bims-tyki2d Biomed News
on Thymidine kinase 2 deficiency
Issue of 2026–05–24
six papers selected by
Zoya Panahloo, UCB
  1. Nucleoside therapy for thymidine kinase 2 deficiency: Long-term outcomes from a Brazilian cohort.
  2. Paying for precision: funding approaches for N-of-1 trials of individualized gene targeted therapies.
  3. Strengthening the evidence base for precision medicine through the utilization of real-world data and real-world evidence: a narrative review from the U.S. perspective.
  4. Harnessing Patient-Generated Data for Rare Disease Knowledge Enrichment: A Pilot Study.
  5. Mavodelpar in patients with primary mitochondrial myopathy: a phase 1 trial.
  6. Genetic biomarker screening for drug-resistant epilepsy in low- and middle-income countries (LMICs).
  1. J Neuromuscul Dis. 2026 May 20. 22143602261432401
    Nucleoside therapy for thymidine kinase 2 deficiency: Long-term outcomes from a Brazilian cohort.
    Cristiane Araujo Martins Moreno, Tatiana Ribeiro Fernandes, Clara Gontijo Camelo, Gabriel Keller, Filipe Di Pace, Gabriella Corrêa Dousseau, Alulin Tácio Quadros Santos Monteiro Fonseca, Eliene Dutra Campos, Ana Paula Dos Anjos Lança, Mariana Cunha Artilheiro, André Macedo Serafim da Silva, Michelle Abdo Paiva, Andres Nascimento, Edmar Zanoteli.
      BackgroundThymidine Kinase 2 deficiency (TK2d) is a rare, mitochondrial DNA (mtDNA) depletion/deletions syndrome leading to a severe and progressive myopathic disorder. Nucleoside supplementation (deoxythymidine and deoxycytidine) has been shown to favorably alter the disease's course, particularly in severe infantile-onset cases. Long-term data on efficacy and safety, especially in the adult patient population, remain limited.MethodsThis is a retrospective, long-term follow-up study of 14 TK2d patients (five children and nine adults with childhood-onset disease) treated with nucleosides. Patients were systematically evaluated over a period ranging from 9 to 36 months, with assessments conducted every 3 months during the first year of treatment, and every 6 months thereafter. Comprehensive functional assessments of motor, respiratory, and bulbar function were performed. Periodic measurements of liver and pancreatic function monitored safety and tolerability.ResultsAll 14 TK2d patients showed beneficial effects across motor, respiratory, and bulbar function domains. Among pediatric patients, a rapid treatment response was observed early on, with functional gains sustained and continuing beyond 12 months of therapy. Adults experienced substantial improvements in motor and respiratory capacity but most of them reported severe gastrointestinal symptoms. Liver and pancreatic enzymes abnormalities were noticed mainly in adults.ConclusionsDeoxythymidine and deoxycytidine were found to be safe and beneficial in this long-term cohort of TK2d patients, but elevation in liver and pancreatic enzymes were present and required regular monitorization. This study provided valuable evidence supporting this therapy as an effective and safe, long-term disease-modifying treatment option for both pediatric and adult patients.
    Keywords:  Mitochondrial Myopahty; TK2 deficiency; deoxythymidine and deoxycytidine; mtDNA depletion syndrome; nucleosides therapy
    DOI:  https://doi.org/10.1177/22143602261432401
  2. Orphanet J Rare Dis. 2026 May 21.
    Paying for precision: funding approaches for N-of-1 trials of individualized gene targeted therapies.
    Nicole Nolen, Annemieke Aartsma-Rus, Christine Caneva, Curtis R Coughlin Ii, Margot A Cousin, Catherine Douthwright, Holm Graessner, Olivia Kim-McManus, Ashley Kuniholm, Stefanie Leonard, Andrea Martinsen, Margaret Meserve, Matthis Synofzik, Booma Yandava, Timothy W Yu, Scott Demarest, Roger J Paxton.
      Individualized medicine has the potential to be a transformative approach to healthcare that tailors medical treatments to the unique makeup of each patient. This report explores the potential of individualized genetic medicines to meet the pressing need for effective treatments for individuals with rare genetic diseases, and funding models to support these treatments. Although recent successes have been achieved, significant administrative and financial challenges remain in implementing individualized treatment trials. This report investigates funding associated with such therapeutics. Funding challenges, key strategic operational factors, potential payor support, historic funding models, and ethical elements ultimately leading to financial support of patient treatment are considered. By addressing these questions, this report aims to provide an overview of the complex issues surrounding individualized medicine, offering insights into balancing its promises with practical and ethical considerations as the field and associated funding models continue to evolve.
    Keywords:  Finance; Funding; Individualized medicine; Personalized healthcare; Precision medicine; Rare disease; Ultra-rare disease
    DOI:  https://doi.org/10.1186/s13023-026-04388-1
  3. Per Med. 2026 May 23. 1-13
    Strengthening the evidence base for precision medicine through the utilization of real-world data and real-world evidence: a narrative review from the U.S. perspective.
    Emily Nagel, Youssef M Roman.
      The expansion of precision medicine has shifted toward individualized care tailored to a patient's genetic profile. While randomized controlled trials (RCTs) remain the gold standard for establishing efficacy, they often struggle to reflect the phenotypic diversity of patients in routine clinical practice. This paper explores the role of Real-World Data (RWD) and Real-World Evidence (RWE) in bridging this translational gap. A structured literature search identified peer-reviewed articles examining RWE applications in identifying rare genetic targets, informing clinical trial design, and supporting U.S. Food and Drug Administration (FDA) regulatory decisions. This review synthesizes recent regulatory advances through early 2026, including frameworks supporting the use of aggregated RWD that expand large-scale, multi-institutional evidence generation. RWE provides a scalable mechanism for identifying rare genetic variants and validating biomarker-driven therapies across heterogeneous patient populations while enabling longitudinal assessment of natural disease history and treatment safety. Operational successes in oncology, transplant medicine, and rare diseases demonstrate regulatory acceptance of RWE alongside critical challenges in data standardization, interoperability, and bias mitigation through causal inference frameworks, including target trial emulation. RWD and RWE serve as necessary complements to RCTs, providing the hybrid evidentiary framework needed to realize precision medicine's potential.
    Keywords:  Biomarkers; clinical trial design; genomics; rare genetic variants; real-world data; real-world evidence; regulatory affairs; targeted therapy
    DOI:  https://doi.org/10.1080/17410541.2026.2678223
  4. Stud Health Technol Inform. 2026 May 21. 336 2415-2419
    Harnessing Patient-Generated Data for Rare Disease Knowledge Enrichment: A Pilot Study.
    Selina Wai Yan Hui, Fangyi Chen, Kai Wang, Chunhua Weng.
      Patients with rare diseases often endure a 4-5-year diagnostic odyssey. Patient-generated data on social media remains an untapped resource for understanding rare diseases. This study characterizes patient descriptions of rare disease from social media and systematically compares patient-reported symptoms to literature-documented ones. 166 unique rare diseases were identified from 229 patient posts. A hybrid human-AI framework using GPT-4 with full manual verification was used to extract and standardize patient-reported symptoms, which were then compared against symptoms documented in PubMed. The most frequent patient-reported symptoms were motor impairment, ataxia, pain, and fatigue. A low average overlap was observed between patient-reported symptoms and clinical literature. Patient narratives emphasized quality-of-life impacts (e.g., fatigue, anxiety), whereas clinical literature focused on diagnostic markers (e.g., dysarthria, dysphagia). Patient-generated data reveals underreported symptoms that are particularly meaningful to patients and complement clinical findings. Harnessing these real-world insights holds immense potential to shorten the diagnostic odyssey, inform patient-centered care, and guide future research priorities for rare diseases.
    Keywords:  Large Language Models; Patient-Generated Health Data; Rare Diseases
    DOI:  https://doi.org/10.3233/SHTI260703
  5. Sci Rep. 2026 May 18.
    Mavodelpar in patients with primary mitochondrial myopathy: a phase 1 trial.
    Renae J Stefanetti, Chiara Pizzamiglio, Alasdair P Blain, Oliver M Russell, Lisa Alcock, Gavin Hudson, Jane Newman, Naomi Thomas, Charlotte Warren, Huizhong Su, Helen A L Tuppen, Philip Brown, David Houghton, Heather Hunter, Albert Z Lim, Yi Shiau Ng, Catherine Feeney, Iwona Skorupinska, Louise Germain, Enrico Bugiardini, Michael G Hanna, Robert McFarland, Robert D S Pitceathly, Gráinne S Gorman.
      Primary mitochondrial myopathies (PMM) are rare, genetically-defined disorders characterised by defects of oxidative phosphorylation, predominantly affecting skeletal muscle. This Phase 1b open-label trial evaluated mavodelpar, a selective peroxisome proliferator-activated receptor delta (PPARδ) agonist, over 12 weeks (Part A), with an optional 36 week extension (Part B) in adults with PMM. The primary objective was to assess safety and tolerability, with secondary assessments of pharmacokinetics, pharmacodynamics, and exploratory performance, patient-reported, and muscle biopsy outcomes. Of the 23 participants who received mavodelpar, 17 completed Part A; none completed Part B due to premature study termination during the COVID-19 pandemic. Adverse events were mild-moderate severity, with headache and constipation most common (4/23 participants; 17.4% each). Exploratory measures showed a mean increase of 104 m in the twelve minute walk test (95% CI: 53 to 156) and a mean reduction of -10.5 points in patient-reported fatigue (95% CI: -16.3 to -4.6). No consistent changes in mitochondrial function were detected in muscle biopsies (n = 10), while transcriptomic profiling (n = 6) revealed modest upregulation of fatty acid-metabolism pathways. Although findings from this Phase 1b trial supported progression to later-phase evaluation, the subsequent Phase 2b trial did not demonstrate clinical efficacy for mavodelpar. The results reported here should be interpreted as exploratory and not indicative of therapeutic benefit. Nevertheless, this Phase 1b trial provides important methodological insights to inform future PMM clinical trial design and outcome measure development.
    Keywords:  Mitochondrial disease; Mitochondrial myopathy; Outcome measures; Peroxisome proliferator-activated receptor delta (PPARδ) agonist; Phase 1 trial; Rare disease
    DOI:  https://doi.org/10.1038/s41598-026-43287-0
  6. Adv Clin Exp Med. 2026 05 20.
    Genetic biomarker screening for drug-resistant epilepsy in low- and middle-income countries (LMICs).
    Dina Kalinina, Alimzhan Muxunov, Zhassulan Utebekov, Gaziz Kyrgyzbay, Darkhan Kimadiev, Guldana Zhumabaeva, Joseph Almazan, Antonio Sarria-Santamera.
      Drug-resistant epilepsy (DRE) presents a major clinical and economic challenge, particularly in lowand middle-income countries (LMICs), where healthcare resources are limited and treatment gaps remain significant. Although epilepsy surgery remains the most effective intervention for eligible DRE patients, outcomes are variable, with success rates ranging from 30% to 70%. Emerging evidence suggests that genetic biomarkers can inform patient selection, predict surgical outcomes, and guide treatment planning. This review explores the potential of integrating genetic testing into presurgical evaluation protocols in LMICs. It examines the role of specific gene mutations in pharmacoresistance, seizure localization, and structural brain abnormalities, with a focus on improving surgical success rates and reducing unnecessary interventions. Incorporating genetic stratification into clinical decision-making could enhance cost-effectiveness, minimize the burden on healthcare systems, and support the development of personalized treatment pathways. Advancing genetic research and building capacity in precision neurology are essential steps toward improving DRE management in resource-constrained settings.
    Keywords:  drug-resistant epilepsy; genetic testing; lowand middle-income countries; patient selection; surgical outcomes
    DOI:  https://doi.org/10.17219/acem/209664
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