ArticleEBioMedicine2019
Bioavailability and cytosolic kinases modulate response to deoxynucleoside therapy in TK2 deficiency.
Article in EBioMedicine, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 26 citations in OpenAlex.
- Disease burden of untreated thymidine kinase 2 deficiency: insights from a large patient dataset.Brain communications · 2026Article
- Efficacy and safety of pyrimidine nucleos(t)ide therapy in thymidine kinase 2 deficiency.Brain communications · 2026Article
- Pyrimidine Nucleos(t)ide Therapy in Patients With Thymidine Kinase 2 Deficiency: A Multicenter Retrospective Chart Review Study.Neurology · 2025Observational
- Novel biallelic TK2 mutations cause mitochondrial DNA depletion syndrome with infantile early-onset lipid storage myopathy.Orphanet journal of rare diseases · 2025Article
- Guanylate Kinase 1 Deficiency: A Novel and Potentially Treatable Mitochondrial DNA Depletion/Deletions Disease.Annals of neurology · 2024Article
- Validation of CRISPR targeting for proliferation and cytarabine resistance control genes in the acute myeloid leukemia cell line MOLM-13.BioTechniques · 2022Article
- Advances in Thymidine Kinase 2 Deficiency: Clinical Aspects, Translational Progress, and Emerging Therapies.Journal of neuromuscular diseases · 2022Review
- Chick early amniotic fluid component improves heart function and protects against inflammation after myocardial infarction in mice.Frontiers in cardiovascular medicine · 2022Article
- Synergistic Deoxynucleoside and Gene Therapies for Thymidine Kinase 2 Deficiency.Annals of neurology · 2021Article
- Therapy Prospects for Mitochondrial DNA Maintenance Disorders.International journal of molecular sciences · 2021Review
- Preferent Diaphragmatic Involvement in TK2 Deficiency: An Autopsy Case Study.International journal of molecular sciences · 2021Article
- Current and Emerging Clinical Treatment in Mitochondrial Disease.Molecular diagnosis & therapy · 2021Review
- Deoxynucleoside therapy for respiratory involvement in adult patients with thymidine kinase 2-deficient myopathy.BMJ open respiratory research · 2020Observational
- Basic biochemical characterization of cytosolic enzymes in thymidine nucleotide synthesis in adult rat tissues: implications for tissue specific mitochondrial DNA depletion and deoxynucleoside-based therapy for TK2-deficiency.BMC molecular and cell biology · 2020Article
- Insights into deoxyribonucleoside therapy for mitochondrial TK2 deficient mtDNA depletion.EBioMedicine · 2019Article
- Age-related metabolic changes limit efficacy of deoxynucleoside-based therapy in thymidine kinase 2-deficient mice.EBioMedicine · 2019Article
- Mitochondrial DNA maintenance defects: potential therapeutic strategies.Molecular genetics and metabolismReview
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundTK2 is a nuclear gene encoding the mitochondrial matrix protein thymidine kinase 2 (TK2), a critical enzyme in the mitochondrial nucleotide salvage pathway. Deficiency of TK2 activity causes mitochondrial DNA (mtDNA) depletion, which in humans manifests predominantly as a mitochondrial myopathy with onset typically in infancy and childhood. We previously showed that oral treatment of the Tk2 H126N knock-in mouse model (Tk2
methodsTo enhance mechanistic understanding and efficacy of dCtd + dThd therapy, we studied the bioavailability of dCtd and dThd in various tissues as well as levels of the cytosolic enzymes, TK1 and dCK that convert the deoxynucleosides into dCMP and dTMP.
findingsParenteral treatment relative to oral treatment produced higher levels of dCtd and dThd and improved mtDNA levels in liver and heart, but did not ameliorate molecular defects in brain or prolong survival. Down-regulation of TK1 correlated with temporal- and tissue-specificity of response to dCtd + dThd. Finally, we observed in human infant and adult muscle expression of TK1 and dCK, which account for the long-term efficacy to dCtd + dThd therapy in TK2 deficient patients. INTERPRETATIONS: These data indicate that the cytosolic pyrimidine salvage pathway enzymes TK1 and dCK are critical for therapeutic efficacy of deoxynucleoside therapy for Tk2 deficiency. FUND: National Institutes of Health P01HD32062.
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