bims-curels 2026-08-02 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2026–08–02
eleven papers selected by
Cure Mito Foundation

MSeqDR PMD-VR: An Expert-Curated Virtual Registry of 11,000 Mitochondrial Disease Cases Established Through Literature Mining and Generative AI Augmentation.
Digital Cognitive Testing in Mitochondrial Disease: Validity and Challenges for Clinical Trial Use.
Mitochondrial Genetic Diseases and Ophthalmic Manifestations: Molecular Pathophysiology, Genetics, and Clinical Management.
Innovative Clinical Pharmacology, Modeling, and Simulation Strategies for Accelerating Rare Disease Drug Development.
Systematic review of Leber's hereditary optic neuropathy - Clinical diagnosis, genetics overview and current concepts of treatment.
In utero gene editing and precision medicine.
From Small Data to Big Decisions: How Clinical Pharmacology Shapes Rare Disease Development.
Bearing the Burden of Clinical Ethics Consultation: Requests, Roles, and Responses.
A scoping review of studies on secure messaging through patient portals: persistent challenges and potential solutions.
A systematic review of early evidence on generative AI for drafting responses to patient messages.
Toward Standard Approaches for Notification and Direct Communication with Families in Pediatric Clinical Ethics Consultation.

Genes (Basel). 2026 Jun 30. pii: 757. [Epub ahead of print]17(7):

MSeqDR PMD-VR: An Expert-Curated Virtual Registry of 11,000 Mitochondrial Disease Cases Established Through Literature Mining and Generative AI Augmentation.

Lishuang Shen, Marie T Lott, Elizabeth M Mccormick, Colleen C Muraresku, Kierstin Keller, Douglas C Wallace, Zarazuela Zolkipli-Cunningham, Shamima Rahman, Marni J Falk, Xiaowu Gai.

  Background/Objectives: Patient registries are essential for rare disease research, yet the extensive genetic and phenotypic heterogeneity of primary mitochondrial diseases (PMDs) makes traditional registry development slow and resource-intensive. We established the MSeqDR PMD virtual registry (PMD-VR) to address this gap through systematic literature mining and semi-automated data harmonization. Methods: The PMD-VR captures, standardizes, and harmonizes published case-level PMD data using a semi-automated curation pipeline. A data transformation framework maps heterogeneous raw data terms to standardized common data elements (CDEs). A generative AI (GenAI) platform leveraging large language models (LLMs), augmented by Human Phenotype Ontology (HPO) and external biomedical knowledge sources, accelerates data transformation and generates simulated clinical reports. Results: Currently, PMD-VR contains approximately 11,000 de-identified literature-derived cases, including over 2300 Leigh syndrome spectrum (LSS), 278 MELAS, and 300 CPEO cases. The pipeline mapped 872 heterogeneous terms to 102 standardized CDEs. Pathogenicity assessments were captured for variants in over 7900 cases, including 3800 with mtDNA pathogenic or likely pathogenic variants. Modes of inheritance were inferred for 5212 cases. PMD-VR has supported ClinGen Mitochondrial Diseases Gene Curation Expert Panel (Mito-GCEP) efforts, providing phenotyped evidence for 440 curated LSS cases across 113 PMD genes. Conclusions: PMD-VR is among the largest single PMD registries, offering a scalable, web-accessible platform for generating analysis-ready cohorts from the published literature. It represents a rich resource enabling comprehensive PMD characterization with unprecedented breadth of genetic and phenotypic knowledge.

Keywords:  Generative AI (GenAI); Leigh syndrome spectrum (LSS); human phenotype ontology (HPO); large language model; literature mining; mitochondrial disease; rare disease

DOI:  https://doi.org/10.3390/genes17070757
Ann Clin Transl Neurol. 2026 Jul 31.

Digital Cognitive Testing in Mitochondrial Disease: Validity and Challenges for Clinical Trial Use.

Oksana Pogoryelova, Jan Smeitink, Herma Renkema, Rosabeth White, Frankie Barton, Rachel Lyon, Jane Newman, Aye Moe, Yi Shiau Ng, Grainne Siobhan Gorman.

   BACKGROUND: Primary mitochondrial disease is a group of genetic disorders caused by pathogenic variants in nuclear or mitochondrial DNA, often resulting in progressive neurodegeneration and cognitive decline. Current management is primarily supportive, though recent research offers hope for disease-modifying treatments in the future. Selecting appropriate therapeutic outcomes for clinical trials in mitochondrial diseases is challenging due to limited sensitivity to changes, small sample sizes, and the burden of study related activities. This study aims to identify an efficient choice of cognitive endpoints for translational research.
METHODS: This study compared digital cognitive assessments with traditional paper-based tools. It included two cohorts: the Newcastle cohort of 45 patients recruited from the mitochondrial clinic Newcastle upon Tyne (UK) and the KHENERGYZE clinical trial cohort of 27 patients recruited from four European countries. Patients in the Newcastle cohort underwent two conventional cognitive assessments (Addenbrooke's Cognitive Examination and Montreal Cognitive Assessment), along with two computerized tests (Cogstate and Test of Attentional Performance). Potential confounding factors were also assessed.
RESULTS: Both cohorts showed a high prevalence of moderate to severe perceived fatigue. Over 50% of patients showed reduced reaction times. Strong correlations were found between conventional and digital assessments. Several confounding factors such as education and employment were identified as influencing cognitive performance.
CONCLUSIONS: The findings support the understanding of mitochondrial disease as a slowly progressive condition, where impaired cognitive function is evident even in patients in the absence of devastating CNS manifestations such as stroke-like episodes. Observed variability in cognitive performance may help detect meaningful changes over time.

Keywords:  minimal clinically important differences; neurocognitive assessments; neurodegeneration; primary mitochondrial disease

DOI:  https://doi.org/10.1002/acn3.70463
Int J Mol Sci. 2026 Jul 09. pii: 6128. [Epub ahead of print]27(14):

Mitochondrial Genetic Diseases and Ophthalmic Manifestations: Molecular Pathophysiology, Genetics, and Clinical Management.

Khaled K Abu-Amero.

  Mitochondrial genetic disorders compromise oxidative phosphorylation (OXPHOS) and cellular energy supply, and the eye is among the first organs to feel the deficit. Photoreceptors and retinal ganglion cells (RGCs) sustain among the highest metabolic rates in the body, so ophthalmic features often dominate the clinical picture and arrive before systemic disease is recognized. More than half of all patients with confirmed mitochondrial disease develop sight-threatening complications. This review integrates mtDNA and nuclear genetics; ophthalmic and extraocular phenotypes; the bioenergetic and apoptotic mechanisms that drive vision loss; the clinical examination and investigations that delineate the problem; the differential diagnoses that must be excluded; the contribution of common mtDNA haplogroup variation to age-related retinal disease; and the diagnostic, therapeutic, and counseling approaches that turn a molecular result into useful care. Recurring themes are heteroplasmy, the threshold effect, and the selective vulnerability of RGCs and extraocular muscle across genetically distinct disorders. Treatment remains largely supportive, but idebenone, gene therapy, mitophagy modulation, and targeted antioxidants now offer mechanism-based intervention for several ophthalmic manifestations.

Keywords:  clinical management; diseases; genetics; mitochondria; ophthalmology; oxidative stress

DOI:  https://doi.org/10.3390/ijms27146128
J Clin Pharmacol. 2026 Aug;66(8): e70246

Innovative Clinical Pharmacology, Modeling, and Simulation Strategies for Accelerating Rare Disease Drug Development.

Rajneet K Oberoi, Cody J Peer, Ashutosh Tripathi, Afroz S Mohammad, Yajing Sun, Kenneth Der, Yang Song, Jiayin Huang, Vijay V Upreti.

  Clinical drug development for rare diseases continues to face significant challenges due to disease heterogeneity, fewer available patients, and incomplete understanding of pathogenesis, resulting in trials with limited clinical data, thus constraining traditional development pathways. Clinical pharmacology, modeling, and simulation-based approaches can help address these challenges by informing decision-making, mitigating uncertainty, and guiding optimal dose and regimen selection for the appropriate patient population. These approaches help streamline trial designs by reducing the scope and number of clinical trial evaluations, using exposure-response analyses to optimize dosing, the use of mechanistic-physiologically based pharmacokinetics (M-PBPK)-based approaches for biopharmaceutical and formulation optimization, evaluations of drug-drug interactions, and organ impairment. These strategies increase development efficiency across all stages of drug development, thereby improving the probability of success. This review highlights case studies that applied innovative clinical and quantitative pharmacology approaches across early and late stages of drug development and regulatory decision-making in rare diseases. The specific examples illustrate the application of pharmacokinetics/pharmacodynamics (PK/PD) and model-informed drug development (MIDD) strategies to support dose and regimen selection, enabling efficient use of direct or adaptive trial designs, facilitating bridging across populations and indications, biopharmaceutics-based transitions, and generating integrated PK/PD evidence to support labeling. Examples include drug repurposing, characterizing PK/PD in early phase to inform late-phase development, population PK analysis to guide trial dosing and label recommendations, using phenotype-targeted study design to address disease heterogeneity, expanding dosing regimen across indications using MIDD, quantitatively evaluating immunogenicity to support mitigation strategies, biomarker bridging, and applying M-PBPK to predict clinical PK in organ impairment populations.

Keywords:  MIDD; Rare Diseases; drug development

DOI:  https://doi.org/10.1002/jcph.70246
Indian J Ophthalmol. 2026 Aug 01. 74(8): 1151-1161

Systematic review of Leber's hereditary optic neuropathy - Clinical diagnosis, genetics overview and current concepts of treatment.

Selvakumar Ambika, Sundaramurthy Srilekha.

  Leber hereditary optic neuropathy (LHON) is the most common mitochondrial disorder, typically causing substantial, often permanent, central vision loss in young adults. It manifests as a subacute optic neuropathy, frequently progressing sequentially in both eyes, due to selective degeneration of retinal ganglion cells (RGCs). The condition is primarily associated with three mitochondrial DNA (mtDNA) point mutations-m.11778G>A, m.14484T>C, and m.3460G>A-located in complex I of the mitochondrial respiratory chain. These mutations impair oxidative phosphorylation, elevate reactive oxygen species (ROS), and trigger apoptosis of RGCs. Although historically considered untreatable, emerging therapies provide new prospects. Idebenone, a synthetic CoQ10 analog, is the first pharmacologic agent approved in Europe, demonstrating partial visual recovery in patients treated early by improving mitochondrial electron transport and reducing oxidative stress. Gene therapy using allotopic expression of ND4 via adeno-associated viral vectors (rAAV2/2-ND4) has shown improvement in both eyes even after unilateral injection. Advanced gene-editing techniques, such as zinc finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs), offer potential approaches for correcting heteroplasmic mutations. High-throughput genetic testing, including whole-genome sequencing and clinical exome analysis, enables precise identification of nuclear modifiers that influence LHON phenotypes, facilitating early diagnosis and intervention. Current clinical trials, including RESTORE and REFLECT, emphasize the importance of prompt treatment to optimize visual outcomes.

Keywords:  Allotopic expression; gene therapy; idebenone; mitochondrial inheritance; mitochondrial mutation; mutation-specific/nonspecific treatment; oxidative stress

DOI:  https://doi.org/10.4103/IJO.IJO_1696_25
Semin Pediatr Surg. 2026 Jul 16. pii: S1055-8586(26)00094-6. [Epub ahead of print] 151678

In utero gene editing and precision medicine.

Olivia L Katz, Kara Kennedy, Natalie F Berger, Nada Fadl, William H Peranteau.

  Advances in preconception and prenatal genetic testing, in combination with the rapid evolution and regulatory acceptance of targeted gene therapy technologies, has unveiled promising opportunities for the antenatal treatment of genetic disease by way of in utero gene editing and precision medicine. Recent regulatory guidance, put forth by the Federal Drug Administration (FDA), on gene editing has the exciting potential to accelerate the development and implementation of therapeutics for rare and ultrarare diseases. In this review, we highlight recent advances that have occurred in the fields of in utero gene editing and precision medicine and the opportune regulatory landscape that may facilitate the clinical translation of therapeutics in the future. We additionally review the indispensable role of prenatal genetic diagnosis, including chorionic villus sampling, amniocentesis, and noninvasive prenatal testing, as the diagnostic gateway through which candidates for in utero gene and precision therapies will be identified.

Keywords:  Amniocentesis; CRISPR; Chorionic villus sampling; Enzyme replacement; Fetal; Gene editing; Gene therapy; Genetic disease; In utero; Noninvasive prenatal testing; Precision medicine; Prenatal diagnosis

DOI:  https://doi.org/10.1016/j.sempedsurg.2026.151678
J Clin Pharmacol. 2026 Aug;66(8): e70250

From Small Data to Big Decisions: How Clinical Pharmacology Shapes Rare Disease Development.

Yan Xu, Alissa Verone-Boyle, Natalie Schmitz, Hamim Zahir, Brian A Willis.

  Rare‑disease drug development is constrained by small and heterogeneous patient populations, limited natural‑history data, and the impracticality of large, randomized trials. Despite increasing regulatory acceptance of totality-of-evidence and mechanism-based development pathways, generating reliable, decision-ready evidence under these constraints remains challenging. This review describes how clinical pharmacology contributes within an evidence‑integration and decision‑support framework through quantitative, model‑informed approaches to address this gap. By integrating nonclinical data, pharmacokinetics, pharmacodynamics, biomarkers, natural‑history information, and clinical efficacy and safety outcomes, and through close collaboration with clinical, statistical, and translational experts, clinical pharmacology supports interpretation of treatment effects and quantitative characterization of uncertainty when conventional evidence is limited. In practice, these approaches inform key development decisions, including dose selection, innovative trial designs, extrapolation and bridging across populations, use of external controls, and evaluation of biomarkers and surrogate endpoints. Importantly, such practices help align regulatory expectations with patient needs, particularly in pediatric and ultra‑rare settings, by enabling appropriate dosing, reduced trial and patient burden, and quantitative assessment of benefit/risk. Examples from rare‑disease programs illustrate how integrated quantitative evidence has supported regulatory decisions, including label expansion and accelerated approval when data may be sparse, heterogeneous, or evolving. Looking ahead, emerging technologies such as artificial intelligence, digital biomarkers, and individualized approaches are expected to further advance rare‑disease drug development. With this evolving landscape, clinical pharmacology is expected to continue playing an important role in evaluating mechanistic plausibility, ensuring analytic rigor, and translating small datasets into meaningful evidence to inform development and regulatory decisions in rare diseases.

Keywords:  benefit‐risk; clinical pharmacology; external controls; extrapolation; model‐informed drug development (MIDD); rare diseases

DOI:  https://doi.org/10.1002/jcph.70250
HEC Forum. 2026 Jul 26.

Bearing the Burden of Clinical Ethics Consultation: Requests, Roles, and Responses.

Anna D Goff, Marsha M Michie, Marcie A Lambrix, Monica L Gerrek.

  The continued evolution of clinical ethics has prompted extensive discussion about the roles clinical ethicists ought to assume in practice, with the discussion focusing largely on what these professionals bring to healthcare. The emotional impact of assuming such roles is less commonly considered despite the fact that clinical ethicists frequently navigate situations of ethical complexity and conflict. We recently interviewed 34 U.S. clinical ethicists about their experiences and learned that the desire to be helpful is resulting in these professionals assuming a wide range of roles and responsibilities. Furthermore, we found that clinical ethicists are regularly emotionally impacted by their work and that they often carry an emotional burden as a result of the roles they assume in patient care. In this article, we explore this burden and discuss what it reveals about the field of clinical ethics at this pivotal point in its development.

Keywords:  Bioethics, Clinical Ethics, Medical Ethics, Professional Development, Empirical Research

DOI:  https://doi.org/10.1007/s10730-026-09597-6
Npj Health Syst. 2026 May 24. pii: 34. [Epub ahead of print]3(1):

A scoping review of studies on secure messaging through patient portals: persistent challenges and potential solutions.

Yawen Guo, Di Hu, Yiliang Zhou, Tianchu Lyu, Ziqi Yang, Tera L Reynolds, Kai Zheng.

Secure messaging (SM) has seen increasing adoption over the past decade, prompting growing interest in understanding its impact on healthcare delivery. This review examines key themes in the existing SM research, such as usage patterns, perceived benefits, and persistent challenges, to identify research gaps and inform opportunities for sociotechnical solutions in the artificial intelligence (AI) era that could enhance patient-provider communication effectiveness. Searches were conducted in PubMed, Scopus, IEEE Xplore, ACM Digital Library, Cochrane CENTRAL, CINAHL, and Web of Science. Following the PRISMA guideline, we identified 366 relevant peer-reviewed studies published from January 2009 to September 2025. Existing research has primarily investigated (1) the effect of SM use on clinical outcomes, (2) adoption patterns, and (3) user experiences. The literature shows that SM promotes patient engagement, care coordination, and patient-provider communication. However, significant challenges persist, including privacy concerns, limited access for vulnerable populations, patient misuse, and increased clinician burden. Educational initiatives and patient-centered design are essential for promoting appropriate and accessible use of SM. Emerging AI solutions also show promise in enhancing SM use, particularly for message triaging and drafting replies. The integration of such AI solutions must be guided by robust governance frameworks to ensure transparency, maintain trust, and align with evolving clinical, billing, and regulatory environments. Future research should include more diverse care settings and populations, prioritizing the development of equitable sociotechnical tools and interventions that can be seamlessly integrated into clinical workflows.

DOI: https://doi.org/10.1038/s44401-026-00091-2
Npj Health Syst. 2025 Jul 23. pii: 27. [Epub ahead of print]2(1):

A systematic review of early evidence on generative AI for drafting responses to patient messages.

Di Hu, Yawen Guo, Yiliang Zhou, Lidia Flores, Kai Zheng.

This systematic review synthesizes currently available empirical evidence on generative artificial intelligence (GenAI) tools for drafting responses to patient messages. Across a total of 23 studies identified, GenAI was found to produce empathetic replies with quality comparable to that of responses drafted by human experts, demonstrating its potential to facilitate patient-provider communication and alleviate clinician burnout. Challenges include inconsistent performance, risks to patient safety, and ethical concerns around transparency and oversight. Additionally, utilization of the technology remains limited in real-world settings, and existing evaluation efforts vary greatly in study design and methodological rigor. As this field evolves, there is a critical need to establish robust and standardized evaluation frameworks, develop practical guidelines for disclosure and accountability, and meaningfully engage clinicians, patients, and other stakeholders. This review may provide timely insights into informing future research of GenAI and guiding the responsible integration of this technology into day-to-day clinical work.

DOI: https://doi.org/10.1038/s44401-025-00032-5
HEC Forum. 2026 Jul 30.

Toward Standard Approaches for Notification and Direct Communication with Families in Pediatric Clinical Ethics Consultation.

Aaron Wightman, Luke Mosley, Brennan Kim, Brittany Greene, Phoebe Winn, Arika Moore, Vanessa Madrigal, Jennifer Kett.

  The ASBH Core Competencies identify two core features of clinical ethics consultation: (1) identify and analyze the nature of the value uncertainty and (2) facilitate the building of a "principled ethical resolution." Central to these processes is understanding the perspective of the patient and/or their surrogate, yet the practices of notification and communication with surrogates, often parents, are varied in pediatric ethics consultation. In this paper we will review guidance on notification and communication with surrogates in clinical ethics consultation, the published literature on practices in US pediatric clinical ethics consultation in particular, and analyze justifications for and against routine notification and communication. Finally, we will present draft guidance for a standard approach to communication with families in pediatric ethics consultation.

Keywords:  Communication; Family notification; Family participation; Moral distress; Pediatric ethics consultation

DOI:  https://doi.org/10.1007/s10730-026-09603-x