ArticleEMBO molecular medicine2014
Deoxypyrimidine monophosphate bypass therapy for thymidine kinase 2 deficiency.
Article in EMBO molecular medicine, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT03639701 (Deoxythymidine and Deoxycytidine Treatment for Thymidine Kinase 2), which is not on this map. Cited by 56 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Deoxythymidine and Deoxycytidine Treatment for Thymidine Kinase 2 (TK2) Deficiency
Who cites it
56 citing papers in PubMed.
- Mitochondrial NADP(H)-dependent de novo dTMP biosynthesis counteracts the cytotoxicity of PARP inhibitors.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Author response to Commentary on "Long-term safety and efficacy of deoxycytidine/deoxythymidine in treatment of POLG-related disorders".Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2026Article
- Use of nucleoside therapy for mitochondrial DNA depletion/deletion syndrome (MDDS).Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2026Article
- Mitochondria transfer in tissue homeostasis and diseases.International journal of biological sciences · 2026Review
- Efficacy and safety of pyrimidine nucleos(t)ide therapy in thymidine kinase 2 deficiency.Brain communications · 2026Article
- Gene therapy and mRNA drugs approach for mitochondrial OXPHOS deficiencies.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Review
- Mitochondrial DNA Replication and Disease: A Historical Perspective on Molecular Insights and Therapeutic Advances.International journal of molecular sciences · 2025Review
- High tide or low tide: the transport and metabolism of mitochondrial nucleotides.The Biochemical journal · 2025Review
- Therapies for Mitochondrial Disease: Past, Present, and Future.Journal of inherited metabolic disease · 2025Review
- Advances in Management of Mitochondrial Myopathies.International journal of molecular sciences · 2025Review
- Deoxynucleoside supplementation ameliorates the disease associated phenotypes in a zebrafish model of RRM2B mtDNA depletion syndrome.Human molecular genetics · 2025Article
- RRM2B deficiency causes dATP and dGTP depletion through enhanced degradation and slower synthesis.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Infantile TK2 Deficiency Causing Mitochondrial Encephalomyopathy With Migrating Focal Seizures.Neurology · 2025Article
- Clinical and molecular spectrum of TK2-deficiency: a large Brazilian cohort.Scientific reports · 2025Article
- Mitochondrial diseases: from molecular mechanisms to therapeutic advances.Signal transduction and targeted therapy · 2025Review
- Safety and efficacy of deoxycytidine/deoxythymidine combination therapy in POLG-related disorders: 6-month interim results of an open-label, single arm, phase 2 trial.EClinicalMedicine · 2024Article
- Decoding the mitochondria without a code: mechanistic insights into mitochondrial DNA depletion syndromes.Journal of biosciences · 2024Review
- Deoxyguanosine kinase deficiency: natural history and liver transplant outcome.Brain communications · 2024Article
- Nucleoside supplements as treatments for mitochondrial DNA depletion syndrome.Frontiers in cell and developmental biology · 2024Article
- The Finnish genetic heritage in 2022 - from diagnosis to translational research.Disease models & mechanisms · 2022Review
Corrections and comments
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Authors and funding
9 authors.
Funding
Abstract
Autosomal recessive mutations in the thymidine kinase 2 gene (TK2) cause mitochondrial DNA depletion, multiple deletions, or both due to loss of TK2 enzyme activity and ensuing unbalanced deoxynucleotide triphosphate (dNTP) pools. To bypass Tk2 deficiency, we administered deoxycytidine and deoxythymidine monophosphates (dCMP+dTMP) to the Tk2 H126N (Tk2(-/-)) knock-in mouse model from postnatal day 4, when mutant mice are phenotypically normal, but biochemically affected. Assessment of 13-day-old Tk2(-/-) mice treated with dCMP+dTMP 200 mg/kg/day each (Tk2(-/-200dCMP/) (dTMP)) demonstrated that in mutant animals, the compounds raise dTTP concentrations, increase levels of mtDNA, ameliorate defects of mitochondrial respiratory chain enzymes, and significantly prolong their lifespan (34 days with treatment versus 13 days untreated). A second trial of dCMP+dTMP each at 400 mg/kg/day showed even greater phenotypic and biochemical improvements. In conclusion, dCMP/dTMP supplementation is the first effective pharmacologic treatment for Tk2 deficiency.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.