Nucleotide Precursors for TK2 Deficiency

Recruiting at 2 trial locations

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Columbia University

Must not be taking: Dietary supplements

Disqualifiers: Bleeding history, Hepatic insufficiency, Renal insufficiency, Inborn errors, others

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

Compensation: Varies

Number of Visits: 1

Duration: Up to 60 months

23 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires participants to stop using all pill-form dietary supplements and non-prescribed medications, unless allowed by the investigator. You also need to avoid other investigational medications or other medications as per the study investigator's guidance.

What data supports the effectiveness of the drug Deoxycytidine (dCyt) and Deoxythymidine (dThd) for TK2 deficiency?

Research shows that treatment with deoxycytidine and deoxythymidine can improve mitochondrial function and extend the lifespan of mice with TK2 deficiency. In these studies, the treatment helped increase levels of mitochondrial DNA and improved the function of mitochondrial enzymes, which are crucial for energy production in cells. ^{1 2 3 4 5}

How does the drug Deoxycytidine (dCyt) and Deoxythymidine (dThd) differ from other treatments for TK2 deficiency?

This drug is unique because it directly supplements the missing nucleotide precursors, deoxycytidine and deoxythymidine, to bypass the enzyme deficiency in TK2 deficiency, effectively increasing mitochondrial DNA levels and improving symptoms, whereas other treatments may not address the root cause of the nucleotide imbalance. ^{1 6 7 8 9}

What is the purpose of this trial?

Patients with confirmed mitochondrial DNA depletion syndrome 2 (thymidine kinase 2 \[TK2\] deficiency) have reduced levels of nucleotides (deoxythymidine monophosphate and deoxycytidine monophosphate) for mitochondrial DNA synthesis. This results in mitochondrial DNA depletion syndrome (i.e less number of functional mitochondrial DNA). Patients with confirmed TK2 deficiency will be treated with open label deoxythymidine (dThd) and deoxycytidine (dCyt), which are nucleotide precursors, with the expectation that the cells could make additional mitochondrial DNA. This in turn may help reduce the clinical symptoms.

Research Team

Michio Hirano, MD

Principal Investigator

Columbia University

Eligibility Criteria

This trial is for patients with genetically confirmed TK2 deficiency, a condition affecting mitochondrial DNA. Participants must not be taking other investigational drugs or certain supplements and should have normal blood counts. They need to consent to the study rules and may require a caregiver's help to follow the protocol.

Inclusion Criteria

I do not take any pill-form dietary supplements or non-prescribed medications.

Abstention from use of other investigational medications or other medications according to the study investigator

My condition is genetically confirmed TK2 deficiency.

Exclusion Criteria

I require dialysis for kidney failure.

My liver tests are more than twice the normal levels.

I have a history of bleeding or abnormal blood clotting times.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive open label deoxythymidine and deoxycytidine to address TK2 deficiency

Up to 60 months

Several outpatient visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Deoxycytidine (dCyt)
• Deoxythymidine (dThd)

Trial Overview The trial tests whether giving patients with TK2 deficiency two substances, deoxythymidine (dThd) and deoxycytidine (dCyt), can increase their mitochondrial DNA levels and improve symptoms. It's an open-label study, meaning everyone knows what treatment they're getting.

Participant Groups

Group I: Open label thymidine and deoxycytidine Experimental Treatment 1 Intervention

All patients will receive open label thymidine and deoxycytidine

Who Is Running the Clinical Trial?

Columbia University

Lead Sponsor

Trials

1,529

Recruited

2,832,000+

Muscular Dystrophy Association

Collaborator

Trials

38

Recruited

60,800+

Centro de Investigación Biomédica en Red Enfermedades Raras (CIBERER), Spain

Collaborator

Trials

1

Recruited

20+

Instituto de Salud Carlos III

Collaborator

Trials

320

Recruited

648,000+

Medical Research Council Mitochondrial Biology Unit

Collaborator

Trials

2

Recruited

40+

Hospitales Universitarios Virgen del Rocío

Collaborator

Trials

70

Recruited

20,000+

Universitat Autonoma de Barcelona

Collaborator

Trials

50

Recruited

7,700+

University of Seville

Collaborator

Trials

137

Recruited

37,200+

Hospital Universitario 12 de Octubre

Collaborator

Trials

87

Recruited

49,300+

Findings from Research

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]

References

1. England pubmed.ncbi.nlm.nih.gov

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

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

Deoxycytidine and Deoxythymidine Treatment for Thymidine Kinase 2 Deficiency. [2022]

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

Synergistic Deoxynucleoside and Gene Therapies for Thymidine Kinase 2 Deficiency. [2023]

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

Age-related metabolic changes limit efficacy of deoxynucleoside-based therapy in thymidine kinase 2-deficient mice. [2020]

5. England pubmed.ncbi.nlm.nih.gov

Metrics of progression and prognosis in untreated adults with thymidine kinase 2 deficiency: An observational study. [2022]

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

Diverging substrate specificity of pure human thymidine kinases 1 and 2 against antiviral dideoxynucleosides. [2021]

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

Mutagenesis of non-conserved active site residues improves the activity and narrows the specificity of human thymidine kinase 2. [2018]

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

Substrate/inhibitor specificities of human deoxycytidine kinase (dCK) and thymidine kinases (TK1 and TK2). [2019]

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

Direct photoaffinity-labelling of human deoxycytidine kinase with the feedback inhibitor dCTP. [2019]