bims-curels Biomed News
on Leigh syndrome
Issue of 2026–04–12
thirteen papers selected by
Cure Mito Foundation
  1. Ophthalmic manifestations of mitochondrial disorders.
  2. Non-invasive biomarkers for diagnosis and monitoring of primary mitochondrial diseases.
  3. MitoEdit: A pipeline for optimizing mtDNA base editing and predicting bystander effects.
  4. Public support for mitochondrial donation: an Australian knowledge and attitudes study.
  5. Mitochondrial Transfer to Endothelial Cells: Mechanisms, Evidence, and Therapeutic Potential.
  6. Mitochondrial transplantation in lung diseases: From mechanisms to application prospects.
  7. The role of real-world data and real-world evidence in advancing regulatory science and targeted therapeutics: a narrative review from the United States perspective.
  8. Optimized ND4 allotopic expression for gene therapy of Leber's hereditary optic neuropathy.
  9. A scalable embryonic stem cell-based platform for efficient generation of mitochondrial DNA mutant mice.
  10. Therapeutic potential of vagus nerve stimulation in neurodegenerative diseases: research progress and mechanisms.
  11. Diagnosis of pediatric mitochondrial diseases via targeted next-generation sequencing (NGS): real-world data with the Blueprint Genetics® platform.
  12. Unifying the odyssey: artificial intelligence for rare disease diagnosis and therapy.
  13. Small but mighty: mitochondrial DNA at the centre of retrograde signalling.
  1. Prog Retin Eye Res. 2026 Apr 03. pii: S1350-9462(26)00032-7. [Epub ahead of print] 101466
    Ophthalmic manifestations of mitochondrial disorders.
    Megan F Baxter, Grace A Borchert, Emma L Blakely, Claire W Ruan, Robert E MacLaren, Robert McFarland, Robert W Taylor.
      Mitochondrial diseases are the most common group of inherited neurometabolic disorders and frequently involve multiple organ systems with high energy demands. Ophthalmic manifestations are a common occurrence in affected individuals and may be the earliest or predominant clinical feature. However, the marked clinical heterogeneity of mitochondrial eye disease often delays recognition and therefore diagnosis. Mitochondria play a central role in cellular metabolism through the process of oxidative phosphorylation. Genetic mutations in either nuclear DNA (nDNA) or mitochondrial DNA (mtDNA) can impair this key metabolic process leading to clinical disease. Diagnosing such mitochondrial diseases is however often complicated - the same genetic change can result in different symptoms (variable expressivity); different genes can cause similar conditions (allelic and locus heterogeneity); a single genetic change may affect multiple body systems (pleiotropy); and the proportion of affected mitochondrial DNA molecules can vary between tissues (mtDNA heteroplasmy). While the diagnostic process will certainly be influenced by the initial clinical presentation, perhaps more important is clinician awareness and early consideration of an underlying mitochondrial disorder. Early and accurate molecular genetic diagnosis is both available and essential, not only for prognostication and management, but also for reproductive counselling, access to appropriate clinical trials, cascade testing of relevant family members and consideration of emerging mitochondrial therapeutics(1,2). In this review, we summarise the biochemical and genetic foundations of mitochondrial eye disease, describe the spectrum of clinical phenotypes, outline diagnostic approaches and considerations, and highlight the importance of precise early diagnosis in guiding management and reproductive decision-making.
    Keywords:  mitochondria; mitochondrial counselling; ophthalmology
    DOI:  https://doi.org/10.1016/j.preteyeres.2026.101466
  2. J Neurol. 2026 Apr 10. pii: 263. [Epub ahead of print]273(5):
    Non-invasive biomarkers for diagnosis and monitoring of primary mitochondrial diseases.
    Ignazio Giuseppe Arena, Shamini Saravanabavan, Rita Horvath, Jelle van den Ameele.
      Primary mitochondrial diseases (PMDs) represent a clinically and genetically heterogeneous group of disorders characterized by impaired oxidative phosphorylation and multisystem involvement, commonly affecting the nervous system. As therapeutic development accelerates, there is a growing need for robust biomarkers capable of supporting diagnosis, stratifying patient subgroups, monitoring disease progression, and providing sensitive pharmacodynamic readouts for clinical trials. This review summarizes recent advances in three major non-invasive biomarker domains relevant to PMDs: circulating serum and molecular biomarkers, functional and digital endpoints, and neuroimaging modalities. Circulating markers, such as FGF21, GDF15, NfL, and NAD⁺-related signatures, have each been proposed for diagnosis and to follow disease progression, while multi-omics approaches are paving the way toward integrated molecular phenotyping. Digital health technologies, including accelerometry and gait analytics, enable objective quantification of real-world functional impairment, although disease-specific validation remains an unmet need. Neuroimaging offers mechanistic insights through metabolic (MRS, CEST), perfusion (ASL), and molecular modalities (mitochondrial PET tracers). Cutting-edge tools, such as Multi-Spectral Optoacoustic Tomography (MSOT), Raman spectroscopy, and Near-Infrared Spectroscopy (NIRS), promise real-time or spatially resolved assessment of mitochondrial function. Together, these developments outline multidimensional biomarker approaches for PMDs, with the potential to directly measure target engagement and clinically meaningful phenotypes in future therapeutic trials. Future progress will depend on longitudinal validation, harmonized acquisition protocols, and the integration of multimodal platforms to support upcoming therapeutic trials and precision medicine strategies.
    Keywords:  Biomarkers; Clinical trials; Digital health technologies; Functional endpoints; Magnetic resonance imaging; Mitochondrial disease; Neuroimaging; Phenotyping; Positron emission tomography; Precision medicine; Wearable devices
    DOI:  https://doi.org/10.1007/s00415-026-13794-1
  3. Comput Struct Biotechnol J. 2025 ;27 1673-1676
    MitoEdit: A pipeline for optimizing mtDNA base editing and predicting bystander effects.
    Devansh Shah, Kelly McCastlain, Ti-Cheng Chang, Xun Zhu, Gang Wu, Mondira Kundu.
      Human mitochondrial DNA (mtDNA) mutations are causally implicated in maternally inherited mitochondrial respiratory disorders; however, the role of somatic mtDNA mutations in both late-onset chronic diseases and cancer remains less clear. Recent advances in mtDNA base editing technologies offer exciting opportunities to model and study these mutations. However, current approaches are hindered by the challenge of unintended bystander edits, which are often identified only through labor-intensive empirical testing, leading to inefficiencies in construct development. To address this limitation, we developed MitoEdit, an innovative computational tool designed to optimize mtDNA base editing by leveraging empirical base editor patterns. MitoEdit enables users to input DNA sequences in a simple text-based format, specify the target base position and define the desired modification. The tool outputs a list of candidate target windows, predicts the number and functional impact of bystander edits and provides flanking nucleotide sequences tailored for TALE (transcription activator-like effectors) array protein binding. In silico evaluations demonstrate that MitoEdit accurately predicts the majority of bystander edits, reducing the number of constructs that need to be tested empirically. By streamlining the design process, MitoEdit accelerates the development of mitochondrial base editing constructs, thereby facilitating functional studies and enabling faster discovery. Ultimately, MitoEdit has the potential to advance disease modeling and support the development of therapeutic strategies for mitochondrial-related disorders.
    Keywords:  Base editing; Genome engineering; Mitochondria; mtDNA
    DOI:  https://doi.org/10.1016/j.csbj.2025.04.027
  4. Reprod Biomed Online. 2026 Jan 12. pii: S1472-6483(26)00005-2. [Epub ahead of print]52(6): 105464
    Public support for mitochondrial donation: an Australian knowledge and attitudes study.
    Ezra Kneebone, Zachary Russell, Ainsley J Newson, Chris Degeling, Karinne Ludlow, Narelle Warren, Catherine Mills.
       RESEARCH QUESTION: What does the Australian public know about mitochondrial donation and think about its potential clinical implementation?
    DESIGN: 1042 people aged ≥18 years living in Australia completed an online anonymous survey between October and December 2022. Participants were recruited through a market research company. The survey included multiple choice and Likert-scale questions gauging respondents' knowledge and attitudes. Bivariate analysis investigated differences in support for mitochondrial donation based on different sociodemographic groups.
    RESULTS: Just 19% of respondents had ever heard of mitochondrial donation prior to participation (n = 202). The average level of agreement with the statement 'If the clinical trial proves mitochondrial donation is safe, I support it becoming available in Australia' was 3.36 out of a possible 4, indicating agreement. Significant differences in the average agreement level were reported across the different 'prior use of assisted reproductive technology', 'sexual orientation', 'genetic condition' and 'mitochondrial disease' groups; however, the average level of agreement in each group was consistently >3.
    CONCLUSIONS: The findings indicate broad public support for the clinical implementation of mitochondrial donation in Australia, provided that clinical trials demonstrate its safety. Although these results may not extrapolate directly to other contexts, they may guide other jurisdictions in considering their position towards mitochondrial donation.
    Keywords:  Assisted reproductive technology; Mitochondrial diseases; Mitochondrial replacement techniques; Public opinion
    DOI:  https://doi.org/10.1016/j.rbmo.2026.105464
  5. Circ Res. 2026 Apr 10. 138(8): e326982
    Mitochondrial Transfer to Endothelial Cells: Mechanisms, Evidence, and Therapeutic Potential.
    Gwang-Bum Im, Juan M Melero-Martin.
      Mitochondria are increasingly recognized as central regulators of vascular health, shaping endothelial cell function through roles that extend far beyond energy production. In addition to coordinating redox balance, calcium dynamics, and biosynthetic support, recent studies have revealed that mitochondria participate in intercellular communication, with evidence of transfer events emerging in vascular contexts. Parallel efforts have advanced the deliberate delivery of exogenous mitochondria from preclinical proof-of-principle studies to first-in-human trials, demonstrating that freshly isolated organelles can be harvested and administered in real-time to critically ill patients with favorable early outcomes. The mechanisms underlying these benefits remain incompletely defined, and strategies for efficient and scalable delivery are still emerging. In this review, we prioritize recent evidence linking mitochondrial function to endothelial cell physiology, highlight the nascent but growing field of mitochondrial transfer in the vasculature, and examine how mitochondrial transplantation is evolving from experimental concept to clinical translation. Together, these advances point to new therapeutic avenues for preserving vascular integrity and treating disease.
    Keywords:  cell communication; endothelial cells; mitochondria; regenerative medicine; therapeutics
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.326982
  6. Genes Dis. 2026 Jul;13(4): 101856
    Mitochondrial transplantation in lung diseases: From mechanisms to application prospects.
    Haoneng Wu, Qiuran Zhao, Ying Zhao, Jinguang Bai, Junxi Pan, Songling Huang.
      Mitochondria are double-membrane organelles in eukaryotic cells, which play an important role in energy metabolism, cell cycle and apoptosis. Therefore, mitochondrial abnormalities can affect various physiological and pathological processes. Extensive research over a long period of time has shown that mitochondrial dysfunction is considered a hallmark of several diseases, including cardiovascular diseases, neurodegenerative diseases, respiratory diseases, and even cancer. Mitochondrial transplantation has emerged in recent years as a novel approach for treating mitochondria-related diseases. This therapy involves transferring viable, functionally intact mitochondria into cells or tissues, either directly or indirectly, to replace dysfunctional mitochondria and restore mitochondrial function, thereby achieving therapeutic goals. Research has indicated that mitochondrial transplantation can alleviate the progression of lung diseases and improve disease outcomes. In this review, we explore the mechanisms underlying mitochondrial dysfunction in lung disease and the potential application of mitochondrial transplantation in the treatment of lung disease.
    Keywords:  Lung disease; Mitochondrial dysfunction; Mitochondrial transplantation; Oxidative stress; Respiratory system
    DOI:  https://doi.org/10.1016/j.gendis.2025.101856
  7. Per Med. 2026 Apr 04. 1-8
    The role of real-world data and real-world evidence in advancing regulatory science and targeted therapeutics: a narrative review from the United States perspective.
    Emily Nagel, Youssef M Roman.
      Randomized controlled trials (RCTs) encounter feasibility gaps when addressing rare genetic disorders and molecularly defined patient subgroups. The U.S. Food and Drug Administration has increasingly integrated real-world evidence (RWE) into the regulatory lifecycle. The objective of this article is to analyze the regulatory evolution following the 21st Century Cures Act and evaluate landmark drug approvals and expansions where real-world data (RWD) provided the primary or supplementary evidentiary foundation. A structured search of electronic databases, including PubMed, Embase, and Web of Science, was performed to identify relevant peer-reviewed articles. The tumor-agnostic approval of pembrolizumab demonstrated how RWE can establish clinical utility across multiple cancer types sharing specific biomarkers. For rare diseases like N-acetylglutamate synthase deficiency (carglumic acid), RWE provided essential external comparators where RCTs were impossible. In cystic fibrosis (ivacaftor), the U.S. Cystic Fibrosis Foundation Patient Registry facilitated indication expansions to ultra-rare genetic variants through longitudinal real-world outcomes. RWE proved vital for post-market surveillance in populations typically excluded from trials. While technical challenges in data interoperability and ethical concerns regarding genomic privacy remain, RWE offers a dynamic model that accelerates access to targeted therapies. The integration of high-fidelity RWD ensures that the safety and efficacy of precision medicines are validated within the complex global clinical practice.
    Keywords:  Real-world evidence; U.S. food and drug administration; data governance; drug development; pharmacovigilance; precision medicine; real-world data; regulatory affairs
    DOI:  https://doi.org/10.1080/17410541.2026.2655298
  8. Front Bioeng Biotechnol. 2026 ;14 1765995
    Optimized ND4 allotopic expression for gene therapy of Leber's hereditary optic neuropathy.
    Evgeniy V Lapshin, Alexander D Egorov, Alexander S Malogolovkin, Nizami B Gasanov, Svetlana A Smirnikhina, Vyacheslav Yu Tabakov, Alexander V Karabelsky.
      Leber's hereditary optic neuropathy (LHON) is a mitochondrial disorder characterized by central vision loss, primarily resulting from mutations disrupting the electron transport chain. The most prevalent LHON-causing mutation is mt.11778G>A in the mitochondrial MT-ND4 gene, which encodes a critical subunit of complex I. Allotopic expression, a promising gene therapy strategy, aims to deliver a functional nuclear version of ND4 into the cell nucleus and target the resulting protein to the mitochondria. The efficiency of this approach critically depends on the mitochondrial targeting signal used. In this study, we screened five different MTS sequences to optimize the allotopic expression of ND4 in a HEK-293 cellular model of LHON harboring the mt.11778G>A mutation. We identified MTS-cox8k as the most effective signal for restoring mitochondrial function. Treatment with this construct significantly mitigated key pathological hallmarks: reactive oxygen species decreased by 72%, mitochondrial calcium levels dropped by 47%, and mitochondrial membrane potential (ΔΨm) increased by 38%. These results underscore the therapeutic potential of allotopic ND4 expression and highlight the critical importance of MTS optimization for developing effective treatments for mitochondrial diseases like LHON.
    Keywords:  Leber’s neuropathy; gene therapy; mitochondrial function test; mitochondrial localization; mitochondrial transport
    DOI:  https://doi.org/10.3389/fbioe.2026.1765995
  9. Proc Natl Acad Sci U S A. 2026 Apr 14. 123(15): e2535453123
    A scalable embryonic stem cell-based platform for efficient generation of mitochondrial DNA mutant mice.
    Weiwei Fan, Tae Gyu Oh, Lillian Crossley, Hunter Robbins, Mingxiao He, Yang Dai, Morgan L Truitt, Annette R Atkins, Michael Downes, Ronald M Evans.
      Mitochondria are central to energy metabolism and cellular signaling, and mutations in mitochondrial DNA (mtDNA) can disrupt these processes and contribute to human disease. However, progress in defining how mtDNA variation influences adaptation, pathophysiology, and disease susceptibility has been limited by the lack of suitable animal models. Although recent base-editing approaches enable direct mtDNA modification, their low efficiency restricts the generation of diverse models reflecting human mtDNA variation. Here, we develop a scalable embryonic stem (ES) cell-based platform for efficient production of mtDNA mutant mice. Random mutagenesis using an error-prone mtDNA polymerase generates a broad spectrum of mtDNA mutations, which are transferred into ES cells via a multiplexed cybrid fusion strategy coupled with sensitive mutation detection. Optimized ES cell-embryo aggregation enables robust contribution of mtDNA mutant ES cells to host embryos, producing chimeric mice with germline transmission. Using this platform, we generate a library of 155 donor fibroblast lines carrying distinct homoplasmic single-nucleotide mtDNA mutations that produce diverse mitochondrial phenotypes, including impaired oxidative phosphorylation, increased reactive oxygen species, and altered mitochondrial membrane potential. We further generate 34 female C57BL/6 ES cell lines harboring 18 mtDNA mutations across a range of heteroplasmy levels, yielding multiple chimeric mice and achieving germline transmission for one mutation. These data reveal a strong correlation between mitochondrial function and early embryonic development, suggesting a minimal energetic threshold required for normal development. This scalable resource enables systematic investigation of mtDNA variation in physiology, adaptation, disease mechanisms, and therapeutic development.
    Keywords:  ES cell; aggregation; mouse model; mtDNA; transgenesis
    DOI:  https://doi.org/10.1073/pnas.2535453123
  10. Front Immunol. 2026 ;17 1811107
    Therapeutic potential of vagus nerve stimulation in neurodegenerative diseases: research progress and mechanisms.
    Qian Hu, Jiasheng Wang, Ruiyang Cao, Wenkai Liu, Lifeng Wang.
      Neurodegenerative diseases are a group of chronic, progressive neurological disorders caused by the degeneration and functional loss of neurons and glial cells, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD). Although numerous treatments are available for these diseases, therapeutic outcomes remain unsatisfactory because of their poorly understood pathogeneses of these diseases. Vagus nerve stimulation (VNS), a noninvasive or minimally invasive neuromodulation technique, has shown significant potential in mitigating neurodegenerative conditions. This review explores the mechanisms of action and clinical applications of VNS in neurodegenerative diseases, providing novel insights for the development of novel treatments.
    Keywords:  mitochondrial dysfunction; neurodegenerative diseases; neuroinflammation; oxidative stress; vagus nerve stimulation
    DOI:  https://doi.org/10.3389/fimmu.2026.1811107
  11. Orphanet J Rare Dis. 2026 Apr 09. pii: 143. [Epub ahead of print]21(1):
    Diagnosis of pediatric mitochondrial diseases via targeted next-generation sequencing (NGS): real-world data with the Blueprint Genetics® platform.
    Annamaria Sapuppo, Grete Francesca Privitera, Vincenzo Sortino, Piero Pavone, Agata Polizzi, Martino Ruggieri, Raffaele Falsaperla.
      
    Keywords:  Blueprint genetics; Buccal swab; Clinical phenotype; Diagnostic sensitivity; Early onset; Mitochondrial diseases; Next-generation sequencing; Pediatric neurology
    DOI:  https://doi.org/10.1186/s13023-026-04213-9
  12. Health Technol (Berl). 2026 Mar 10.
    Unifying the odyssey: artificial intelligence for rare disease diagnosis and therapy.
    Mai-Lan Ho, Marinka Zitnik, Ronen Azachi, Sanjay Basu, Pranav Rajpurkar, Richard Sidlow.
       Purpose: To summarize current challenges in rare disease (RD) diagnosis and therapy, highlight recent advances in artificial intelligence (AI) for RDs, and propose a model future state for RD patient care.
    Methods: Multidisciplinary expert-led narrative review summarizing modern practical challenges and rate-limiting steps in RD patient care, citing key clinical and research considerations with respect to regulatory and economic constraints.
    Results: Over 10,000 known RDs collectively affect 1 in 10 Americans, a total of over 30 million people. Annually, RDs account for over $1 trillion of annual US healthcare expenditures. Despite advances in genomic medicine, it takes 5-8 years on average to obtain an accurate diagnosis, and less than 5% of RDs currently have FDA-approved therapies. In this article, we review the history of RD diagnosis and current healthcare gaps underlying the major failures in patient care. Next, we will highlight emerging advances in genomic medicine and AI that are rapidly changing the RD landscape. Finally, we propose a target future state that integrates agentic AI for diagnosis and therapy with human-in-the-loop feedback.
    Conclusions: The rare disease diagnostic and therapeutic odyssey represents healthcare's most persistent failure mode. Ongoing challenges for clinical implementation involve biological modeling, manufacturing bottlenecks, and clinical trial design. We propose strategies for artificial intelligence to restructure the traditional sequence of diagnosis-then-therapy into a proactive orchestrated system delivering personalized cures at scale.
    Keywords:  Artificial intelligence; Genetic; Genome; Omics; Orphan; Rare
    DOI:  https://doi.org/10.1007/s12553-026-01057-y
  13. Cell Commun Signal. 2026 Apr 06.
    Small but mighty: mitochondrial DNA at the centre of retrograde signalling.
    Eve Harding, Veronica Bazzani, Carlo Vascotto.
      
    Keywords:  Mito-nuclear crosstalk; Mitochondria; Mitochondrial DNA; Mitochondrial-derived Peptides; Mitochondrial-derived non-coding RNAs; Retrograde signalling
    DOI:  https://doi.org/10.1186/s12964-026-02858-4
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