria

This trial is for children and adults (0-60 years old) with a confirmed diagnosis of Mitochondrial Depletion Disorder. Participants must have specific genetic mutations (POLG, C10orf2, RRM2B, MPV17, SUCLA2, SUCLG1, FBXL4). Women who can bear children must test negative for pregnancy and agree to use contraception.

Inclusion Criteria

I am between the ages of 0 and 60.

I have been diagnosed with a mitochondrial depletion disorder.

I have been diagnosed with a mitochondrial depletion disorder.

Exclusion Criteria

I have long-term severe diarrhea.

Inability of a parent or legal guardian to give informed consent for any reason

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a mix of Deoxycytidine and Deoxythymidine as early treatment for Mitochondrial Depletion Disorders

104 weeks

Regular visits for neurological and genetic follow-up, bloodwork assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

Treatment Details

Interventions

• Deoxycytidine and Deoxythymidine (Other)

Trial Overview The trial tests a combination of deoxycytidine and deoxythymidine as an early treatment for Mitochondrial Depletion Syndrome. This phase II trial aims to confirm the safety and effectiveness of these compounds in improving mitochondrial function.

Participant Groups

Group I: dC/dT100-400 Arm Experimental Treatment 1 Intervention

Children \& Adult (0-60 Y), who takes the investigational product deoxynucleosides pyrimidine (mix of deoxycytidine and deoxythymidine), following the protocol.

Who Is Running the Clinical Trial?

McGill University Health Centre/Research Institute of the McGill University Health Centre

Lead Sponsor

Trials

476

Recruited

170,000+

Dr. Lucie Opatrny

McGill University Health Centre/Research Institute of the McGill University Health Centre

President and Executive Director since 2023

MDCM and Master's in Epidemiology and Biostatistics from McGill University, Master's in Healthcare Management and Diploma in Advanced Negotiation from Harvard University

Dr. Patrizia Cavazzoni

McGill University Health Centre/Research Institute of the McGill University Health Centre

Chief Medical Officer

MD from McGill University, residency in Psychiatry and fellowship in Mood Disorders at the University of Ottawa

Findings from Research

Primary mitochondrial diseases are common inherited metabolic disorders affecting about 1 in 4,300 live births, but there are currently no licensed disease-modifying therapies, and most management is supportive.

Recent advances in therapy development have led to small molecules moving from preclinical studies to early-phase human trials, indicating progress in finding effective treatments for these complex disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Moving towards clinical trials for mitochondrial diseases. Pitceathly, RDS., Keshavan, N., Rahman, J., et al.[2021]

In vitro studies show that supplementing deoxyribonucleosides (dNs) like deoxyguanosine or deoxycytidine can prevent mitochondrial DNA (mtDNA) depletion in cells with dNTP metabolism defects, suggesting a potential therapeutic approach for mitochondrial DNA depletion syndrome (MDS).

In an animal model of mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), systemic administration of dCtd or the inhibitor tetrahydrouridine (THU) successfully modulated mitochondrial dNTP content, indicating that enhancing dNTP availability could be a viable treatment strategy for MDS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Administration of deoxyribonucleosides or inhibition of their catabolism as a pharmacological approach for mitochondrial DNA depletion syndrome. Cámara, Y., González-Vioque, E., Scarpelli, M., et al.[2021]

Recent advances in understanding mitochondrial diseases have led to the development of new therapies, moving beyond just supportive care to include dietary supplements, exercise, and emerging treatments in clinical trials.

Therapies can be broadly categorized into non-tailored approaches, like activating mitochondrial biogenesis and mitochondrial replacement therapy, and tailored strategies, such as gene therapy and scavenging toxic compounds, which target specific biochemical defects in mitochondrial function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emerging therapies for mitochondrial diseases. Hirano, M., Emmanuele, V., Quinzii, CM.[2018]

Mitochondrial disease research has made significant progress, but effective treatments are still lacking due to reliance on anecdotal evidence rather than rigorous clinical trials.

The author emphasizes the importance of learning from early randomized controlled trials in mitochondrial diseases to improve future research and utilize new resources for patient-oriented studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Why are there no proven therapies for genetic mitochondrial diseases? Stacpoole, PW.[2021]

Nucleoside analogs like azidothymidine and dideoxyguanosine can deplete normal mitochondrial DNA (mtDNA) while increasing levels of deleted mtDNA in fibroblasts from patients with Kearns-Sayre syndrome, suggesting a potential mechanism for worsening mitochondrial dysfunction.

The study indicates that these nucleoside analogs may selectively inhibit the growth of cells with low levels of deleted mtDNA, potentially leading to an increase in the relative amount of deleted mtDNA in a mixed population of cells, which could have implications for treatment strategies in mitochondrial diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zidovudine and dideoxynucleosides deplete wild-type mitochondrial DNA levels and increase deleted mitochondrial DNA levels in cultured Kearns-Sayre syndrome fibroblasts. Wang, H., Lemire, BD., Cass, CE., et al.[2019]

A new, validated method using high performance liquid chromatography (HPLC-UV) allows for the accurate and efficient measurement of thymidine (dThd) and deoxyuridine (dUrd) in plasma, specifically for patients with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE).

This method shows high recovery rates (>90%) and excellent precision and accuracy (less than 10% variability), making it a reliable tool for clinical assessment of these nucleosides in human plasma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

HPLC-UV analysis of thymidine and deoxyuridine in plasma of patients with thymidine phosphorylase deficiency. Mohamed, S., Caporali, L., De Giorgio, R., et al.[2020]

Nucleoside reverse transcriptase inhibitors (NRTIs) like zidovudine (ZDV) and stavudine (d4T) cause significant mitochondrial damage and depletion of mitochondrial DNA (mtDNA) in transgenic mice, indicating potential toxicity in heart tissue.

In contrast, lamivudine (3TC) did not show the same detrimental effects on mtDNA or mitochondrial structure, suggesting it may be a safer option among NRTIs for preserving mitochondrial function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antiretroviral nucleosides, deoxynucleotide carrier and mitochondrial DNA: evidence supporting the DNA pol gamma hypothesis. Lewis, W., Kohler, JJ., Hosseini, SH., et al.[2020]

Supplementation with deoxycytidine and deoxythymidine monophosphates (dCMP+dTMP) in a mouse model of thymidine kinase 2 (TK2) deficiency significantly increased mitochondrial DNA levels and improved mitochondrial function, leading to a prolonged lifespan from 13 days to 34 days with treatment.

This study represents the first effective pharmacological treatment for TK2 deficiency, demonstrating that dCMP/dTMP can effectively bypass the enzyme deficiency and ameliorate biochemical defects associated with the condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Deoxypyrimidine monophosphate bypass therapy for thymidine kinase 2 deficiency. Garone, C., Garcia-Diaz, B., Emmanuele, V., et al.[2021]

Mutations in nuclear genes that affect deoxyribonucleotide levels can lead to serious mitochondrial DNA (mtDNA) issues, including depletion and mutations, which are linked to severe clinical symptoms.

Enhancing the availability of deoxyribonucleosides through targeted administration may prevent mtDNA depletion, suggesting a potential pharmacological treatment strategy for these genetic disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Feeding the deoxyribonucleoside salvage pathway to rescue mitochondrial DNA. Cámara, Y., González-Vioque, E., Scarpelli, M., et al.[2013]

References

1. United States pubmed.ncbi.nlm.nih.gov

Moving towards clinical trials for mitochondrial diseases. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Administration of deoxyribonucleosides or inhibition of their catabolism as a pharmacological approach for mitochondrial DNA depletion syndrome. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Emerging therapies for mitochondrial diseases. [2018]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Why are there no proven therapies for genetic mitochondrial diseases? [2021]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Zidovudine and dideoxynucleosides deplete wild-type mitochondrial DNA levels and increase deleted mitochondrial DNA levels in cultured Kearns-Sayre syndrome fibroblasts. [2019]

6. Netherlands pubmed.ncbi.nlm.nih.gov

HPLC-UV analysis of thymidine and deoxyuridine in plasma of patients with thymidine phosphorylase deficiency. [2020]

7. England pubmed.ncbi.nlm.nih.gov

Antiretroviral nucleosides, deoxynucleotide carrier and mitochondrial DNA: evidence supporting the DNA pol gamma hypothesis. [2020]

8. England pubmed.ncbi.nlm.nih.gov

Deoxypyrimidine monophosphate bypass therapy for thymidine kinase 2 deficiency. [2021]

9. England pubmed.ncbi.nlm.nih.gov

Feeding the deoxyribonucleoside salvage pathway to rescue mitochondrial DNA. [2013]