bims-polgdi Biomed News
on POLG disease
Issue of 2026–05–31
fifty-one papers selected by
Luca Bolliger, lxBio
  1. Cholesterol in Mitochondrial Diseases-Friend or Foe?
  2. Mitochondrial extracellular vesicles between pathology and regeneration.
  3. Mitochondrial transfer: A comprehensive analysis of mechanistic insights, preclinical applications, and technological innovations.
  4. Mitochondrial drivers of stem cell aging and inflammaging.
  5. Mito_Plot: open-source pipeline for quantification and visualization of mitochondrial DNA heteroplasmy.
  6. Mitochondrial myopathy biomarkers.
  7. MNGIE with TYMP and POLG variants presenting as decade-long capsule retention: A case report.
  8. Synonym Augmentation for Rare Disease Identification in Unstructured Data.
  9. Interoperable Integration of a National Rare Disease Registry Into a Rare Eye Disease Data Warehouse: Implementation Study.
  10. MICOS and MIMAS, multifunctional assemblies linking mitochondrial biogenesis, architecture, and function.
  11. Mitochondrial dysfunction in neurodegenerative disorders: mechanisms and therapeutic advances.
  12. Clinical and Genetic Characteristics of Mitochondrial DNA Depletion Syndrome Associated with SUCLG1 Variants in China.
  13. Implementation of a neuromuscular clinical trial network: a rare disease model for enhancing clinical trial readiness, capacity, and access in Canada.
  14. Unfolding Resilience: Molecular Integration of the Integrated Stress Response and Mitochondrial UPR in Skeletal Muscle Homeostasis.
  15. The Use of Single-Cell Mitochondrial DNA SNP Combinations for Distinguishing Organ-Specific Cell Types.
  16. The Evidence Aggregator: AI reasoning applied to rare disease diagnostics.
  17. Research Progress on How Multimodal Signals Regulate Neuronal Mitochondrial Homeostasis to Affect Diabetic Cognitive Impairment.
  18. A high-throughput screening platform to facilitate treatment development in Rett syndrome.
  19. Orchestrating mitochondrial protein import: The emerging role of DYRK1A in health and disease.
  20. MitoPG: An engineered biocompatible nanocarrier for drug delivery to neuronal mitochondria.
  21. Genetic spectrum of rare neurogenetic and neurometabolic disorders in a clinically heterogeneous cohort: insights from whole-exome sequencing.
  22. Mitochondrial Stress Orchestrates Tumor Immune Evasion and Immunotherapy Resistance.
  23. Non-viral delivery of genome-editing tools for treatment of genetic disorders.
  24. MyD88 deficiency modestly attenuates disease in a Leigh syndrome mouse model while enrofloxacin accelerates disease.
  25. External controls for rare disease drug development: Lessons for emerging and advanced therapeutic modalities.
  26. Mitochondrial dynamics in depression: friend or foe?
  27. Mitochondrial Transfer-Driven Immune Evasion in the Tumor Microenvironment.
  28. Progressive Visual Recovery in a Patient with Leber Hereditary Optic Neuropathy Harboring a Rare Heteroplasmic (MT-ND5):m.13042G>A, p(Ala236Thr) Variant with Low Mutant Load: A Case Report.
  29. Circulating Mitochondrial DNA Aggravates Post-Ischemic Functional and Metabolic Recovery in an Isolated Rat Heart Model of Donation After Circulatory Death.
  30. Societal Preferences for Assessment Pathways of Rare Disease Drugs: A Discrete Choice Experiment.
  31. Stratified obstetric management for heterogeneous rare diseases: a precision medicine framework based on four genetic archetypes.
  32. Ketogenic diet as a therapeutic strategy for neurodegenerative diseases: from mechanisms to translational challenges.
  33. NMN/NAD+ enhances SIRT2-modulated microtubule dynamics to improve mitochondrial and mitophagy functions in senescent cells.
  34. Redox-Sensitive m6A Epitranscriptomic Remodeling in Cadmium Stress and Toxicity.
  35. Extracellular Vesicles as Enabling Biomarkers for New Approach Methodologies to Support the US Food and Drug Administration Modernization Act 3.0.
  36. [The Current Landscape of Clinical Implementation of Whole Genome Sequencing].
  37. Translational stem cell therapy for neurodegeneration and CNS trauma: a focused review.
  38. Mitochondrial genetic variation across tissues of the human body.
  39. MitoFREQ: A novel approach for mitogenome frequency estimation from top-level haplogroups and single nucleotide variants.
  40. Mechanism of age-related accumulation of mtDNA mutations in human blood.
  41. Expanding African contributions to ClinVar through genetic counselor-led variant curation.
  42. Artificial Intelligence Across the Drug Development Lifecycle.
  43. Global Research Trends of Induced Pluripotent Stem Cells: A Data-Driven Bibliometric Analysis.
  44. Why promising ATMPs fail to reach patients: a qualitative stakeholder-informed analysis of cell therapy access in Europe.
  45. Perturbation of RNA homeostasis impairs mitochondrial respiration during poxvirus infection through excess RNA accumulation.
  46. Delivery of mRNA Therapeutics Beyond Infectious Diseases: Design Innovations and Applications in Oncology, Cardiovascular, and Rare Genetic Diseases.
  47. Natural Product Treatment for Metabolic Dysfunction-Associated Steatotic Liver Disease: Targeted Mitochondrial Quality Control.
  48. Uncovering the initial response: Intra-mitochondrial surveillance activates the UPRmt.
  49. Use of Real-World Evidence in Health Technology Assessments of Non-Oncology Rare Disease Therapies.
  50. Regulatory T cell therapy in autoimmune and immune-mediated diseases: from basic research to clinical practice and future perspectives.
  51. Special Issue "Research in iPSC-Based Disease Models".
  1. Int J Mol Sci. 2026 May 13. pii: 4353. [Epub ahead of print]27(10):
    Cholesterol in Mitochondrial Diseases-Friend or Foe?
    Mila Taylor, Michal Halicki, Paul Chazot.
      Serving as central signalling organelles and hubs of metabolism, mitochondria are essential for cellular homeostasis. Mitochondrial disease can arise from mutations to nuclear or mitochondrial DNA, which result in disruptions to normal mitochondrial function. This generates a suite of rare disorders which are multi-system and often fatal. Variable tissue distribution of mitochondria, alongside a high degree of heterogeneity in associated phenotype, has resulted in an inadequate understanding and characterisation of mitochondrial disease. Addressing this issue is therefore crucial for better clinical management and patient outcomes. Cholesterol dyshomeostasis is a potential pathological hallmark of numerous mitochondrial diseases. Cholesterol is an essential lipid and bioactive compound involved in numerous mitochondrial and cellular processes. A growing number of studies have reported perturbations to cholesterol biosynthesis, cholesterol import, and cholesterol ratios in cell and animal models and individuals with mitochondrial disease, suggesting it could be a unifying feature of these disparate and variable disorders. This review summarises the current experimental evidence for the role of cholesterol dyshomeostasis in mitochondrial disease. It will further discuss reports of statin intolerance, generally attributed to off-target action on mitochondrial structures, in the context of this evidence. Ultimately, the necessity of further integrative clinical and experimental studies exploring the potential of cholesterol dyshomeostasis as a pathological hallmark of mitochondrial disease will be highlighted.
    Keywords:  cholesterol; dyshomeostasis; lipid; mitochondria; statin
    DOI:  https://doi.org/10.3390/ijms27104353
  2. Neural Regen Res. 2026 May 14.
    Mitochondrial extracellular vesicles between pathology and regeneration.
    Paola Margutti, Silvia Zamboni.
      Mitochondria are central regulators of cellular energy production, metabolic homeostasis, and stress responses, and their dysfunction represents a critical hallmark of neurodegenerative and neuroinflammatory diseases. To preserve mitochondrial integrity, cells rely on an intricate mitochondrial quality control system encompassing mitochondrial dynamics, mitophagy, biogenesis, and vesicle-mediated pathways. Emerging evidence highlights the pivotal role of mitochondria-derived vesicles as vehicles for trafficking mitochondrial components within cells, thereby contributing significantly to intracellular communication and mitochondrial quality control. In parallel, mitochondrial extracellular vesicles have been identified as dynamic mediators of intercellular communication, enabling the transfer of mitochondrial proteins, lipids, and even mitochondrial DNA between cells. Mitochondria-derived vesicles selectively remove damaged mitochondrial components and coordinate intracellular stress responses, whereas mitochondrial extracellular vesicles can transfer mitochondrial material, including proteins, mitochondrial DNA, and even intact mitochondria, between cells, thereby modulating inflammation, immune activation, and cellular bioenergetics. Interestingly, mitochondrial extracellular vesicles play a dual, context-dependent role: they can exacerbate pathology when carrying damaged or dysfunctional mitochondrial cargo, or promote cellular resilience when delivering healthy, functional mitochondrial components. Likewise, extracellular vesicles derived from mesenchymal stem cells, including larger extracellular vesicle populations capable of transferring functional mitochondria, are emerging as promising cell-free therapeutic candidates with the potential to restore mitochondrial function and promote tissue repair across multiple diseases, including neurodegenerative disorders. Collectively, these insights establish mitochondrial vesicular trafficking as a transformative frontier for diagnostic innovation, biomarker development, and novel therapeutic strategies in neurodegenerative and mitochondria-related central nervous system disorders. Implications for the field include: the recognition of mitochondrial vesicular pathways as fundamental regulators of central nervous system homeostasis highlights their crucial roles in sustaining neuronal function, cellular resilience, and overall brain health. When enriched with dysfunctional mitochondrial cargo, mitochondrial extracellular vesicles are emerging as key contributors to the etiopathogenesis of neurodegenerative and neuroinflammatory diseases, thereby driving disease initiation and progression. In parallel, their ability to reflect mitochondrial status positions mitochondrial extracellular vesicles - particularly those containing mitochondrial DNA and mitochondrial proteins - as promising biomarkers for monitoring mitochondrial stress, disease activity, and therapeutic response. At the translational level, advancing mitochondrial extracellular vesicles and mitochondrial vesicular pathways as therapeutic tools opens new opportunities to restore mitochondrial integrity, modulate neuroinflammation, and potentially modify disease trajectories. The objectives of this review are to: (1) delineate the mechanisms of mitochondrial dysfunction and mitochondrial quality control failure in neurodegenerative and neuroinflammatory diseases; (2) comprehensively characterize the biogenesis, trafficking pathways, and functional roles of mitochondria-derived vesicles; (3) evaluate experimental and clinical evidence supporting the role of mitochondrial extracellular vesicles as mediators of neuroimmune communication and mitochondrial transfer; (4) critically assess the therapeutic potential of mesenchymal stem cell-derived mitochondrial extracellular vesicles.
    Keywords:  autophagy; extracellular vesicles; lysosome; mesenchymal stem cells; mitochondria; mitochondrial damage-associated molecular patterns; mitochondrial transfer; mitophagy; neurodegeneration; neuroinflammation
    DOI:  https://doi.org/10.4103/NRR.NRR-D-25-00964
  3. Neural Regen Res. 2026 May 14.
    Mitochondrial transfer: A comprehensive analysis of mechanistic insights, preclinical applications, and technological innovations.
    Yao Wang, Zitong Wang, Jie Zhao, Yimin Zhou, Dong Wei, Jingjing Zhao, Zhongqing Sun, Wen Jiang.
      Mitochondrial transfer, the intercellular exchange of functional mitochondria, is crucial for maintaining cellular homeostasis and promoting tissue repair, particularly in neurological disorders associated with mitochondrial dysfunction. This review addresses the mechanisms through which mitochondrial transfer occurs, including tunneling nanotubes, extracellular vesicles, gap junction channels, and cell fusion. Mitochondrial transfer and transplantation have demonstrated positive therapeutic effects in various disease models, such as cerebral hemorrhage, ischemic stroke, Alzheimer's disease, and multiple sclerosis. Exogenous mitochondria can integrate into recipient cells, enhancing adenosine triphosphate production, restoring redox balance, and improving cellular survival under stress conditions. However, clinical translation faces significant hurdles, including immune rejection, limited recipient cell uptake capacity, a lack of standardized manufacturing protocols, and unresolved ethical concerns regarding mitochondrial sourcing. To address these challenges, cutting-edge biotechnological strategies, such as mitochondrial surface modification, nanocarrier-based delivery, biomaterial-assisted transplantation, and the use of engineered vesicles, are being developed to enhance the precision, stability, and biocompatibility of mitochondrial delivery. Furthermore, innovative approaches, including CRISPR-based genome editing, 3D-bioprinted tissue models, and artificial intelligence-assisted predictive platforms, are being explored to enhance mitochondrial function and delivery efficiency. Current strategies to harness mitochondrial transfer include pharmacological agents that enhance mitochondrial dynamics, stem cell-based delivery of healthy mitochondria, and the aforementioned bioengineered platforms. In conclusion, the integration of mitochondrial transfer as a groundbreaking treatment option for neurological disorders relies on addressing two to three fundamental challenges. These include the establishment of standardized and scalable protocols for production and quality control, formulating approaches to minimize immune reactions and improve the efficiency of mitochondrial integration, and creating a well-defined ethical and regulatory framework for sourcing and utilizing mitochondria. The primary contribution of this work lies in its integrated analysis of mechanistic insights, preclinical applications, and technological innovations, providing a consolidated roadmap for advancing mitochondrial transplantation from bench to bedside.
    Keywords:  artificial cells; biomaterial-assisted transplantation; extracellular vesicles; mesenchymal stem cells; mitochondrial dysfunction; mitochondrial surface modification; mitochondrial transfer; mitochondrial transplantation; neurological disorders; tunneling nanotubes
    DOI:  https://doi.org/10.4103/NRR.NRR-D-25-01156
  4. NPJ Aging. 2026 May 28.
    Mitochondrial drivers of stem cell aging and inflammaging.
    Jhommara Bautista, Andrés López-Cortés.
      Mitochondria are increasingly recognized as master regulators of aging, integrating bioenergetics, redox control, stem cell fate, and innate immune signaling. This review synthesizes evidence that mitochondrial dysfunction is not only a hallmark but also an upstream driver of stem cell exhaustion and inflammaging. We discuss how age-associated mitochondrial DNA (mtDNA) mutations and clonal mosaicism impair respiration and reshape metabolite availability, thereby reprogramming long-lived epigenetic states that govern quiescence, lineage commitment, and regenerative output. In parallel, erosion of mitochondrial quality control (MQC), including fission-fusion balance, mitophagy, and the mitochondrial unfolded protein response (UPRmt), permits the persistence of reactive oxygen species (ROS)-producing organelles and lowers containment of mitochondrial danger signals. A central advance is that mitochondrial damage can be decoded as inflammation: cytosolic mtDNA and other mitochondrial damage-associated molecular patterns (mtDAMPs) activate cGAS-STING and NF-κB pathways, reinforcing senescence-linked cytokine circuits and chronic inflammatory tone. We further highlight nicotinamide adenine dinucleotide (NAD⁺) depletion as a metabolic bottleneck that compromises sirtuin-dependent resilience and can enforce mitochondrial dysfunction-associated senescence (MiDAS), linking redox collapse to altered senescence phenotypes and regenerative decline. Finally, we evaluate emerging mitochondria-targeted rejuvenation strategies, NAD⁺ repletion, mitophagy enhancers, mitochondrial transplantation/engineering, and precision elimination of mutant mtDNA using mitochondria-targeted transcription activator-like effector nucleases (mitoTALENs) or zinc-finger nucleases (mitoZFNs), emphasizing tissue-specific thresholds and context dependence for effective healthspan extension.
    DOI:  https://doi.org/10.1038/s41514-026-00422-5
  5. BMC Bioinformatics. 2026 May 25.
    Mito_Plot: open-source pipeline for quantification and visualization of mitochondrial DNA heteroplasmy.
    Kohta Nakamura, Naoyuki Matsumoto, Yasushi Okazaki.
       BACKGROUND: Mitochondrial DNA heteroplasmy plays a crucial role in mitochondrial function, aging, and a wide range of human diseases. Recent advances in high-throughput sequencing have enabled large-scale detection of heteroplasmic variants; however, effective cohort-level integration, comparison, and visualization of Mutant Allele Frequency (MAF) values remain challenging. Existing tools often focus on single-sample visualization or require substantial manual preprocessing, limiting their scalability and usability for large cohorts. To address these challenges, we developed Mito_Plot, an open-source computational pipeline designed for standardized quantification and intuitive visualization of Mitochondrial DNA (mtDNA) heteroplasmy across multiple samples.
    RESULTS: Mito_Plot accepts standard mitochondrial VCF files and automatically calculates MAF based on allelic depth information. MAF data from multiple samples are aggregated into a unified matrix aligned by genomic position, enabling direct cross-sample comparison. The pipeline provides interactive two-dimensional circular plots that map MAF onto the mitochondrial genome with gene-level annotations, facilitating rapid identification of mutation hotspots and sample-specific patterns. In addition, Mito_Plot offers optional three-dimensional visualizations that enhance exploration of large cohorts by separating variant distributions across samples and genomic regions. Application of Mito_Plot to multi-sample mitochondrial sequencing datasets demonstrated robust handling of both variants with low and high MAF values, efficient processing of large cohorts, and improved interpretability compared with static or single-sample visualizations.
    CONCLUSIONS: Mito_Plot is a scalable, user-friendly software pipeline for cohort-scale quantification and visualization of mtDNA MAF. By integrating standardized MAF calculation with interactive 2D and 3D visualizations, Mito_Plot facilitates comprehensive exploration of mitochondrial variant landscapes across large datasets. The open-source and modular design of the software supports reproducible research and flexible integration into existing analysis workflows, making Mito_Plot a practical resource for mitochondrial genomics research and clinical investigations.
    Keywords:  Circular genome; Cohort-scale analysis; Data visualization; Mitochondrial DNA; Mitochondrial heteroplasmy; Variant analysis
    DOI:  https://doi.org/10.1186/s12859-026-06476-2
  6. Adv Clin Chem. 2026 ;pii: S0065-2423(26)00021-1. [Epub ahead of print]133 161-216
    Mitochondrial myopathy biomarkers.
    Marco Refrigeri, Alessandra Tola, Rosangela Mogavero, Maria Michela Pietracupa, Giulia Gionta, Roberto Scatena.
      Mitochondrial myopathies comprise a heterogeneous group of disorders arising from structural or functional mitochondrial impairments that disrupt oxidative phosphorylation and cellular ATP production. The resulting energy deficit manifests not only in muscle but frequently leads to multi-systemic disease involving the brain, heart, kidneys, and endocrine system, creating a complex and often confounding clinical presentation. A critical, often overlooked aspect of their pathophysiology is that mitochondrial dysfunction extends far beyond bioenergetics. These organelles are vital hubs for biosynthetic pathways, calcium homeostasis, thermogenesis, apoptosis, and redox-sensitive signaling pathways that govern gene expression. The disruption of these integrated functions, whose molecular consequences are still being elucidated, is central to the disease's progression and heterogeneity. This clinical and molecular complexity contributes to significant diagnostic delay, with many remaining undiagnosed. Therefore, the development and strategic implementation of reliable biomarkers are essential. This review critically evaluates current and emerging biomarkers, proposing a diagnostic framework designed to improve diagnostic accuracy, limit unnecessary procedures, and ensure timely access to therapeutic interventions and genetic counseling.
    Keywords:  Biomarkers; Cell-free circulating mtDNA; Creatine; Diagnosis; Exercise intolerance; FGF21; GDF-15; Genetics; Mitochondrial disease; Mitochondrial medicine; Mitochondrial myopathy; Neurofilaments; Oxidative phosphorylation
    DOI:  https://doi.org/10.1016/bs.acc.2026.01.007
  7. Neurol Sci. 2026 May 26. pii: 521. [Epub ahead of print]47(6):
    MNGIE with TYMP and POLG variants presenting as decade-long capsule retention: A case report.
    Yuan Xia, Yufen She, Ruiqi Zhao, Yan Zhang.
       BACKGROUND: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare multisystem mitochondrial disorder caused by thymidine phosphorylase (TYMP) deficiency, leading to toxic nucleoside accumulation and mitochondrial DNA instability. Pathogenic variants in POLG, encoding mitochondrial DNA polymerase γ, have been associated with overlapping mitochondrial syndromes. However, the coexistence of TYMP-related MNGIE and a concurrent heterozygous POLG variant has not been reported.
    CASE PRESENTATION: A 57-year-old woman presented with a 10-year history of recurrent dizziness, chronic diarrhea, and 20 kg weight loss. Laboratory investigations revealed chronic anemia, hypoproteinemia, and positivity for anti-centromere protein B and anti-mitochondrial M2 antibodies. Abdominal CT revealed multiple small-bowel diverticula, splenomegaly, and a retained capsule endoscope, whereas brain MRI showed diffuse white-matter hyperintensities. Electromyography showed sensorimotor neuropathy, and neurological examination revealed bilateral ptosis, ophthalmoplegia, and distal weakness. Whole-exome sequencing confirmed a homozygous TYMP variant (c.708C>A, p.Phe236Leu) and a heterozygous POLG variant (c.1781 T>C, p.Leu594Pro). Surgical removal of the retained capsule together with supportive therapy, including enteral nutrition and coenzyme Q10, resulted in clinical improvement. To our knowledge, this is the first reported case of MNGIE with a homozygous TYMP variant and a concurrent heterozygous POLG variant.
    CONCLUSION: While the homozygous TYMP variant provides the primary molecular basis for the diagnosis, the concurrent heterozygous POLG variant may represent a potential phenotypic modifier. This case expands the genotypic context of MNGIE and highlights the importance of early genetic testing and multidisciplinary management in patients with unexplained gastrointestinal and neurological manifestations.
    Keywords:  Capsule endoscopy; Mitochondrial disease; Mitochondrial neurogastrointestinal encephalomyopathy; POLG; TYMP
    DOI:  https://doi.org/10.1007/s10072-026-09131-z
  8. medRxiv. 2026 May 13. pii: 2026.05.11.26352910. [Epub ahead of print]
    Synonym Augmentation for Rare Disease Identification in Unstructured Data.
    Jaber Valinejad, Sungrim Moon, Yanji Xu, Qian Zhu.
      The significant challenges associated with rare diseases in the medical and research domains include the scarcity of information, which is often confined to unstructured formats. Although existing approaches provide valuable insights, there is a need to develop effective methods to identify information pertinent to rare diseases for advancing rare disease research. We identified mentions of rare diseases in relevant texts and assessed their relevance using derived scores, the confidence score and semantic similarity from a fine-tuned BioMedBERT encoder. This encoder was fine-tuned using rare disease related text from Online Mendelian Inheritance in Man (OMIM), Orphanet, a manually validated dataset, and STS benchmark datasets. The process of identifying meaningful rare disease mentioned was presented through two case studies that retrieved relevant NIH-funded projects, utilizing a generated knowledge graph in Neo4j to host data on 2,067 GARD diseases with over 320,000 NIH funded projects. Through various case studies with NIH-funded projects related to rare diseases, we demonstrated the effectiveness of our approach in systematically providing rare disease related data to enhance our understanding of rare diseases for future investigations.
    DOI:  https://doi.org/10.64898/2026.05.11.26352910
  9. JMIR Med Inform. 2026 May 26. 14 e79378
    Interoperable Integration of a National Rare Disease Registry Into a Rare Eye Disease Data Warehouse: Implementation Study.
    Camille Beluffi Marin, Marilyne Oswald, Laura Ratenet, Matthieu Stoll, Kirsley Chennen, Hélène Dollfus.
       Background: In France, clinical data on rare diseases are primarily collected through BaMaRa (Base Maladies Rares), a software platform used by national expert centers to populate the BNDMR (Banque Nationale de Données Maladies Rares), the French national rare disease data warehouse. BaMaRa ensures standardized and structured data collection across all rare disease networks, with a focus on care coordination and epidemiological reporting. In 2024, FREDD (French Rare Eye Disease Database), a health data warehouse dedicated to rare eye diseases, was developed within the framework of the third French National Rare Disease Plan by the SENSGENE sector. Despite overlapping datasets, there is no native interoperability between BaMaRa and FREDD, requiring the development of a dedicated, traceable pipeline to transform BaMaRa exports into data suitable for inclusion in FREDD. This transformation involves complex business rules to address structural, semantic, and specific differences between the two systems.
    Objective: This study aims to describe the design and implementation of a robust data transformation pipeline that enables the automated conversion of BaMaRa clinical records into a structured dataset aligned with the FREDD data model. The primary goal is to ensure that the data remain semantically consistent and reusable for the secondary use of health data.
    Methods: We developed a Python-based application called FREDDEX that integrates several configuration files and encodes the domain-specific business rules required to align BaMaRa data with the FREDD schema. These rules include patient filtering, mapping of variable names and values, management of multisource redundancy, and prevention of overwriting. The system was designed to be modular, auditable, and usable by clinical data managers with minimal technical expertise.
    Results: FREDDEX was tested and validated on a BaMaRa export of 1000 real patients from Strasbourg University Hospital. The tool successfully filtered and created 641 patient profiles in FREDD, with a 99% success rate for attempted imports and full concordance (100%) for directly mapped and inferred variables. Genetic data reconstruction was confirmed on a random sample of 30 patients with genetic information, showing 100% accuracy, and multidiagnostic blocks were correctly handled in all manually reviewed cases. Beyond validation, FREDDEX processed up to 5000 patient records, enabling the rapid onboarding of new clinical sites and significantly reducing manual curation time, while runtime and memory usage demonstrated near-linear scaling. Importantly, the tool established a facilitated reproducible framework adaptable to other rare disease contexts and interoperable with national and European platforms, such as European Reference Network-EYE.
    Conclusions: This work demonstrates that transforming structured national rare disease registry data into a research-oriented health data warehouse is feasible when clinical business rules are explicitly formalized within an auditable extract-transform-load framework. Beyond the FREDD use case, this approach illustrates how interoperability between care-based and research infrastructures can be operationalized in rare diseases while preserving semantic integrity and regulatory compliance.
    Keywords:  BaMaRa (French national registry for rare diseases); data interoperability; extract-transform-load; health data warehouse; rare diseases; secondary use of health data
    DOI:  https://doi.org/10.2196/79378
  10. Protein Sci. 2026 Jun;35(6): e70653
    MICOS and MIMAS, multifunctional assemblies linking mitochondrial biogenesis, architecture, and function.
    Patrick Horten, Kuo Song, Nikolaus Pfanner, Heike Rampelt.
      Mitochondrial cristae architecture is central for optimal oxidative phosphorylation and a healthy mitochondrial physiology. The intricate architecture of the inner mitochondrial membrane relies on protein complexes that compartmentalize the membrane by imposing membrane curvature, forming membrane contact sites or membrane subdomains, regulating the partitioning of mitochondrial proteins between the different subcompartments and thereby enabling functional asymmetry, and by governing membrane dynamics. Studies in recent years have expanded our understanding of the machineries and mechanisms underlying the manifold functions of the inner membrane. This review focuses on the mitochondrial contact site and cristae organizing system (MICOS), a protein complex that stabilizes the narrow entry gates of cristae, and on a novel inner membrane megacomplex, the mitochondrial multifunctional assembly (MIMAS), as well as on their roles in organizing the inner membrane.
    Keywords:  cristae; membrane organization; metabolism; mitochondria; respiratory chain
    DOI:  https://doi.org/10.1002/pro.70653
  11. Mol Biomed. 2026 May 28. pii: 78. [Epub ahead of print]7(1):
    Mitochondrial dysfunction in neurodegenerative disorders: mechanisms and therapeutic advances.
    Yan Tong, Jing Na He, Linbin Zhou, Jiaxin Zhang, Bo Man Ho, Lin Du, Yolanda Wong Ying Yip, Hemlata Bisnauthsing, Poemen P Chan, Clement C Tham, Chi Pui Pang, Wai Kit Chu.
      Mitochondrial dysfunction is a core pathogenic mechanism underlying a broad spectrum of neurodegenerative disorders, from Alzheimer's and Parkinson's diseases to inherited optic neuropathies and mitochondrial ataxias. This review provides a comprehensive analysis of how defects in mitochondrial and nuclear DNA converge to disrupt oxidative phosphorylation, mitochondrial dynamics, calcium homeostasis, and quality control pathways, leading to energy depletion, oxidative stress, and neuronal degeneration across multiple disease contexts. Building on this mechanistic foundation, we examine how these shared pathogenic principles manifest distinctly in major neurodegenerative diseases, while also discussing representative mitochondrial optic neuropathies as tractable disease models that have yielded critical mechanistic and therapeutic insights. We further review recent advances in diagnostic technologies that enhance our ability to detect and stratify mitochondrial pathologies for therapeutic intervention. On the therapeutic front, we provide a comprehensive evaluation of the rapidly evolving landscape, analyzing strategies ranging from metabolic modulators and antioxidants to pioneering gene-targeted therapies, organelle replacement approaches, and emerging epitranscriptomic interventions. Finally, we identify persistent challenges in clinical translation and outline pivotal future directions essential for developing effective, mechanism-informed combination therapies against mitochondrial dysfunction in neurodegeneration.
    Keywords:  Clinical translation; Gene therapy; Mitochondrial dynamics; Mitochondrial dysfunction; Neurodegenerative diseases; Oxidative phosphorylation
    DOI:  https://doi.org/10.1186/s43556-026-00480-x
  12. Physiol Res. 2026 May 12. 75(2): 293-299
    Clinical and Genetic Characteristics of Mitochondrial DNA Depletion Syndrome Associated with SUCLG1 Variants in China.
    G-X Zhang, K-J Ji, Z-W Wang, N-N Wang.
      This study aimed to summarize the genetic variants and clinical characteristics of mitochondrial DNA depletion syndrome (MDS) associated with SUCLG1 mutations in children from China. A systematic review of cases reported in a Chinese literature database was conducted. Clinical data and genetic findings of children with MDS caused by SUCLG1 mutations were analyzed. A total of 13 cases from 9 articles were identified. The primary clinical features included hypotonia, psychomotor retardation, feeding difficulties, growth retardation, hearing impairment, and liver function impairment. Urine organic acid analysis demonstrated a mild increase in methylmalonic acid, while plasma concentrations of propionylcarnitine and/or butyrylcarnitine were elevated. Additionally, increased lactate and pyruvic acid levels were observed in both plasma and cerebrospinal fluid. Brain magnetic resonance imaging identified basal ganglion lesions and/or cerebral atrophy. A total of 14 SUCLG1 variants were identified: c.550G>A, c.751C>T, c.809A>C, c.961C>G, c.826-2A>G, c.713T>C, c.916G>T, c.619T>C, c.980dupT, c.40A>G, c.142C>T, c.601A>G, c.871G>C, and c.721_c.722delGA. Among these, the c.826-2A>G variation was the most frequently detected, present in 4 children, followed by c.550G>A. No significant correlation was found between genotype and phenotype. All 13 children were treated with vitamin B complex and coenzyme Q10. Among them, 2 died, while the remaining children exhibited clinical improvement. MDS associated with SUCLG1 mutations presents with nonspecific clinical manifestations and can affect multiple organ systems. Genetic testing is necessary for diagnosis, and no definitive treatment is currently available.
  13. Orphanet J Rare Dis. 2026 May 26.
    Implementation of a neuromuscular clinical trial network: a rare disease model for enhancing clinical trial readiness, capacity, and access in Canada.
    Kerri Lynn Schellenberg, Homira Osman, Maria Masnata, Rhiannon Hicks, Corinne Kagan, Ana Stosic, Stacey Lintern, Erin Beattie, Hanns Lochmuller, Craig Campbell, Jean K Mah.
       BACKGROUND: Rare diseases affect over 300 million people globally, yet clinical trial conduct in rare disease populations remains complex due to small patient numbers, geographic dispersion, heterogeneous phenotypes, and limited trial infrastructure. Neuromuscular diseases (NMDs) exemplify these challenges. Coordinated trial networks have emerged as a strategy to improve feasibility, access, and trial performance.
    METHODS: Guided by the Consolidated Framework for Implementation Research (CFIR), we conducted a multi-phase qualitative needs assessment involving neuromuscular investigators and clinical trial personnel across Canada (n = 34) and clinical trial personnel (n = 16) across Canada. Data were analyzed using conventional qualitative content analysis to identify barriers, facilitators, and capacity-building needs informing the early implementation of a Canadian Neuromuscular Clinical Trial Network (CTN).
    RESULTS: Key barriers included burdensome feasibility processes, limited workforce capacity, lack of centralized trial visibility, and fragmented coordination across stakeholders. Trial personnel highlighted unmet needs in disease-specific training, mentorship, peer networking, and workforce sustainability. Early Neuromuscular CTN strategies, including centralized feasibility triage, a national Community of Practice, one-on-one operational monitoring, mentorship, and alignment with patient and registry infrastructures directly addressed these challenges.
    CONCLUSION: The Neuromuscular CTN describes a pragmatic and potentially transferable model for strengthening rare disease clinical trial ecosystems. By ensuring trials not only occur but are optimally supported and performed, coordinated networks can enhance trial readiness, equity of access, and long-term sustainability in rare disease research.
    CLINICAL TRIAL NUMBER: Not applicable.
    Keywords:  Clinical trials; Clinical trials network; Community of practice; Neuromuscular; Rare disease
    DOI:  https://doi.org/10.1186/s13023-026-04393-4
  14. Muscles. 2026 May 22. pii: 39. [Epub ahead of print]5(2):
    Unfolding Resilience: Molecular Integration of the Integrated Stress Response and Mitochondrial UPR in Skeletal Muscle Homeostasis.
    Victoria C Sanfrancesco, Daniella Della Mea, David A Hood.
      To maintain homeostatic conditions and optimal function during stressors, mitochondria initiate retrograde signaling. The mitochondrial integrated stress response (ISR) and unfolded protein response (UPRmt) are critical quality control mechanisms activated during instances of mitochondrial perturbations. Restoration of mitochondrial homeostasis is orchestrated by three transcription factors, ATF4, CHOP, and ATF5, which upregulate protective genes to counteract stress. As the health and function of skeletal muscle are heavily dependent on a highly adaptive mitochondrial network, defining how mitochondrial health is maintained across various conditions is essential. Although several studies demonstrate the importance of these responses following instances of stress, the signaling mechanisms required to initiate such pathways remain poorly characterized in skeletal muscle. This review examines how the mitochondrial ISR/UPRmt and related transcription factors respond to organellar stress by emphasizing the molecular events that occur during exercise, aging and muscle disuse. By consolidating the literature, this work aims to highlight the current understanding of mitochondrial stress response signaling within skeletal muscle and thus emphasize areas for future research and potential therapeutic strategies during divergent metabolic conditions.
    Keywords:  ATF4; ATF5; CHOP; adaptation; aging; exercise; integrated stress response; mitochondria; muscle inactivity; skeletal muscle; stress response; unfolded protein response
    DOI:  https://doi.org/10.3390/muscles5020039
  15. Cells. 2026 May 21. pii: 947. [Epub ahead of print]15(10):
    The Use of Single-Cell Mitochondrial DNA SNP Combinations for Distinguishing Organ-Specific Cell Types.
    Shuai Wang, Xinyue Tu, Haozhe Zhu, Ce Gao, Jianan Gao, Jinsong Wei, Hui Shi, Jinrong Peng.
      Cell lineage relationship studies in developmental and regenerative biology have been greatly advanced using techniques such as fluorescent labeling driven by cell-type-specific promoters. Nevertheless, unbiased non-invasive tools for distinguishing cell lineages are inevitably desired. Mitochondrial DNA (mtDNA) exhibits wide-range single-nucleotide polymorphisms (SNPs) among individual cells. Here, we aim to distinguish cell types in organs/tissues of the same individual and in the regenerated liver based on the use of mtDNA SNPs. For this, two approaches-"Mitochondrial Alteration Enrichment and Sequencing" (MAESTER) and "mitochondrial single-cell assay for transposase-accessible chromatin with sequencing" (mtscATAC-seq)-were adopted to facilitate the detection of mtDNA SNPs in single cells. With MAESTER, we show that specific cell types in the liver and spleen of the same individual can be successfully defined using collective individual-specific markers composed of panels of unique mtDNA SNP combinations. For its application, we performed partial hepatectomy (PH) on a Krt19:DreERT2/+;R26:Rox-ZsGreen-Stop-Rox-tdTomato/+ mouse harboring tdTomato-labeled cholangiocytes following tamoxifen injection and demonstrated that utilizing panels of unique mtDNA SNP combinations detected by mtscATAC-seq in the pre-PH cholangiocytes as markers can faithfully trace the cell fate in the post-PH liver samples. Hence, this approach may serve as an unbiased tool for investigating cell lineage relationships in relevant research areas such as liver regeneration.
    Keywords:  MAESTER; cell lineage; mitochondrial DNA; single nucleotide polymorphism (SNP); single-cell sequencing
    DOI:  https://doi.org/10.3390/cells15100947
  16. Genet Med. 2026 May 27. pii: S1098-3600(26)00930-5. [Epub ahead of print] 102612
    The Evidence Aggregator: AI reasoning applied to rare disease diagnostics.
    Hope Twede, Lynn Pais, Samantha Bryen, Emily O'Heir, Greg Smith, Ron Paulsen, Christina A Austin-Tse, Alex Bloemendal, Cas Simons, Amanda K Hall, Scott Saponas, Miah Wander, Daniel G MacArthur, Heidi L Rehm, Ashley Mae Conard.
       PURPOSE: Variant assessment of rare disease diagnostics depends on using domain knowledge in the time-intensive process of retrieving, reviewing, and synthesizing clinical and technical information.
    METHODS: To address these challenges, we developed the Evidence Aggregator (EvAgg), an open-source, generative-AI-based tool designed to support rare disease diagnosis that systematically extracts relevant information from the scientific literature for any human gene. Further, we constructed an expert-curated dataset and evaluated EvAgg's performance for the tasks of relevant paper selection, finding observations of human genetic variation within those papers, and extracting specific details about those observations (e.g. zygosity, variant inheritance, variant type, functional study. phenotype, and study type). A user study evaluated utility and user experience in rare disease case analysis.
    RESULTS: Our evaluation study revealed that EvAgg achieved 92% recall in identifying relevant papers, 96% recall in detecting instances of genetic variation within those papers, and ∼80% accuracy in extracting individual case and variant-level content. Our subsequent user study evaluated the utility and user experience in rare disease case analysis. We found that EvAgg reduced review time by 34% (p-value < 0.002) and increased the number of papers, variants, and cases evaluated per unit time.
    CONCLUSION: EvAgg provides a thorough and current summary of observed genetic variants and their associated clinical features, supporting the process of manual literature review and enabling rapid synthesis of evidence concerning gene-disease relationships. The demonstrated time savings have the potential to reduce diagnostic latency and increase solve rates for challenging rare disease cases.
    Keywords:  entity recognition and linking; evidence aggregation; generative AI; information retrieval; rare disease
    DOI:  https://doi.org/10.1016/j.gim.2026.102612
  17. J Integr Neurosci. 2026 May 19. 25(5): 45956
    Research Progress on How Multimodal Signals Regulate Neuronal Mitochondrial Homeostasis to Affect Diabetic Cognitive Impairment.
    Ying Li, Pengwei Zhuang.
      Diabetic cognitive impairment (DCI) affects approximately 25%-35% of patients with diabetes and is characterized by progressive cognitive decline. Dysfunction of mitochondria-the energy factories within neurons-is considered a potential pathogenic factor of DCI, involving processes such as oxidative stress, calcium overload, autophagic dysfunction, and genetic mutations, ultimately disrupting normal neuronal function. Maintaining mitochondrial quality and function is critical for neuronal health. Recent studies have shown that there are multiple ways in which cells can communicate signals, such as extracellular vesicles (EVs), tunneling nanotubes and gap junctions, which can repair and replace damaged mitochondria within receptor cells. Notably, EV-mediated mitochondrial transplantation has demonstrated significant potential by transferring healthy mitochondria to impaired neurons and restoring energy metabolism and antioxidant defences, thereby offering novel therapeutic strategies for intervening in DCI progression with valuable clinical translation potential. This review systematically elucidates multimodal signalling strategies targeting mitochondrial homeostasis, with a focused analysis on the role of EV-mediated mitochondrial transplantation in restoring neuronal energy balance, providing a theoretical foundation for the development of innovative DCI interventions.
    Keywords:  cell communication; cognitive dysfunction; diabetes mellitus; mitochondria; neurons; type 2
    DOI:  https://doi.org/10.31083/JIN45956
  18. Front Neurol. 2026 ;17 1759410
    A high-throughput screening platform to facilitate treatment development in Rett syndrome.
    Yanhong Yin, Anxin Wang, Qiping Dong, Ziyao Zhang, Qian Bu, Runfeng Wang, Qiang Chang.
      Rett syndrome (RTT) is a rare X-linked progressive neurodevelopmental disorder affecting predominantly females with no cure and a prevalence of ~1 in 10,000 female birth worldwide. Before mutations in the methyl-CpG binding protein 2 (MECP2) gene were identified to cause classic RTT, there were suggestions that RTT is a mitochondrial disease. Being an essential organelle for all eukaryotic cells, the mitochondria produce energy, buffer calcium, and regulate the generation of reactive oxygen species. Indeed, accumulated reports documented mitochondrial abnormalities in RTT patient biopsies, and animal models and human stem cell models of RTT, including reduced ATP production, altered mitochondrial structure, increased systemic oxidative stress, abnormal calcium activity, mtDNA copy number, and deficiencies in mitochondrial enzyme activity. While it remains unclear how loss of MECP2 function leads to wide-ranging mitochondrial deficits, improving mitochondrial function could still bring benefits to RTT patients. After defining the mitochondrial membrane potential deficit in astrocytes differentiated from RTT patient-specific induced pluripotent stem cells (iPSC), we established a novel high-throughput screening (HTS) platform based on the JC-10 mitochondrial membrane potential (MMP) assay, which served as a rapid primary readout. All primary hits were subsequently validated by independent functional assays to confirm their effects on mitochondrial health. Using this system, we performed a small-molecule screening of 1,134 selected US Food and Drug Administration (FDA)-approved drugs and a small interfering RNA (siRNA) screening of 336 genes upregulated in RTT astrocytes and identified candidate drugs and candidate genes that reversed the MMP deficits in RTT astrocytes. Among the candidate drug hits, isradipine, a dihydropyridine calcium-channel blocker, provided preliminary evidence of neuroprotective effects both in vitro and in vivo. Among the candidate gene hits, LRRC17, a gene encoding a secreted protein, emerged as a strong candidate mediator whose elevated levels are strongly associated with and likely contribute to various observed cellular deficits. siRNA knockdown of LRRC17 not only rescued mitochondrial dysfunction in RTT astrocytes but also reversed deficits in neurons cultured in astrocyte-conditioned media. Our study provides new insights into mitochondrial dysfunction in RTT and establishes an HTS platform for the initial identification of novel therapeutic targets for follow-up studies.
    Keywords:  JC-10-based mitochondrial membrane potential (MMP) assay; Rett syndrome (RTT); high-throughput screening (HTS); human embryonic stem cells (hESCs)/induced pluripotent stem cells (iPSCs) derived neurons/astrocytes; isradipine; leucine rich repeating containing 17 (LRRC17); methyl-CpG-binding protein 2 (MECP2)
    DOI:  https://doi.org/10.3389/fneur.2026.1759410
  19. Protein Sci. 2026 Jun;35(6): e70631
    Orchestrating mitochondrial protein import: The emerging role of DYRK1A in health and disease.
    Sahana Shankar, Chris Meisinger.
      The translocase of the outer mitochondrial membrane (TOM complex) serves as the central entry gate for more than 1000 nuclear-encoded precursor proteins imported into the organelle. Recently, the human import receptor TOM70 has been identified as a substrate of the serine/threonine kinase DYRK1A. DYRK1A activates the metabolite carrier import pathway, and its impairment triggers a transcriptional adaptive response that induces remodeling of the TOM complex. This compensatory mechanism activates additional import pathways to mitigate reduced DYRK1A signaling. Patients with dysfunctional DYRK1A signaling exhibit clinical manifestations that resemble classical features of mitochondriopathies. The emerging DYRK1A-TOM70 axis therefore represents a central signaling platform coordinating mitochondrial protein import pathways in health and disease.
    Keywords:  DYRK1A; DYRK1A‐related syndrome; Down syndrome; TOM complex; mitochondrial protein import; organellar signaling
    DOI:  https://doi.org/10.1002/pro.70631
  20. Nanomedicine. 2026 May 25. pii: S1549-9634(26)00060-2. [Epub ahead of print]75 102959
    MitoPG: An engineered biocompatible nanocarrier for drug delivery to neuronal mitochondria.
    Nishad Keethedeth, Goutam Chandra, B Prakash Kumar, G Ganga Anand, Rajesh A Shenoi.
      Mitochondrial dysfunction is a key contributor to the pathogenesis of major neurodegenerative diseases such as Parkinson's disease. Targeted drug delivery to neuronal mitochondria is often limited by the inherent toxicity and inefficiency of drug carriers. Here we report the mitochondrial targeting ability of MitoPG, a novel nanocarrier based on dendritic polyglycerol (PG) conjugated with triphenylphosphonium (TPP+). Among a library of MitoPGs studied, MitoPG3 demonstrated superior mitochondrial localization and minimal cytotoxicity, without adverse effects on mitochondrial functions. Notably, it retained high mitochondrial targeting efficiency even under MPP+-induced mitochondrial dysfunction in neuronal cells. MitoPG 3 exhibited excellent blood brain permeability in vitro. To the best of our knowledge, this is the first report of a dendritic polymer-based nanocarrier with high mitochondrial localization and reduced toxicity and without impairing mitochondrial functions. These results highlight MitoPG as a safe and effective platform for delivering therapeutics to neuronal mitochondria, with the potential for clinical translation.
    Keywords:  Mitochondria targeting; Mitochondrial dysfunction; Polyglycerol; Targeted drug delivery; Triphenyl phosphonium
    DOI:  https://doi.org/10.1016/j.nano.2026.102959
  21. Neurogenetics. 2026 May 30. pii: 42. [Epub ahead of print]27(1):
    Genetic spectrum of rare neurogenetic and neurometabolic disorders in a clinically heterogeneous cohort: insights from whole-exome sequencing.
    Jasodhara Chaudhuri, Dipanwita Sadhukhan, Amrita Karmakar, Joydeep Mukherjee, Soma Gupta, Saranya Roy, Kallol Das, Shashi Shekhar Jayswal, Debasis Maity, Souvik Mondal, Bonny Sen, Akash Manna, Manamita Mandal, Kartik Chandra Ghosh, Samar Biswas, Amar Kumar Mishra, Gautam Gangully, Atanu Biswas, Priyankar Pal, Apurba Ghosh, Arindam Biswas.
      Rare neurogenetic and neurometabolic disorders comprise a clinically and genetically heterogeneous group of conditions, frequently presenting with overlapping neurological manifestations such as developmental delay, seizures, and cognitive impairment. Whole-exome sequencing (WES) has emerged as a robust approach for elucidating the molecular basis of these disorders. A total of 184 patients with suspected rare neurological disorders were enrolled in this study. Detailed demographic and clinical data were collected, and WES was performed to identify pathogenic and likely pathogenic variants. Variants were annotated and interpreted using standard guidelines, and inheritance patterns were determined. The cohort showed a slight male predominance, with the majority of cases presenting in early childhood (mean age at onset: 29.62 ± 27.69 months). The most common clinical features included developmental delay (82.06%), seizures (74.4%), and cognitive decline (41.3%), followed by dystonia (25%) and ataxia (17.9%). This study delineates the genetic spectrum of rare neurogenetic and neurometabolic disorders in a clinically heterogeneous cohort and underscores the diagnostic utility of WES. Early implementation of genomic testing can facilitate accurate diagnosis, guide clinical management, and improve genetic counseling in affected individuals.
    Keywords:  Indians; Movement disorders; Mutations; Rare diseases; Wilson’s disease
    DOI:  https://doi.org/10.1007/s10048-026-00912-4
  22. Cells. 2026 May 13. pii: 890. [Epub ahead of print]15(10):
    Mitochondrial Stress Orchestrates Tumor Immune Evasion and Immunotherapy Resistance.
    Ayhan Bilir, Berna Yıldırım, Mete Hakan Karalök.
      Mitochondrial stress has emerged as a key regulator of tumor-immune interactions, extending beyond its classical bioenergetic role to coordinate metabolic adaptation and immune regulation. Rather than merely accompanying tumor progression, mitochondrial dysfunction contributes to immune evasion and resistance to immunotherapy. Here, we propose that mitochondrial stress functions as a unifying axis governing three key determinants of anti-tumor immunity: immune visibility, immune cell fitness, and the metabolic architecture of the tumor microenvironment. Mechanistically, mitochondrial reactive oxygen species, mitochondrial DNA release, and mitophagy modulate antigen presentation and T cell function. We further highlight emerging experimental platforms, including 3D spheroid and organoid systems, that enable physiologically relevant investigation of mitochondria-driven tumor-immune interactions. Together, this perspective provides a mechanistic framework for understanding and targeting resistance to immune checkpoint blockade.
    Keywords:  3D tumor models; PD-1/PD-L1 axis; immune checkpoint blockade; immunotherapy resistance; metabolic competition; mitochondria; mitochondrial stress; mitophagy; mtDNA–cGAS–STING; organoids; tumor immune evasion; tumor microenvironment
    DOI:  https://doi.org/10.3390/cells15100890
  23. Acta Pharm Sin B. 2026 May;16(5): 2903-2928
    Non-viral delivery of genome-editing tools for treatment of genetic disorders.
    Jiamin Yang, Yuxuan Chen, Xiaohong Chen, Yuan Ping.
      Pathogenic mutations within protein-coding regions of genomic DNA can disrupt protein structure and lead to hereditary disorders. Genome-editing technologies, particularly those based on clustered, regularly interspaced, short palindromic repeats-associated protein (CRISPR-Cas), are promising therapeutic tools for correcting genetic abnormalities. To date, viral delivery vectors for genome-editing biomacromolecules have shown numerous promises in treating genetic disorders. However, safe viral delivery for genome-editing components remains challenging, largely due to the immunogenicity of viruses. As an alternative, non-viral delivery systems are emerging as a safer choice and may offer solutions to address the safety challenges. In this review, we first introduce CRISPR-Cas9-based genome editing tools and their delivery formats. Then, we outline the pathology of major genetic disorders and both preclinical and clinical approaches for these diseases by therapeutic genome editing, and provide an overview of current non-viral delivery strategies and their potential to overcome existing limitations. Finally, we discuss the current challenges and future outlooks of non-viral delivery of gene-editing components in treating genetic diseases.
    Keywords:  CRISPR-Cas; Gene therapy; Genetic diseases; Genome editing; Lipid nanoparticle; Non-viral delivery; Selective organ targeting; Virus-like particle
    DOI:  https://doi.org/10.1016/j.apsb.2026.02.014
  24. bioRxiv. 2026 May 17. pii: 2026.05.13.724988. [Epub ahead of print]
    MyD88 deficiency modestly attenuates disease in a Leigh syndrome mouse model while enrofloxacin accelerates disease.
    Allison R Hanaford, Elizaveta A Olkhova, Ryan Liao, Ashley Ching, Alvin Huang, Erin Shien Hsieh, Kino Watanabe, Yihan Chen, Megan Wichman, Noelle Hwang, Katerina James, Michael Mulholland, Vivian Truong, Holly Coulson, Kerry Gibbins, Owen Cairns, Anastasia Dimitriou, Bernhard Kayser, Brittany M Johnson, Surojit Sarkar, Vandana Kalia, Simon C Johnson.
      Primary genetic mitochondrial diseases (GMDs) are a clinically and genetically diverse group of diseases estimated to impact over 1 in 4,000 individuals. Leigh syndrome (LS) is the most common pediatric presentation of GMD. LS typically presents within the first years of life and is a severe progressive multi-system disorder. Symmetric progressive inflammatory brain lesions are a defining feature of the disease. Patients can also present with seizures, metabolic dysfunction, muscle weakness, and other symptoms. No effective clinical treatments currently exist. Recent data from the Ndufs4 (-/-) mouse model shows that peripheral macrophages contribute to brain lesions in LS, that disease is causally driven by innate immune populations, and that depletion of innate immune cells prevents LS disease. However, the precise mechanisms underlying immune activation remain unknown. Certain mitochondrial macromolecules retain bacterial signatures and can act as potent agonists for innate immune pathways. For example, cytoplasmic mitochondrial RNA and mitochondrial DNA are detected by Toll-like receptors (TLRs) 7 and 9, respectively, at the endosome. Accordingly, these are considered strong candidates for mediating innate immune activation in LS. Here, we generated TLR signaling deficient Ndufs4 (-/-)/ MyD88 (-/-) animals to assess whether TLR signaling plays a role in disease onset or progression in LS. Loss of MyD88 in Ndufs4 (-/-) animals statistically significantly increased survival and delayed the onset of some symptoms, but the benefits were modest compared to CSF1R inhibition from prior work. We conclude that Myd88 -mediated immune signaling is not a primary driver of LS. Notably, prophylactic enrofloxacin treatment, which was necessary for production of innate immune deficient MyD88 (-/-) animals, modestly decreased survival and accelerated disease. The impact of enrofloxacin and similar drugs in the context of mitochondrial disease warrants further investigation.
    DOI:  https://doi.org/10.64898/2026.05.13.724988
  25. Mol Ther Adv. 2026 Jun 11. 34(2): 201754
    External controls for rare disease drug development: Lessons for emerging and advanced therapeutic modalities.
    Samuel H Hughes, Lauren A Beretich, Matthew Fuller, Kimberly Goodspeed, Melissa Penn, Leonard A Valentino, Caitlin McCombs.
      External controls, particularly natural history studies, play an increasingly important role in rare disease therapeutic development where traditional randomized trials are often infeasible. This review examines regulatory acceptance patterns for gene and cell therapies approved between 2019 and 2025, analyzing successful cases like onasemnogene abeparvovec (Zolgensma) for spinal muscular atrophy and elivaldogene autotemcel (Skysona) for cerebral adrenoleukodystrophy alongside unsuccessful applications. Key success factors include systematic data collection, clinically meaningful endpoints, appropriate patient matching, and disease characteristics that preclude randomization. Recent FDA initiatives, including the Rare Disease Evidence Principles program, signal growing regulatory flexibility, although acceptance remains context-dependent and requires robust data quality standards.
    DOI:  https://doi.org/10.1016/j.omta.2026.201754
  26. Metab Brain Dis. 2026 May 23. pii: 113. [Epub ahead of print]41(1):
    Mitochondrial dynamics in depression: friend or foe?
    Oluwagbenga M Adu, Edem E Edem, Chidubem F Emereonye, Stephanie E Areloegbe, Busayo O Oguntola, Abiola O Obisesan, Kehinde S Olaniyi.
      Depression represents a significant global health burden characterized by complex, multifactorial pathophysiology. While traditional theories have focused on monoamine neurotransmitter imbalances, emerging evidence implicates mitochondrial dysfunction as a critical contributor to depressive disorders. This review examines the bidirectional relationship between mitochondrial dynamics, fusion, fission, biogenesis, and mitophagy and depression pathophysiology. The study synthesizes recent preclinical and clinical findings demonstrating alterations in mitochondrial morphology and dynamics in depressed subjects and explores the paradoxical nature of these changes, which can serve both adaptive and maladaptive roles. The review further evaluates therapeutic approaches targeting mitochondrial dynamics, including conventional antidepressants, lifestyle interventions, and novel mitochondria-targeted compounds. Ultimately, the relationship between mitochondria and depression is explained to serve as enlightenment and to find better approaches for using mitochondrial approaches in therapy for Depression.
    Keywords:  Depression; Major depressive disorder; Mitochondrial biogenesis; Mitochondrial dynamics; Mitochondrial dysfunction; Mitochondrial fission; Mitochondrial fusion; Mitophagy; Neurotransmitter imbalance
    DOI:  https://doi.org/10.1007/s11011-026-01876-y
  27. Int Immunol. 2026 May 29. pii: dxag027. [Epub ahead of print]
    Mitochondrial Transfer-Driven Immune Evasion in the Tumor Microenvironment.
    Li Zhu, Yosuke Togashi.
      The tumor microenvironment (TME) is a complex landscape where metabolic interactions significantly dictate antitumor immunity. Immune evasion in cancer is typically discussed in terms of inhibitory receptors and ligands, suppressive cytokines, defective antigen presentation, and metabolic competition. However, recent evidence reveals that intercellular mitochondrial transfer adds a new mechanism of immune evasion in the TME. The mitochondrial fitness of T cells is central to sustained effector function, memory formation, and responsiveness to immune checkpoint blockade. Tumor cells can act as pathogenic mitochondrial donors, transferring functional or dysfunctional mitochondria to neighboring T cells via tunneling nanotubes and extracellular vesicles. This process involves a mitophagy imbalance that leads to the homoplasmic replacement of endogenous mitochondria, thereby driving T-cell senescence, impairing memory formation and long-term antitumor function, and ultimately weakening cancer immunosurveillance. Overall, mitochondrial transfer should be considered a new part of the tumor immune evasion framework. It also provides new therapeutic opportunities for improving cancer immunotherapy.
    Keywords:  Mitochondrial transfer; T-cell exhaustion; immune checkpoint blockade; tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.1093/intimm/dxag027
  28. Case Rep Ophthalmol. 2026 Jan-Dec;17(1):17(1): 423-432
    Progressive Visual Recovery in a Patient with Leber Hereditary Optic Neuropathy Harboring a Rare Heteroplasmic (MT-ND5):m.13042G>A, p(Ala236Thr) Variant with Low Mutant Load: A Case Report.
    Tom Buelens, Audrey Meunier, Sara Seneca, François Willermain.
       Introduction: The majority of Caucasian patients with Leber hereditary optic neuropathy (LHON) harbor one of three primary pathogenic mitochondrial DNA (mtDNA) variants, which are usually present in homoplasmy in leukocytes. Most of the remaining cases have been linked to rare heteroplasmic pathogenic variants, which typically require a mutational load of more than 60% to result in phenotypic expression.
    Case Presentation: An 18-year-old Caucasian man presented with sudden visual loss in the left eye. Eye examination revealed hyperemic optic discs with retinal vascular tortuosity and subtle peripapillary telangiectasia, reminiscent of LHON, but initial mtDNA analysis was negative. Best corrected visual acuity (BCVA) continued to decrease despite systemic corticotherapy and subsequent treatment with plasma exchange. The patient then experienced visual loss in the fellow eye, with BCVA in both eyes deteriorating to "counting fingers". Subsequent screening of complete mtDNA by massive parallel sequencing of leukocyte DNA identified a variant NC_012920.1(MT-ND5):m.13042G>A, p.(Ala236Thr), in heteroplasmy, with a variant load of around 23.8%. Progressive visual recovery was observed in both eyes, resulting in BCVA of 20/29 in both eyes after 4 years of follow-up.
    Conclusion: In patients with a strong clinical suspicion of LHON, complete mitochondrial genome sequencing should be considered when initial testing, typically limited to the three primary mutations, is negative. Furthermore, the diagnosis of LHON should not be dismissed if "low" blood mutant loads are found, as important discrepancies of heteroplasmy levels between different tissues have been reported for variants located in the mitochondrial ND5 gene.
    Keywords:  Case report; Heteroplasmy; Leber hereditary optic neuropathy; MT-ND5; Optic neuropathy
    DOI:  https://doi.org/10.1159/000551571
  29. Int J Mol Sci. 2026 May 14. pii: 4360. [Epub ahead of print]27(10):
    Circulating Mitochondrial DNA Aggravates Post-Ischemic Functional and Metabolic Recovery in an Isolated Rat Heart Model of Donation After Circulatory Death.
    Maria Nieves Sanz, Maria Arnold, Adrian Segiser, Michelle Hofmann, Matthias Siepe, Sarah L Longnus.
      During donation after circulatory death (DCD), circulating levels of mitochondrial damage-associated molecular patterns (mtDAMPs) may increase, thereby exposing donor hearts to mtDAMPs prior to procurement and during machine perfusion. Mitochondrial DNA (mtDNA) is a pro-inflammatory mtDAMP that may stimulate several intracellular cascades including that of toll-like receptor 9 (TLR9). We administered mtDNA or ODN2088 (TLR9 antagonist) to hearts at reperfusion onset using an isolated rat heart model of DCD transplantation to investigate their effects. Four experimental groups were compared: (1) no ischemia; (2) ischemia; (3) ischemia + mtDNA; (4) ischemia + ODN2088. During reperfusion, cardiac power in ischemic hearts was significantly reduced compared to non-ischemic hearts (p < 0.01), and was further decreased with mtDNA (p < 0.05), but remained unchanged with ODN2088. Reduced ventricular recovery in mtDNA-treated hearts likely resulted from lower recovery of oxidative metabolism, demonstrated by reduced oxygen efficiency (p < 0.05) and a strong tendency for increased cytochrome c release (p < 0.06),indicating mitochondrial dysfunction and disruption, respectively. ODN2088 phosphorylated IκBα (NF-κB inhibitor alpha) and appeared to decrease cardiomyocyte death compared to ischemic hearts. Given the detrimental effects of circulating mtDNA on cardiac functional and metabolic recovery, circulating mtDAMPs, and particularly mtDNA, are of clinical relevance as potential therapeutic targets for optimizing graft quality and post-transplant outcomes.
    Keywords:  donation after circulatory death; heart transplantation; ischemia–reperfusion injury; mitochondrial damage-associated molecular patterns
    DOI:  https://doi.org/10.3390/ijms27104360
  30. Appl Health Econ Health Policy. 2026 May 27.
    Societal Preferences for Assessment Pathways of Rare Disease Drugs: A Discrete Choice Experiment.
    Constanza Vargas, Richard De Abreu Lourenco, Deborah J Street, Manuel Espinoza, Stephen Goodall.
       BACKGROUND: Countries have implemented different assessment pathways for public funding of drugs for rare diseases, resulting in inequities in access. Understanding public preferences for these processes could enhance decision-making legitimacy and acceptance.
    OBJECTIVE: We aimed to elicit societal preferences for different assessment pathways that lead to public reimbursement to drugs for rare diseases.
    METHODS: A discrete choice experiment was conducted among adults from the general population in Australia who were asked to assume the role of a government advisor and chose between two different assessment pathways. Attributes describing the assessment pathways were identified through a literature review and expert focus groups. Each respondent completed eight choice tasks. Data were analysed using conditional logit, mixed logit and latent class models. Willingness to wait was calculated as the ratio of attribute coefficients to access time.
    RESULTS: There were 1099 respondents who completed the survey. Overall, respondents preferred assessment pathways that incorporated comprehensive evidence and stakeholder input. The mixed logit model revealed preference heterogeneity across four of the five attributes, with the latent class analysis identifying three groups: Class 1 (28.1%) preferred use of all available evidence, Class 3 (20.2%) opposed long wait times, and Class 2 (52%) showed no strong preferences. On average, respondents were willing to wait 32 additional months to incorporate all types of evidence into the decision-making process, and an additional 14 months for broad stakeholder involvement. Acceptable delays indicate the value placed on greater certainty and broader consultation rather than recommended policy waiting times.
    CONCLUSIONS: This study examined societal preferences for assessment pathways for rare disease medicines. Robust evidence, covering safety, clinical effectiveness and cost effectiveness, and enhanced stakeholder involvement were the most influential factors. Respondents were also willing to delay patient access to ensure decisions were supported by strong evidence.
    DOI:  https://doi.org/10.1007/s40258-026-01047-1
  31. Front Med (Lausanne). 2026 ;13 1820341
    Stratified obstetric management for heterogeneous rare diseases: a precision medicine framework based on four genetic archetypes.
    Shangling Lv, Haipeng Yang, Yuying Cui, Haiyan Yang.
      Rapid advances in genomic sequencing increasingly expose obstetricians to complex and heterogeneous genetic information in routine clinical practice. Traditional disease-specific screening models are no longer sufficient to guide decision-making across the broad spectrum of rare disorders encountered in reproductive medicine. Frontline clinicians require a universal yet clinically intuitive framework that links the biological logic of disease to the most appropriate obstetric intervention. In this review, we selected seven representative rare diseases as clinical models and reorganized them into four genetic archetypes according to inheritance pattern, age of onset, testability, and maternal-fetal risk. These archetypes illustrate distinct management pathways: targeted mid-trimester interception of de novo dominant mutations, preconception prevention of inherited late-onset tumor syndromes, early defense against highly heterogeneous recessive disorders, and recognition of current predictive blind spots in complex polygenic disease. We further emphasize that some genetic conditions pose direct and potentially life-threatening risks to the pregnant patient and therefore require a maternal protection strategy in parallel with fetal evaluation. This archetype-based framework is intended to facilitate communication between obstetricians and geneticists, improve the clinical interpretation of genomic findings, and provide a practical blueprint for precision obstetric management in the genomic era.
    Keywords:  expanded carrier screening; maternal-fetal medicine; noninvasive prenatal testing (NIPT); precision medicine; preimplantation genetic testing; prenatal diagnosis; rare diseases
    DOI:  https://doi.org/10.3389/fmed.2026.1820341
  32. Transl Neurodegener. 2026 May 25. pii: 24. [Epub ahead of print]15(1):
    Ketogenic diet as a therapeutic strategy for neurodegenerative diseases: from mechanisms to translational challenges.
    Ana Margarida Salgueiro, Marisa Ferreira-Marques, Rodrigo F N Ribeiro, Sara M Lopes, Dina Pereira, Daniela G Costa, Magda M Santana, Luís Pereira de Almeida, Cláudia Cavadas.
      The ketogenic diet (KD) is increasingly recognized as a promising therapeutic strategy for neurodegenerative disorders because of its multifaceted impacts on key pathophysiological mechanisms. This review explores the molecular pathways through which KD may protect against neurodegeneration, including the use of ketone bodies as alternative energy substrates, reduction of oxidative stress and inflammation, modulation of autophagy and protein aggregation, and impact on the gut microbiome. The potential benefits of KD are explored across neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis, based on both preclinical and clinical evidence that supports its feasibility. However, challenges in long-term safety, patient adherence, and clinical practicality limit its widespread adoption. This review underscores the potential of KD for treating neurodegeneration on the basis of current scientific evidence while highlighting the need for further research to optimize its application and address existing gaps.
    Keywords:  Ketogenic diet; Neurodegenerative diseases; Neuroinflammation; Therapeutic strategy
    DOI:  https://doi.org/10.1186/s40035-026-00557-1
  33. Autophagy. 2026 May 24. 1-19
    NMN/NAD+ enhances SIRT2-modulated microtubule dynamics to improve mitochondrial and mitophagy functions in senescent cells.
    Jie Cui, Shifeng Ren, Bingjie Wang, Nan Zhang, Shanshan Zhu, Yajun Zhang, Xiangqing Qi, Weixue Meng, Liwei Shao, Shan Gao, Lijie Xing, Zengjun Li, Xiaodong Mu.
      The effect of NAD+ in enhancing mitochondrial function and energy metabolism in human cells is closely linked to NAD+-dependent sirtuins (i.e. SIRT1 and SIRT3). SIRT2 primarily functions in the cytoplasm, where it can serve as a key deacetylase for tubulin and modulates stability of microtubules. Microtubule plays a pivotal role in regulating mitochondrial dynamics, including mitochondrial movement, fission/fusion, repair, and mitophagy-dependent clearance. However, the potential role of NAD+ in modulating SIRT2-related microtubule stability, and the potential involvement of the NAD+-SIRT2-microtubule axis in regulating mitochondrial and mitophagy functions remains unexplored. In this study, we demonstrate that senescent muscle cells exhibit microtubule hyper-stabilization and reduced dynamics, concomitant with SIRT2 inactivation and tubulin hyperacetylation. These alterations impair microtubule-dependent mitochondrial repair and mitophagy function, resulting in mtDNA leakage, CGAS-STING1 activation and subsequently accelerated senescence. Notably, treatment with nicotinamide mononucleotide (NMN) effectively reactivates SIRT2, restores microtubule dynamics, and enhances mitochondrial quality control by promoting repair and mitophagy. Consequently, NMN mitigates CGAS-STING1-driven senescence. Our findings reveal a novel mechanism by which NMN preserves mitochondrial health in senescent cells via a SIRT2-microtubule axis, highlighting its protective role beyond canonical NAD+-sirtuin pathways, and suggesting microtubule dynamics as a promising therapeutic target for improving cellular defects associated with mitochondrial and mitophagy dysfunctions.Abbreviations: D-gal: D-galactose; EdU: 5-ethynyl-20-deoxyuridine; HDAC6: histone deacetylase 6; LAMP1: lysosome associated membrane protein 1; MSCs: mesenchymal stem/stromal cells; mtDNA: mitochondrial DNA; NAD+: nicotinamide adenine dinucleotide; NMN: nicotinamide mononucleotide; PBS: phosphate-buffered saline; SA-GLB1/β-gal: senescence-associated galactosidase beta 1; SIRT2: sirtuin 2.
    Keywords:  Cellular senescence; cytoskeleton; innate immunity; mechanical stress; mitochondrial damage; mitophagy dysfunction
    DOI:  https://doi.org/10.1080/15548627.2026.2677181
  34. Free Radic Biol Med. 2026 May 25. pii: S0891-5849(26)00823-3. [Epub ahead of print]
    Redox-Sensitive m6A Epitranscriptomic Remodeling in Cadmium Stress and Toxicity.
    Shuyan Niu, Yán Wāng.
      Environmental stressors that disrupt redox homeostasis pose a significant threat to metabolic balance, tissue integrity, and organismal development. Increasing evidence identifies N6-methyladenosine (m6A), a dynamic and stress-responsive RNA modification, as a central regulator that translates oxidative cues into functional changes in RNA metabolism and cellular behavior. Redox imbalance can recalibrate the activity, localization, and substrate selectivity of m6A writers, erasers, and readers, thereby reshaping transcriptomic programs that control inflammation, antioxidant defense, proteostasis, mitochondrial quality, and stress-adaptive cell fate decisions. These m6A-dependent responses manifest across diverse tissues, including the liver, kidney, pancreas, lung, brain, and reproductive organs, where they influence unfolded protein responses, β-cell resilience, epithelial plasticity, fibrotic remodeling, neurodegenerative processes, and gametogenic stability. m6A dysregulation also contributes to placental stress signaling, developmental vulnerability, and intergenerational transmission of metabolic and reproductive outcomes following environmental perturbation. In this work, we integrate emerging evidence to propose a unified framework illustrating how redox-sensitive m6A signaling orchestrates cellular and physiological responses to environmental stress, using cadmium as an exemplar due to its well-established role as an oxidative stress inducer. We highlight mechanistic convergence across tissues, note sources of exposure specificity, and discuss technological advances that are redefining the resolution of m6A mapping. Finally, we outline opportunities for leveraging m6A as a biomarker, mechanistic probe, and potential therapeutic target in the study of environmental cadmium stress and associated diseases.
    Keywords:  Cellular stress; Environmental stress; Epigenetic inheritance; Mitochondrial dysfunction; Oxidative signaling pathways; Post-transcriptional regulation
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.05.319
  35. J Extracell Vesicles. 2026 Jun;15(6): e70313
    Extracellular Vesicles as Enabling Biomarkers for New Approach Methodologies to Support the US Food and Drug Administration Modernization Act 3.0.
    Andrew Rowland, Carl Kirkpatrick, A David Rodrigues, Uli Frevert, Franziska Haderk, David W Greening, Andrew J McLachlan, Ashley Hopkins, Fabrice Lucien, Rienk Nieuwland.
      The FDA Modernization Act 3.0 represents a pivotal shift in biomedical research by formally removing the requirement for animal testing and enabling regulatory acceptance of New Approach Methodologies (NAMs). This transition creates an urgent need for robust, human-relevant biomarkers that can anchor NAM-generated data within regulatory decision-making, particularly for first-in-human studies. Extracellular vesicles (EVs), owing to their biological stability, accessibility and rich molecular cargo, may be well positioned to fulfil this role. EVs reflect dynamic cellular states and intercellular communication, making them mechanistically informative readouts of pharmacology, toxicity, immune modulation and disease biology across human-derived model systems. This Perspective outlines how EV-based biomarkers can support the qualification, standardization, and regulatory acceptance of NAMs, with particular emphasis on ex vivo platforms such as organoids, microtissue systems, organ-on-chip devices and perfused tissue slices. We highlight the advantages of EVs for longitudinal, non-destructive sampling, representation of human variability, and integration with quantitative systems pharmacology and physiologically based pharmacokinetic models. Finally, we discuss the scientific, operational and regulatory challenges that must be addressed and argue that coordinated leadership from the International Society for Extracellular Vesicles (ISEV) is essential. The convergence of regulatory reform and EV science presents a timely call to action to establish EVs as foundational biomarkers in next-generation, human-centric drug development.
    DOI:  https://doi.org/10.1002/jev2.70313
  36. Gan To Kagaku Ryoho. 2026 Apr;53(4): 237-243
    [The Current Landscape of Clinical Implementation of Whole Genome Sequencing].
    Hiroyuki Fujii, Kuniko Sunami, Takashi Kohno.
      Whole genome sequencing (WGS) interrogates the entire approximately 3-billion-base-pair human genome and uniquely enables integrated capture of multilayered information, including variants in noncoding regions, repeat elements, complex structural variants, viral genomes, the mitochondrial genome, HLA types, and pharmacogenomic markers. Compared with comprehensive genomic profiling (CGP), which targets predefined cancer genes, WGS offers a vastly broader scope but entails substantial challenges in specimen requirements, computational infrastructure, and standardization of variant interpretation. Recent large-scale clinical studies have shown that WGS provides actionable insights that inform therapy selection and prompt diagnosis, and preparations for clinical deployment are advancing in both oncology and rare-disease medicine. Internationally, initiatives such as the UK 100,000 Genomes Project and the Netherlands' WIDE study/OncoAct® have marked key implementation milestones, while in Japan the"Action Plan for Whole Genome Analysis 2022"is establishing the framework for translation to practice and patient benefit. This review surveys WGS from technical foundations to clinical utility, global implementation, ongoing efforts and infrastructure in Japan, and remaining challenges. It sets out the case for repositioning WGS from a research tool to a patient-oriented foundational technology and outlines its potential to deliver patient benefit and accelerate drug development.
  37. Mol Biol Rep. 2026 May 27. pii: 842. [Epub ahead of print]53(1):
    Translational stem cell therapy for neurodegeneration and CNS trauma: a focused review.
    Rasa Khosrofar, Parmida Nafei, Farshad Zare, Amirhossein Sadrmohammadbagheri, Faranak Zargari, Nassim Rastgar, Sarvin Radvar, Naiyereh Alipour Eskandani, Fateme Hoseinzade, Reza Akhavan Sigari.
      Central nervous system (CNS) disorders, including spinal cord injury (SCI) and traumatic brain injury (TBI), often result in severe and irreversible functional impairments due to complex pathophysiological processes such as neuroinflammation, axonal damage, and neuronal cell death. Conventional treatment strategies have shown limited efficacy in restoring neurological function. Stem cell therapy has emerged as a promising avenue for CNS repair, offering potential benefits such as neuronal regeneration, modulation of immune responses, and secretion of neurotrophic factors. Various stem cell types, including neural stem cells (NSCs), mesenchymal stem cells (MSCs), and induced pluripotent stem cells (iPSCs), have demonstrated therapeutic potential in the preclinical and early clinical studies for conditions such as TBI, SCI, stroke, Parkinson's disease, and multiple sclerosis. Despite significant progress, challenges such as cell delivery optimization, risk of tumorigenesis, immune compatibility, and ethical concerns must be addressed to enable broader clinical application. This review highlights the recent advances in stem cell-based therapies for CNS disorders, discusses the mechanisms underlying their therapeutic effects, and outlines future directions for research and clinical translation.
    Keywords:  Central nervous system disorders; Neural regeneration; Spinal cord injury; Stem cell therapy; Traumatic brain injury
    DOI:  https://doi.org/10.1007/s11033-026-12011-6
  38. Nucleic Acids Res. 2026 May 20. pii: gkag513. [Epub ahead of print]54(10):
    Mitochondrial genetic variation across tissues of the human body.
    Nathaniel Fisher, Liying Xue, Karan K Smith, Brian Tao, Jason A Cunha, Scott Ladenheim, Jesse D Moreira-Bouchard, Zachary J Milstone, Anna Zhebrun, Xiaoling Zhang, Gyungah R Jun, Thor D Stein, Ting Fang Alvin Ang, Lindsay A Farrer, Melissa G Farb, Robert F Padera, Emelia J Benjamin, Daniel Levy, Deepa M Gopal, R Stefan Isaac, Marc E Lenburg, Seung Hoan Choi, Jessica L Fetterman.
      Each mitochondrion contains 2-10 copies of the mitochondrial genome. Multiple mitochondria in a cell allow for mitochondrial genomes carrying different variants to co-exist within a cell or tissue, termed heteroplasmy. The extent to which mitochondrial genetic variation differs across tissues of the human body and the origins of heteroplasmic variants is largely unknown. Using next-generation sequencing of 47 paired tissues from 947 donors in the Genotype-Tissue Expression dataset, we found that 39% of unique mitochondrial DNA variants identified were present in one tissue (tissue-specific) and 7% of unique variants were found in several but not all tissues of a donor. Tissue-specific variants were more likely to be transversions, nonsynonymous, deleterious, and present at lower variant allele fractions compared to variants shared across all tissues within a donor. Tissues primarily composed of proliferative cell types had the most tissue-specific variants, while highly energetic tissues had the least. The number of tissue-specific variants was associated with donor age for the tissues with the most tissue-specific variants. We determined that most of the heteroplasmic variants likely arise de novo after tissue differentiation. Our study suggests that mitochondrial DNA variants arise throughout an individual's lifetime in a tissue-dependent manner, which may have disease implications.
    DOI:  https://doi.org/10.1093/nar/gkag513
  39. Forensic Sci Int Genet. 2026 May 26. pii: S1872-4973(26)00107-9. [Epub ahead of print]85 103526
    MitoFREQ: A novel approach for mitogenome frequency estimation from top-level haplogroups and single nucleotide variants.
    Mikkel Meyer Andersen, Nicole Huber, Kimberly Sturk-Andreaggi, Tóra Oluffa Stenberg Olsen, Walther Parson, Charla Marshall.
      Forensic lineage markers pose a challenge in forensic genetics as their evidential value can be difficult to quantify. Lineage marker population frequencies can serve as one way to express evidential value. However, for some markers, e.g., high-quality whole mitochondrial DNA genome sequences (mitogenomes), population data remain limited. In this paper, we offer a new method, MitoFREQ, for estimating the population frequencies of mitogenomes. MitoFREQ uses the mitogenome resources HelixMTdb and gnomAD, harbouring information from 195,983 and 56,406 mitogenomes, respectively. Neither HelixMTdb nor gnomAD can be queried directly for individual mitogenome frequencies, but offers single nucleotide variant (SNV) allele frequencies for each of 30 "top-level" haplogroups (TLHG), which mainly correspond to the first letter of major mitochondrial DNA (mtDNA) haplogroups (e.g., A, B, C, D, E, etc.) except for the L0, L1, L2, L3, L4-6, HV, and R/B haplogroups. We propose using the HelixMTdb and gnomAD resources by classifying a given mitogenome within the TLHG scheme and subsequently using the frequency of its rarest SNV within that TLHG weighted by the TLHG frequency. We show that this method is guaranteed to provide a higher population frequency estimate than if a refined haplogroup and its SNV frequencies were used. Further, we show that top-level haplogrouping can be achieved by using only 227 specific positions for 99.9% of the tested mitogenomes, potentially making the method available for low-quality samples. The method was tested on two types of datasets: high-quality forensic reference datasets and a diverse collection of scrutinized mitogenomes from GenBank. This dual evaluation demonstrated that the approach is robust across both curated forensic data and broader population-level sequences. This method produced likelihood ratios in the range of 100-100,000, demonstrating its potential to strengthen the statistical evaluation of forensic mtDNA evidence. We have developed an open-source R package mitofreq that implements our method, including a Shiny app where custom TLHG frequencies can be supplied.
    Keywords:  Evidential weight; Forensic genetics; Likelihood ratio; Match probability; mtDNA
    DOI:  https://doi.org/10.1016/j.fsigen.2026.103526
  40. Nature. 2026 May 27.
    Mechanism of age-related accumulation of mtDNA mutations in human blood.
    Rahul Gupta, Timothy J Durham, Grant Chau, Masahiro Kanai, Md Mesbah Uddin, Wenhan Lu, M Austin Argentieri, Konrad J Karczewski, Daniel Howrigan, Pradeep Natarajan, Wei Zhou, Benjamin M Neale, Vamsi K Mootha.
      Accumulation of mutant mitochondrial DNA (mtDNA) heteroplasmy is among the strongest signatures of ageing1. Here we investigated the underlying mechanism by calling mtDNA sequence, mtDNA abundance and mtDNA heteroplasmic variants in human blood using whole-genome sequences from approximately 750,000 individuals. We observed that mtDNA single-nucleotide variants (mtSNVs) accumulate sharply at age 60 years, occur at low levels of heteroplasmy, exhibit little evidence of positive selection and are likely to be predominantly neutral. The mutational spectrum of mtSNVs does not reflect oxidative lesions, as is commonly invoked, but is more consistent with mtDNA replication errors. To understand why mtSNVs become detectable with age, we performed a genome-wide association study for heteroplasmic mtSNV burden, identifying germline variants near TERT, TCL1A and SMC4, all of which have been linked to clonal haematopoiesis (CH)2. Rare-variant analysis also showed that high mtSNV burden is associated with mutations in numerous CH driver genes. These genetic associations persisted even after exclusion of individuals with known CH driver mutations. Our results support a model in which 'cryptic' mtDNA mutations initially arise randomly as replication errors but are undetectable in bulk. They then become apparent only through age-related expansion of cellular clones in blood. We propose that the high copy number and mutation rate of mtDNA make it a sensitive blood-based marker of somatic mosaicism due to CH. Our work mechanistically unifies three prominent signatures of ageing: common germline variants in TERT, CH and observed accrual of mtDNA mutations.
    DOI:  https://doi.org/10.1038/s41586-026-10569-6
  41. J Genet Couns. 2026 Jun;35(3): e70235
    Expanding African contributions to ClinVar through genetic counselor-led variant curation.
    Nabeelah Peerbhai, Nolene Ramsunder, Tarin Europa, Jeannine Heckmann, Melissa Nel.
      Global variant databases such as ClinVar are vital in linking genetic variation to clinical significance and enabling shared interpretation across laboratories. However, African genetic variants remain underrepresented, comprising under 2% of global ClinVar submissions. This gap reflects inequities in access to genome sequencing, workforce capacity, and data-sharing systems, which limit visibility, contextual interpretation, and re-evaluation of African genetic variation. We describe our experiences of genetic counselor-led variant curation, ClinVar submissions, and ongoing monitoring of germline genetic variants identified in African neuromuscular and amyotrophic lateral sclerosis research cohorts. Between March 2023 and August 2025, the Clinical Omics and Informatics Unit (University of Cape Town) submitted 93 DNA sequence variants to ClinVar spanning 58 genes, including 27 first-time submissions to the database. ClinVar submissions require valid Monarch Disease Ontology (Mondo) identifiers; gaps or inaccuracies were identified (n = 3) and updated, or Mondo disease entities were created to ensure gene-disease pairs were correctly represented. Using African Genome Variation Database frequencies to guide variant classification provided sub-regional context, highlighting population differences and refining interpretations. Furthermore, we maintained a structured follow-up of variant records using ClinVar's "follow" feature. This enabled passive monitoring of new submissions or classification changes, which were evaluated to assess whether reinterpretation or resolution of variants of uncertain significance or those with conflicting assertions were warranted. This work highlights the critical role that African genetic counselors can play as contributors to variant curation in an underrepresented geography, given their expertise in human genetics and clinical reasoning. By embedding African-specific frequency data and locally trained expertise into variant curation pipelines, a sustainable, equity-driven model for genomic knowledge production in Africa is developed. African-led ClinVar contributions can strengthen interpretative accuracy, foster collaborative curation, and position genetic counselors as active agents in global genomic data sharing and interpretation.
    Keywords:  African genomic data equity; ClinVar data sharing; amyotrophic lateral sclerosis; disease ontology; genetic counselor; genomics; neuromuscular diseases; variant curation
    DOI:  https://doi.org/10.1002/jgc4.70235
  42. Med Sci (Basel). 2026 May 10. pii: 248. [Epub ahead of print]14(2):
    Artificial Intelligence Across the Drug Development Lifecycle.
    Grigory Demyashkin, Mikhail Parshenkov, Sergey Zyryanov, Alexander Yavorskiy, Petr Shegai, Andrey Kaprin.
      Artificial intelligence (AI) is becoming a central driver of change across the drug development lifecycle. However, its integration is evolving so rapidly that it remains essential to understand how these technologies are currently positioned within the field. Because reliable access to high-quality (effective and safe) drugs is essential to public health, the pharmaceutical product lifecycle (PPL) offers a coherent framework for evaluating how AI can enhance evidence and data creation across all stages. To understand where AI genuinely adds value, this review examines its contribution across the major stages of the PPL. Rather than treating drug discovery, nonclinical evaluation, clinical research, and post-marketing assessment as separate domains, we view them as a continuous chain of data, where digital technologies enhance different decision points in distinct ways. In early discovery, AI narrows the search space by integrating diverse datasets to prioritize candidates most likely to succeed. Nonclinical models increasingly rely on machine-learning systems designed to improve the human relevance of safety predictions. Within clinical trials, AI supports cohort formation, real-time monitoring, and new analytic strategies that supplement empirical evidence. Case studies from leading pharmaceutical companies illustrate that the most meaningful advances emerge when AI is embedded not as a standalone tool but as part of a broader data strategy that links information across stages. Taken together, current evidence suggests that AI is beginning to transform data generation and integration throughout the PPL. Given the accelerating pace of digital innovation, it is essential for the field to maintain continuous awareness of emerging methodologies and evolving regulatory frameworks to ensure that these technologies are implemented in a reliable, transparent, and scientifically grounded manner.
    Keywords:  artificial intelligence; clinical trials; drug development; drug discovery; machine learning; nonclinical trials; precision medicine
    DOI:  https://doi.org/10.3390/medsci14020248
  43. Tissue Eng Part B Rev. 2026 May 23. 19373368261450045
    Global Research Trends of Induced Pluripotent Stem Cells: A Data-Driven Bibliometric Analysis.
    Xiaoying Jin, Fanyu Meng, Qirui Hu, Yizhou Wang, Zhongqing Wang, Bo Liu.
      This study analyzed 10,461 iPSC-related publications retrieved from the Web of Science Core Collection-Science Citation Index Expanded, focusing on annual publication, journal, author, institution, country/region, reference, and author keyword, with networkvisualization performed using VOSviewer. The annual publication has shown remarkable growth, first exceeding 500 in 2013 and reaching 1,107 in 2021. Stem Cell Research published the most publications (n = 1,472) and received the highest citations (n = 6,561), followed by PLoS One and Scientific Reports. The United States was the most productive country with 3,525 publications and 208,413 citations. Among the institutions, Kyoto University ranked first in productivity with 480 publications and 33,455 citations. Wu Joseph C. was the most prolific author, having 119 publications and 8,855 citations. Five main clusters were identified through the co-occurrence analysis of the top 177 author keywords: iPSCs differentiation & tissue engineering, neurodegenerative diseases & neurobiology, regenerative medicine in Parkinson's disease, cardiac disease models & gene editing, and ESCs & reprogramming mechanisms. This study presented the first comprehensive bibliometric analysis of global iPSC research, aiming to map the domain's intellectual structure and collaborative networks. It revealed the global landscape, drivers of the growth trajectory, knowledge base, research hotspots, and future perspectives in the domain, thereby offering a strategic roadmap to accelerate progress and innovation.
    Keywords:  ESCs; bibliometric analysis; induced Pluripotent Stem Cells; neurodegenerative diseases
    DOI:  https://doi.org/10.1177/19373368261450045
  44. J Transl Med. 2026 May 23.
    Why promising ATMPs fail to reach patients: a qualitative stakeholder-informed analysis of cell therapy access in Europe.
    Giuseppe Di Mauro, Maria Pachetti, Christian Ploner, Michele De Luca, Graziella Pellegrini, Elisa Gambini, Massimo Moretti, Antonio Sfiligoj, Teodor E Yordanov, Miomir Knezevic, Giulia Benedetta Sidoti, Giovanni Papa, Serena Zacchigna.
       BACKGROUND: Advanced therapy medicinal products (ATMPs) comprise gene therapies, somatic cell therapies, tissue engineered products (TEPs), and combined ATMPs. These modalities have the potential to deliver durable or curative benefit in oncological, genetic, chronic, and rare diseases with high unmet medical need. Yet in Europe, access remains limited, uneven, and often commercially unsustainable: clinically promising therapies frequently fail to progress beyond early development or are withdrawn after regulatory approval for reasons related to scalability and reimbursement rather than lack of clinical benefit.
    METHODS: This study was designed as a qualitative, interview-based analysis to identify the major barriers faced by ATMP stakeholders to the clinical translation and patient access of cell therapies in Europe. We collected structured oral and written questionnaire/interview input from six stakeholders operating in the European ATMP landscape and synthesized the material into cross-cutting themes related to health technology assessment, manufacturing, regulatory implementation, and market dynamics.
    RESULTS: Stakeholders consistently report that HTA approaches optimized for conventional pharmacological therapies often overemphasize short-term budget impact and insufficiently account for long-term clinical benefit, downstream healthcare and societal costs, and the durability of therapeutic effects. In parallel, substantial variability across donors, batches, manufacturing and delivery settings, together with fragmented GMP infrastructure, uneven national execution of clinical trial and access pathways, and chronic underinvestment, undermines reproducibility and scalability. Although the European Medicines Agency (EMA) offers facilitation instruments including early scientific dialogue and accelerated or supportive regulatory pathways, their potential to improve predictability is frequently attenuated by Member State heterogeneity and discontinuities across regional innovation ecosystems.
    CONCLUSION: From a stakeholder's perspective, key recommendations including revising HTA frameworks to better reflect long-term lifetime value, investing to improve the accessibility to GMP facilities, strengthening ATMP regulatory expertise and access to early scientific advice, enabling cross-border ecosystems, and addressing structural market failure through public risk-sharing mechanisms.
    Keywords:  ATMPs; Funding; GMP; HTA; Innovation; Manufacturing; Regulatory; Scalability; Tech transfer
    DOI:  https://doi.org/10.1186/s12967-026-08303-x
  45. Proc Natl Acad Sci U S A. 2026 Jun 02. 123(22): e2605194123
    Perturbation of RNA homeostasis impairs mitochondrial respiration during poxvirus infection through excess RNA accumulation.
    Djamal Brahim Belhaouari, Anil Pant, Santiago Navarro-Forero, Fernando Cantu, Zhilong Yang.
      Induction of RNA degradation in infected cells is a strategy used by many viruses to promote efficient replication. Vaccinia virus, the prototype poxvirus and the vaccine platform for smallpox and mpox, encodes two decapping enzymes to accelerate mRNA and double-stranded RNA (dsRNA) degradation during infection, through functional coordination with host cell RNA exonuclease. Previous studies have largely focused on RNA degradation as a mechanism for regulating viral gene expression and evading innate immune sensing. Here, we show that impaired RNA degradation in vaccinia virus-infected cells, due to either depletion of viral decapping enzymes or cellular exonuclease, severely compromises mitochondrial respiration and integrity. We further demonstrated that accumulation of excess dsRNA and mRNA, including pseudouridine-modified RNAs, is sufficient to induce profound defects in mitochondrial respiration and integrity. Notably, this impairment occurs independently of interferon induction and dsRNA innate immune sensor Protein Kinase R. Moreover, excess RNA suppresses respiration in purified cell-free mitochondria and physically associates with mitochondria in cell-free and cellular contexts, supporting an immune-independent mechanism. Excess mRNA and dsRNA reduce mitochondrial membrane potential in both cells and purified mitochondria, indicating disruption of the proton gradient as the mechanism underlying impaired mitochondrial respiration and integrity. Together, these findings identify excess mRNA and dsRNA as perturbants of mitochondrial homeostasis in cells with dysfunctional RNA degradation during vaccinia virus infection, revealing a paradigm-shift concept linking RNA metabolism to mitochondrial function. The finding carries broad implications for understanding RNA and mitochondrial biology and RNA-based therapeutics and vaccines.
    Keywords:  RNA degradation; dsRNA; mRNA; mitochondrial respiration; poxvirus
    DOI:  https://doi.org/10.1073/pnas.2605194123
  46. Pharmaceuticals (Basel). 2026 Apr 24. pii: 663. [Epub ahead of print]19(5):
    Delivery of mRNA Therapeutics Beyond Infectious Diseases: Design Innovations and Applications in Oncology, Cardiovascular, and Rare Genetic Diseases.
    Snehitha Akkineni, Mahek Gulani, Samir A Kouzi, Martin J D'Souza, Mohammad N Uddin.
      Empowered by nanotechnology, messenger RNA (mRNA) therapeutics have shown a rapid evolution post COVID-19 from a conceptual platform to a clinically validated modality, and they diversified into oncology, cardiovascular diseases, and rare disorders. As a template for in situ protein production, it offers several advantages over traditional proteins and DNA drugs. The intrinsic stability of mRNA and its sensitivity to innate immune sensing hinder its capacity for immediate cellular entry, necessitating its need for a delivery system to obtain optimal therapeutic potential. This review explores the innovations in nanocarrier engineering, design principles for lipid nanoparticles-mRNA (LNPs) platforms, and their clinical translation across the prominent indications. It also addresses their safety, immunogenicity, and scalability while addressing the key limitations and manufacturing scalability through comparative platform analysis. Although LNPs usually dominate their delivery through encapsulation and manufacturability, their limitations, like repeat dose reactogenicity and liver tropism, require next-generation designs like SORT lipids, stimuli-responsive hybrids for extrahepatic targeting. In oncology, LNP-mRNA drives the neoantigen vaccines, and rare diseases leverage the transient enzyme replacement. While the safety profiles highlight the innate immune tuning through nucleoside mods and lipid biodegradability, chronic administration risks are still persistent. While there are novel scalability options like microfluidic mixing to support the production gaps in organ selectivity and durability, their adoption is hindered. We outline the future directions to perceive mRNA's full potential as a broader therapeutic class.
    Keywords:  design principles; lipid nanoparticles; mRNA; mRNA therapeutics; nanocarrier engineering
    DOI:  https://doi.org/10.3390/ph19050663
  47. Drug Des Devel Ther. 2026 ;20 610273
    Natural Product Treatment for Metabolic Dysfunction-Associated Steatotic Liver Disease: Targeted Mitochondrial Quality Control.
    Jing Liu, Fuxing Li, Qianru Zeng, Wenxiao Hu, Le Yang, Shengping Luo, Fang Lv, Dingxiang Li, Yihui Deng.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by progressive mitochondrial dysfunction that disrupts hepatocellular metabolism, redox homeostasis, and inter-organelle communication. Hepatic metabolic zonation, maintained by spatially specialized mitochondrial networks, coordinates β-oxidation, oxidative phosphorylation, and lipid synthesis under physiological conditions. Chronic nutrient excess and insulin resistance disrupt this zonal organization, particularly in pericentral hepatocytes, leading to oxidative imbalance, defective mitochondrial quality control (MQC), and lipid accumulation. Mitochondrial injury is not confined to hepatocytes. The release of mitochondrial DNA (mtDNA), cardiolipin, and other mitochondrial danger-associated molecular patterns activates Kupffer cells and hepatic stellate cells through TLR9- and cGAS-STING-dependent pathways, thereby amplifying inflammatory and fibrogenic responses. Recent studies indicate that selected natural compounds improve mitochondrial function by enhancing AMPK-SIRT1-PGC-1α-dependent biogenesis, promoting PINK1/Parkin-mediated mitophagy, and attenuating mito-DAMP-driven innate immune activation. This review integrates liver metabolism and mitochondrial stress signaling pathways, elucidates the mechanistic framework of liver-mitochondrial interactions in MASLD, and explores pharmacological strategies targeting organelles to restore liver metabolic homeostasis.
    Keywords:  lipid metabolism; metabolic dysfunction-associated steatotic liver disease; mitochondrial quality control; natural products; oxidative stress
    DOI:  https://doi.org/10.2147/DDDT.S610273
  48. Mol Cell. 2026 May 26. pii: S1097-2765(26)00308-4. [Epub ahead of print]
    Uncovering the initial response: Intra-mitochondrial surveillance activates the UPRmt.
    Asli Aras Taskin, Sahana Shankar, Carlotta Peselj, Annette Flotho, Maria Gomez-Fabra Gala, Daniel Poveda-Huertes, Lisa Myketin, Duygu Mutlu, Adinayarana Marada, Sebastian Schuck, Mandy Jeske, Sabrina Büttner, Marcin Luzarowski, Chris Meisinger, F-Nora Vögtle.
      The mitochondrial unfolded protein response (UPRmt) protects mitochondria from proteotoxic stress. Current models induce acute and severe mitochondrial disruption and propose cytosolic detection following the release of mitochondrial damage signals into the cytosol. However, this mode of toxicity contrasts sharply with physiological stress, such as the gradual accumulation of reactive oxygen species (ROS) during aging or chronic respiratory chain defects. Here, we employ a chemogenetic strategy in yeast to induce low levels of hydrogen peroxide (H2O2) in the mitochondrial matrix and show that mild oxidative stress activates the UPRmt independently of cytosolic damage. We identify the presequence proteases MPP and Oct1 as early ROS targets, thereby linking redox imbalance to UPRmt activation: oxidative stress induces glutathionylation of critical cysteines, impairing protease activity and causing the accumulation of unprocessed precursors in proteotoxic matrix aggregates. These aggregates are detected by intra-mitochondrial surveillance, activating UPRmt signaling. Thus, mitochondrial self-surveillance initiates rapid protective signaling as a primary response to mitochondrial dysfunction.
    Keywords:  mitochondria-nucleus communication; mitochondrial protein biogenesis; mitochondrial unfolded protein response; oxidative stress; presequence processing; reactive oxygen species
    DOI:  https://doi.org/10.1016/j.molcel.2026.05.002
  49. J Mark Access Health Policy. 2026 May 21. pii: 32. [Epub ahead of print]14(2):
    Use of Real-World Evidence in Health Technology Assessments of Non-Oncology Rare Disease Therapies.
    Oliver Blandy, Pierluigi Lembo, Rebecca Folorunso, Karl-Johan Myren, Helene Chevrou-Severac, Simu K Thomas.
      Background: Real-world evidence (RWE) can complement clinical trials to inform health technology assessments (HTAs). This study examined the extent to which RWE is considered in HTAs of non-oncology orphan medicinal products across six agencies globally. Methods: Published European Medicines Agency decisions were reviewed to identify approved non-oncology orphan medicinal products (2018-2023) that included RWE within their submission package, which was anticipated to align with the inclusion of RWE in HTA submissions. Data were extracted from the corresponding HTA reports published by six national agencies (Australia, Canada, France, Germany, Sweden, and the UK). Results: RWE was included in 105 regulatory submissions and 52.6% of the corresponding HTA reports (range: 29.9% [Germany] to 78.8% [Canada]), nearly 90% of which received a positive decision (range: 44.4% [Australia] to 100.0% [Germany]). RWE was derived from a variety of study designs and commonly supported clinical efficacy across many therapeutic areas. Conclusions: RWE commonly supports HTAs of recently approved non-oncology orphan medicinal products, strengthening the evidence base and contributing to demonstration of product value.
    Keywords:  health technology assessment; non-oncology orphan medicinal products; orphan drug; orphan medicine; rare disease; real-world data; real-world evidence
    DOI:  https://doi.org/10.3390/jmahp14020032
  50. Front Immunol. 2026 ;17 1772001
    Regulatory T cell therapy in autoimmune and immune-mediated diseases: from basic research to clinical practice and future perspectives.
    Shihao Duan, Junyan Zhang, Zhongxiu Chen, Yong He, Yingzhi Zhang, Hong Guo.
      Regulatory T cells (Tregs) are pivotal immune modulators essential for maintaining immune homeostasis and preventing aberrant immune responses. In recent years, Treg-based therapies have emerged as a promising strategy for treating a variety of non-malignant diseases, including autoimmune disorders, transplantation-related complications, and allergic conditions. This review provides a comprehensive overview of the discovery and evolution of Tregs, detailing their immunoregulatory mechanisms that underpin their therapeutic potential. We systematically evaluate current clinical applications of Treg therapy in diverse non-tumor pathologies, highlighting both the efficacy and safety outcomes reported in ongoing clinical trials. Additionally, the review addresses the challenges faced in translating Treg therapies from bench to bedside, such as cell stability, expansion methodologies, and functional heterogeneity. Finally, we explore future directions in Treg research, including innovative therapeutic approaches, advances in gene engineering technologies, and improvements in cell expansion techniques, all aimed at enhancing the clinical translation and therapeutic efficacy of Treg-based interventions. This article aims to provide a thorough theoretical foundation and practical guidance to advance the application of Treg therapy in non-malignant diseases.
    Keywords:  CAR-Treg; adoptive cell therapy; autoimmune diseases; immune-mediated diseases; regulatory T cells
    DOI:  https://doi.org/10.3389/fimmu.2026.1772001
  51. Int J Mol Sci. 2026 May 17. pii: 4489. [Epub ahead of print]27(10):
    Special Issue "Research in iPSC-Based Disease Models".
    Eric Deneault.
      Biomedical research has been transformed by the discovery of human induced pluripotent stem cells (iPSCs), providing unlimited access to patient-specific human cell types for disease modeling and mechanistic studies [...].
    DOI:  https://doi.org/10.3390/ijms27104489
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