bims-polgdi Biomed News
on POLG disease
Issue of 2026–06–21
fifty-one papers selected by
Luca Bolliger, lxBio
  1. From Pharmacodynamic Biomarker to Evaluating Treatment Response: Biomarkers in Primary Mitochondrial Diseases.
  2. Mitochondria and brain aging: From cell-specific dysfunction to intercellular cooperation.
  3. Common Principles Underlie Mitochondrial DNA Heteroplasmy Dynamics in the Germline and Soma.
  4. Editorial: Beyond energy production: exploring mitochondrial dynamics and disease.
  5. Enrichment of Rare Mitochondrial DNA Variants Among Individuals With Kidney Disease Reveals Undiagnosed Mitochondrial Disease.
  6. Mitochondrial genome microhomology-mediated editing by donor DNA delivery into mitochondria in human cells.
  7. Activation of AMPK as a therapeutic strategy for FBXL4-related mitochondrial DNA depletion syndrome.
  8. Identifying barriers and policy priorities for rare disease research in underrepresented European countries.
  9. Generation of a patient-derived iPSC line from a clinically diagnosed MELAS case carrying the mtDNA m.3243A > G variant.
  10. Menopause in rare diseases: Shared research concerns and the case for a dedicated subfield.
  11. Co-translational protein targeting to mitochondria in the context of co-translational protein maturation.
  12. Rewiring Mitochondrial Phosphatidylethanolamine Metabolism Identifies New and Unaccounted Trafficking Steps.
  13. Mitochondrial cardiomyopathy: bridging molecular mechanisms and clinical frontiers.
  14. Gene therapy for aging and longevity.
  15. Inferring accumulation times of mitochondrial DNA deletion mutants from cross-sectional single-cell data: methodological framework and validation.
  16. Extracting homogenous data from heterogenous diseases: RaraSwed, the Swedish national rare disease quality registry.
  17. Rare disease monitoring plans: a case study within a clinical decision support system.
  18. Evaluating the Impact of Different Natural History Modeling Methods on Cost-Effectiveness Decisions: A Case Study in Duchenne Muscular Dystrophy.
  19. Mitochondrial DNA in Lung Cancer: from biology to clinical implications.
  20. Targeting lysosomal pH restores mitochondrial quality control in GBA1-mutant Parkinson's disease.
  21. Expertise of European Clinical Trial Units in Conducting and Managing Cross-Border Pediatric Clinical Trials for Rare Diseases.
  22. PTEN modulates mitochondrial dysfunction in podocytes via the PINK1/Parkin signal pathway.
  23. Detection of NADH/NAD+ dysregulation in MELAS via diazo-carboxyl click derivatization mass spectrometry.
  24. Beyond proteostasis: LONP1 as an immunometabolic checkpoint in health and disease.
  25. The evolving landscape of gene editing therapies for human genetic diseases: a twenty-year bibliometric analysis.
  26. Long-term safety and efficacy of deoxycytidine/deoxythymidine in treatment of POLG-related disorders.
  27. Exercise-Induced Extracellular Vesicles as Mediators of Mitochondrial Biogenesis and Insulin Sensitivity in Metabolic Adaptation.
  28. Exploring barriers to clinical trial readiness among the myotonic dystrophy community: a mixed-methods study.
  29. Inheritance patterns of mitochondrial DNA in multi-generational maternal pedigrees: Insights from mitochondrial whole-genome sequencing.
  30. Adeno-Associated Virus Gene Therapy Translation: Lessons from Early Regulatory Meetings.
  31. Limiting neurodegeneration in ALS: A phosphatase paves the way.
  32. Cardiolipin remodelling in mitochondrial therapeutics: translational evidence chains from elamipretide to emerging strategies.
  33. Challenges in Implementing Revocation of Oncology Drugs Under Conditional Early Approval in Japan: Regulatory Insights From Comparisons With FDA/EMA.
  34. The senescence-stiffening loop: Extracellular matrix remodeling, hypoperfusion, and mitochondrial dysfunction drive tissue aging.
  35. Mitochondrial proteases maintain cellular protein homeostasis and tissue integrity.
  36. Tiny Messengers, Big Impact: The Role of Endogenous Extracellular Vesicles in Neurological Diseases.
  37. Clinical Spectrum, Heteroplasmy-Phenotype Correlation, and Prognosis of the MT-ND3 m.10191 T > C Mutation.
  38. Mitochondrial transfer in the tumor microenvironment: a dynamic determinant of cancer plasticity, immune dysfunction, and therapeutic opportunity.
  39. Restoring the interplay between the endoplasmic reticulum and mitochondria by gene therapy improves Charcot-Marie-Tooth type 2A disease.
  40. Case Study on the Use of Real-World Evidence in a Feasibility Assessment of a Randomized Controlled Trial Design to Support the Fulfillment of Pediatric Requirements with the FDA and EMA.
  41. From autophagy to mitophagy: Quality control mechanisms in skeletal muscle.
  42. From complexity to approval in the European Union: Regulatory pathways and data challenges in the evaluation of non-oncology orphan medicines.
  43. Impact of different exercise modalities on mitophagy in human skeletal muscle.
  44. Post-translational modifications of mitochondrion-related proteins: integrative orchestrators of cell fate networks in cardiovascular disease.
  45. An aminoacyl-tRNA synthetase governs dsRNA-mediated trade-off between longevity and innate immunity.
  46. Elevated mitochondrial protein import in acute myeloid leukemia increases reliance on mitochondrial protease LONP1.
  47. Basket and umbrella trials in pediatric precision medicine: a systematic review of designs, opportunities, and challenges.
  48. Pharmacoeconomics of high-cost therapies: real world challenges.
  49. The Open Syndrome Definition as a Machine-Readable Standard for Public Health: Design and Implementation Study.
  50. Mitochondria at the crossroad: Mechanisms of nanoplastic-induced neurotoxicity and brain accumulation.
  51. Most-Favored-Nation pricing meets Joint Clinical Assessment: early evidence of compounding pressure on European drug launches.
  1. Clin Transl Sci. 2026 Jun;19(6): e70634
    From Pharmacodynamic Biomarker to Evaluating Treatment Response: Biomarkers in Primary Mitochondrial Diseases.
    Sydney Stern, Karryn Crisamore, John Patton, Robert Schuck, Michael Pacanowski.
      Primary mitochondrial diseases (PMDs) result from genetic variants in nuclear DNA and mitochondrial DNA which commonly lead to aberrant oxidative phosphorylation. The clinical complexity, often attributed to the underlying genetics, includes several distinct syndromes (e.g., Barth syndrome; Pearson syndrome; Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes), some with overlapping symptoms. PMDs are highly heterogenous and affect multiple organs and tissues, prominently those with high energy demand such as muscle and neurologic tissues. Disease-modifying therapies for PMDs approved by the United States Food and Drug Administration are few and disease-specific, and treatment remains largely supportive in nature. The lack of robust biomarkers contributes to challenges associated with quantifying treatment responses in drug development. Recognizing this area of critical need, we sought to understand the landscape of molecular biomarkers that may inform treatment response, support clinical trials, and may be useful for regulatory decision-making. In this review, we assess the extent of evidence and challenges for each biomarker. We propose considerations for future biomarker development to measure treatment response and facilitate early drug development in PMDs by guiding dose selection and trial enrichment.
    DOI:  https://doi.org/10.1111/cts.70634
  2. Neuron. 2026 Jun 16. pii: S0896-6273(26)00371-5. [Epub ahead of print]
    Mitochondria and brain aging: From cell-specific dysfunction to intercellular cooperation.
    Amandine Grimm, Undine Lang, Anne Eckert.
      Mitochondria are essential for brain energy metabolism and are increasingly recognized as key contributors to brain aging. Although neurons are exceptionally vulnerable to age-related mitochondrial decline, emerging evidence reveals that glial and vascular cells also exhibit distinct mitochondrial impairments. This review synthesizes recent advances in our understanding of mitochondrial dysfunction across specific brain regions and diverse cell types, highlighting subcellular compartmentalization and metabolic rewiring. We further explore intercellular mitochondrial transfer as a novel form of metabolic cooperation, as well as the therapeutic potential of mitochondrial transplantation. Finally, we highlight recent clinical trials evaluating mitochondria-targeted interventions aimed at preserving brain function in older adults. Together, these findings reposition mitochondria as both integrators and amplifiers of brain aging processes across diverse cell populations. By broadening the focus beyond neurons and emphasizing translational efforts, we offer a comprehensive framework for understanding and therapeutically targeting mitochondrial dysfunction in age-related cognitive decline and neurodegeneration.
    Keywords:  aging; astrocytes; blood-brain barrier; brain; intercellular mitochondrial transfer; microglia; mitochondria; mitochondrial transplantation; neurons; oligodendrocytes
    DOI:  https://doi.org/10.1016/j.neuron.2026.04.048
  3. Annu Rev Genomics Hum Genet. 2026 Jun 15.
    Common Principles Underlie Mitochondrial DNA Heteroplasmy Dynamics in the Germline and Soma.
    Cameron Ryall, Patrick F Chinnery, Jelle van den Ameele.
      Heteroplasmy is the mixture of mutant and wild-type mitochondrial DNA (mtDNA) within each of our cells. Heteroplasmy levels in cells, tissues, and organisms change over time, thus contributing to mitochondrial disease, aging, and evolution. Germline and pedigree studies first revealed heteroplasmy shifts between generations and have long offered a window into the dynamics of mtDNA inheritance through single oocytes. Single-cell technologies are now uncovering similar mechanisms that operate in somatic tissues throughout life. Stochastic processes (relaxed replication and vegetative segregation, enhanced through genetic bottlenecks) generate cell-to-cell variation, while selection mechanisms such as intercellular competition, mitophagy, and preferential replication allow or drive directional shifts. Single-cell sequencing, mtDNA imaging, and genetic screening, combined with mtDNA-editing technology and heteroplasmic model systems, have transformed our ability to dissect these processes, revealing heteroplasmy dynamics at molecular resolution. These approaches are uncovering quantifiable principles governing heteroplasmy across cell types and life stages, transforming our understanding from descriptive observations to predictive mechanistic models and novel therapeutic avenues.
    DOI:  https://doi.org/10.1146/annurev-genom-120324-032239
  4. Front Cell Dev Biol. 2026 ;14 1872916
    Editorial: Beyond energy production: exploring mitochondrial dynamics and disease.
    Nahid A Khan, Ruben Torregrosa-Muñumer.
      
    Keywords:  cell fate regulation; metabolic signaling; mitochondria; mitochondrial disease; mitochondrial dynamics; mitochondrial quality control; mitochondrial therapy; redox metabolism
    DOI:  https://doi.org/10.3389/fcell.2026.1872916
  5. Kidney Int Rep. 2026 Jul;11(7): 106578
    Enrichment of Rare Mitochondrial DNA Variants Among Individuals With Kidney Disease Reveals Undiagnosed Mitochondrial Disease.
    Daniel R Schecter, Rory J Tinker, Patrick O'Connell, Jiuhong Pang, Simon SzeKing Lee, Meltem Ece Kars, Aysegul Guvenek, Michael Preuss, Yuval Itan, Eva Morava, Tamas Kozicz, Michio Hirano, Ali Naini, Jaya Ganesh.
       Introduction: Pathogenic mitochondrial DNA (mtDNA) variants cause multisystem disease, yet their contribution to kidney disease remains incompletely characterized, partly because of exclusion of the mitochondrial genome from genetic studies.
    Methods: We evaluated mtDNA variation in 27,747 participants from the Mount Sinai Million Health Discoveries Program (MSM), an ancestrally diverse biobank with whole-exome sequencing and linked electronic health records (EHR). mtDNA variants were identified using MitoVerse and classified with MITOMAP. Kidney disease was defined using renal PheCodes for glomerular disease (GU_580) and renal failure (GU_582). Previous mitochondrial diagnoses were ascertained from EHR to identify undiagnosed individuals. Associations were adjusted for age, self-reported gender, and ancestry, with genotype-phenotype review.
    Results: Among 3935 individuals with kidney disease, 45 carried clinically associated mtDNA variants, 42 of whom had no previous clinical mitochondrial diagnosis. mtDNA variants were enriched among individuals with kidney disease and associated with increased odds of renal involvement (odds ratio [OR] = 1.72). Associations were strongest for chronic kidney disease (CKD; GU_582.2; OR = 1.55) and renal failure (GU_582; OR = 1.53). Among undiagnosed carriers, genotype-phenotype review identified concordant manifestations in 14%, including mitochondrial CKD with hyperuricemia. Variant-level analysis identified enrichment of m.1630A>G in MT-TV (OR = 5.56), with additional variants showing trends. Both renal- and nonrenal-associated pathogenic mtDNA variants were observed.
    Conclusion: Pathogenic mtDNA variants are overrepresented among individuals with kidney disease, often without a known mitochondrial diagnosis. These findings support a contributory role for mtDNA in renal disease and highlight the value of mtDNA analysis into kidney disease research and clinical evaluation, particularly for identifying unrecognized mitochondrial disease with renal involvement.
    Keywords:  mitochondrial DNA; mitochondrial disease; population biobank; precision medicine; variant-level association
    DOI:  https://doi.org/10.1016/j.ekir.2026.106578
  6. Mol Ther Nucleic Acids. 2026 Jun 16. 37(2): 102959
    Mitochondrial genome microhomology-mediated editing by donor DNA delivery into mitochondria in human cells.
    Vadim V Maximov, Nikita Shebanov, Natalia Nikitchina, Rachel Rapoport, Yehoshua Maor, Ivan Tarassov, Ophry Pines, Nina Entelis.
      Mutations in mitochondrial DNA (mtDNA) are associated with severe human diseases, lacking efficient therapies. Direct correction of mtDNA mutations may offer a cure for such diseases. We propose a novel strategy based on double-stranded DNA (dsDNA) oligonucleotide delivery into mitochondria and intrinsic microhomology-mediated end joining (MMEJ) for mtDNA editing. This strategy enables the introduction of multiple predefined nucleotide changes in mtDNA. For this, the presence of MMEJ activity in the human mitochondrial lysates was confirmed. Forty-nine bp DNA oligonucleotide duplexes, fused to an RNA hairpin previously identified as a mitochondrial import signal, were delivered into the mitochondria of cultured human cells. Delivery of these donor dsDNA molecules, homologous to an ND4 site of mtDNA and bearing designed nucleotide changes, led to a low but statistically significant introduction of the intended nucleotide changes into mtDNA. Donor dsDNA delivery combined with the CRISPR-mito-AsCas12a system also resulted in a statistically significant number of an expected concomitant change of five nucleotides distributed across a 16 nt ND4 site of the mitochondrial genome. The proposed strategy may become an efficient mtDNA editing tool suitable for the correction of near-homoplasmic mutations, such as Leber's hereditary optic neuropathy (LHON)-associated mutations in the ND4 gene of mtDNA.
    Video Abstract:
    Keywords:  MT: oligonucleotides: therapies and applications; microhomology-mediated mtDNA editing; mitochondria; mitochondrial CRISPR; mitochondrial DNA delivery; mitochondrial genome editing
    DOI:  https://doi.org/10.1016/j.omtn.2026.102959
  7. EMBO Mol Med. 2026 Jun 17.
    Activation of AMPK as a therapeutic strategy for FBXL4-related mitochondrial DNA depletion syndrome.
    Aniketh Bishnu, Juan Zapata-Muñoz, Robert W Taylor, Kei Sakamoto, Ian G Ganley.
      Distinct mitophagy pathways can eliminate not only damaged mitochondria but also healthy ones. In Mitochondrial DNA Depletion Syndrome 13 (MTDPS13), dysregulated BNIP3/NIX-driven mitophagy of functional mitochondria is thought to be the key pathological driver. Patient mutations in the E3 ubiquitin ligase FBXL4 impair the proteasomal degradation of the mitophagy receptors BNIP3 and NIX, causing their accumulation and excessive mitophagy. As a result, mitochondrial content and oxidative phosphorylation decline sharply across multiple tissues, leading to early mortality, with no effective treatments currently existing. Here, we build on our work showing that AMPK can inhibit mitophagy via sequestration of the ULK1 autophagy-initiating kinase ULK1 and demonstrate that it is also critically relevant for mitophagy induced by FBXL4 disruption. Using FBXL4-deficient cells, as well as fibroblasts derived from MTDPS13 patients and a chemically-induced mouse model, we show that small molecule AMPK activation inhibits BNIP3/NIX-mediated mitophagy and recovers functional mitochondrial content. This work therefore validates AMPK as a realistic target in treating MTDPS13.
    DOI:  https://doi.org/10.1038/s44321-026-00471-z
  8. Eur J Public Health. 2026 Jun 10. pii: ckag103. [Epub ahead of print]36(4):
    Identifying barriers and policy priorities for rare disease research in underrepresented European countries.
    ERDERA UC Stakeholder Panel
      The European Joint Programme on Rare Diseases successfully advanced rare disease research and also revealed challenges for underrepresented countries, those less frequently holding or leading grants. This study aimed to survey Rare Disease researchers in these countries, identify barriers to participation in research, and propose solutions. A modified Delphi approach without formal consensus thresholds of 186 respondents highlighted fragmented or outdated policies and heterogeneous funding. Nearly all participants prioritized the need for EU-wide policies defining minimum quality standards for Rare Disease care. Key priorities include access to genetic testing and essential services to support uniform care and shared research capacity.
    DOI:  https://doi.org/10.1093/eurpub/ckag103
  9. Stem Cell Res. 2026 Jun 18. pii: S1873-5061(26)00134-0. [Epub ahead of print]95 104038
    Generation of a patient-derived iPSC line from a clinically diagnosed MELAS case carrying the mtDNA m.3243A > G variant.
    Gautam Sharma, Abhay Srivastava, Cheryl Rockman-Greenberg, Sanjiv Dhingra.
      MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes) represents a multisystemic mitochondrial disease mainly triggered by heteroplasmic m.3243A > G mutation in mtDNA MT-TL1, the gene for tRNA^Leu(UUR). Here we report the successful reprogramming of peripheral blood mononuclear cells (PBMCs) from a female MELAS patient into induced pluripotent stem cells (iPSCs). This patient-specific iPSC line provides a valuable platform to investigate MELAS pathophysiology and screen therapeutic interventions targeting mitochondrial dysfunction in a genetically relevant context.
    DOI:  https://doi.org/10.1016/j.scr.2026.104038
  10. Maturitas. 2026 Jun 04. pii: S0378-5122(26)00188-X. [Epub ahead of print]211 109011
    Menopause in rare diseases: Shared research concerns and the case for a dedicated subfield.
    Sandy Sufian.
      Scientific knowledge about menopause in females with rare diseases remains scarce, despite emerging evidence that symptoms of rare diseases and the menopausal transition may interact in clinically significant ways. This narrative review synthesizes the literature on menopause across eight rare diseases: Ehlers-Danlos syndrome (EDS), cystic fibrosis (CF), Huntington's disease (HD), lymphangioleiomyomatosis (LAM), myasthenia gravis (MG), systemic scleroderma (SSc), sickle cell disease (SCD), and Turner syndrome (TS), to identify shared research priorities and propose a coordinated agenda for future investigation. Eight cross-cutting themes emerge: (1) hormonal modulation of disease pathophysiology; (2) sex disparities in populations with rare diseases; (3) earlier onset of menopause; (4) overlapping disease and menopausal symptoms that complicate diagnosis and care; (5) disease-specific symptom profiles and menopause outcomes; (6) menopause hormone therapy; (7) quality-of-life issues; and (8) unmet educational needs among rare-disease specialists and gynecologists. Based on these converging themes, we propose establishing a dedicated subfield within menopause research focused on populations with rare diseases. Such a subfield would enable cross-disease comparative inquiry, promote methodological innovation compatible with small populations, support the development of disease-specific clinical guidelines and a registry that proposes hormonal therapy risks and safe options, and advance provider training at the intersection of rare disease and women's health.
    Keywords:  Hormone therapy; Menopausal transition; Menopause; Rare disease; Specialized research
    DOI:  https://doi.org/10.1016/j.maturitas.2026.109011
  11. Protein Sci. 2026 Jul;35(7): e70682
    Co-translational protein targeting to mitochondria in the context of co-translational protein maturation.
    Nikita A Kvasov, Yury S Bykov.
      Mitochondria import the majority of their proteins from the cytosol, creating a fundamental challenge: precursor proteins must be synthesized, maintained in an import-competent state, and delivered to mitochondrial translocases without premature folding or aggregation. While mitochondrial protein import has been considered a post-translational process, growing evidence shows that a subset of mitochondrial proteins is synthesized in proximity to the organelle. We term this process co-translational targeting, or local translation. It may lead to direct structural coupling of protein synthesis and import, which we term co-translational translocation. New approaches, including selective ribosome profiling, proximity labeling, and RNA imaging, reveal that mitochondrial mRNA localization is highly dynamic and can be driven by both RNA-based and translation-dependent mechanisms. In contrast to the well-defined signal recognition particle pathway at the endoplasmic reticulum, mitochondrial targeting appears to rely on more flexible mechanisms shaped by nascent-chain properties, translation elongation, and coding-sequence features beyond the targeting signal. We discuss how these processes may support mitochondrial biogenesis and proteostasis while also creating vulnerabilities associated with ribosome stalling and precursor quality control. Together, recent findings position mitochondrial protein targeting as an integral part of cellular protein biogenesis and highlight key open questions in the coordination of translation and organelle function.
    Keywords:  NAC; chaperones; co‐translational import; mRNA localization; mitochondria; protein targeting; translation
    DOI:  https://doi.org/10.1002/pro.70682
  12. J Lipid Res. 2026 Jun 19. pii: S0022-2275(26)00109-4. [Epub ahead of print] 101083
    Rewiring Mitochondrial Phosphatidylethanolamine Metabolism Identifies New and Unaccounted Trafficking Steps.
    Rashima Prem, Erica Avery, Juliana M Marquez, Chi Xie, Steven M Claypool.
      The distinct compositions of the two mitochondrial membranes are generated through a combination of phospholipids that mitochondria can make and those they take; both processes depend on a series of distinct lipid trafficking steps. Mitochondria make phosphatidylethanolamine (PE) through the action of the phosphatidylserine decarboxylase Psd1, an intermembrane space (IMS)-facing integral inner membrane (IM) protein. Psd1 has been proposed to act on its endoplasmic reticulum-derived substrate, phosphatidylserine (PS), after its transport to the mitochondrial outer membrane (OM) and either following its Ups2/Mdm35-mediated transport across the IMS to the IM or instead, on the IMS-side of the OM in a process enabled by the mitochondrial contact site and cristae organizing system (MICOS). Here, we implement a two-pronged Psd1 rewiring-based strategy predicted to either 1) circumvent the need for Ups2/Mdm35 and/or MICOS; or 2) selectively ablate the ability of Psd1 to work in trans. Our results with yeast harboring Psd1 targeted to the OM demonstrate that, with respect to mitochondrial PE production, Ups2/Mdm35 and MICOS indeed function within the IMS. Using yeast expressing a topologically inverted Psd1 chimera that faces the matrix, we identify previously unappreciated transbilayer lipid trafficking steps within the IM and show that Psd1 does not operate via a MICOS-organized in trans mechanism. Further, retained flux through inverted Psd1 when both Ups2/Mdm35 and MICOS are absent strongly implicates the existence of a major, yet presently unknown, mediator(s) of lipid movement across the IMS. Collectively, these data suggest a new model of how mitochondrial membrane diversity is established and maintained.
    Keywords:  Glycerophospholipids; membrane diversity; metabolic rewiring; mitochondria; phospholipids; phospholipids/biosynthesis; phospholipids/metabolism; phospholipids/trafficking
    DOI:  https://doi.org/10.1016/j.jlr.2026.101083
  13. Nat Rev Cardiol. 2026 Jun 18.
    Mitochondrial cardiomyopathy: bridging molecular mechanisms and clinical frontiers.
    Atsuko Imai-Okazaki, Liming Pei, Douglas C Wallace.
      Genetic cardiomyopathies caused by pathogenic variants in nuclear DNA (nDNA) that encodes contractile sarcomere proteins are among the best understood of all the cardiomyopathies. By contrast, mitochondrial cardiomyopathy is caused by a dysfunction in mitochondrial oxidative phosphorylation due to pathogenic variants in either nDNA or the maternal mitochondrial DNA (mtDNA). Unlike contractile protein defects, which generally follow predictable Mendelian inheritance patterns, mitochondrial cardiomyopathy is genetically complex as a result of the distinctive characteristics of the mitochondrial genome, which influence patterns of maternal inheritance, heteroplasmy and tissue-specific variations in mtDNA variant load. Both single-gene nDNA and mtDNA variants can impair cardiac energetics, resulting in a wide clinical spectrum ranging from severe, childhood-onset to milder, adult-onset cardiomyopathy. Furthermore, the intricate metabolic demands of the heart mean that mitochondrial dysfunction can be influenced by a broad array of genetic and environmental modifiers. A greater recognition of these complexities and the integration of genomic sequencing, novel biomarkers and functional imaging have advanced diagnostic and therapeutic approaches. Emerging treatment strategies, such as metabolic supplementation, gene therapy and genome editing, are under investigation. In this Review, we synthesize the molecular and clinical landscape of mitochondrial cardiomyopathy, highlighting the ongoing challenges and prospects of precision medicine in this rapidly evolving field.
    DOI:  https://doi.org/10.1038/s41569-026-01301-y
  14. Trends Mol Med. 2026 Jun 17. pii: S1471-4914(26)00116-4. [Epub ahead of print]
    Gene therapy for aging and longevity.
    Stacia P A Everts, Michael Florea, João Pedro de Magalhães.
      Aging affects virtually all organs and biological processes, and age-related diseases remain the leading causes of death worldwide. Genetic factors play a central role in modulating lifespan, and discoveries in the genetic manipulation of the aging process in animal models have transformed our perception of aging. However, translating these findings into clinical therapies remains challenging. Recent breakthroughs demonstrate that gene therapies can directly target aging mechanisms. Single-gene therapies have ameliorated multiple age-related pathologies, such as pediatric Parkinson disease. In this review, we discuss recent advances and prospects for developing gene therapies for aging and age-related diseases, highlighting potential targets, delivery strategies, cellular rejuvenation, and lessons from long-lived species. Despite remaining challenges, longevity gene therapy offers a promising avenue to reprogram aging and delay age-related decline.
    Keywords:  AAV; geroscience; healthspan; lifespan; rejuvenation
    DOI:  https://doi.org/10.1016/j.molmed.2026.05.007
  15. NPJ Aging. 2026 Jun 16. pii: 83. [Epub ahead of print]12(1):
    Inferring accumulation times of mitochondrial DNA deletion mutants from cross-sectional single-cell data: methodological framework and validation.
    Axel Kowald, Thomas B L Kirkwood.
      The accumulation of mitochondrial DNA (mtDNA) deletion mutants in post-mitotic cells is a hallmark of mammalian ageing and a key contributor to tissue decline in skeletal muscle and neurons. A transcription-coupled replication model predicts that deletions affecting a negative feedback mechanism gain a selective replication advantage, leading to relatively short accumulation times for mutant takeover. However, these accumulation times are experimentally inaccessible since single-cell measurements are destructive. Here, we present a framework to infer such accumulation times from cross-sectional single-cell RNA sequencing (scRNAseq) data, exploiting the fact that mtDNA deletions are also reflected at the transcript level. To establish feasibility, we generated synthetic datasets using two stochastic models of the mitochondrial life cycle and used these as a gold standard. We then applied the Moran process, a stochastic birth-death model, to calculate distributions of accumulation times and to extract key parameters. The Moran model reproduced the distributions obtained from stochastic simulations with high fidelity across different assumptions about mitochondrial regulation. Fitting the model to synthetic data, successfully recovered mutation probability, selection advantage, and the fraction of advantageous mutants. These results establish a methodological framework for quantifying mtDNA mutant dynamics from single-cell transcriptomic data and provide a foundation for analysing large experimental datasets in ageing research.
    DOI:  https://doi.org/10.1038/s41514-026-00431-4
  16. BMC Glob Public Health. 2026 Jun 16. pii: 58. [Epub ahead of print]4(1):
    Extracting homogenous data from heterogenous diseases: RaraSwed, the Swedish national rare disease quality registry.
    Sanna Mansoob, Dan Hellström, Magnus Burstedt, Malin Grände, Cecilia Gunnarsson, Stephanie Juran, Lovisa Lovmar, Katarina Sandgren, Maria Johansson Soller, Anna Wedell, Cecilia Soussi Zander, Alexandra Wennberg, Marie Stenmark Askmalm.
      In the Swedish universal healthcare system, persons living with rare diseases (PLWRD) face major challenges in receiving diagnosis and accessing care,stemming in part from heterogeneity of disease and systemic barriers to care. This contributes to health inequity and a lack of visibility for PLWRD within thehealth system. This Perspective paper provides an overview of the facilitators and challenges during the development and implementation of a national raredisease (RD) quality registry, RaraSwed. The registry collects data on RD diagnosis. Adopting a social innovation and systems thinking methodology, inaddition to governance, have proven beneficial. RaraSwed supports RD research, evidence-based RD care, and Sweden's National Quality Policy and Strategy(NQPS) for RD. Future modules on patient-reported and physician-reported data on care coordination, treatment and clinical attributes will capture the holisticpatient experience. RaraSwed may contribute to health equity for PLWRD in Sweden and in turn facilitate international RD data harmonisation.
    Keywords:  Health equity; Health policy; Rare diseases; Registries; Sweden; Universal health care
    DOI:  https://doi.org/10.1186/s44263-026-00276-9
  17. Comput Biol Med. 2026 Jun 18. pii: S0010-4825(26)00378-1. [Epub ahead of print]213 111814
    Rare disease monitoring plans: a case study within a clinical decision support system.
    Letícia Nunes Campos, Rashid Benítez Yazbek, Israel Dávila Rivera, Ivo Valentin Rudzinski, Gabriela Oriana Pintos, Santino Curto, Santiago Miguel Maximowicz, Ayla Gerk, Federico Fernandez Zelcer, Carlos Stegmann, Carina Francisca Argüelles, Jorgelina Stegmann.
       INTRODUCTION: Clinical decision support systems (CDSS) have emerged as valuable tools for enhancing healthcare for rare diseases. Nonetheless, most tools focus on diagnosis, while few support patient monitoring. We aim to report the methods to develop an evidence-based CDSS for monitoring rare diseases, using Bardet-Biedl Syndrome (BBS) as a case study.
    METHODS: We assembled a multidisciplinary team of over 40 healthcare providers from 11 specialities to develop rare disease monitoring plans. We conducted a scoping review to map the existing literature on BBS monitoring, followed by the systematic development of a plan framework with four sections: a tailored medical record with clinical manifestations, a multidisciplinary appointment schedule, a questionnaire tracker, and a complementary exam tracker. We extracted data from articles, books, guidelines, and point-of-care resources.
    RESULTS: We included 128 references in the analysis. Common study designs included case reports (37.5%), case series (19.5%), and cohort studies (16.4%). We documented 108 clinical manifestations of BBS across ten body systems. The multidisciplinary appointment schedule identified 24 healthcare professionals essential for BBS follow-up, and primary consultations were recommended with 13 specialities. We identified 28 scales and questionnaires, 8 sets of laboratory analyses, 7 electrophysiological studies, and 6 imaging studies for patient follow-up.
    CONCLUSION: Our CDSS provides a structured, evidence-based approach to monitoring BBS and improving patient outcomes. This model can be adapted for other rare diseases, promoting comprehensive and multidisciplinary patient care.
    Keywords:  Case management; Comprehensive health care; Follow-up studies; Patient care team; Rare diseases
    DOI:  https://doi.org/10.1016/j.compbiomed.2026.111814
  18. MDM Policy Pract. 2026 Jan-Jun;11(1):11(1): 23814683261447231
    Evaluating the Impact of Different Natural History Modeling Methods on Cost-Effectiveness Decisions: A Case Study in Duchenne Muscular Dystrophy.
    Jonathan Broomfield, Keith R Abrams, Michael J Crowther, Michela Guglieri, Nicholas R Latimer, Mark J Rutherford.
      Introduction. Cost-effectiveness analyses are vital in guiding decisions on treatment reimbursement. Natural history models are central to these, enabling the estimation of long-term costs and quality-adjusted life-years (QALYs) in the absence of lifetime trial data. Rare disease data are often scarce, resulting in disease progression being estimated through clinical assumptions. This study aims to evaluate how different modeling approaches influence cost-effectiveness estimates in rare disease health technology assessments (HTAs), using Duchenne muscular dystrophy (DMD) as a case study. Methods. A published economic model was used to compare 2 approaches for estimating disease progression: an assumption-based method relying on clinical plausibility and data-driven methods using data from 1,005 patients with DMD across 8 studies. Transition probabilities were estimated assuming increasing flexibility of study heterogeneity and compared with a simulated treatment cohort. Models were evaluated by comparing incremental cost-effectiveness ratios (ICERs) across approaches. No gold standard exists, so the plausibility of predictions was evaluated by comparing survival and disease progression estimates to published milestones. Results. Results showed that although the assumption-based model was clinically plausible, it predicted higher QALY gains (0.77) and lower ICERs (£1.96M per QALY) than data-driven methods did, which estimated QALY gains of 0.25, 0.26, 0.27, and 0.28 and ICERs of £6.2M, £6.2M, £5.8M, and £5.7M per QALY for the least to most flexible models, respectively. Limitations. No covariate effects or updated cost and utility data were incorporated, as the study purpose was a methodological comparison between approaches. Analyses were deterministic not probabilistic. Conclusions and Implications. This study emphasizes the critical role of model selection for HTA in rare diseases, showing that cost-effectiveness estimates from robust data-driven approaches can differ from clinically plausible assumption-based models.
    Highlights: The choice of a natural history modeling method can drastically alter the cost-effectiveness results in rare disease evaluations.A case study in Duchenne muscular dystrophy demonstrates how different modeling approaches yield divergent cost-effectiveness outcomes.Assumption-based models, even when clinically plausible, may underestimate measures of cost-effectiveness and result in less reliable guidance for decision makers.Data-driven models using real-world patient data provide more reliable estimates for health technology assessment (HTA).This study offers practical guidance for analysts and HTA bodies on selecting robust modeling approaches in rare disease contexts.
    Keywords:  Duchenne muscular dystrophy; economic evaluation; rare diseases
    DOI:  https://doi.org/10.1177/23814683261447231
  19. Crit Rev Oncol Hematol. 2026 Jun 18. pii: S1040-8428(26)00318-5. [Epub ahead of print] 105431
    Mitochondrial DNA in Lung Cancer: from biology to clinical implications.
    José Lucio-Lozada, Diddier Prada, Luiza Beato-González, Fred R Hirsch, Andres F Cardona, Norma Hernández-Pedro, Oscar Arrieta.
      Mitochondrial DNA (mtDNA) is emerging as a relevant component of the molecular landscape in non-small cell lung cancer (NSCLC). Due to its inherent vulnerability to environmental carcinogens, the mitochondrial genome accumulates alterations-such as D-loop variants and Electron Transport Chain variants- increasingly identified as potential mediators of tumor development and metabolic shifts. Recent findings highlight specific areas with potential for clinical application. In diagnostics, emerging models based on cf-mtDNA fragmentomics and tRNA-derived fragments have shown promising capabilities for early-stage detection. Prognostically, somatic variants in Complex I and specific mitochondrial lncRNA signatures have been evaluated as independent indicators of overall survival and metastatic risk. Furthermore, in regard to therapeutics, mitochondrial mass may potentially support chemotherapy election. Additionally, landmark evidence regarding the horizontal transfer of mitochondria to tumor-infiltrating lymphocytes offers a novel framework for understanding resistance to immunotherapy. While these preliminary results provide a promising roadmap for molecular stratification, their integration into routine practice remains a goal that requires further prospective validation in larger, multi-ethnic cohorts to ensure reproducibility and to distinguish functional drivers from passenger variants. Collectively, these emerging findings suggest that mtDNA analysis represents a valuable complementary approach to precision oncology in lung cancer.
    Keywords:  Mitochondrial DNA; biomarkers; mtDNA copy number; mtDNA variants; non-small cell lung cancer
    DOI:  https://doi.org/10.1016/j.critrevonc.2026.105431
  20. Transl Neurodegener. 2026 Jun 17. pii: 27. [Epub ahead of print]15(1):
    Targeting lysosomal pH restores mitochondrial quality control in GBA1-mutant Parkinson's disease.
    Preethi Sheshadri, Maria Alicia Costa-Besada, Alessia Fisher, Szilvia Kiraly, Kritarth Singh, Ioanna Kourouzidou, Thomas S Blacker, Jialiu Zeng, Orian S Shirihai, Mark W Grinstaff, Michael R Duchen.
       BACKGROUND: Heterozygous mutations in the glucocerebrosidase gene (GBA1), which encodes the lysosomal enzyme β-glucocerebrosidase (GCase), are a genetic risk factor for Parkinson's disease (PD). The pathophysiological consequences of GBA1 mutations on dopaminergic neuronal function, especially their impact on lysosomal function, mitophagy, and mitochondrial bioenergetics, remain unclear.
    METHODS: Fibroblasts and dopaminergic neurons generated from induced pluripotent stem cells (iPSCs) derived from patients with GBA1-PD were used in the study. Live-cell imaging was performed to measure lysosomal acidification, protease activity, mitochondrial membrane potential, and mitophagy. Mitochondrial morphology and autophagic vesicles were examined using transmission electron microscopy. Oxygen consumption rate was measured by Seahorse assay. V-ATPase assembly was quantified using fluorescence lifetime imaging with Förster resonance energy transfer (FLIM-FRET), and pharmacological interventions included rapamycin and acidic nanoparticles.
    RESULTS: GCase activity, lysosomal acidification, protease activity, mitophagy and mitochondrial bioenergetic function were all impaired in GBA1 mutant dopaminergic neurons. Mitochondria were fragmented, with reduced membrane potential and oxygen consumption. Mechanistic target of rapamycin complex 1 (MTORC1) was constitutively phosphorylated and FLIM-FRET measurements confirmed impairment of lysosomal V-ATPase assembly, which was reversed by rapamycin treatment. Rapamycin and lysosome-targeting acidic nanoparticles rescued lysosomal pH and restored mitophagy, mitochondrial membrane potential and mitochondrial oxidative phosphorylation complex level in the GBA1 mutant dopaminergic neurons.
    CONCLUSIONS: We revealed a novel mechanistic link between GBA1 mutations and mitochondrial dysfunction, as the disruption of V-ATPase assembly driven by MTORC1 activation impairs lysosomal acidification. This causes impairment of mitophagy, leading to mitochondrial dysfunction, undermining dopaminergic cell function and fate. Pharmacological intervention with rapamycin or acidic nanoparticles restores lysosomal pH and rescue mitochondrial function, representing a novel therapeutic approach for GBA1-PD .
    Keywords:  Acidic nanoparticles; GBA1; Lysosomal pH; Lysosomes; MTORC1; Mitochondria; Parkinson’s disease
    DOI:  https://doi.org/10.1186/s40035-026-00559-z
  21. Ther Innov Regul Sci. 2026 Jun 18.
    Expertise of European Clinical Trial Units in Conducting and Managing Cross-Border Pediatric Clinical Trials for Rare Diseases.
    Begonya Nafria, Segolene Gaillard, Martine Dehlinger-Kremer, Pamela Dicks, Ricardo M Fernandes, Pirkko Lepola, Gunter F Egger, Lucy Bray, Barbara E Bierer, Bob Phillips.
       INTRODUCTION: Conducting pediatric clinical trials across borders in Europe presents unique challenges, especially when studies target rare conditions, require specialized expertise at participating sites, and demand active family involvement in the research process. Including international patients in clinical trials is essential for both scientific development and equity in healthcare, but it requires adapting study protocols, informed consent processes, and patient-reported outcome measures (PROMs) to ensure trial feasibility in diverse linguistic and cultural contexts. The current regulatory and legislative frameworks offer limited solutions to address the language barriers and logistical complexities that still limit cross-border access to clinical trials. The aim of this study was to investigate the experience, expertise, and practices of managing international participants in the pediatric clinical trials conducted by clinical trial units (CTUs) in 17 European countries.
    METHODS: To assess experiences with cross-border pediatric clinical trials for rare diseases across multiple domains, three online surveys were developed and disseminated to Clinical Trial Units (CTUs) within healthcare organizations across Europe. The first survey captured information on general expertise, the second focused on reported good practices in trials involving international patients, and the third aimed to identify documented cases of discrimination, particularly those related to native language requirements. All surveys were reviewed by an expert advisory board and distributed through multiple European research networks and other channels. Data were analyzed using descriptive statistics and thematic analysis.
    RESULTS: A total of 43 CTUs from 17 European countries participated in this study, representing a mix of children's hospitals, general hospitals, and university hospitals. International patients who travelled to the 43 CTUs to participate in clinical trials came from 81 different European and non-European countries, mostly from Morocco, Ukraine, Ecuador, and Venezuela. Among the reported good practices supporting cross-border access (N = 113), the most common involved providing written and verbal translations of informed consent documents, patient-reported outcome measures (PROMs), and quality of life (QoL) scales when these were not available in patients' native languages. Twenty cases of discrimination were reported, primarily due to language requirements included in eligibility criteria, which negatively affected trial access for non-native speakers. Most of these cases occurred in industry-sponsored trials for rare diseases (65%, n = 13), which imposed significant logistical burdens, including frequent visits and overnight stays at the hospitals conducting the trial.
    CONCLUSIONS: While some progress has been made in enabling cross-border access to pediatric clinical trials in Europe, substantial barriers remain, particularly regarding native language diversity and support services for international patients and their families. Systemic changes are needed, including routine translations of study materials, professional interpretation, adaptation of PROMs, and the establishment of dedicated support structures. Collaboration across Europe will be necessary to harmonize language requirements when scientifically justified in the eligibility criteria, promote decentralized trial models, and ensure equitable access to clinical trials for all children, regardless of native language or nationality.
    Keywords:  Clinical trial units; Cross-border clinical trials; Informed consent process; Language accommodation; PROMs; Pediatric; Quality of life scales; Rare diseases
    DOI:  https://doi.org/10.1007/s43441-026-00997-x
  22. Transl Pediatr. 2026 May 31. 15(5): 180
    PTEN modulates mitochondrial dysfunction in podocytes via the PINK1/Parkin signal pathway.
    Qi Ren, Shengyou Yu.
       Background: Mitochondrial dysfunction and impaired autophagy in podocytes contribute to the pathogenesis of kidney diseases, and the phosphatase and tensin homolog (PTEN)-PTEN-induced putative kinase 1 (PINK1)/Parkin signaling axis has emerged as a critical regulator of mitochondrial quality control and podocyte survival; however, the precise underlying mechanisms remain unclear. This study investigates how the PTEN-PINK1/Parkin axis governs mitochondrial quality control in podocytes.
    Methods: In vitro podocyte models with PTEN gene overexpression and silencing were developed to assess changes in podocyte mitochondrial function. Podocyte apoptosis was quantified using an apoptosis detection kit, while mitochondrial membrane potential alterations were measured with the JC-1 Mitochondrial Membrane Potential Detection Kit across all experimental groups. Immunofluorescence and Western blot were used to evaluate the expression and distribution of mitophagy-related proteins, while transmission electron microscopy was employed to observe mitochondrial autophagosomes.
    Results: PTEN depletion markedly suppressed PINK1 accumulation, leading to attenuated Parkin recruitment and LC3-I to LC3-II conversion. This defect correlated with defective clearance of depolarized mitochondria and exacerbated organelle damage. Conversely, PTEN upregulation potentiated PINK1 stabilization, enhanced Parkin translocation to mitochondria, and promoted LC3-II-mediated autophagosome formation, collectively restoring mitophagic autophagosome formation.
    Conclusions: Podocyte-specific PTEN overexpression confers protection against glomerular podocyte injury by mitigating mitophagy dysfunction via the PTEN-PINK1/Parkin signal pathway, highlighting a potential therapeutic target for glomerular diseases.
    Keywords:  Podocytes; apoptosis; mitophagy; phosphatase and tensin homolog (PTEN)
    DOI:  https://doi.org/10.21037/tp-2026-1-0135
  23. Clin Chim Acta. 2026 Jun 13. pii: S0009-8981(26)00354-2. [Epub ahead of print]591 121172
    Detection of NADH/NAD+ dysregulation in MELAS via diazo-carboxyl click derivatization mass spectrometry.
    Jiaqi Hu, Tongling Liufu, Cong Li, Qijin Zhao, Meng Yu, Yun Yuan, Li Quan, Zhixing Chen, Zhaoxia Wang.
       OBJECTIVES: Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a mitochondrial disorder driven by mutations in mitochondrial or nuclear DNA, involving an altered NADH/NAD+-associated redox metabolism as a key pathological mechanism. The traditional metabolomic analyses in MELAS face sensitivity and sample volume limitations, particularly for carboxylic acid metabolites. This study employed a recently established diazo-carboxyl/hydroxylamine-ketone double-click derivatization (DQmB-HA) mass spectrometry method to overcome these barriers, enabling highly sensitive quantification of NADH/NAD+-related serum metabolites in minimal sample volumes.
    METHODS: Using DQmB-HA mass spectrometry, we analyzed lactate, pyruvate, β-hydroxybutyrate, acetoacetate, α-hydroxybutyrate, and malate in 5-μL serum samples from each of the MELAS patients (n = 70), healthy controls (n = 29), and CPEO patients (n = 17). Individual metabolite levels were quantified, and the lactate/pyruvate ratio and β-hydroxybutyrate/acetoacetate ratio were used as surrogate indicators of cytoplasmic and mitochondrial NADH/NAD+ redox states, respectively. Following this, analyses were performed to assess between-group differences in these indicators and to determine their correlations with disease duration.
    RESULTS: MELAS patients exhibited significantly elevated lactate, β-hydroxybutyrate, α-hydroxybutyrate, and malate levels, together with increased lactate/pyruvate and β-hydroxybutyrate/acetoacetate ratios compared with healthy controls. Among the evaluated biomarkers, the lactate/pyruvate ratio achieved the highest diagnostic performance (AUC = 0.993, 95% CI = 0.979-1.000), followed by lactate (AUC = 0.976) and β-hydroxybutyrate (AUC = 0.864). Although the β-hydroxybutyrate/acetoacetate ratio showed high sensitivity (95.7%), its overall diagnostic accuracy was limited by lower specificity. However, none of these serum markers show a significant correlation with the disease duration course in MELAS patients. Relative to MELAS, lower concentrations of α-hydroxybutyrate (p < 0.001) and malate (p = 0.026) and elevated lactate/pyruvate ratio (p < 0.001) were observed in CPEO.
    CONCLUSION: The DQmB-HA method enabled high-sensitivity metabolomic profiling in low-volume clinical samples and revealed broad alterations in metabolites and metabolite ratios associated with NADH/NAD + -related redox metabolism in MELAS, providing a useful framework for metabolomic screening in mitochondrial diseases.
    Keywords:  MELAS; Metabolic dysfunction; Mitochondrial disease; NADH/NAD(+) ratio
    DOI:  https://doi.org/10.1016/j.cca.2026.121172
  24. Biochem Pharmacol. 2026 Jun 16. pii: S0006-2952(26)00508-3. [Epub ahead of print]251(Pt 2): 118170
    Beyond proteostasis: LONP1 as an immunometabolic checkpoint in health and disease.
    Lin Xie, Li-Hong Wu, Xin-Cheng Ni, Jiang-Nan Zhang.
      Mitochondrial Lon protease 1 (LONP1) is an ATP-dependent protease involved in mitochondrial protein quality control, mitochondrial DNA (mtDNA) maintenance, and stress adaptation. Beyond this canonical role, accumulating evidence links LONP1 to metabolic rewiring, inflammatory signaling, immune-cell polarization, and disease-associated mitochondrial dysfunction. Recent human LONP1 cryo-electron microscopy (cryo-EM) structures have revealed nucleotide- and substrate-dependent conformational states, including fold-sensing intermediates, pore-loop rearrangements, and catalytic-site organization, providing a structural framework for substrate processing and state-dependent ligandability. Functionally, LONP1 regulates the turnover or stability of metabolic enzymes such as pyruvate dehydrogenase kinase 4 (PDK4), 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), and aconitase 2 (ACO2), thereby influencing carbon flux, epigenetic regulation, and immune-related metabolic programs. LONP1 deficiency or dysfunction can promote mitochondrial stress responses, including mtDNA release and cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING)-dependent inflammation, with implications for aging, pulmonary fibrosis, developmental disorders such as cerebral, ocular, dental, auricular, and skeletal anomalies (CODAS) syndrome, and organ injury. Conversely, increased LONP1 activity or expression has been associated with tumor progression, desmoplastic remodeling, ferroptosis resistance, and viral pathogenesis in selected models, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coxsackievirus B3 (CVB3). Pharmacological studies, including activators, dual-target inhibitors, and bortezomib-bound structural complexes, support the potential ligandability of LONP1 but also highlight unresolved issues in selectivity, target engagement, mitochondrial toxicity, and context-dependent therapeutic windows. This review summarizes current structural, mechanistic, and pharmacological evidence for LONP1 as a context-dependent immunometabolic regulatory node and discusses limitations and open questions that must be addressed before clinical translation.
    Keywords:  Enzyme activators; Immunity; LONP1protease; Metabolic reprogramming; Mitochondria
    DOI:  https://doi.org/10.1016/j.bcp.2026.118170
  25. Front Med (Lausanne). 2026 ;13 1872028
    The evolving landscape of gene editing therapies for human genetic diseases: a twenty-year bibliometric analysis.
    Xinhao Zhou, Tengfei Ma, Xu Ding, Zhenzhao Luo, Changqing Yin, Zhe Lu.
       Background/Objectives: Despite the transformative potential of gene editing technologies, a systematic mapping of their translational trajectory from bench to bedside remains scarce. This bibliometric analysis aims to chart the bench-to-bedside evolution, identify leading disease targets and therapeutic strategies, and uncover emerging clinical trends and challenges.
    Methods: We analyzed 1,571 peer-reviewed articles and reviews explicitly addressing gene editing therapies for human genetic diseases, published between 2005 and 2025 and retrieved from Web of Science Core Collection and Scopus. Science mapping was conducted using CiteSpace and VOSviewer to visualize collaboration networks, thematic clusters, and research fronts.
    Results: Publication output followed a three-phase exponential growth: engineered nucleases (2005-2012), CRISPR revolution (2013-2018), and precision translation (2019-2025). The United States and China dominated productivity; Harvard and the University of California were key institutional hubs. Hematologic disorders-particularly sickle cell disease and β-thalassemia-constituted the primary disease focus. Emerging frontiers include base and prime editing, epigenetic modulation, multiplex editing, and AI-assisted design. Collaboration networks remain predominantly national, with limited global integration.
    Conclusions: This study delineates the rapid evolution of gene editing therapies, highlighting robust clinical translation for hematological conditions while exposing critical gaps in non-hematopoietic tissues, delivery efficiency, long-term safety, and equitable access. These findings provide a strategic roadmap to broaden the therapeutic reach of gene editing across diverse disease domains.
    Keywords:  CRISPR-Cas; Gene Therapy; bibliometric analysis; gene editing; human genetic diseases
    DOI:  https://doi.org/10.3389/fmed.2026.1872028
  26. Neurotherapeutics. 2026 Jun 15. pii: S1878-7479(26)00115-7. [Epub ahead of print]23(4): e00945
    Long-term safety and efficacy of deoxycytidine/deoxythymidine in treatment of POLG-related disorders.
    Anthony C T Cheung, Saoussen Berrahmoune, Christelle Dassi, Heather Pekeles, Tommy Gagnon, Paula J Waters, Ralf Eberhard, Daniela Buhas, Kenneth A Myers.
      We evaluated the safety and efficacy of enteral deoxycytidine/deoxythymidine combination therapy in treatment of POLG-related disorders, genetic mitochondrial diseases characterized by progressive neurological degeneration. A single-centre open-label phase II trial was conducted. Inclusion criteria included: age 3 months to 60 years, clinical diagnosis of POLG-related disorder, and biallelic pathogenic POLG variants. Participants received deoxycytidine/deoxythymidine initially at 100 mg/kg/day (50 mg/kg deoxycytidine and 50 mg/kg deoxythymidine), titrated to 400 mg/kg/day over three weeks. The current protocol is a 60-month treatment period with primary outcomes the Newcastle Mitochondrial Disease Scale sections I-III and serum growth differentiation factor 15. Secondary outcomes include quality of life questionnaires, seizure diary, EEG, and blood and urine laboratory tests assessing end organ function. Outcomes were assessed at baseline, 1-month, 2-month, 3-month, and 6-month timepoints, then every 6 months thereafter. Twenty-five individuals (14 male, 11 female; mean age 12.3 years) started deoxycytidine/deoxythymidine. Five died during the trial and five withdrew. The most common treatment-related adverse event was diarrhea. Newcastle Mitochondrial Disease Scale sections I-III score decreased (improved) from baseline at all timepoints from 1 month to 24 months (p < 0.05). Serum growth differentiation factor 15 significantly decreased (improved) from baseline at 1-month, 2-month, and 3-month timepoints (p < 0.05). Quality of life score improved at 3-month, 12-month, and 18-month timepoints (p < 0.05). In summary, our data suggest deoxycytidine/deoxythymidine is safe and effective for POLG-related disorders; however, further study is needed to clarify the therapeutic mechanism(s) so that the treatment can be refined and optimized.
    Keywords:  DNA polymerase gamma; Deoxynucleoside; Mitochondrial DNA depletion disorder; Mitochondrial disorder; POLG
    DOI:  https://doi.org/10.1016/j.neurot.2026.e00945
  27. Endocrinol Diabetes Metab. 2026 Jul;9(4): e70257
    Exercise-Induced Extracellular Vesicles as Mediators of Mitochondrial Biogenesis and Insulin Sensitivity in Metabolic Adaptation.
    Jian Wang, Lei Wu.
       BACKGROUND: Metabolic diseases like type 2 diabetes and obesity share insulin resistance as a common feature, driven partly by mitochondrial dysfunction. Exercise-induced extracellular vesicles (EVs) have emerged as mediators of inter-organ communication in metabolic regulation.
    OBJECTIVE: To synthesize evidence on exercise-induced EVs in mitochondrial adaptation and insulin sensitivity, and propose an integrative framework linking EV-mediated communication to systemic metabolic benefits: METHODS: Narrative synthesis of mechanistic, animal, EV transfer/inhibition, translational, and human studies.
    RESULTS: Exercise alters EV abundance and cargo, including mitochondrial proteins, metabolic enzymes, and microRNAs. These cargoes may activate energy-sensing, NAD+-dependent, transcriptional, and post-transcriptional pathways to enhance mitochondrial biogenesis and oxidative metabolism. By improving substrate utilization and reducing lipotoxicity, mitochondrial ROS, ER stress, and inflammation, EV-mediated mitochondrial adaptation may boost insulin sensitivity and insulin signaling. EV transfer/inhibition studies support a contributory role for exercise-induced EVs in glucose homeostasis, though evidence remains context-dependent.
    CONCLUSIONS: Exercise-induced EVs may link exercise stimuli to mitochondrial adaptation and systemic insulin sensitivity. The proposed "exercise-EV-mitochondrial adaptation-insulin sensitivity" framework offers a conceptual basis for understanding systemic metabolic adaptation and highlights translational potential for metabolic diseases. Future work should clarify causality, tissue specificity, pharmacokinetics, and standardization.
    Keywords:  exercise; extracellular vesicles; insulin sensitivity; metabolic homeostasis; mitochondrial biogenesis
    DOI:  https://doi.org/10.1002/edm2.70257
  28. Orphanet J Rare Dis. 2026 Jun 18.
    Exploring barriers to clinical trial readiness among the myotonic dystrophy community: a mixed-methods study.
    Julia Stellmann Wrenn, Ali Ryan-Mosley, Jonah Watt, Erin Hellthaler, Tanya Stevenson, Andy Rohrwasser.
      Myotonic dystrophy (DM) is a multisystemic disorder characterized by significant heterogeneity in symptom manifestation, progression, and severity. This variability complicates clinical trial design and implementation, thereby affecting therapeutic development. This study aimed to identify barriers to clinical trial readiness in DM and explore actionable solutions by incorporating perspectives from pharmaceutical partners, clinical trial site staff, people living with DM (PLDM), and caregivers. Focus groups, surveys, and interviews were conducted with pharmaceutical partners (n = 65), PLDM and caregivers (n = 35), principal investigators (n = 12), and clinical research coordinators (n = 12). Qualitative findings were thematically analyzed and triangulated with survey data to enhance validity. Three major barriers consistently emerged: (1) a lack of comprehensive, validated endpoints that capture outcomes meaningful to patients; (2) insufficient data sharing and coordination across industry; and (3) challenges in trial design, recruitment, and participant burden. PLDM emphasized under-studied but debilitating symptoms-such as dysphagia, fatigue, and cognitive impairment-that are rarely prioritized in clinical trials. Pharmaceutical partners cited regulatory uncertainty surrounding composite outcome measures as well as the value of quantitative myotonia indicators as informative holistic disease indicators. Limited access to natural history data, often prohibitively costly for smaller companies, reinforces competitive rather than collaborative dynamics. PLDM and caregivers also highlighted substantial financial, logistical, and accessibility challenges associated with trial participation. Participants favored several strategies to address these barriers: (1) convening a multi-stakeholder scientific session with the U.S. Food and Drug Administration (FDA) and establishing a working group to define and standardize patient-centered, clinically relevant endpoints; (2) developing a comprehensive, coordinated registry that integrates existing data sources, longitudinal health and study data, genetic diagnostic data, supports recruitment and refinement of study inclusion criteria, and enables post-market surveillance; (3) strengthening trial site preparedness and anticipating recruitment needs, including biomarker-driven cohorts; and (4) adopting patient-centered trial designs that minimize burden, with patient advocacy groups (PAGs) serving a central convening and advocacy role by bringing various groups together to discuss these topics. While barriers to DM clinical trial readiness are significant, they are addressable. Coordinated action among industry, regulators, clinicians, and advocacy groups-guided by patient priorities-will be essential. Implementing these strategies could accelerate therapeutic development, improve trial inclusivity, and ultimately enhance quality of life for individuals living with DM.
    Keywords:  Clinical trial barriers; Mixed-methods; Myotonic dystrophy; Patient advocacy groups; Rare disease; Registry
    DOI:  https://doi.org/10.1186/s13023-026-04408-0
  29. Forensic Sci Int Genet. 2026 Jun 08. pii: S1872-4973(26)00142-0. [Epub ahead of print]86 103561
    Inheritance patterns of mitochondrial DNA in multi-generational maternal pedigrees: Insights from mitochondrial whole-genome sequencing.
    Miaoqiang Lun, Xingyi Yang, Guichao Xiao, Quyi Xu, Changhui Liu, Xiaolong Han, Chengliang Yang, Weibin Wu, Linying Ye, Zhiyong Liu, Peng Yang, Xiaohui Chen, Ling Chen, Chao Liu.
      Mitochondrial DNA (mtDNA) exhibits unique advantages in forensic analysis and maternal lineage identification. However, its inherent heteroplasmy presents a moderate limitation to its application in forensic genetics. The purpose of this study is to explore the inheritance patterns of mtDNA across three-generation and two-generation maternal pedigrees. Employing the Ion S5™ XL System in conjunction with the Precision ID mtDNA Whole Genome Panel, we conducted mtDNA whole-genome sequencing on mtDNA extracted from buccal swabs of 248 individuals from 73 maternal pedigrees. Our results indicate that the sequencing depth in the 8622-8796 region was relatively low with the Precision ID mtDNA Whole Genome Panel, leading to a relatively high occurrence of missing variants in this region. We recommend performing multiple checks for this region to ensure accurate variant detection, particularly in maternal lineage identification. Notably, no homoplasmic mutations were detected within the same maternal pedigree, 35 heteroplasmic variants were identified among 30 samples from 18 pedigrees, accounting for 12.10% of individuals. Sanger sequencing corroborated the presence of heteroplasmic variants at the corresponding nucleotide positions in most heteroplasmic samples from three-generation pedigrees. Heteroplasmic variants demonstrated instability during maternal transmission, with allelic frequencies exhibiting erratic fluctuations across different maternal pedigrees. Although some point heteroplasmies were transmitted, no significant correlation was found in the frequencies of variant alleles between mothers and their offspring. Heteroplasmic variants should not be considered as exclusionary indicators in maternal lineage identification. However, when two samples with identical haplotypes exhibit identical point heteroplasmies, particularly when the minor alleles are consistent, these shared variants may serve as corroborative evidence supporting the hypothesis of a common maternal origin.
    Keywords:  Forensic genetics; Heteroplasmy; Massively parallel sequencing; Maternal lineage identification; Mitochondrial DNA
    DOI:  https://doi.org/10.1016/j.fsigen.2026.103561
  30. Hum Gene Ther. 2026 Jun 19. 10430342261452217
    Adeno-Associated Virus Gene Therapy Translation: Lessons from Early Regulatory Meetings.
    PaVe-GT Team
      The Platform Vector-Gene Therapy (PaVe-GT) program is a National Institutes of Health (NIH) initiative that aims to develop adeno-associated virus (AAV) gene therapies for four monogenic rare diseases, two organic acidemias and two congenital myasthenic syndromes. PaVe-GT's platform-based approach identifies and diminishes redundancies and applies efficiencies in preclinical, clinical, and regulatory activities. The program's hypothesis is that implementing these efficiencies can accelerate clinical trial initiation. Based on its platform-centric experience and public-serving mission, the PaVe-GT program actively shares its scientific and regulatory learnings with the public to benefit the development of similar gene therapy products for rare diseases. PaVe-GT's first investigational AAV gene therapy candidate is AAV serotype 9 human propionyl-CoA carboxylase alpha subunit (AAV9-hPCCA) for propionic acidemia caused by PCCA deficiency, which received initial feedback from the Food and Drug Administration (FDA) in an INitial Targeted Engagement for Regulatory Advice on CBER/Center for Drug Evaluation and Research (CDER) ProducTs (INTERACT) meeting. Upon further product development that took into consideration the FDA's initial advice, the program obtained the Agency's feedback in pre-investigational new drug (IND) (Type B) and Type C meetings. Here, we share our experience from these meetings, including strategy, preparation, pre- and post-meeting feedback from the FDA, and lessons learned during the AAV9-hPCCA regulatory process, which the program plans to apply across the PaVe-GT platform. Topics discussed in the regulatory meetings included animal model and efficacy studies, toxicology study plans, manufacturing of the investigational AAV product, and clinical trial design. The main lessons learned from the pre-IND and Type C meetings for AAV9-hPCCA are: (1) Pharmacology/Toxicology studies in a single rodent species are sufficient for filing an initial IND; (2) FDA feedback guides product quality improvements and early development of a quantitative potency assay; (3) use of biomarkers as potential surrogate endpoints in a future efficacy trial benefits from collection of data in the natural history study and the first-in-human Phase 1/2 study; and (4) evidence from the Phase 1/2 clinical trial could be leveraged to support a license application. Lightly redacted regulatory documents and comprehensive templates developed by the PaVe-GT team are available on the PaVe-GT website.
    Keywords:  AAV9; FDA type B meeting; FDA type C meeting; PCCA; PaVe-GT; gene therapy; pre-IND meeting; propionic acidemia; rare diseases
    DOI:  https://doi.org/10.1177/10430342261452217
  31. Neuron. 2026 Jun 17. pii: S0896-6273(26)00325-9. [Epub ahead of print]114(12): 2073-2075
    Limiting neurodegeneration in ALS: A phosphatase paves the way.
    Elena I Rugarli, Thomas Langer.
      Zheng et al. identify phosphatase PGAM5 as a novel promising target for the treatment of different amyotrophic lateral sclerosis subtypes. PGAM5 dephosphorylates and activates the stress-regulated mitochondrial peptidase OMA1, which elicits a maladaptive mitochondrial integrated stress response in motor neurons.
    DOI:  https://doi.org/10.1016/j.neuron.2026.04.030
  32. Front Physiol. 2026 ;17 1813119
    Cardiolipin remodelling in mitochondrial therapeutics: translational evidence chains from elamipretide to emerging strategies.
    Ke Di, Yusheng Hu, Hechen Sun, Tianwei Meng, Tingquan Han, Rui Qie.
      Mitochondrial therapeutics have repeatedly fallen short of disease modification, in part because inner-membrane architecture constrains both molecular access and the reversibility of bioenergetic failure. Cardiolipin (CL), the signature phospholipid of the inner mitochondrial membrane, provides a mechanistically cohesive axis that links membrane mechanics to cristae organisation, respiratory-chain supercomplex stability and redox vulnerability. This Review summarises how CL biosynthesis and remodelling shape tissue-specific lipid species and how pathological remodelling can amplify oxidative injury. The MLCL: CL ratio is discussed as a rare lipid biomarker with direct interpretability for diagnosis, stratification and target engagement. Clinical evidence for CL-targeting stabilisers is evaluated to delineate settings in which structural support yields functional benefit and those in which organ-level remodelling limits translation despite improved respiration. Emerging approaches that improve tissue distribution, modulate membrane phase behaviour or rebalance upstream lipid flux are considered alongside trial designs that couple target-proximal readouts to patient-relevant endpoints, paving the way for precision medicine in mitochondrial lipodystrophies.
    Keywords:  cardiolipin; cardiolipin remodelling; elamipretide; inner mitochondrial membrane; target engagement
    DOI:  https://doi.org/10.3389/fphys.2026.1813119
  33. Clin Transl Sci. 2026 Jun;19(6): e70642
    Challenges in Implementing Revocation of Oncology Drugs Under Conditional Early Approval in Japan: Regulatory Insights From Comparisons With FDA/EMA.
    Takahiro Handa, Arata Tanaka, Mayumi Shikano, Rika Wakao.
      Expedited pathways in the United States (U.S.), European Union (EU), and Japan (JP) enable earlier access to innovative therapies for rare and serious diseases. In 2025, Japan explicitly introduced revocation provisions to its Conditional Early Approval (CEA). Considering the challenges in a related prior scheme-conditional and time-limited approval for regenerative medical products-particularly withdrawals prior to full approval, this study examined oncology cases under the U.S. Accelerated Approval (AA) and EU Conditional Marketing Authorization (CMA) pathways to identify operational challenges for revocation under Japan's CEA. We conducted a descriptive comparative analysis of oncology drugs granted AA or CMA between January 2015 and December 2024 using publicly available data. Post-authorization outcomes and JP approval/development status were summarized. AA encompassed 97 products (138 indications), CMA included 27 products (30 indications), and CEA covered 4 products (4 indications). Approximately half of AA/CMA indications were approved in Japan, while some remained undeveloped. The mean time from AA to full approval was 2.7 years and to withdrawal was 3.6 years. Overall, about 15% of AA indications were withdrawn, primarily due to failed confirmatory trials; 8 products/10 indications underwent Oncologic Drugs Advisory Committee deliberations prior to withdrawal or continuation. With recent policy changes aligning CEA eligibility with AA/CMA, broader implementation of CEA is anticipated. For revocation operations, three priorities emerge: (1) timely confirmatory trials and alternative approaches to reduce uncertainty; (2) transparent public evaluation and decision-making; and (3) flexible patient-access systems following withdrawal. Continued discussion is required to support effective use of CEA.
    Keywords:  FDA; drug development; oncology; patients; public policy; regulatory
    DOI:  https://doi.org/10.1111/cts.70642
  34. Cell Metab. 2026 Jun 15. pii: S1550-4131(26)00193-2. [Epub ahead of print]
    The senescence-stiffening loop: Extracellular matrix remodeling, hypoperfusion, and mitochondrial dysfunction drive tissue aging.
    Luigi Ferrucci, Stefano Donega, Allison B Herman, Rafael de Cabo, Myriam Gorospe.
      Aging tissues experience a gradual decline in perfusion and metabolic resilience due to complex interactions among extracellular matrix (ECM) remodeling, vascular dysfunction, and mitochondrial impairment. Stiffening of the ECM that results from collagen crosslinking, elastin loss, and basement membrane thickening reduces vascular compliance and impairs local angiogenesis. The consequent reduction in capillaries and diminished endothelial reactivity leads to ongoing or intermittent hypoxia, which triggers changes in transcriptomic and proteomic programs that inhibit oxidative phosphorylation and facilitate the production of reactive oxygen species. Under these conditions, mitochondria produce less ATP than is needed for homeostatic repair. This energetic breakdown triggers cellular senescence and inflammation, further increasing ECM stiffening, and thus creating a self-sustaining feedback loop that accelerates tissue aging and functional decline. Such a continuum from ECM stiffening to mitochondrial dysfunction may be considered a new therapeutic target for strategies aimed at maintaining vascular integrity, mitochondrial health, and cellular homeostasis during aging.
    Keywords:  extracellular matrix; hypoperfusion; mitochondrial dysfunction; senescence
    DOI:  https://doi.org/10.1016/j.cmet.2026.05.008
  35. Cell Biosci. 2026 Jun 19.
    Mitochondrial proteases maintain cellular protein homeostasis and tissue integrity.
    Kexin Shi, Hao Liu, Hong Xu, Weina Shang, Liquan Wang, Chao Tong.
       BACKGROUND: Mitochondrial proteases are essential for mitochondrial protein import and constitute the core of the organelle's intrinsic protein quality control system. However, their physiological functions across tissues, as well as their influence on cytosolic proteostasis, remain incompletely understood.
    RESULTS: We generated loss- and gain-of-function alleles for 15 conserved mitochondrial proteases in Drosophila melanogaster to systematically dissect their in vivo functions. Disruption of specific proteases caused male sterility or organismal lethality, whereas tissue-specific knockouts in the eye, muscle, or fat body led to mitochondrial protein aggregates, structural defects, and age-dependent degeneration. Loss of UQCR-C1 or Afg3l2 robustly increased mitophagy, while overexpression of several proteases severely impaired muscle integrity. Loss of UQCR-C1, Mppa, or CG11771 promoted HTT72Q aggregation, and reducing UQCR-C1 or Afg3l2 markedly elevated cytosolic HTT72Q levels. Conversely, overexpressing Mppa-but with reduced efficacy in its disease-associated variants-suppressed HTT96Q aggregation and neuronal toxicity. Mppa forms a complex with UQCR-C1 to regulate mitochondrial pre-protein processing and import, indicating that enhancing mitochondrial protein import is sufficient to alleviate cytosolic proteotoxic stress caused by HTT polyglutamine (polyQ) proteins.
    CONCLUSIONS: This work establishes a comprehensive in vivo resource for mitochondrial protease functions and their roles in shaping cytosolic proteostasis.
    Keywords:   Drosophila ; Huntington disease (HTT) polyQ proteins; Mitochondria; Protease
    DOI:  https://doi.org/10.1186/s13578-026-01612-0
  36. Curr Neuropharmacol. 2026 Jun 16.
    Tiny Messengers, Big Impact: The Role of Endogenous Extracellular Vesicles in Neurological Diseases.
    Lluis Alzamora Llull, Zhiyu Lin, Wenlu Li, Eng H Lo.
      Extracellular Vesicles (EVs) are membrane-enclosed structures released by cells, encapsulating bioactive molecules such as proteins, lipids, and nucleic acids. They play a pivotal role in intercellular communication and have emerged as critical mediators in both physiological and pathological processes, particularly in neurological diseases. This review summarizes the current knowledge of endogenous EVs in neurological diseases, including cerebrovascular disorders, neurodegenerative diseases, autoimmune disorders, epilepsy, trauma, and cancer. We highlight their role in disease progression, their potential as biomarkers, and their therapeutic implications, while identifying critical gaps such as exosome biogenesis, selective cargo loading, and recipient cell specificity that warrant further research. By addressing these gaps, future studies can better harness the potential of exosomes in diagnosing and treating neurological diseases.
    Keywords:  Extracellular vesicles; exosomal cargo; extracellular vesicles-based biomarker; extracellular vesicles-based therapy.; intracellular messenger; neurological diseases
    DOI:  https://doi.org/10.2174/011570159X387438250823212133
  37. CNS Neurosci Ther. 2026 Jun;32(6): e70997
    Clinical Spectrum, Heteroplasmy-Phenotype Correlation, and Prognosis of the MT-ND3 m.10191 T > C Mutation.
    Zimeng He, Huafang Jiang, Tongyue Li, Yang Liu, Ying Zou, Chaolong Xu, Zhimei Liu, Danmin Shen, Ruoyu Duan, Minhan Song, Yunxi Zhang, Zixuan Zhang, Mingxi Sun, Rui Shen, Hong Xue, Fang Fang.
       AIM: To systematically characterize the phenotypic spectrum, neuroimaging features, heteroplasmy-phenotype correlation, and prognosis of the m.10191 T > C mutation.
    METHODS: We collected and analyzed data from 52 patients (14 newly recruited; 38 from literature). Phenotypes were pre-classified as Leigh syndrome (LS), Leigh-like syndrome (LLS), MELAS/LS overlap syndrome, and MELAS-like syndrome. Neuroimaging data were subjected to statistical analysis to explore inter-lesional associations and lesion-symptom correlations. Heteroplasmy level underwent k-means clustering and latent class analysis (LCA) to define data-driven subgroups and model genotype-phenotype correlations. Prognostic factors were evaluated through Bayesian logistic regression, and survival analysis was conducted.
    RESULTS: The cohort exhibited phenotypic heterogeneity, dominated by LS (46.2%). Key features included epilepsy, developmental delay, and dystonia. Globus pallidus involvement frequently co-occurred with midbrain and pontine lesions. Heteroplasmy level differed significantly across phenotypes. LCA identified three classes corresponding to clinical phenotypes. High heteroplasmy level, medullary involvement, and severe hyperlactatemia were associated with disease progression. Survival analysis indicated a 5 year survival rate of 80.0%, with high heteroplasmy level, hypotonia, and cerebellar lesions predicting poorer survival.
    INTERPRETATION: The m.10191 T > C mutation is linked to a continuous clinical spectrum correlated with heteroplasmy level. Specific clinical and neuroimaging features serve as valuable biomarkers for phenotypic classification and prognostic assessment.
    Keywords:   MT‐ND3 ; complex I deficiency; leigh syndrome; m.10191 T > C; mitochondrial encephalomyopathy with lactate acidosis and stroke‐like episodes (MELAS)
    DOI:  https://doi.org/10.1002/cns.70997
  38. Front Immunol. 2026 ;17 1871148
    Mitochondrial transfer in the tumor microenvironment: a dynamic determinant of cancer plasticity, immune dysfunction, and therapeutic opportunity.
    Zhenyuan Xu, Qingli Zhou, Jifei Miao.
      Intercellular mitochondrial transfer has emerged as a significant mode of communication within the tumor microenvironment (TME). We propose that this process operates as a stress-adaptive organelle economy, redistributing three biologically decisive assets (respiratory competence, redox tolerance, and stress history) among tumor, immune, and stromal cells according to local metabolic asymmetry. Cancer cells acquire healthy mitochondria from stromal and immune populations, thereby restoring oxidative phosphorylation, expanding metabolic plasticity, and driving chemoresistance. Tumor cells also engage in outward transfer that is recipient-selective. Damaged mitochondria may be exported to CD8+ T cells and fibroblasts, corrupting effector function and reprogramming the stroma, whereas functional mitochondria may be delivered to pro-tumor immune populations such as M2 tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells to sustain their immunosuppressive activity. Functional mitochondria therefore play a dual role in tumorigenesis. The consequences for antitumor immunity depend on donor identity, cargo quality, and recipient lineage rather than on transfer itself. The principal transport routes are tunneling nanotubes, extracellular vesicles, and cell fusion, but biological outcome is ultimately governed by a post-transfer fate checkpoint involving PINK1/Parkin-mediated mitophagy and USP30-facilitated retention. Therapeutically, the goal is not to block or enhance transfer globally but to achieve context-selective modulation within an inherently bidirectional system.
    Keywords:  cancer plasticity; extracellular vesicles; mitochondrial transfer; t cell exhaustion; tumor microenvironment; tunneling nanotubes
    DOI:  https://doi.org/10.3389/fimmu.2026.1871148
  39. Proc Natl Acad Sci U S A. 2026 Jun 23. 123(25): e2530774123
    Restoring the interplay between the endoplasmic reticulum and mitochondria by gene therapy improves Charcot-Marie-Tooth type 2A disease.
    Marine Tessier, Zeinab Hamze, Nathalie Bonello-Palot, Nathalie Roeckel-Trévisiol, Nathalie Da Silva, Ilian Verlet, Natacha Broucqsault, Karine Bertaux, Emilien Delmont, Shahram Attarian, Marc Bartoli, Valérie Delague, Bernard L Schneider, Nathalie Bernard-Marissal.
      Charcot-Marie-Tooth disease type 2A (CMT2A) is the most common axonal CMT and is associated with an early onset and severe motor neuropathy. CMT2A is mainly caused by dominant mutations in the MFN2 gene, encoding mitofusin-2, a GTPase located in the outer membrane of the mitochondria and endoplasmic reticulum (ER). Mutations in MFN2 affect mitochondrial dynamics. We previously demonstrated that mutated MFN2 further disrupts contacts between the ER and the mitochondria, leading to axonal degeneration. There are no treatments for CMT2A, and those currently under development primarily focus on restoring mitochondrial function. Here, we provide proof of concept that neuronal overexpression of wild-type MFN2 (MFN2WT) provides therapeutic benefit in transgenic CMT2A mice as well as in CMT2A-motor neurons derived from induced pluripotent stem cells. Intrathecal delivery of an AAV9 vector expressing MFN2WT effectively targets motor and sensory neurons, restoring ER-mitochondria contacts and mitochondrial morphology, thereby preserving both neuromuscular junction integrity and motor function. Strikingly, therapeutic efficacy is also achieved by administering the vector after the onset of symptoms. Importantly, AAV administration was well tolerated, with no evidence of hepatotoxicity or dorsal root ganglion inflammation. We further show that CMT2A pathology can be corrected in vitro and in vivo using an ER-targeting MFN1 isoform that selectively enhances ER-mitochondria contacts. These results establish that restoring contacts between the ER and mitochondria using gene therapy is a promising therapeutic avenue for CMT2A.
    Keywords:  Charcot–Marie–Tooth disease; MFN2; endoplasmic reticulum; gene therapy; mitochondria
    DOI:  https://doi.org/10.1073/pnas.2530774123
  40. Ther Innov Regul Sci. 2026 Jun 19.
    Case Study on the Use of Real-World Evidence in a Feasibility Assessment of a Randomized Controlled Trial Design to Support the Fulfillment of Pediatric Requirements with the FDA and EMA.
    Neal E Storm, Christine Kubik, Ghislaine Priem, Min Kim, Tzu-Chieh Lin, Jeff Lange, Chelsea O'Connell, Anthony Glennane, Brian D Bradbury, Mark J Taisey.
       INTRODUCTION: Regulatory agencies may require industry sponsors of new drugs or biologics to conduct clinical trials that assess the benefits versus the risks of these new medicines in pediatric patients as a means of facilitating their development and availability for children when there is a medical need. Amgen Inc. (henceforth "the company") agreed to conduct a randomized, controlled trial (RCT) in pediatric subjects with Glucocorticoid-induced Osteoporosis (GiOP) under a Paediatric Investigation Plan (PIP) and Pediatric Study Plan (PSP) with the European Medicines Agency (EMA) and the United States (US) Food and Drug Administration (FDA), respectively, as one of the pediatric studies that were a condition of registration for Prolia (denosumab). Enrollment of pediatric subjects with GiOP into the agreed clinical study was exceedingly low despite the implementation of multiple mitigation measures. As a result, the company explored the use of real-world epidemiological analyses of the disease in children with GiOP for further insight into the clinical feasibility challenges with the RCT design.
    MATERIALS AND METHODS: We initiated a phase 3 randomized, double-blind, placebo-controlled, parallel-group study to evaluate the safety and efficacy of denosumab in pediatric subjects with GiOP (Study 20140444). Following difficulties in recruiting we re-assessed the enrollment potential and overall clinical trial feasibility of Study 20140444 using real-world epidemiological analyses evaluating the size of the pediatric GiOP population using real-world data (RWD) from 3 different databases: (1) the US MarketScan, (2) the United Kingdom (UK) Clinical Practice Research Datalink (CPRD), and (3) the IQVIA Disease Analyzer (Germany).
    RESULTS: The results from the RWD show that very few pediatric patients met the clinical diagnosis of GiOP, irrespective of the database used. In sum, approximately 1 eligible subject per 1,000,000 people per year was estimated to be available for Study 20140444.
    CONCLUSIONS AND RECOMMENDATIONS: The results suggest a lack of feasibility of conducting an adequate and well-controlled randomized trial in a population of pediatric patients with GiOP. The results also called into question the feasibility of other types of clinical trial designs, including potential single-arm or hybrid study designs, to fulfill the regulatory requirements. Recommendations include considering the use of RWD-based epidemiological analyses prior to agreeing with health authorities to conduct postmarketing required pediatric studies or studies in other rare diseases. This approach to clinical trial feasibility using RWD helps ensure research goals are balanced with the needs of the individual patient, further ensuring the ethical conduct of clinical trials. CLINICAL TRIAL REGISTRATION (STUDY 20140444): ClinicalTrials.gov / NCT03164928 / URL: https://clinicaltrials.gov/search? term=NCT03164928 . EudraCT / 2016-003083-39 / URL: https://www.clinicaltrialsregister.eu/ctr-search/search? query=2016-003083-39 .
    Keywords:  Denosumab; Glucocorticoid-induced osteoporosis; Pediatric; Prolia; Real-world evidence; Regulatory decision-making
    DOI:  https://doi.org/10.1007/s43441-026-00977-1
  41. Int Rev Cell Mol Biol. 2026 ;pii: S1937-6448(25)00162-5. [Epub ahead of print]404 1-61
    From autophagy to mitophagy: Quality control mechanisms in skeletal muscle.
    Eduardo Antuña, Nerea Menéndez-Coto, Paula Fernández-Guisasola, Ana Coto-Montes.
      Autophagy is a process which is responsible for the maintenance of cellular homeostasis. This is achieved through the orchestration of both highly selective and non-selective degradation pathways, the purpose of which is the elimination of damaged structures. Recent findings have revealed that, in addition to its intracellular function, this organelle exhibits a remarkable "social life" and forms relationships with other cellular organelles. This has led to the discovery that mitochondrial quality is maintained not only through mitophagy, but also through extracellular mechanisms between cells. This has significantly expanded our understanding of tissue integrity. In skeletal muscle, autophagy, or autophagy, is a finely tuned process that plays a crucial role in maintaining physiological performance and adaptation. Disruption of autophagy has been linked to accelerated degeneration, metabolic dysfunction, and frailty. Although therapeutic manipulation of autophagy and mitophagy shows promise in restoring muscle health, major translational barriers persist. A more profound and nuanced exploration of autophagy flux in human muscle is imperative, underpinned by novel advanced cell biology technologies and predicated on satellite cells as the primary agents in muscle regeneration. The full therapeutic potential of autophagy could be harnessed to redefine interventions against muscle ageing and associated diseases. However, this would still require critical scrutiny of the long-term effects and systemic consequences.
    Keywords:  Aging; Autophagy; Mitochondria; Quality control mechanisms; Skeletal muscle
    DOI:  https://doi.org/10.1016/bs.ircmb.2025.11.006
  42. Drug Discov Today. 2026 Jun 16. pii: S1359-6446(26)00120-0. [Epub ahead of print] 104715
    From complexity to approval in the European Union: Regulatory pathways and data challenges in the evaluation of non-oncology orphan medicines.
    Gaёlle Andriantafika, Heidi Janssen, Ewa Balkowiec-Iskra, Christian Gartner, Bruno Sepodes, Bart Van der Schueren.
      Generating comprehensive evidence for regulatory evaluation of non-oncology orphan medicines (NOOMS) at the marketing authorisation stage remains challenging. We assessed patterns observed across NOOMS applications between 2006 and 2024 comparing standard with non-standard regulatory pathways: conditional marketing authorisation and marketing authorisation under exceptional circumstances. We examined how uncertainties in quality of evidence, efficacy, safety and therapeutic context affect regulatory decisions based on additional benefit-risk considerations in the EU regulatory context. This work highlights how data maturity, uncertainty in results and biological plausibility - rather than unmet medical need alone - shape the choice of regulatory pathway. Early proactive engagement with regulators, innovative development strategies and enhanced collaboration among stakeholders are needed to address these challenges and accelerate patient access to NOOMS.
    Keywords:  European Medicines Agency; Orphan medicines; benefit–risk assessment; conditional marketing authorisation; marketing authorisation under exceptional circumstances; rare diseases; regulatory pathways
    DOI:  https://doi.org/10.1016/j.drudis.2026.104715
  43. Int Rev Cell Mol Biol. 2026 ;pii: S1937-6448(25)00153-4. [Epub ahead of print]404 63-79
    Impact of different exercise modalities on mitophagy in human skeletal muscle.
    Cristóbal Muñoz-Medina, Alfonso Carriel-Nesvara, Javier Botella, Mauricio Castro-Sepulveda.
      Exercise induces profound mitochondrial adaptations in skeletal muscle, with different modalities uniquely influencing different branches of mitochondrial quality control (MQC). This review examines how endurance, resistance, and high-intensity interval training (HIIT) regulate mitophagy, the selective degradation of damaged mitochondria, in skeletal muscle (SkM). Research in rodents has shown that endurance exercise upregulates mitophagy primarily through the AMPK/PGC-1α signaling axis, promoting mitochondrial turnover and ensuring metabolic efficiency. In humans, high-intensity exercise increases mitophagy to a larger extent when compared to traditional endurance exercises. On the other hand, resistance exercise triggers alternative MQC mechanisms, including potential mitochondrial ejection. Collectively, these results suggest that mitophagy and MQC pathways are regulated in human SkM following exercise, but the specific molecular pathways seem to be specific to each exercise mode. Future studies should aim at disentangling the multiple mitophagy and MQC pathways in human SkM following exercise.
    Keywords:  Aging; Exercise training; Metabolic health; Mitochondrial autophagy; Skeletal muscle plasticity
    DOI:  https://doi.org/10.1016/bs.ircmb.2025.10.005
  44. Cell Commun Signal. 2026 Jun 13.
    Post-translational modifications of mitochondrion-related proteins: integrative orchestrators of cell fate networks in cardiovascular disease.
    Lei Liu, Saiteng Wu, Lei Zhang, Li Zhong, Rui Guo.
      Cardiovascular disease remains the leading cause of global mortality, with mitochondrial dysfunction playing a central pathogenic role. Post-translational modifications act as fundamental regulators of mitochondrial quality control. Yet, how mitochondrial post-translational modifications integrate stress signals to direct cell fate among diverse regulated cell death pathways in cardiovascular disease remains incompletely understood. This review proposes a conceptual framework in which mitochondrial post-translational modifications act as the master conductors of an integrated network linking mitochondrial homeostasis to cellular demise. We first outline the pivotal roles of mitochondrial quality control in cardiovascular disease and detail their precise mechanisms governed by mitochondrial post-translational modifications over each process. We then delineate how mitochondrial post-translational modifications critically regulate the initiation and execution of apoptosis, necroptosis, pyroptosis, ferroptosis, and cuproptosis, evaluating their distinct contributions to cardiovascular pathophysiology. Furthermore, we highlight the extensive crosstalk and convergence among these death modalities at the mitochondrial level, emphasizing the role of mitochondrial post-translational modification signatures in amplifying death signals or triggering modality switching. By synthesizing recent discoveries, this work connects dynamic protein-level modifications to cell fate outcomes, offering a theoretical basis for future therapeutic strategies aimed at rebalancing the network of mitochondrial post-translational modifications to combat heart failure and other cardiovascular diseases.
    Keywords:  Cardiovascular disease; Cell death; Dynamic equilibrium.; Mmitochondrial quality control; Post-translational modifications
    DOI:  https://doi.org/10.1186/s12964-026-03002-y
  45. Mol Cell. 2026 Jun 18. pii: S1097-2765(26)00322-9. [Epub ahead of print]86(12): 2237-2239
    An aminoacyl-tRNA synthetase governs dsRNA-mediated trade-off between longevity and innate immunity.
    Haruka Ozaki, Nobunari Sasaki, Shunsuke Kitajima.
      In this issue of Molecular Cell, Sohn et al.1 explore how endogenous dsRNAs influence organismal aging and identify an unexpected function of the aminoacyl-tRNA synthetase FARS-1/FARSA in regulating mitochondrial dsRNA homeostasis to balance longevity and innate immunity.
    DOI:  https://doi.org/10.1016/j.molcel.2026.05.016
  46. J Clin Invest. 2026 Jun 16. pii: e196687. [Epub ahead of print]
    Elevated mitochondrial protein import in acute myeloid leukemia increases reliance on mitochondrial protease LONP1.
    Matthew Tcheng, Veronique Voisin, Geethu Emily Thomas, Anastasija A Piric, Marcela Gronda, Rose Hurren, Dakai Ling, Yongran Yan, Lan Xin Zhang, Yue Feng, Ali Chegini, Nathan Duong, Ross S Mancini, Stefan Quinn W Currie, Zaynab Mamai, Brady Stock, Shahbaz Khan, Yulia Jitkova, Chaitra Sarathy, Edward Ayoub, Po Yee Mak, Andrea Arruda, Thomas Kislinger, Mark Reed, Bing Z Carter, Michael Andreeff, Steven M Kornblau, Mark D Minden, Siavash Vahidi, Aaron D Schimmer.
      Most mitochondrial proteins are nuclear encoded, translated in the cytosol, and imported into the mitochondria. Through gene expression analysis and functional assays, we demonstrated that mitochondrial protein import is increased in acute myeloid leukemia (AML) cells compared to normal hematopoietic cells. Increased mitochondrial protein import was positively correlated with increased mitochondrial unfolded protein response (UPRmt), a stress activated pathway of mitochondrial proteases and chaperones that maintains protein solubility and prevents the formation of toxic aggregates. The UPRmt protease LONP1 (Lon Peptidase 1) was upregulated in AML and positively correlated with increased mitochondrial protein import and UPRmt. Genetically or chemically inhibiting the LONP1 ATPase domain induced mitochondrial protein aggregation and selectively killed AML cells with high LONP1 expression while sparing AML cells with low LONP1 expression and normal hematopoietic cells in vitro and in vivo. Thus, we uncovered a critical role of the UPRmt protease LONP1 in buffering stress from mitochondrial protein import in AML.
    Keywords:  Cancer; Cell biology; Metabolism; Oncology
    DOI:  https://doi.org/10.1172/JCI196687
  47. BMC Med Res Methodol. 2026 Jun 17.
    Basket and umbrella trials in pediatric precision medicine: a systematic review of designs, opportunities, and challenges.
    Mohd Rashid Khan, Mariarita Stendardo, Silvia Bressan, Luca Vedovelli, Paola Berchialla, Ileana Baldi, Dario Gregori, Danila Azzolina.
       BACKGROUND: Personalized medicine, driven by genomic insights, has catalyzed the emergence of innovative clinical trial designs such as basket and umbrella trials. These designs are particularly suited for evaluating targeted therapies in biomarker-defined subgroups and rare pediatric conditions where traditional trials face challenges of small sample sizes and disease heterogeneity.
    OBJECTIVES: This systematic review aimed to characterize and synthesize the current literature on basket and umbrella trial designs in pediatric drug development, with a focus on their methodological, regulatory, and statistical aspects.
    METHODS: A systematic search was conducted in the electronic databases PubMed, Scopus, and Web of Science to identify all literature related to basket and umbrella trials. A text mining analysis using unsupervised machine learning technique was performed with relevant articles to automatically identify the primary topics within publications on basket and umbrella trials. A systematic search of PubMed, Scopus, and Web of Science identified 1867 records. After screening and eligibility assessment, 28 studies were included in the final review. Topic modelling using Latent Dirichlet Allocation (LDA) was performed on 76 pertinent articles to identify dominant themes. Statistical convergence, topic coherence, and classification accuracy (> 85%) were validated.
    RESULTS: A systematic search of PubMed, Scopus, and Web of Science identified 1867 records. After screening and eligibility assessment, 28 studies were included in the final review. Basket trial designs were more prevalent than umbrella trials, particularly in early-phase oncology and rare disease research. Topic modelling using Latent Dirichlet Allocation (LDA) was performed on 76 relevant articles to identify dominant themes. Statistical convergence, topic coherence, and classification accuracy (> 85%) were validated.
    CONCLUSIONS: Basket and umbrella trials offer substantial advantages for pediatric drug development by increasing trial efficiency, enabling precision targeting, and supporting adaptive decision-making. Their success depends on robust statistical planning, careful use of Bayesian methods, and attention to regulatory guidance.
    Keywords:   Topic Modelling ; Basket Trials; Pediatrics; Platform Trials; Precision Medicine; Statistical Methodologies; Umbrella Trials
    DOI:  https://doi.org/10.1186/s12874-026-02914-0
  48. Expert Rev Pharmacoecon Outcomes Res. 2026 Jun 19.
    Pharmacoeconomics of high-cost therapies: real world challenges.
    Elvira Meni Maria Gkrinia, Andrej Belančić, Ivana Stević, Dinko Vitezić, Slobodan Janković.
       INTRODUCTION: The emergence of high-cost therapies, particularly in oncology, rare diseases, and advanced therapy medicinal products, has increased the need for robust pharmacoeconomic evaluations to support healthcare decision-making. These innovative interventions often promise substantial clinical benefits but also pose challenges due to limited long-term data, high upfront costs, and uncertain cost-effectiveness.
    AREAS COVERED: This narrative review critically examines key pharmacoeconomic frameworks, e.g. cost-effectiveness analysis and cost-utility analysis, and highlights their limitations in assessing such novel therapies. The role of real-world evidence, advanced modeling techniques, and patient-reported outcomes is explored, alongside the ethical and policy considerations that arise in pricing, access, and reimbursement. Recent literature and case studies involving gene and cell therapies are reviewed, illustrating the complexity of determining value under uncertainty.
    EXPERT OPINION: The paper advocates for a more flexible, transparent, and patient-centered approach to health technology assessment, integrating societal values and dynamic reassessment mechanisms. Such strategies are essential for achieving sustainable access to high-value therapies while maintaining health system efficiency and equity.
    Keywords:  Cost-effectiveness; Cost-utility; Real-world evidence; health technology assessment; novel therapies; pharmacoeconomic evaluation
    DOI:  https://doi.org/10.1080/14737167.2026.2691186
  49. J Med Internet Res. 2026 Jun 18. 28 e86249
    The Open Syndrome Definition as a Machine-Readable Standard for Public Health: Design and Implementation Study.
    Ana Paula Gomes Ferreira, Aleksandar Anžel, Izabel Marcilio, Helen Hughes, Alex J Elliot, Jude Dzevela Kong, Madlen Schranz, Alexander Ullrich, Georges Hattab.
       Background: Case definitions are essential for effectively communicating public health threats. However, the absence of a standardized, machine-readable format poses significant challenges to interoperability, epidemiological research, data sharing, and the application of computational methods, including artificial intelligence. These barriers complicate collaboration across regions and organizations and hinder technological progress in public health.
    Objective: This study aims to propose and release the first open, machine-readable format for representing case and syndrome definitions, together with tools and resources that enable their standardized and scalable use.
    Methods: We developed the Open Syndrome Definition, a structured, machine-readable schema for representing case and syndrome definitions. We compiled official public health case definitions from multiple institutions and converted them into standardized, machine-readable representations using open-source tools. These tools, available through GitHub under the Massachusetts Institute of Technology license, automate the translation of narrative definitions into structured data. We also created a platform for browsing, analyzing, and contributing new definitions on our initiative website.
    Results: The Open Syndrome Definition format enabled consistent, automated representation of case definitions across different diseases and jurisdictions. The conversion tools achieved high semantic fidelity, as assessed by qualitative expert review, between narrative and structured representations, supporting human verification and automated analysis. The dataset and accompanying tools demonstrated structural and semantic interoperability by standardizing definitions from various health systems into a unified format and integrating existing medical ontologies through JSON for Linked Data. To further illustrate practical applicability and downstream usage, we introduced a data filtering prototype that allows users to upload their own datasets and verify the results against the standardized definitions.
    Conclusions: The Open Syndrome Definition establishes a foundation for consistent and machine-readable public health definitions, facilitating reproducible research and interoperability at scale. By enabling systematic data exchange and artificial intelligence-driven analysis, it strengthens public health preparedness and supports more rapid, coordinated responses to emerging health threats.
    Keywords:  AI; artificial intelligence; data standardization; epidemiological monitoring; health information exchange; public health; public health surveillance
    DOI:  https://doi.org/10.2196/86249
  50. Environ Sci Pollut Res Int. 2026 Jun 19.
    Mitochondria at the crossroad: Mechanisms of nanoplastic-induced neurotoxicity and brain accumulation.
    Meesala Krishna Murthy.
      Widespread environmental contamination with nanoplastics (NPs) poses a significant risk to human health, particularly their accumulation in the central nervous system (CNS). This review examines how NPs can breach biological barriers, including the blood-brain barrier (BBB), olfactory system, and gut-brain axis, to access the brain. After their uptake by neurons through endocytosis, NPs primarily accumulate in the mitochondria, triggering cascades of neurotoxic changes in the brain. Existing evidence shows that NP exposure impairs mitochondrial bioenergetics, causes severe oxidative damage, disrupts calcium (Ca2+) signaling, and impairs vital regulatory quality control processes, such as mitophagy. These effects extend throughout the cell, leading to synaptic dysfunction, altered neurotransmitter levels, chronic neuroinflammation, and the activation of various pathways associated with neuronal cell death, such as apoptosis and ferroptosis. However, despite these effects, current studies often have shortcomings, as they tend to use high acute doses instead of chronic exposures. Overall, this review identifies mitochondrial dysfunction as a critical crossroads in NP neurotoxic responses and calls for standardized and environmentally relevant experiments to assess the long-term risks of NP to the brain.
    Keywords:  Blood–brain barrier; Mitochondrial dysfunction; Nanoplastics; Neuroinflammation; Neurotoxicity
    DOI:  https://doi.org/10.1007/s11356-026-37939-x
  51. J Comp Eff Res. 2026 Jun 19. e260110
    Most-Favored-Nation pricing meets Joint Clinical Assessment: early evidence of compounding pressure on European drug launches.
    Sreeram V Ramagopalan, Michael L Ryan.
      
    Keywords:  EU Joint Clinical Assessment; Most-Favored-Nation pricing; advanced therapy medicinal products; international reference pricing; market access; oncology; pharmaceutical launches; rare diseases
    DOI:  https://doi.org/10.57264/cer-2026-0110
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