Treatment of TK2 Deficiency With Thymidine and Deoxycytidine

Deoxythymidine and Deoxycytidine Treatment for Thymidine Kinase 2 (TK2) Deficiency

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Thymidine Kinase 2 Deficiency; Mitochondrial DNA Depletion Syndrome 2 Myopathic Type
• Intervention / Treatment: Drug: Thymidine

Detailed Description

Mitochondrial are responsible for the production of cellular energy. Mitochondria contain DNA which is the encoding system ( "recipe") for making the proteins that allow the mitochondria to function. Reduced amount of mitochondrial DNA, caused by genetic mutations in certain genes, Mitochondrial DNA Depletion Syndrome. This can result in symptoms; such as fatigue, weakness, and deficiencies in various body systems. TK2 deficiency is considered a mitochondrial depletion syndrome. Patients with TK2 deficiency have weakness and walking difficulty. They also have depleted levels of chemicals (phosphorylated deoxythymidine and deoxycytidine) used to make mitochondrial DNA. Based on previous studies with a similar compound, patients reported more energy and better motor skills.

Eligible patients include those with genetic mutations in the TK2 gene who are willing to attend several outpatient visits, and have motor skills testing, neurological exam by doctor, and blood samples.

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10032
      • Columbia University Irving Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Genetically confirmed diagnosis of TK2 deficiency
• Deemed by principle investigator to be symptomatic with TK2 deficiency
• Single gene disease; absence of polygenic disease
• Hematocrit within normal range for age group
• Patient or patient's guardian able to consent and comply with protocol requirements
• Presence of caregiver to ensure study compliance (if needed)
• Abstention from use of all pill-form dietary supplements and non-prescribed medications (except as allowed by the investigator)
• Abstention from use of other investigational medications or other medications according to the study investigator

Exclusion Criteria:

• Clinical history of bleeding or abnormal prothrombin time (PT)/partial thromboplastin time (PTT)
• Hepatic insufficiency with liver function tests (LFTs) greater than two times normal
• Renal insufficiency requiring dialysis
• Any other concurrent inborn errors of metabolism
• Severe end-organ hypo-perfusion syndrome secondary to cardiac failure resulting in lactic acidosis

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Open label thymidine and deoxycytidine; All patients will receive open label thymidine and deoxycytidine	Drug: Thymidine; Mitochondrial DNA nucleotide precursors. Dose escalation: 130mg/kg/day x 14 days, 260 mg/kg/day x 14 days, and 400mg/kg/day as tolerated. Compounds are taken orally and divided into 3 doses daily.; Other Names: Deoxycytidine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Alanine aminotransferase	Number of participants with treatment-related elevated alanine aminotransferase (ALT) serum level relative to upper limit of normal (expressed as ratios) grade 3 or higher as defined by CTCAE 4.03.	Up to 60 months
Aspartate aminotransferase	Number of participants with treatment-related elevated aspartate aminotransferase (AST) serum level relative to upper limit of normal (expressed as ratios) grade 3 or higher as defined by CTCAE 4.03.	Up to 60 months
Gamma-glutamyltransferase	Number of participants with treatment-related elevated gamma-glutamyltransferase (GGT) serum level relative to upper limit of normal (expressed as ratios) grade 3 or higher as defined by CTCAE 4.03.	Up to 60 months
Blood lymphocyte count	Blood lymphocyte count increased relative to upper limit or normal or decreased relative to lower limit of normal (expressed as ratios) grade 3 or higher as defined by CTCAE 4.03.	Up to 60 months
Creatinine	Serum creatinine level increased relative to upper limit of normal (expressed as ratios) grade 3 or higher as defined by CTCAE 4.03.	Up to 60 months
Electrocardiogram	Number of patients with treatment related electrocardiogram (ECG) QT corrected interval (QTc) grade 3 or higher as defined by CTCAE version 4.03.	Up to 60 months
Diarrhea	Patient-Reported Outcome Measurement Information System (PROMIS) Scale v1.0 - Gastrointestinal Diarrhea 6a score (score range 0-30 with higher scores indicating more severe diarrhea)	Up to 60 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event-free survival	Time to mechanical ventilation, death, or both will be assessed.	Up to 60 months
6-minute walk test	Distance walked in meters over 6 minutes will be measured in ambulatory patient.	Up to 60 months
Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND)	Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) score (0-64 point range with higher scores indicating better function) will be assessed in infants to assess motor function.	Up to 60 months
Hammersmith Functional Motor Scale Expanded (HFMSE)	Hammersmith Functional Motor Scale Expanded (HFMSE) score (0-66 point range with higher scores indicating better function) will be measured in subjects >1 year-old.	Up to 60 months
Vital Capacity	Vital capacity (percent of predicted normal based on age and height) will be measure by spirometry	Up to 60 months
Time on Mechanical Ventilation	Number of hours per day that subjects use mechanical ventilation will be recorded.	Up to 60 months
euro Quality of Life (Neuro-QoL) in adults	Neuro Quality of Life (Neuro-QoL) short forms will be used to assess effects of muscle weakness on motor function and activities of daily living. In adults, Lower and Upper Extremity scales will be assessed (0-80 points with higher scores indicating better function).	Up to 60 months
Neuro Quality of Life (Neuro-QoL) in pediatric subjects	Neuro Quality of Life (Neuro-QoL) forms will be used to assess effects of muscle weakness on motor function and activities of daily living. In pediatric subjects (<18 years-old), Lower and Upper Extremity scales will be assessed (0-160 points with higher scores indicating better function).	Up to 60 months
Suicidal Ideation	Suicidal ideation will be assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS), which contains 6 "yes" or "no" questions. Answer of "yes" to any question indicates possible suicide risk and answer of "yes: to questions 4, 5, or 6 indicates high-risk.	Up to 60 months

Collaborators and Investigators

• Sponsor: Columbia University
• Collaborators: Universitat Autonoma de Barcelona; Instituto de Salud Carlos III; University of Seville; Hospital Universitario 12 de Octubre; Hospitales Universitarios Virgen del Rocío; Muscular Dystrophy Association; Medical Research Council Mitochondrial Biology Unit; Centro de Investigación Biomédica en Red Enfermedades Raras (CIBERER), Spain
• Investigators: Principal Investigator: Michio Hirano, MD, Columbia University

Publications and helpful links

General Publications

• Garone C, Taylor RW, Nascimento A, Poulton J, Fratter C, Dominguez-Gonzalez C, Evans JC, Loos M, Isohanni P, Suomalainen A, Ram D, Hughes MI, McFarland R, Barca E, Lopez Gomez C, Jayawant S, Thomas ND, Manzur AY, Kleinsteuber K, Martin MA, Kerr T, Gorman GS, Sommerville EW, Chinnery PF, Hofer M, Karch C, Ralph J, Camara Y, Madruga-Garrido M, Dominguez-Carral J, Ortez C, Emperador S, Montoya J, Chakrapani A, Kriger JF, Schoenaker R, Levin B, Thompson JLP, Long Y, Rahman S, Donati MA, DiMauro S, Hirano M. Retrospective natural history of thymidine kinase 2 deficiency. J Med Genet. 2018 Aug;55(8):515-521. doi: 10.1136/jmedgenet-2017-105012. Epub 2018 Mar 30.
• Lopez-Gomez C, Levy RJ, Sanchez-Quintero MJ, Juanola-Falgarona M, Barca E, Garcia-Diaz B, Tadesse S, Garone C, Hirano M. Deoxycytidine and Deoxythymidine Treatment for Thymidine Kinase 2 Deficiency. Ann Neurol. 2017 May;81(5):641-652. doi: 10.1002/ana.24922. Epub 2017 May 4.
• Garone C, Garcia-Diaz B, Emmanuele V, Lopez LC, Tadesse S, Akman HO, Tanji K, Quinzii CM, Hirano M. Deoxypyrimidine monophosphate bypass therapy for thymidine kinase 2 deficiency. EMBO Mol Med. 2014 Aug;6(8):1016-27. doi: 10.15252/emmm.201404092.
• Chanprasert S, Wang J, Weng SW, Enns GM, Boue DR, Wong BL, Mendell JR, Perry DA, Sahenk Z, Craigen WJ, Alcala FJ, Pascual JM, Melancon S, Zhang VW, Scaglia F, Wong LJ. Molecular and clinical characterization of the myopathic form of mitochondrial DNA depletion syndrome caused by mutations in the thymidine kinase (TK2) gene. Mol Genet Metab. 2013 Sep-Oct;110(1-2):153-61. doi: 10.1016/j.ymgme.2013.07.009. Epub 2013 Jul 17.

Study record dates

Study Major Dates

• Study Start (Actual): May 16, 2017
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: August 7, 2018
• First Submitted That Met QC Criteria: August 18, 2018
• First Posted (Actual): August 21, 2018

Study Record Updates

• Last Update Posted (Actual): January 28, 2026
• Last Update Submitted That Met QC Criteria: January 27, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: Thymidine; Deoxycytidine
• Additional Relevant MeSH Terms: Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleic Acids, Nucleotides, and Nucleosides; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Nucleosides; Deoxyribonucleosides; Deoxycytidine; Thymidine
• Other Study ID Numbers: AAAQ7552

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Since there are very few patients in the world with TK2 Deficiency, we may share de-identified data with other researchers who are treating patients with TK2 Deficiency

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No