Treatment of TK2 Deficiency With Thymidine and Deoxycytidine

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.

• Thymidine (Drug), also known as Deoxycytidine: 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.

Primary outcomes

• Alanine aminotransferase [Up to 60 months]: 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.
• Aspartate aminotransferase [Up to 60 months]: 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.
• Gamma-glutamyltransferase [Up to 60 months]: 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.
• Blood lymphocyte count [Up to 60 months]: 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.
• Creatinine [Up to 60 months]: Serum creatinine level increased relative to upper limit of normal (expressed as ratios) grade 3 or higher as defined by CTCAE 4.03.
• Electrocardiogram [Up to 60 months]: Number of patients with treatment related electrocardiogram (ECG) QT corrected interval (QTc) grade 3 or higher as defined by CTCAE version 4.03.
• Diarrhea [Up to 60 months]: 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)

Secondary outcomes

• Event-free survival [Up to 60 months]: Time to mechanical ventilation, death, or both will be assessed.
• 6-minute walk test [Up to 60 months]: Distance walked in meters over 6 minutes will be measured in ambulatory patient.
• Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) [Up to 60 months]: 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.
• Hammersmith Functional Motor Scale Expanded (HFMSE) [Up to 60 months]: 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.
• Vital Capacity [Up to 60 months]: Vital capacity (percent of predicted normal based on age and height) will be measure by spirometry
• Time on Mechanical Ventilation [Up to 60 months]: Number of hours per day that subjects use mechanical ventilation will be recorded.
• euro Quality of Life (Neuro-QoL) in adults [Up to 60 months]: 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).
• Neuro Quality of Life (Neuro-QoL) in pediatric subjects [Up to 60 months]: 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).
• Suicidal Ideation [Up to 60 months]: 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.

Sex: All

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

• Results publication: 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. PMID 29602790
• Results publication: 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. PMID 28318037
• Results publication: 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. PMID 24968719
• Results publication: 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. PMID 23932787

• Michio Hirano, MD, Principal investigator, Columbia University