Deoxynucleoside Therapy for Mitochondrial Disease

(dC-dT-MDS Trial)

Recruiting at 1 trial location

Overseen By Saoussen Dr Berrahmoune, PhD

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Kenneth Myers, MD

Disqualifiers: Chronic severe diarrhea, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 104 weeks

200 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment for mitochondrial DNA depletion syndromes (MDS), serious conditions affecting energy production in the body's cells. The treatment combines deoxycytidine and deoxythymidine, which have shown promise in maintaining healthy mitochondrial function. Suitable candidates for this trial include individuals, particularly children, diagnosed with MDS and specific gene mutations linked to the disorder, often causing neurological symptoms like muscle weakness or developmental delays. The researchers aim to provide the first effective treatment for MDS by confirming the safety and potential benefits of this new therapy. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people, offering participants a chance to contribute to groundbreaking advancements in MDS treatment.

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.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that the treatments deoxycytidine and deoxythymidine are generally safe and may help treat mitochondrial DNA depletion disorders. Studies have found that these treatments can safely improve symptoms and quality of life for patients with conditions like POLG-related mitochondrial disease. Other clinical trials have used these treatments at the same dose planned here, and they appear effective and safe for children with these rare disorders. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for mitochondrial disease?

Unlike the standard treatments for mitochondrial disease, which often focus on managing symptoms and providing supportive care, deoxycytidine and deoxythymidine offer a different approach. These treatments are unique because they involve deoxynucleosides, which are the building blocks of DNA. By supplementing these specific nucleosides, the treatment aims to address the root cause of mitochondrial disease, potentially improving cellular energy production. Researchers are excited about this innovative approach because it targets the underlying issue at the molecular level, offering hope for more effective and long-lasting relief for patients.

What evidence suggests that deoxynucleoside therapy could be an effective treatment for mitochondrial disease?

Research has shown that two substances, deoxycytidine and deoxythymidine, could help treat disorders affecting the body's energy production due to mitochondrial DNA issues. One study found that this treatment reduced the risk of death by 95% in some patients. Another study confirmed its safety and potential effectiveness for certain genetic disorders, such as those related to the POLG gene. In this trial, participants will receive a combination of deoxycytidine and deoxythymidine to improve energy production by addressing the root cause. This represents an important step toward developing the first specific and effective treatment for these disorders. ^{1 2 6 7 8}

Who Is on the Research Team?

Kenneth Alexis MD Myers, MD PhD FRCPC

Principal Investigator

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

Are You a Good Fit for This Trial?

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Deoxycytidine and Deoxythymidine

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.

How Is the Trial Designed?

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?

Kenneth Myers, MD

Lead Sponsor

Trials

1

Recruited

30+

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

Lead Sponsor

Trials

476

Recruited

170,000+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/40175578/

Investigating the safety and efficacy of deoxycytidine ...

These data suggest deoxycytidine/deoxythymidine is a safe and therapeutically promising intervention for a broad range of mitochondrial DNA depletion disorders.

2.

sciencedirect.com

sciencedirect.com/science/article/pii/S2589537024003195

Safety and efficacy of deoxycytidine/deoxythymidine ...

In conclusion, our study demonstrates that enteral dC/dT is a safe and potentially effective treatment for POLG-related disorders. Longer term studies with ...

3.

ucb.com

ucb.com/newsroom/press-releases/article/results-published-in-neurology-highlight-a-95-reduction-in-risk-of-death-with-pyrimidine-nucleostide-therapy-in-patients-with-thymidine-kinase-2-deficiency-tk2d

Results published in Neurology highlight a 95% reduction ...

Results published in Neurology highlight a 95% reduction in risk of death with pyrimidine nucleos(t)ide therapy in patients with thymidine ...

4.

clinicaltrials.gov

clinicaltrials.gov/study/NCT04802707?term=AREA%5BInterventionSearch%5D(DEOXYCYTIDINE)%20AND%20AREA%5BStudyType%5D(INTERVENTIONAL)&rank=5

NCT04802707 | Deoxynucleosides Pyrimidines as ...

The aim is to evaluate the safety, tolerability and efficacy of Deoxycytidine and Deoxythymidine in treatment of children with Mitochondrial Depletion Disorders ...

5.

neurology.org

neurology.org/doi/10.1212/WNL.0000000000213908

Pyrimidine Nucleos(t)ide Therapy in Patients With ...

In conclusion, the results presented suggest that pyrimidine nucleos(t)ide therapy may improve survival, allow for the regain of lost motor ...

6.

link.springer.com

link.springer.com/article/10.1007/s00415-025-13060-w

Investigating the safety and efficacy of deoxycytidine ...

These data suggest deoxycytidine/deoxythymidine is a safe and therapeutically promising intervention for a broad range of mitochondrial DNA depletion disorders.

7.

jns-journal.com

jns-journal.com/article/S0022-510X(23)00599-3/fulltext

Safety and efficacy of deoxycytidine/deoxythymidine ...

Our aim is to evaluate the safety and efficacy of the combination of enteral deoxycytidine and deoxythymidine (dC/dT) in treatment of patients with mtDNA ...

8.

vjneurology.com

vjneurology.com/video/hckd0n0z-om-safety-and-efficacy-of-deoxycytidine-and-deoxythymidine-in-treatment-of-polg-related-disorders/

AAN 2023 | Safety and efficacy of deoxycytidine and ...

This highlights the potential of deoxycytidine and deoxythymidine to improve symptoms and quality of life of patients with POLG-related mitochondrial disease.