bims-curels 2026-06-28 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2026–06–28
thirteen papers selected by
Cure Mito Foundation

Gene Therapy Tools for Diseases Caused by Mutations of the Mitochondrial Genome.
Mitochondrial DNA heteroplasmy drives cortical neuronal disturbances in human organoids harbouring the common m.3243A>G mutation.
Clinical development in primary mitochondrial diseases at a translational inflection point: Lessons, mechanisms, and emerging therapeutic strategies.
Targeting mtDNA to Modulate Mitochondrial Dysfunction in Neurodegenerative Diseases.
Evolving landscape of drug development for pediatric rare diseases-from successes to strategies for addressing unmet needs.
Building CRISPR-Based Gene-Editing Platforms for Personalized Medicine: The Next Step in Interventional Genetics.
After the Diagnosis.
Generation and characterization of a human induced pluripotent stem cell line (SNUi001-A) harboring the MT-ND4 m.11778G>A mutation.
Methodological Advances in Mitochondrial DNA Analysis for Forensic Genetics.
Shifting sands: How parents engage with the idea of their child's death.
Deciding "what" to screen for and "when": The importance of natural history information.
Cell type-specific contextualisation of the human phenome: towards the systematic treatment of all rare diseases.
Real-World Evidence for Drug Approvals: Moving Toward Greater Regulatory Clarity.

Int J Mol Sci. 2026 Jun 18. pii: 5517. [Epub ahead of print]27(12):

Gene Therapy Tools for Diseases Caused by Mutations of the Mitochondrial Genome.

Vladislav Simonov, Sergey Rastorguev.

  Mitochondrial DNA (mtDNA) mutations are associated with a diverse spectrum of diseases and pose a significant threat to human health. Despite their importance as therapeutic targets, the unique structural and electrochemical properties of mitochondria-most notably the impermeable inner mitochondrial membrane and the high membrane potential-present formidable challenges for the targeted delivery of therapeutic agents. Currently, there are no approved curative treatments for patients harboring pathogenic mtDNA mutations. In this review, we discuss recent advancements in gene therapy for mitochondrial genome-related disorders, with a particular focus on allotopic expression of mtDNA-encoded genes and mitochondrial genome editing technologies. We conclude that allotopic expression currently stands as the most promising approach for near-term clinical implementation. But we also pay great attention to programmable nucleases and base editors utilizing RNA-independent DNA recognition which are evolving with remarkable speed.

Keywords:  DdCBE; allotopic expression; gene therapy; mitoCRISPR; mitoTALEN; mitoZFN; mitochondrial manipulation; mtDNA

DOI:  https://doi.org/10.3390/ijms27125517
Nat Commun. 2026 Jun 21.

Mitochondrial DNA heteroplasmy drives cortical neuronal disturbances in human organoids harbouring the common m.3243A>G mutation.

Denisa Hathazi, Camilla Lyons, Daniel Lagos, Oliver Podmanicky, Mariana Zarate-Mendez, Yu Nie, Juliane S Müller, Kieren S J Allinson, Huw Naylor, Majlinda Lako, Ibrahim Elsharkawi, Irena Muffels, Eva Morava, Tamas Kozicz, Patrick Chinnery, András Lakatos, Rita Horvath.

Mitochondrial diseases frequently affect the brain leading to severe and disabling neurological symptoms. The heteroplasmic m.3243 A > G mutation in MT-TL1, encoding mt-tRNALeu, is responsible for ~80% of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), which is one of the most characteristic mitochondrial syndromes, leading to disability and early death. There are no animal models harbouring this mutation to provide precise mechanistic insights informing therapeutic interventions. Here, we generate a human iPSC-derived cerebral organoid slice model that recapitulates cortical architecture and mitochondrial pathology. Using biological assays and single-cell RNA sequencing, we uncover heteroplasmy-dependent transcriptional shifts and changes in key cellular processes in cortical neurons. Organoids with high heteroplasmy show a predominant impairment of deep-layer neurons triggered by mitochondrial stress, leading to axonal degeneration and apoptosis, similar to brain autopsy of a MELAS patient. Our findings provide insights into the vulnerability of long-range projection neurons in mitochondrial diseases, advancing our understanding of disease mechanisms with a view to potential therapeutic strategies.

DOI: https://doi.org/10.1038/s41467-026-74103-y
Biomed Pharmacother. 2026 Jun 26. pii: S0753-3322(26)00735-3. [Epub ahead of print]201 119699

Clinical development in primary mitochondrial diseases at a translational inflection point: Lessons, mechanisms, and emerging therapeutic strategies.

Li-Tzu Wang, Han-Ying Jhuang.

  Clinical development for primary mitochondrial diseases (PMDs) has spanned more than two decades, yet therapeutic success remains limited. In this Review, we provide a comprehensive, pharmacology-focused analysis of the PMD clinical trial landscape and identify key mechanistic and translational determinants underlying recent progress. A systematic survey of ClinicalTrials.gov covering January 2010 to April 2026 identified 159 registered studies across PMD subtypes after deduplication, including 110 interventional trials. Progress has been constrained by marked genetic and phenotypic heterogeneity, small and geographically dispersed patient populations, and the lack of validated pharmacodynamic and disease-specific endpoints. Consequently, several well-designed late-stage trials have yielded negative or inconclusive outcomes, and regulatory approvals have historically been scarce. Recent advances, however, indicate a shift in trajectory. Four therapies have achieved regulatory authorization, including idebenone for Leber hereditary optic neuropathy, taurine for MELAS, and recent FDA approvals of doxecitine and doxribtimine (Kygevvi) for thymidine kinase 2 deficiency and elamipretide (FORZINITY) for Barth syndrome. These successes share a convergent translational framework integrating mechanism-based pharmacology, genotype-driven patient selection, and biologically aligned endpoints. Clinical activity has also accelerated, with approximately half of PMD interventional trials initiated since 2020 and 50 studies currently active or recruiting. Emerging strategies include NAD⁺ augmentation, soluble guanylate cyclase stimulation, mTOR modulation, gene therapies, and heteroplasmy-targeting approaches. Collectively, these advances mark an emerging inflection point and suggest a path toward greater regulatory success in the coming decade.

Keywords:  Clinical trials; Gene therapy; Leber hereditary optic neuropathy; MELAS; Primary mitochondrial disease; Translational medicine; Trial design

DOI:  https://doi.org/10.1016/j.biopha.2026.119699
Mol Neurobiol. 2026 Jun 26. pii: 728. [Epub ahead of print]63(1):

Targeting mtDNA to Modulate Mitochondrial Dysfunction in Neurodegenerative Diseases.

Sanket Pramanik, Biplab Debnath, Aganta Chakraborty, Anas Islam, Shrabasti Mullick, Priya Chaudhary, Rajarshi Nath, Dinesh Kumar Chellappan, Mohini Mondal, Sumel Ashique.

  Mitochondrial dysfunction is a common pathological feature of neurodegenerative diseases namely Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Although these disorders are primarily driven by disease-specific genetic and proteopathic mechanisms, increasing evidence suggests that secondary mitochondrial DNA (mtDNA) damage and heteroplasmy shifts may exacerbate bioenergetic failure and neuronal vulnerability. Distinguishing primary disease mechanisms from downstream mtDNA alterations is critical to accurately evaluate emerging therapeutic strategies. Recent advances in mtDNA-targeted genome editing have enabled the direct manipulation of mitochondrial genomes. Mitochondrially targeted zinc finger nucleases and TALENs can selectively alter mutant mtDNA to induce heteroplasmy shifts, whereas DddA-derived cytosine base editors allow precise base editing without double-strand breaks. However, each platform has distinct limitations related to the target scope, off-target risk, design complexity, and delivery efficiency. The application of CRISPR/Cas-based systems to mammalian mtDNA remains constrained by the unresolved challenges in guiding RNA import. This review critically examines mitochondrial dysfunction and mutant mtDNA accumulation in neurodegenerative diseases. It also evaluates current and emerging mtDNA-editing techniques, and highlights key translational barriers. We highlighted that mtDNA-targeted interventions can be a promising approach for disease-modifying or adjunctive strategies, rather than curative approaches.

Keywords:  DdCBE (DddA-derived Cytosine Base Editors); Heteroplasmy Correction; MitoTALENs; Mitochondria-Targeted CRISPR/Cas Systems; Mitochondrial Genome Editing; Neurodegenerative Disorders; Oxidative Stress & Mitochondrial Dysfunction; Precision Medicine

DOI:  https://doi.org/10.1007/s12035-026-06008-2
J Pharm Sci. 2026 Jun 20. pii: S0022-3549(26)00250-9. [Epub ahead of print] 104401

Evolving landscape of drug development for pediatric rare diseases-from successes to strategies for addressing unmet needs.

Sydney Stern, Yifei Zhang, Michelle Pressly, Xinning Yang, Susan Abdel-Rahman, Jie Wang, Mei-Chuan Chen, Chun-Han Chen, Salvatore Pepe, Mary Doi, Gilbert J Burckart, Lynne P Yao, Robert Schuck, Jane Pf Bai.

  Over 7,000 rare diseases have been identified and 50-75% of them impact pediatrics. Pediatric rare diseases represent a critical unmet need, as nearly 95% of these conditions lack FDA-approved therapies. Progress, through scientific innovation and focused public health initiatives, has contributed to addressing the unmet needs of patients with rare diseases and promoting the development of novel therapies. However, key challenges remain, including demonstrating meaningful effects in small, heterogeneous populations, lack of validated biomarkers, designing trials that maximize patient participation, and optimizing doses often without independent dose-finding studies. In this review, we describe the landscape of FDA-approved products for rare diseases and highlight examples of pediatric drug development where approvals were informed by novel strategies. Acknowledging that rare disease drug development requires flexibility and innovations, these approaches include leveraging adult data for diseases affecting both adults and pediatric populations, extrapolating efficacy and/or safety evidence across pediatric age groups in diseases that occur only in pediatric populations, and the use of mechanistic modeling, biomarkers, innovative trial designs, and new approach methodologies to bridge gaps in knowledge for successful development of drug products for these diseases. Reviews of the ontogeny of drug metabolizing enzymes and transporters that affect drug disposition are summarized to lay the foundation for mechanistic modeling. Lastly, future perspectives illuminate the path forward to meet the unmet medical needs for treating rare pediatric diseases.

Keywords:  Pharmacodynamic biomarkers; drug-metabolizing enzymes; mechanistic modeling; ontogeny; pediatric extrapolation; rare diseases; transporters

DOI:  https://doi.org/10.1016/j.xphs.2026.104401
Genes (Basel). 2026 May 30. pii: 631. [Epub ahead of print]17(6):

Building CRISPR-Based Gene-Editing Platforms for Personalized Medicine: The Next Step in Interventional Genetics.

Sebastian Hernandez Rodriguez, Toshifumi Yokota.

  Recent advances in CRISPR technology have expanded beyond traditional double-strand break-based genome editing to include base editors and prime editors, enabling precise and programmable sequence modifications. This evolution marks a shift from conventional mutation correction toward platform-based therapeutic systems capable of targeting a broad spectrum of pathogenic variants. Such versatility holds promise for addressing a substantial proportion of known disease-causing mutations in rare monogenic disorders. This review discusses the technological progression of CRISPR systems, highlighting the principles, applications, and limitations of emerging editing modalities. We will explore their translation into personalized gene therapies, emphasizing delivery challenges, off-target safety, and the need for regulatory innovation. The paper will also introduce the concept of interventional genetics, an emerging medical framework linking genomic diagnosis directly to therapeutic intervention through adaptive gene-editing platforms. Finally, we will outline strategies for establishing unified, scalable, and regulatory-ready editing platforms that can accelerate the clinical implementation of individualized therapies for rare diseases.

Keywords:  CRISPR; gene editing; interventional genetics; monogenic disorders; personalized medicine

DOI:  https://doi.org/10.3390/genes17060631
Adv Kidney Dis Health. 2026 Jan;pii: S2949-8139(26)00028-5. [Epub ahead of print]33(1): 9-14

After the Diagnosis.

Anthony J Bleyer, Stanislav Kmoch.

  The diagnosis of a rare genetic disease begins an odyssey toward treatment and cure for patients, clinicians, and researchers. Even though a treatment may not have been identified, there are many ways in which the clinician can help the patient. Information available to patients and their participation in research is dependent on how many individuals have previously been diagnosed with the condition and how much prior research has been conducted. When only a few cases have been reported, information will be limited to case reports, and each newly diagnosed patient is critical to learning about the disease. As more information becomes available, patient foundations form and researchers develop a long-term interest in the condition. In addition to informing the patient about diagnosis, prognosis, and the genetics of the underlying condition, clinicians should also help to guide the patient toward patient foundations and provide information about research participation to help better characterize the condition and find treatments. In rare disease research, each patient is important in providing clinical information as well as genetic and other biological samples for study. Researchers take this information provided by patients, analyze the data, and provide patients information about their condition. As patients and researchers work together, progress in research occurs, eventually leading to a treatment. The clinician, patient, clinical researcher, and basic scientist are all critical to success toward a potential therapy.

Keywords:  Autosomal dominant tubulointerstitial kidney disease; Kidney; Patient foundations; Rare disease; Rare disease research

DOI:  https://doi.org/10.1053/j.akdh.2026.02.004
Stem Cell Res. 2026 Jun 20. pii: S1873-5061(26)00139-X. [Epub ahead of print]95 104043

Generation and characterization of a human induced pluripotent stem cell line (SNUi001-A) harboring the MT-ND4 m.11778G>A mutation.

Hun Ji Choi, Young Sam Im, Taehun Yoon, Se Hee Min, Jae Ryong Song, Jae Ho Jung.

Leber hereditary optic neuropathy (LHON) is a maternally inherited optic neuropathy caused by mutations in mitochondrial DNA. To facilitate disease modeling and the investigation of pathogenetic mechanisms, we generated an induced pluripotent stem cell (iPSC) line, SNUi001-A, derived from the peripheral blood mononuclear cells (PBMCs) of a patient carrying the m.11778G>A mutation in the MT-ND4 gene. The iPSCs were generated using non-integrating episomal vectors. These reprogrammed cells maintained the patient-specific mutation, expressed key pluripotency markers, and demonstrated the potential for multilineage differentiation into all three germ layers.

DOI: https://doi.org/10.1016/j.scr.2026.104043
Genes (Basel). 2026 May 28. pii: 609. [Epub ahead of print]17(6):

Methodological Advances in Mitochondrial DNA Analysis for Forensic Genetics.

Víctor Daniel Carrillo-Rodríguez, Carina Amalinalli Ruiz-Villavicencio, María Teresa Navarro-Romero, Héctor Rangel-Villalobos, Cecilia Martínez-Campos.

  Mitochondrial DNA (mtDNA) analysis is a fundamental tool in forensic genetics, particularly when biological samples exhibit severe degradation or low nuclear DNA content. Its unique biological characteristics, such as a high copy number per cell, strict matrilineal inheritance, and lack of recombination, enable human identification and reconstruction of maternal lineages in complex contexts, including disaster victim identification, historical cases, and missing persons investigations. This narrative review examines contemporary methodological approaches for investigating the human mitogenome. We discuss recent advancements in extraction and enrichment techniques, emphasizing their efficacy in reducing the interference of nuclear mitochondrial DNA sequences (NUMTs) and enhancing the recovery of informative fragments. Moreover, the shift from traditional Sanger sequencing to Massive Parallel Sequencing (MPS) is examined, as MPS has markedly enhanced the sensitivity and capability of contemporary methods to detect low-frequency heteroplasmies. Additionally, the advent of Third-Generation Sequencing (TGS), exemplified by nanopore platforms, is evaluated, which facilitates the reading of full-length native molecules without the biases introduced by PCR amplification. Despite the interpretive challenges posed by heteroplasmy, contamination, and limitations in population databases, ongoing methodological advances in mitochondrial DNA analysis continue to strengthen its reliability and expand its potential in forensic genetics.

Keywords:  forensic genetics; human identification; massive parallel sequencing; mitochondrial DNA; third-generation sequencing (TGS)

DOI:  https://doi.org/10.3390/genes17060609
Palliat Support Care. 2026 Jun 25. 24 e180

Shifting sands: How parents engage with the idea of their child's death.

Naomi T Katz, Jenny L Hynson, Lynn Gillam.

   OBJECTIVES.: While parental prognostic awareness is a vital concept, its complexity can sometimes be underestimated. Our study aimed to understand how parents of children with serious illness engage with the idea of their child's death from a lived experience perspective.
METHODS.: Bereaved parents of children known to a statewide pediatric palliative care service, who died at the age of 16 years or younger from any medical condition, participated in semi-structured interviews. Reflexive thematic analysis was employed, informed by a phenomenological framework.
RESULTS.: Twenty bereaved parents (6 fathers) participated; children ranged in age from 1 day to 16 years. Findings were categorized into 2 main themes: (1) Daily realities of engaging with the idea of death, with subthemes: variability in contemplating death, conversations with their child, conversations with family and friends, conversations with clinicians, making treatment decisions, and not engaging with death, and (2) factors influencing engagement, with subthemes: implicit factors, changes in clinical condition, and clinician communication.
SIGNIFICANCE OF RESULTS.: Parents' engagement with the idea of their child's death was individual and dynamic. Our findings offer tangible examples of how parents contemplate and operationalize this engagement over time, helping clinicians appreciate the complex and non-binary nature of prognostic awareness. Clinicians should explore how parents engage with the idea of their child's death both during and outside clinical encounters over time, acknowledge their role in supporting and guiding parents, and recognize that there is no single way for parents to process the idea of their child's death.

Keywords:  Prognostic awareness; bereaved parents; death; pediatric palliative care; serious illness

DOI:  https://doi.org/10.1017/S1478951526103046
Am J Hum Genet. 2026 Jun 23. pii: S0002-9297(26)00227-2. [Epub ahead of print]

Deciding "what" to screen for and "when": The importance of natural history information.

Jahnelle Jackson, Jonathan S Berg.

  Genomic medicine promises to leverage research on human genetic variation to improve health. As technology improves, our increasing ability to determine an individual's genomic sequence must be matched with increased understanding of underlying mechanisms of disease and how phenotypes arise because of genetic variation. Knowledge about the etiology of rare monogenic conditions can be leveraged for medical and public health purposes through diagnostic testing and predictive screening. However, policy decisions about the use of genetic and genomic analysis in a predictive setting must consider the penetrance and expressivity of each monogenic condition and how these factors influence the timing of genomic screening and its potential benefits and harms. This means that high-quality data are required on the nature of genetic diseases and how they impact human health across populations. The objective of this paper is to address the inherent challenges in determining the onset of symptoms for rare monogenic conditions and underscore the importance of curating natural history data. By elucidating the natural progression of rare monogenic conditions, we can optimize screening strategies and guide clinical decision-making. Detailed information about natural history is critical to understanding the optimal timing of population screening and subsequent intervention for any given condition.

Keywords:  actionability; age of onset; monogenic; natural history; pediatric; penetrance; population screening; rare disease

DOI:  https://doi.org/10.1016/j.ajhg.2026.06.001
Genome Med. 2026 Jun 26.

Cell type-specific contextualisation of the human phenome: towards the systematic treatment of all rare diseases.

Brian M Schilder, Kitty B Murphy, Hiranyamaya Dash, Yichun Zhang, Robert Gordon-Smith, Jai Chapman, Momoko Otani, Nathan G Skene.

   BACKGROUND: Rare diseases (RDs) are a highly heterogeneous and underserved group of conditions. Most RDs have a strong genetic basis but their causal pathophysiological mechanisms remain poorly understood, limiting the development of targeted therapies.
METHODS: We systematically characterised the cell type-specific mechanisms underlying all genetically defined RD phenotypes by integrating the Human Phenotype Ontology (HPO) with whole-body single-cell transcriptomic atlases from embryonic, foetal, and adult samples. Associations were validated against orthogonal biomedical knowledge graphs and then prioritised by strength of supporting evidence, clinical severity, and gene-therapy compatibility.
RESULTS: We identified significant associations between 201 cell types and 9,575/11,028 (86.7%) phenotypes across 8,628 RDs, substantially expanding knowledge of phenotype-cell type links. Prioritisation by severity (e.g. lethality, motor or mental impairment) and gene-therapy compatibility (e.g. cell type specificity, postnatal treatability) identified candidate phenotypes and cell types for therapeutic targeting.
CONCLUSIONS: We present a scalable, reproducible framework for phenome-wide, cell type-specific mechanism prediction in rare diseases, providing a major step toward systematic therapeutic development for patients across a broad spectrum of serious RDs.
SOFTWARE AND DATA AVAILABILITY: Interactive web portal: https://neurogenomics-ukdri.dsi.ic.ac.uk/. R packages introduced in this study: KGExplorer (https://github.com/neurogenomics/KGExplorer), HPOExplorer (https://github.com/neurogenomics/HPOExplorer), and MSTExplorer (https://github.com/neurogenomics/MSTExplorer). Manuscript analyses and reproducibility code: https://github.com/neurogenomics/rare_disease_celltyping.

Keywords:  Cell type specificity; Gene therapy; Human phenotype ontology; Phenotype-cell type associations; Rare disease; Single-cell transcriptomics; Therapeutic target identification

DOI:  https://doi.org/10.1186/s13073-026-01692-0
Ther Innov Regul Sci. 2026 Jun 22.

Real-World Evidence for Drug Approvals: Moving Toward Greater Regulatory Clarity.

Tala H Fakhouri, Rasika Kalamegham, Nicole Mahoney, Rose Purcell, Mike D'Ambrosio.

Despite a decade of investments and regulatory enthusiasm, real-world evidence (RWE) generated from real-world data (RWD) remains underutilized in drug approvals. Beyond the fundamental need for relevant and reliable RWD, three interdependent operational barriers constrain otherwise fit‑for‑use RWD: (1) FDA submission requirements and data standards policies are centered on CDISC and optimized for traditional trials rather than heterogeneous RWD sources; (2) expectations about when patient‑level datasets must be submitted to FDA and how and when FDA may access or inspect source records are unclear; and (3) uncertainty remains regarding the application of 21 CFR Parts 50/56 to non-interventional studies. On one hand, the resulting regulatory ambiguity around these issues may lead sponsors and data providers to expend resources on RWE that is ultimately unfit for regulatory purposes. On the other, potentially suitable RWD may be ignored. In either case, patient access to effective therapies may be delayed. In this perspective, we offer targeted, actionable recommendations in each category to inform FDA's current efforts to better leverage RWE in regulatory submissions.

DOI: https://doi.org/10.1007/s43441-026-01000-3