bims-curels Biomed News
on Leigh syndrome
Issue of 2025–06–15
eighteen papers selected by
Cure Mito Foundation
  1. Diagnostic Moments in the Rare Disease Life Narratives of Mitochondrial Disease Patients in Germany.
  2. Hepatic bioenergetics and metabolism in mitochondrial disease: insights from the Ndufs4 KO mouse model.
  3. Disruption of adaptive immunity does not attenuate disease in the Ndufs4(-/-) model of Leigh syndrome.
  4. Tissue-specific mitochondrial DNA, MT-TF, pathogenic variants in mitochondrial myopathies.
  5. Acute Management of Neurological Events in Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS) Syndrome: A Case Report.
  6. Open-label pilot study using hydroxytyrosol as dietary supplements in patients with mitochondrial diseases.
  7. Nitric Oxide may Adversely Affect the Metabolism and Viability of Retinal Organoids Derived from Patients with Leber Hereditary Optic Neuropathy.
  8. The burden of mitochondrial disease: healthcare and societal costs.
  9. Advances in Management of Mitochondrial Myopathies.
  10. Mitochondrial Transplantation: A Novel Therapeutic Approach for Treating Diseases.
  11. mitoLEAF: mitochondrial DNA Lineage, Evolution, Annotation Framework.
  12. Mechanism of age-related accumulation of mitochondrial DNA mutations in human blood.
  13. Mitochondrial Transplantation/Transfer: Promising Therapeutic Strategies for Spinal Cord Injury.
  14. Brain Organoids and Assembloids-From Disease Modeling to Drug Discovery.
  15. In Defence of Causing Patients to Worry: Ethical Issues in the Communication of Diagnostic Uncertainty.
  16. Empowering Precision Medicine for Rare Diseases through Cloud Infrastructure Refactoring.
  17. Personalized Medicine in Treating Rare Genetic Disorders: A Review.
  18. Intentional heterogeneity in autologous cell-based gene therapies: strategic considerations for first-in-human trials.
  1. Med Anthropol. 2025 Jun 08. 1-13
    Diagnostic Moments in the Rare Disease Life Narratives of Mitochondrial Disease Patients in Germany.
    Jacquelyne Luce.
      I draw on interviews I conducted in Germany with four individuals who were eventually diagnosed with mitochondrial disease, a category of rare neurogenetic disorders. Rather than the diagnosis of mitochondrial disease serving as a threshold between a before and after, I show how multiple ″diagnostic moments″ generate and shape mitochondrial disease life narratives as affected individuals embody emergent medical knowledge and navigate scientific unknowns. Attending to the plurality of diagnostic moments in rare disease life narratives illuminates the fragmented temporalities and incoherencies of illness experiences, which are often erased by an emphasis on a singular diagnostic moment.
    Keywords:  Germany; diagnosis; diagnostic moments; mitochondrial disease; narrative; rare disease
    DOI:  https://doi.org/10.1080/01459740.2025.2504366
  2. Metabolomics. 2025 Jun 11. 21(4): 76
    Hepatic bioenergetics and metabolism in mitochondrial disease: insights from the Ndufs4 KO mouse model.
    Karin Terburgh, Nastassja Sweeney, Roan Louw.
       INTRODUCTION: Mitochondrial complex (CI) deficiency frequently manifests as a severe neurometabolic disorder called Leigh syndrome (LS). Research on the Ndufs4 knockout (KO) mouse model has identified neuronal vulnerability to CI deficiency as a major driver of the disease, yet its effects on hepatic function remain unclear. Considering the importance of the liver, and its interconnection with the brain, in regulating whole-body metabolic balance, further investigation into the effects of whole-body Ndufs4 KO on the liver is warranted.
    OBJECTIVES: This study investigated liver bioenergetics and metabolism in Ndufs4 KO and WT mice at the late stage of LS.
    METHODS: Bioenergetic investigations of liver mitochondria (n ≥ 3) included spectrophotometric respiratory chain enzyme (CI-IV) activity assays and high-resolution respirometry. Hypothesis-generating metabolomics of whole-liver extracts (n ≥ 19) utilised 1H-NMR, GC-TOFMS, and LC-MS/MS. Significant alterations were identified via t-tests and effect size calculations.
    RESULTS: Ndufs4 KO livers displayed a significant ~ 86% reduction in CI activity and a ~ 43% decrease in CI contribution to CI + II-driven respiration. CII-driven respiration remained unaffected, providing the predominant electron flux in both genotypes. Metabolic profiling revealed widespread perturbations in Ndufs4 KO hepatic metabolism including glucose-, amino acid-, purine/pyrimidine metabolism and the TCA-cycle.
    CONCLUSION: Despite severe CI deficiency, respiration in the Ndufs4 KO liver remains largely unaffected due to reliance on CII. Nonetheless, advanced LS significantly disrupts liver metabolism, with O-GlcNAcylation and mTOR signalling suggestsed as key areas for future investigation. Altogether, our findings underscore the importance of interorgan metabolic dynamics and the liver-brain axis in neurometabolic disorders like LS.
    Keywords:   Ndufs4 knockout mice; Complex I deficiency; Leigh syndrome; Liver metabolism
    DOI:  https://doi.org/10.1007/s11306-025-02275-7
  3. PLoS One. 2025 ;20(6): e0324268
    Disruption of adaptive immunity does not attenuate disease in the Ndufs4(-/-) model of Leigh syndrome.
    Allison R Hanaford, Asheema Khanna, Vivian Truong, Katerina James, Ryan Liao, Yihan Chen, Michael Mulholland, Ernst-Bernhard Kayser, Kino Watanabe, Erin Shien Hsieh, Philip G Morgan, Surojit Sarkar, Vandana Kalia, Simon C Johnson.
      Leigh syndrome (LS) is the most common pediatric presentation of genetic mitochondrial disease and characterized by neurological and metabolic abnormalities. The hallmark of the disease is the presence of progressive, bilateral, symmetric neurodegenerative lesions in the brainstem and/or basal ganglia. Recent studies in the Ndufs4(-/-) mouse model of LS indicate that disease is causally driven by the immune system. Both microglia and peripherally originating macrophages are enriched in the lesions of Ndufs4(-/-) mice and pharmacologic elimination of these cell types prevents disease indicating a crucial role for innate immune cells. Here, we investigated the role of the adaptive immune system in Ndufs4(-/-) disease pathogenesis. We crossed Ndufs4(-/-) mice with mice expressing a null form of interleukin 2 receptor gamma (Il2rg) and monitored disease onset and progression. Il2rg knockout (KO) mice have dramatically depleted numbers of B-, T-, the adaptive immune system's key cellular actors, and NK-cells. We observed no difference in neurological disease progression or overall survival between Ndufs4(-/-)/Il2rg(WT) and Ndufs4(-/-)/Il2rg(KO) mice, strongly suggesting that T cells, B cells, and NK cells do not play a significant role in CNS disease pathogenesis in Ndufs4(-/-) mice. Combined with previous studies indicating a causal role for macrophages, we conclude that LS CNS pathology is primarily driven by the monocyte/macrophage innate immune system.
    DOI:  https://doi.org/10.1371/journal.pone.0324268
  4. Mol Genet Metab Rep. 2025 Jun;43 101230
    Tissue-specific mitochondrial DNA, MT-TF, pathogenic variants in mitochondrial myopathies.
    Sylvia Rose, Aurélien Trimouille, Didier Lacombe, Edoardo Malfatti, Zahra Assouline, Julie Steffann, Isabelle Desguerre, Arnold Munnich, Agnès Rötig, Giulia Barcia.
      Mitochondrial myopathies are progressive muscle disorders caused by impaired mitochondrial oxidative phosphorylation, leading to reduced adenosine triphosphate production. Skeletal muscles have a high energy demand and are often the first to be affected. In addition to muscular symptoms (muscle weakness, effort intolerance, fatigue), the disease can affect the central and peripheral nervous systems, as well as the heart, liver, kidneys and endocrine system (diabetes). Molecular genetic diagnostic is currently based on leukocyte DNA obtained from blood samples, considered less invasive than muscle biopsy. We report four patients from three families with mitochondrial myopathy associated with ptosis, sensorineural hearing loss, epilepsy, tubulointerstitial nephropathy and cardiomyopathy. Genetic studies identified MT-TF variants (m.586G > A, m.601G > A, m.616 T > C) with highly variable heteroplasmy levels in the same patient from one tissue to another (5 % to 70 % mutant load in circulating blood leukocytes and in muscle respectively). We emphasize the importance of performing mtDNA analysis on muscle DNA, even in patients with negative blood leukocytes mtDNA sequencing, if there is strong clinical suspicion of mitochondrial myopathy.
    Keywords:  Heteroplasmy; MT-TF; Mitochondrial myopathy; Muscle biopsy; mtDNA
    DOI:  https://doi.org/10.1016/j.ymgmr.2025.101230
  5. Cureus. 2025 May;17(5): e83959
    Acute Management of Neurological Events in Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS) Syndrome: A Case Report.
    Zaza Aladashvili, Thalia B Rodriguez, Guillermo Izquierdo-Pretel.
      Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a rare mitochondrial disorder characterized by recurrent stroke-like episodes, seizures, and progressive neurological decline. We presented the case of an 18-year-old female, diagnosed with MELAS syndrome at age 11, who presented with acute vision loss and seizures. Neuroimaging revealed acute infarcts in the occipital and parietal lobes, consistent with MELAS syndrome-related strokes. Elevated lactate levels confirmed metabolic dysfunction. Management included arginine supplementation, seizure medication optimization, and a high-fat, low-carbohydrate diet. The patient's vision improved, seizures subsided, and lactate levels normalized. This case highlights the importance of early recognition and a multidisciplinary approach in optimizing the metabolic and neurological management of MELAS syndrome.
    Keywords:  arginine therapy; case report; lactate; melas syndrome; metabolic dysfunction; mitochondrial disease; multidisciplinary care; seizures; stroke-like episodes
    DOI:  https://doi.org/10.7759/cureus.83959
  6. Orphanet J Rare Dis. 2025 Jun 06. 20(1): 283
    Open-label pilot study using hydroxytyrosol as dietary supplements in patients with mitochondrial diseases.
    Tsz Sum Wong, Emily Man, Ian Chi Kei Wong, Shirley Xue Li, Hui Zhi, Ka Man Carmen Yeung, Ka Yee Yip, Anna Ka Yee Kwong, Kiran Moti Belaramani, Suet Na Wong, Anne Mei Kwun Kwok, Miu Mak, Toby Chun Hei Chan, Pui Yee Lau, Yee Ling Elaine Kan, Kwok Chun Wong, Freddie Poon, Vansie Kwok, Chun Yin Dick Li, Paul Lau, Sze Man Lam, Vanessa Chu, Chi Fung Godfrey Chan, Cheuk Wing Fung.
       BACKGROUND: Mitochondrial Diseases (MDs) refers to a heterogeneous group of inherited metabolic disorders resulting in defective cellular energy production due to abnormal oxidative phosphorylation (OXPHOS) caused by pathogenic mitochondrial DNA or nuclear DNA variants. As mitochondria are pivotal for cell bioenergetics, MDs could potentially affect multisystem, leaving a devastating and life-threatening impact. The treatment of MDs present significant challenges due to the complexity of the disease and the wide heterogeneity of its molecular defects. Thus, the need for innovative and more comprehensive therapeutic approaches is evident.
    METHODS: This longitudinal, open-label study was a pilot trial involving 9 paediatric MD patients, aiming to gain a better understanding on the impact of hydroxytyrosol (HT) on the clinical outcomes of MD patients and to assess the feasibility and logistics of using HT as a dietary supplement for MD patients. Subjects received HT daily as dietary supplements for 12 months. Following this period, patients were then randomly assigned to either discontinue HT or continue receiving HT as their dietary supplements for an additional 6 months. Outcome measures that were assessed included the International Paediatric Mitochondrial Disease Scores, biochemical parameters, and quality of life assessments.
    RESULTS: Among the outcome measures assessed, HT supplementation demonstrated the most considerable impact on improving the health-related quality of life according to the PedsQL scoring system and potential effects on a subgroup of MD patients with Mitochondrial encephalopathy, lactic acidosis, and stroke-like episode (MELAS).
    DISCUSSION: This study demonstrated that HT supplementation resulted in improvement in health-related quality of life in MD patients, while the subgroup of MELAS patients showed additional potential beneficial effect from HT use. As a pilot trial, this study importantly highlighted HT's tolerability in MD patients, which would facilitate trials of larger scale to be performed in the future.
    CONCLUSION: This study highlights the use of HT as a health supplement and its potential therapeutic effects in paediatric patients diagnosed with MDs, especially in MELAS patients. The results lay the foundation for future large-scale clinical trials. Consequently, further clinical intervention studies and investigations into HT's potential therapeutic mechanisms at the molecular and intercellular levels are strongly encouraged.
    Keywords:  Hydroxytyrosol; MELAS; Mitochondrial diseases; Pilot study
    DOI:  https://doi.org/10.1186/s13023-025-03795-0
  7. Am J Pathol. 2025 Jun 09. pii: S0002-9440(25)00188-9. [Epub ahead of print]
    Nitric Oxide may Adversely Affect the Metabolism and Viability of Retinal Organoids Derived from Patients with Leber Hereditary Optic Neuropathy.
    Fumio Takano, Megumi Kitamura, Kaori Ueda, Makoto Nakamura.
      Leber hereditary optic neuropathy (LHON) is a bilateral optic neuropathy associated with mitochondrial DNA (mtDNA) mutations characterized by parapapillary telangiectasia during the acute phase. However, its precise mechanism remains unclear. This study evaluated the effects of nitric oxide (NO) on retinal organoids (ROs) generated from induced pluripotent stem (iPS) cells derived from patients with LHON. Established iPS cells from three patients with the m.11778G>A mutation (patient group) and three healthy individuals (control group) were differentiated into ROs. Changes in cell death ratios, mtDNA copy number, and metabolite profiles in the ROs following exposure to sodium nitroprusside (SNP), which was an NO donor, were compared between the two groups. At baseline, terminal d-UTP nick end labeling (TUNEL)-positive cell ratios did not differ significantly, whereas the mtDNA copy number was significantly higher in the patient group. SNP exposure significantly increased the proportion of TUNEL-positive cells in the patient group but did not affect the mtDNA copy number. Relative concentrations of metabolites, including taurine and GABA, initially reduced in the patient group, increased following SNP exposure. These findings suggest that NO may promote retinal cell death and disrupt metabolite profiles in ROs derived from patients with LHON.
    Keywords:  Leber hereditary optic neuropathy; induced pluripotent stem cell; nitric oxide; retinal organoid
    DOI:  https://doi.org/10.1016/j.ajpath.2025.05.006
  8. Value Health. 2025 Jun 07. pii: S1098-3015(25)02377-0. [Epub ahead of print]
    The burden of mitochondrial disease: healthcare and societal costs.
    Deborah Schofield, Katherine Lim, Owen Tan, Rupendra Shrestha, Sameen Haque, Karen Crawley, Sarah West, Adam Percival, Jayamala Parmar, Joshua Kraindler, Carolyn Sue.
       OBJECTIVES: To estimate the burden of mitochondrial disease by measurement of healthcare, societal and lifetime costs of mitochondrial disease.
    METHODS: We recruited patients aged 18 years or over with a clinical confirmation of mitochondrial disease and their carer from a mitochondrial disease referral centre to complete a survey for our study. The survey responses and linked administrative data from the patients and carers were used in a microsimulation model to estimate the healthcare and societal costs of mitochondrial disease.
    RESULTS: 92.5% recruited agreed to participate in our study. We estimated total annual average costs at AU$ 112,721 per household. Of the total annual average costs, a large proportion were societal costs (92%). 4%, 10% and 86% of societal costs were borne by the Commonwealth government, state government and private out-of-pocket, respectively. 8% of the total annual average costs were healthcare, with 61%, 9% and 30% of the annual average health costs borne by the Commonwealth government, state government and private out-of-pocket, respectively. We estimated the total lifetime cost of mitochondrial disease at AU$ 7.6 million per household and the national annual cost is estimated at AU$ 8.6 billion.
    CONCLUSIONS: Mitochondrial disease is an expensive condition with the majority of the costs comprising of societal costs with substantial costs borne privately out-of-pocket. The findings from this study can be used in other studies such as cost-effectiveness analysis to examine the benefits of interventions to treat or prevent mitochondrial disease.
    Keywords:  Economic: Simulation model; cost-of-illness; mitochondrial disease; unit costing
    DOI:  https://doi.org/10.1016/j.jval.2025.05.016
  9. Int J Mol Sci. 2025 Jun 05. pii: 5411. [Epub ahead of print]26(11):
    Advances in Management of Mitochondrial Myopathies.
    Athanasios Bangeas, Vasiliki Poulidou, Ioannis Liampas, Chrysa Marogianni, Athina-Maria Aloizou, Zisis Tsouris, Markos Sgantzos, Marianthi Arnaoutoglou, Dimitrios P Bogdanos, Efthimios Dardiotis, Vasileios Siokas.
      Mitochondria, the energy factories of human organisms, can be the cause of a variety of genetic disorders called mitochondrial myopathies. Mitochondrial diseases arise from genetic alterations in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) and can manifest with great heterogeneity, leading to multiorgan dysfunction. The purpose of this article is to concisely review the pathophysiology, genetics and main clinical features of mitochondrial myopathies, focusing mainly on the treatment and management of these disorders. Currently, a particular treatment for mitochondrial myopathies does not exist, while the available guidelines concerning management are based on experts' opinions. The therapeutic options currently applied largely aim at symptom relief and amelioration of patients' quality of life. The most commonly used regimens involve the administration of vitamins and cofactors, although hard evidence regarding their true benefit for patients is still lacking. Recent studies have demonstrated promising results for elamipretide; however, phase III clinical trials are still ongoing. Regarding patient management, a multidisciplinary approach with the collaboration of different specialties is required. Further clinical trials for the already applied treatment options, as well as on novel experimental therapies, are of utmost importance in order to improve patients' outcomes.
    Keywords:  management; mitochondrial myopathies; treatment
    DOI:  https://doi.org/10.3390/ijms26115411
  10. MedComm (2020). 2025 Jun;6(6): e70253
    Mitochondrial Transplantation: A Novel Therapeutic Approach for Treating Diseases.
    Xinglu Miao, Pei Jiang, Zhaoping Wang, Weihua Kong, Lei Feng.
      Advances in mitochondrial biology have led to the development of mitochondrial transplantation as a novel and promising therapeutic strategy. This review provides a comprehensive analysis of the multifaceted roles of mitochondria in health and disease, highlighting their central functions in energy production, antioxidant defense, calcium signaling, apoptosis regulation, and mitochondrial homeostasis maintenance. We explore the mechanisms by which transplanted mitochondria exert their therapeutic effects, including restoring ATP production, attenuating oxidative stress, modulating inflammatory responses, reducing cellular apoptosis, promoting cell repair and regeneration, facilitating neural circuit reconstruction, and exhibiting antitumor properties. Key preclinical studies demonstrating the efficacy of mitochondrial transplantation across in vitro and in vivo disease models are discussed, along with the status of clinical trials. The review also critically compares mitochondrial transplantation with other mitochondria-targeted therapies, evaluating their relative advantages and limitations. Finally, we discuss the current challenges of translating this innovative therapy into clinical practice, such as mitochondrial isolation and purification, storage, targeted delivery, potential immune responses, and long-term safety and efficacy concerns. This review aims to stimulate further research and development in this promising field, paving the way for novel therapeutic interventions for various diseases.
    Keywords:  disease therapy; mitochondria; mitochondrial transplantation; therapeutic strategy
    DOI:  https://doi.org/10.1002/mco2.70253
  11. NAR Genom Bioinform. 2025 Jun;7(2): lqaf079
    mitoLEAF: mitochondrial DNA Lineage, Evolution, Annotation Framework.
    Nicole Huber, Noah Hurmer, Arne Dür, Walther Parson.
      The study of mitochondrial DNA (mtDNA) provides invaluable insights into genetic variation, human evolution, and disease mechanisms. However, maintaining a consistent and reliable classification system requires continuous updates. Since Phylotree updates ended in 2016, the accumulation of new haplogroup findings in individual studies has highlighted the critical need for a centralized resource to ensure consistent classifications. To address this gap, we present mitoLEAF, a collaborative, freely accessible, and academically driven repository for mitochondrial phylogenetic analyses. Unlike commercial alternatives that restrict access to their customers through subscription or purchase, mitoLEAF is openly accessible and replicable, ensuring transparency and scientific reproducibility. Hosted as a GitHub repository and supported by an interactive website, mitoLEAF provides an evolving, quality-controlled phylogenetic resource derived from GenBank, EMPOP, and peer-reviewed literature. In this first release, it expands the haplogroup landscape from 5435 to 6409 haplogroups, integrating recent findings and improving phylogenetic accuracy. By excluding known pathogenic variants, mitoLEAF aims to mitigate ethical concerns associated with reporting medically relevant variants. By prioritizing open science over commercial interests, mitoLEAF serves as a vital, community-driven platform for mitochondrial research, fostering collaboration and continuous development.
    DOI:  https://doi.org/10.1093/nargab/lqaf079
  12. bioRxiv. 2025 May 28. pii: 2025.05.25.655566. [Epub ahead of print]
    Mechanism of age-related accumulation of mitochondrial DNA mutations in human blood.
    Rahul Gupta, Timothy J Durham, Grant Chau, Md Mesbah Uddin, Wenhan Lu, Konrad J Karczewski, Daniel Howrigan, Pradeep Natarajan, Wei Zhou, Benjamin M Neale, Vamsi K Mootha.
      One of the strongest signatures of aging is an accumulation of mutant mitochondrial DNA (mtDNA) heteroplasmy. Here we investigate the mechanism underlying this phenomenon by calling mtDNA sequence, abundance, and heteroplasmic variation in human blood using whole genome sequences from ∼750,000 individuals. Our analyses reveal a simple, two-step mechanism: first, individual cells randomly accumulate low levels of "cryptic" mtDNA mutations; then, when a cell clone proliferates, the cryptic mtDNA variants are carried as passenger mutations and become detectable in whole blood. Four lines of evidence support this model: (1) the mutational spectrum of age-accumulating mtDNA variants is consistent with a well-established model of mtDNA replication errors, (2) these mutations are found primarily at low levels of heteroplasmy and do not show evidence of positive selection, (3) high mtDNA mutation burden tends to co-occur in samples harboring somatic driver mutations for clonal hematopoiesis (CH), and (4) nuclear GWAS reveals that germline variants predisposing to CH (such as those near TERT , TCL1A , and SMC4 ) also increase mtDNA mutation burden. We propose that the high copy number and high mutation rate of mtDNA make it a particularly sensitive blood-based marker of CH. Importantly, our work helps to mechanistically unify three prominent signatures of aging: common germline variants in TERT , clonal hematopoiesis, and observed mtDNA mutation accrual.
    DOI:  https://doi.org/10.1101/2025.05.25.655566
  13. J Orthop Translat. 2025 May;52 441-450
    Mitochondrial Transplantation/Transfer: Promising Therapeutic Strategies for Spinal Cord Injury.
    Xiaochun Xiong, Chao Zhou, Yijun Yu, Qiong Xie, Linying Xia, Qingping Li, Hongming Lin, Songou Zhang, Wenqing Liang.
      Spinal cord injury (SCI) remains an unresolved and complex medical challenge. In SCI, mitochondrial dysfunction leads to calcium overload and an increase in reactive oxygen species (ROS). Intercellular mitochondrial transfer has the potential to rescue surviving neurons, while exogenous mitochondrial transplantation can be performed through direct injection or cell-assisted methods. This review explored the current state of research on mitochondrial transplantation and transfer as potential treatments for SCI. It also analyzed the therapeutic implications, influencing factors, and advanced delivery methods for both endogenous mitochondrial transfer and exogenous mitochondrial transplantation. Furthermore, future research directions, including optimizing mitochondrial delivery methods, determining optimal dosages for different delivery approaches, were discussed based on larger animal models and clinical trials. The goal of this review was to introduce novel concepts and prospects for SCI therapy and to contribute to the advancement of medical research in this field.
    The Translational Potential of This Article: At present, SCI lacks effective therapies, with mitochondrial dysfunction playing a central role in neuronal damage. Mitochondrial transplantation holds promise for restoring bioenergetic function. However, key challenges remain, including optimizing delivery methods, determining appropriate dosages, scalability, donor mitochondrial sourcing, regulatory hurdles and ensuring successful integration. Addressing these issues requires non-invasive platforms, validation in large-animal models, and clinical trials. This approach may bridge mitochondrial biology with translational engineering, thereby advancing the development of regenerative therapies for SCI.
    Keywords:  Autologous; Exogenous; Mitochondrial transplantation; Spinal cord injury
    DOI:  https://doi.org/10.1016/j.jot.2025.04.017
  14. Cells. 2025 Jun 04. pii: 842. [Epub ahead of print]14(11):
    Brain Organoids and Assembloids-From Disease Modeling to Drug Discovery.
    Aderonke O Ajongbolo, Sigrid A Langhans.
      Brain organoids are self-organized, three-dimensional (3D) aggregates derived from human embryonic stem cells, induced pluripotent stem cells, or primary organs with cell types and cellular architectures resembling those of the developing human brain. Recent studies have shown the use of region-specific brain organoids for modeling various diseases ranging from neurodevelopmental and neurodegenerative diseases to different brain cancers, which have numerous applications in fundamental research and the development of new drugs, personalized treatment, and regenerative medicine. Consequently, the use of brain organoids in drug discovery is complex and challenging and still an emerging area in this field. This review article summarizes the primary stem cells used in brain organoid generation, region-specific brain organoids, and the functional assays used in their characterization. In addition, we discuss the use of brain organoids in modeling neurodevelopmental and neurodegenerative diseases and pediatric brain cancers, as well as the application of organoids, assembloids, and tumoroids in cancer neuroscience. We further explore the recent advances in using brain organoids in high-throughput screening to improve their use for drug discovery.
    Keywords:  brain; brain cancer; cancer neuroscience; cerebellum; drug discovery; high-throughput screening (HTS); neurodegeneration; neurodevelopmental disease; neuropsychiatric disorder; organoid; substance abuse
    DOI:  https://doi.org/10.3390/cells14110842
  15. Bioethics. 2025 Jun 11.
    In Defence of Causing Patients to Worry: Ethical Issues in the Communication of Diagnostic Uncertainty.
    Caitríona Cox, Zoë Fritz.
      Doctors are often motivated by a desire to avoid causing their patients worry. In this paper, we provide a defence of disclosing diagnostic uncertainty information to patients, even if such disclosures are worrying. We first consider whether making a patient worry harms them, arguing that worry can be harmful in some-but not all-situations. Although worry is an aversive emotion, sometimes, worry can be beneficial (e.g., if the worry drives adaptive behaviours that are ultimately good for the patient's well-being). In contrast, worry that is excessive, or is related to events outside the patient's control, can be considered harmful. Even if worry is harmful, communicating worrying information can still sometimes be justified-for example, by applying a consequentialist harm-benefit analysis to consider whether the other benefits of the disclosure (broadly defined) might outweigh the harm created by the worry. We summarise the growing empirical evidence that suggests that patients often prefer their doctors to communicate transparently throughout the diagnostic process, even if the acknowledgement of serious but uncertain diagnoses induces some worry. We do, however, note the difficulty in predicting how an individual patient will respond to the disclosure of potentially worrying information (as the preference for greater communication of diagnostic uncertainty may not be universal). We conclude that a holistic consideration of the expected consequences of communication-including self-assessment by the doctor to avoid unwitting bias or unwarranted projection of their own values-often supports the communication of diagnostic uncertainty information, even if it worries the patient.
    Keywords:  communication; diagnostic uncertainty; doctor–patient relationship; ethics; worry
    DOI:  https://doi.org/10.1111/bioe.13436
  16. AMIA Jt Summits Transl Sci Proc. 2025 ;2025 300-311
    Empowering Precision Medicine for Rare Diseases through Cloud Infrastructure Refactoring.
    Hui Li, Jinlian Wang, Hongfang Liu.
      Rare diseases affect approximately 1 in 11 Americans, yet their diagnosis remains challenging due to limited clinical evidence, low awareness, and lack of definitive treatments. Our project aims to accelerate rare disease diagnosis by developing a comprehensive informatics framework leveraging data mining, semantic web technologies, deep learning, and graph-based embedding techniques. However, our on-premises computational infrastructure faces significant challenges in scalability, maintenance, and collaboration. This study focuses on developing and evaluating a cloud-based computing infrastructure to address these challenges. By migrating to a scalable, secure, and collaborative cloud environment, we aim to enhance data integration, support advanced predictive modeling for differential diagnoses, and facilitate widespread dissemination of research findings to stakeholders, the research community, and the public and also proposed a facilitated through a reliable, standardized workflow designed to ensure minimal disruption and maintain data integrity for existing research project.
  17. J Pharm Bioallied Sci. 2025 May;17(Suppl 1): S59-S62
    Personalized Medicine in Treating Rare Genetic Disorders: A Review.
    Ansari Zebanaz, Affan M Kareem, Ashwini A Aher, Sunil N Thitame.
      Personalized medicine creates revolutionary treatments for rare genetic disorders through medicine that adjusts to individual genetic information. The development of next-generation sequencing and whole-genome sequencing through genomic research has made precise medical diagnoses along with personalized treatments possible. The current therapies using CRISPR-Cas9 and gene therapy methods tend to fix harmful mutations effectively. Biomarker discovery, along with precise diagnostic techniques enables doctors to develop precise treatment methods through targeted therapeutic approaches. The ongoing revolution in rare disease management through personalized medicine faces hurdles of affordability and barrier to access and ethical questions but continues to create better individualized therapeutic solutions.
    Keywords:  CRISPR-Cas9; genetic profiling; multi-omics; personalized medicine; rare genetic disorders
    DOI:  https://doi.org/10.4103/jpbs.jpbs_583_25
  18. J Immunother Cancer. 2025 Jun 05. pii: e011301. [Epub ahead of print]13(6):
    Intentional heterogeneity in autologous cell-based gene therapies: strategic considerations for first-in-human trials.
    Christopher R Cabanski, EnJun Yang, Mark D Stewart, Jeff D Allen, John E Connolly, Ute Dugan, Philip D Greenberg, Crystal L Mackall, Carl H June, Alexander Marson, Marcela V Maus, Antoni Ribas.
      Cell-based gene therapies, including chimeric antigen receptor-T, T-cell receptor-T, and tumor-infiltrating lymphocyte therapies, have transformed the treatment landscape for certain cancers, yet their efficacy in solid tumors remains limited. Next-generation therapies aim to overcome biological barriers, enhance potency and safety, and streamline development timelines through innovative approaches. Recent advances in genome editing technologies have identified hundreds of gene edits that improve T-cell functionality in preclinical models. However, the limited direct translatability of these findings and the impracticality of testing each of the individual edits in a traditional clinical trial highlight the need for more efficient strategies.This article provides an overview of genome-wide screens that identify gene knockouts and knock-ins to enhance T-cell function and the limitations with translating these results to human trials. Next, we propose a novel clinical trial design for testing multiple gene modifications simultaneously within a single T-cell infusion product. This approach would enable head-to-head evaluation of edits in an internally controlled setting, accelerating the identification of promising candidate edits. Key considerations for Chemistry, Manufacturing, and Controls, non-clinical evaluation, and clinical protocols are discussed, with an emphasis on patient safety and ethical transparency.This framework is informed by insights shared at the "Unlocking Complex Cell-based Gene Therapies" workshop, held on May 6, 2024. Co-hosted by Friends of Cancer Research and the Parker Institute for Cancer Immunotherapy, the event brought together participants from academia, the US Food and Drug Administration, and patient advocacy groups. By fostering collaboration among these stakeholders, this innovative approach aims to accelerate the development of effective cell-based therapies for complex diseases.
    Keywords:  Adoptive cell therapy - ACT; Chimeric antigen receptor - CAR; Gene therapy; Solid tumor; T cell Receptor - TCR
    DOI:  https://doi.org/10.1136/jitc-2024-011301
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