bims-curels 2026-07-12 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2026–07–12
eleven papers selected by
Cure Mito Foundation

Non-invasive urinary heteroplasmy screening outperforms blood testing for certain mitochondrial DNA variants in mitochondrial disease patients.
Perianesthetic Complications in Genetic Mitochondrial Disease: A Review of Case Reports.
An optimized "hypoxia in a pill" regimen reverses neurodegenerative disease phenotypes in multiple preclinical models.
Psychological safety and shared decision-making for patient engagement in care quality.
Bridging perspectives: experiences and future directions for patient involvement in clinical registries - a survey-based study.
Medicinal Chemistry Perspectives on Drug Repurposing: Innovative Approaches and Therapeutic Breakthrough.
Restoring the powerhouse: mitochondrial transplantation in regenerative medicine and cancer therapy.
The experiences of partners of individuals with pre-symptomatic Huntington's disease: a reflexive thematic analysis.
[THE BLOGOSPHERE AS SPACE OF PHYSICIAN-PATIENT COMMUNICATION].
Vulnerability, protection and fairness: ethical and regulatory limits in small-N gene therapy trials.
Beyond the ethics deflection: Why patient burden is a scientific review question, not just an IRB concern.

Mol Genet Metab. 2026 Jun 26. pii: S1096-7192(26)00481-6. [Epub ahead of print]148(4): 110198

Non-invasive urinary heteroplasmy screening outperforms blood testing for certain mitochondrial DNA variants in mitochondrial disease patients.

Atsuko Okazaki, Yukiko Yatsuka, Takuya Fushimi, Takanori Onuki, Yuko Aida, Hisato Aihara, Toshiyuki Imasawa, Akira Ohtake, Kei Murayama, Yasushi Okazaki.

   BACKGROUND: Mitochondrial diseases present diagnostic challenges due to variations in heteroplasmy levels of mitochondrial DNA (mtDNA) in different tissues. Current diagnostic approaches primarily rely on blood testing, which may miss pathogenic variants present at higher levels in other accessible tissues.
METHODS: We analyzed tissue samples from 164 individuals (125 probands and 39 family members) with genetically confirmed mitochondrial diseases using droplet digital PCR (ddPCR). We quantified heteroplasmy levels in five tissue types: blood, urine, cardiac muscle, skeletal muscle, and kidney tissue.
RESULTS: Among the 108 blood samples and 87 urine samples from patients carrying the m.3243A>G variant, urine samples demonstrated significantly higher heteroplasmy levels than blood samples (median: 76.6% [interquartile range (IQR): 50.8-91.8%] vs. 20.9% [IQR: 11.3-41.4%], p < 0.001). In a paired analysis of 80 patients with the m.3243 A > G variant who provided both blood and urine samples, urine heteroplasmy exceeded blood levels in all cases (median difference: 44.6% [interquartile range (IQR): 26.9-56.7%], p < 0.001). Moderate positive correlations were observed between blood and urine heteroplasmy (all variants: r = 0.68, n = 94 pairs; m.3243 A > G: r = 0.66, n = 80 pairs; both p < 0.001). Using an exploratory 10% heteroplasmy threshold based on prior reports for m.3243A>G, blood classified 24 of the 94 paired cases (25%, or one in four patients) as <10% while urine was ≥10%. Cardiac tissue exhibited the highest heteroplasmy levels (mean: 86% ±8% in m.3243A>G patients), though this likely reflects selection bias, as cardiac biopsies were obtained only from patients with cardiac involvement.
CONCLUSIONS: Urine specimens demonstrate higher heteroplasmy levels and more often place individuals above an exploratory 10% heteroplasmy threshold compared with blood specimens for certain mitochondrial DNA (mtDNA) variants, most notably m.3243A>G. Using this exploratory threshold, 24 of 94 paired blood-urine samples (25%) had blood heteroplasmy <10% while urine heteroplasmy was ≥10%, supporting the use of urine as an important noninvasive complementary specimen, and in many cases a preferred specimen, for suspected m.3243A>G. However, blood testing remains appropriate for variants that typically show high blood heteroplasmy and a relatively high threshold for clinical expressivity, such as m.8993 T > G. These findings support the implementation of urine-based screening protocols for suspected m.3243A>G cases, which may reduce underestimation of variant load and improve diagnostic evaluation.

Keywords:  Droplet digital PCR; Heteroplasmy; Inherited metabolic disorder; Mitochondrial disease; Tissue-specific diagnosis; m.3243A>G

DOI:  https://doi.org/10.1016/j.ymgme.2026.110198
Paediatr Anaesth. 2026 Jul 07.

Perianesthetic Complications in Genetic Mitochondrial Disease: A Review of Case Reports.

Brittany M Johnson, Simon C Johnson.

   BACKGROUND: Genetic mitochondrial diseases (GMDs) are a large group of genetically and clinically heterogeneous disorders caused by defects in genes encoding mitochondrial components. GMDs are grouped into named syndromes based on clinical presentation, for example, Leigh syndrome (LS). Surgical interventions are often required in GMDs, necessitating the use of general anesthesia (GA). Some GMD animal models show both a marked reduction in anesthetic concentrations necessary for sedation and toxic sequelae resulting from anesthetic exposures. Hypersensitivity to sedation by anesthetic agents, most notably volatile anesthetic agents (VAs), occurs in a subset of GMD patients, and some evidence suggests toxicities are also present. Reported complications of anesthesia in GMD are varied, including minor metabolic changes, acceleration of underlying disease, and death. The potential toxicity of anesthetics in the setting of GMDs has recently been underscored by deaths among pediatric and young adult patients of Venezuelan descent putatively linked to a specific mitochondrial DNA haplotype. Interpretation of clinical findings is limited by the lack of a thorough review of case reports for anesthetic exposures in GMD patients. Here, we provide a comprehensive review of published case reports for GMD patients undergoing anesthetic exposures.
METHODS: Using search terms "anesthesia mitochondrial disease," "anesthesia mitochondrial disease case report," and "anesthesia Leigh syndrome" we identified case reports published up to May 2025. Non-English articles were translated and included where possible. Only reports of GMD patients undergoing GA with total intravenous anesthesia (TIVA) or VAs containing outcome information were included, totaling 148 cases from 123 reports. We examined relationships between complications and GA type, clinical diagnosis, perianesthetic drugs, procedure length and type, and general demographics. We performed a narrative review of clinical and pre-clinical literature.
RESULTS: Overall complication rate was significantly higher in VA versus TIVA cases (42% vs. 18%, Fisher's exact p-value **p = 0.0022), as was rate of severe complications (*p = 0.01). Encephalomyelopathies, including LS, were overrepresented among cases resulting in death. Complication rate has remained relatively stable over time. Sex and age were not associated with significant differences in complication rate. Complication rate varied significantly by procedure type, and severe complications were associated with procedure length. While not statistically significant, older VAs had higher complication rates than newer VAs. Similarly, older neuromuscular blockade agents may be less safe than newer drugs. N2O and ketamine were notably safe among drugs used in TIVA procedures.
CONCLUSIONS: Available case-report data support the notion that GMD patients are at increased risk of a variety of perianesthetic complications. Clinical symptoms and procedure length appear most strongly predictive of severe complications. Clinical and pre-clinical findings suggest more research is needed to understand the mechanisms of toxicity and more detailed reporting is needed in clinical case reports to identify potential risk factors.

Keywords:  anesthesia; anesthetic complications; anesthetic outcomes; anesthetic toxicity; mitochondrial diseases

DOI:  https://doi.org/10.1002/pan.70257
bioRxiv. 2026 Jul 03. pii: 2026.06.30.734089. [Epub ahead of print]

An optimized "hypoxia in a pill" regimen reverses neurodegenerative disease phenotypes in multiple preclinical models.

Hong Wang, Eizo Marutani, Luca Zazzeron, Marissa Menard, Laura Volpicelli-Daley, Fumito Ichinose, Vamsi K Mootha.

A growing body of pre-clinical research has demonstrated the therapeutic potential of chronic, continuous hypoxia (11% FIO2) for treating both rare and common forms of neurodegeneration (1). However, the chronic delivery of hypoxic gas poses both practical challenges and long-term safety concerns. We previously introduced a small molecule, "hypoxia-in-a-pill" regimen that combines the hemoglobin affinity enhancer (GBT440) -- which limits oxygen delivery to tissues -- with a HIF-2α inhibitor (PT2399) to prevent compensatory erythropoiesis that can be detrimental. While this regimen extended the lifespan of the Ndufs4 KO mouse model of Leigh syndrome, its efficacy still did not match that of chronic 11% FIO2. Here we report an optimized combination that now utilizes GBT601, a second-generation hemoglobin affinity enhancer with longer half-life and greater hemoglobin occupancy, again with PT2399. Here we report that the GBT601/PT2399 combination achieved therapeutic hypoxia and demonstrated strong efficacy comparable to continuous breathing of 11% FIO2 by halting neurodegeneration and even reversing neurological symptoms in three different mouse models: Leigh syndrome, Friedreich's ataxia, and Parkinson's disease. The dual targeting regimen led to a striking extension in median lifespan in the Leigh syndrome model, from a median of ∼62 day to 158 days, when initiated after onset of advanced disease. Importantly, body weight was stable with the combination and it did not induce any signs of pulmonary hypertension, likely due to attenuation of HIF-2α. Our findings motivate additional pre-clinical and even clinical studies to evaluate the safety and efficacy of the GBT601/PT2399 combination.

DOI: https://doi.org/10.64898/2026.06.30.734089
BMJ Open Qual. 2026 07 06. pii: e004224. [Epub ahead of print]15(3):

Psychological safety and shared decision-making for patient engagement in care quality.

Tatsuya Fukami.

   BACKGROUND: Patient engagement is increasingly recognised as a core component of healthcare quality and safety. However, many patients remain reluctant to voice concerns, ask questions or participate meaningfully in clinical decisions. While patient safety initiatives have traditionally focused on preventing errors through system-level controls, less attention has been paid to the relational conditions that enable patients to contribute actively to safety and quality in everyday care.
OBJECTIVE: This narrative review aims to conceptualise psychological safety and shared decision-making (SDM) as interdependent mechanisms that enable patient engagement and shape patient experience and to examine how their absence contributes to defensive medical practices.
METHODS: We conducted a narrative review of interdisciplinary literature spanning patient safety science, quality improvement, patient experience research and organisational psychology. Conceptual frameworks and illustrative clinical examples were synthesised to clarify how psychological safety and SDM function together within routine clinical encounters.
RESULTS: Psychological safety enables patients to express concerns, uncertainty and preferences without fear of dismissal or negative judgement, while SDM provides a structured process through which patient values and clinical evidence can jointly inform decisions. When these relational mechanisms are weak or absent, defensive medical practices-often framed as actions taken 'just to be safe'-may proliferate. Although intended to reduce risk, such practices can undermine patient engagement by limiting dialogue, increasing anxiety and reinforcing paternalistic decision-making. In contrast, integrating psychological safety and SDM reframes patient engagement as an active safety mechanism that supports learning, transparency and trust.
CONCLUSIONS: Reframing patient engagement as a core safety and quality mechanism highlights the importance of psychological safety and SDM in everyday clinical practice. Rather than treating patient experience as a downstream outcome, healthcare organisations should recognise it as an integral component of safe, high-quality care. Embedding psychologically safe communication and SDM into routine decision-making may reduce reliance on defensive medicine while promoting safer, more participatory and more respectful healthcare.

Keywords:  Healthcare quality improvement; Organizational Culture; Patient Participation; Patient safety; Shared decision making

DOI:  https://doi.org/10.1136/bmjoq-2026-004224
BMJ Open Qual. 2026 07 08. pii: e004228. [Epub ahead of print]15(3):

Bridging perspectives: experiences and future directions for patient involvement in clinical registries - a survey-based study.

Lars van de Sanden, Jacqueline Ter Stege, Jitske Tiemensma, Dominique Sprengers, Liesbeth M Timmermans, Misha D P Luyer, Mira S Staphorst.

   BACKGROUND: In the Netherlands, patient participation is mandatory in clinical registries. However, the practical implementation of this requirement remains unclear, and collaboration between patient representatives, chairs of Clinical Audit Boards (CABs) and registry coordinators has not been examined from a multistakeholder perspective.
OBJECTIVE: To explore experiences, perceptions and needs regarding collaboration between patient representatives, CAB chairs and registry coordinators and to identify strategies to strengthen patient participation in clinical registries.
METHODS: An online survey across 26 clinical registries was distributed in 2025 to three stakeholder groups: patient representatives, chairs of CABs and registry coordinators from the Dutch Institute for Clinical Auditing. The questionnaire assessed frequency and quality of collaboration, perceived value of patient input, challenges and improvement needs. Responses were analysed using descriptive statistics and thematic analysis.
RESULTS: 48 respondents participated. Overall, attitudes towards patient participation were positive. CAB chairs expressed the most favourable views on collaboration, whereas registry coordinators reported more mixed experiences, reflecting their intermediary role between governance and daily operational practice. Key challenges included limited structural clarity and role definition, methodological complexity of indicator development and data interpretation, questions of representativeness and differences between patient-identified priorities and registry requirements. Across all groups, there was a strong call for improved onboarding, training and more structured and consistent engagement.
CONCLUSIONS: Although patient participation in clinical registries is formally established, experiences with its implementation vary widely across stakeholder groups. Strengthening structural support, mutual understanding and feedback mechanisms is essential to move from symbolic to substantive participation. Developing and evaluating a structured framework for patient engagement in clinical registries may enhance the contribution of these registries to learning, quality improvement and shared decision-making in clinical practice.

Keywords:  Audit and feedback; Continuous quality improvement; Healthcare quality improvement; Qualitative research; Surveys

DOI:  https://doi.org/10.1136/bmjoq-2026-004228
Ther Innov Regul Sci. 2026 Jul 06.

Medicinal Chemistry Perspectives on Drug Repurposing: Innovative Approaches and Therapeutic Breakthrough.

Sapna Ahuja, Divya Kanwar, Pragati Silakari, Sanjeev Kumar Sahu, Paranjeet Kaur.

  Drug repurposing involves the discovery of new therapeutic uses of existing drugs that have already been approved by the regulatory authorities. It provides an alternative with more efficient approaches to traditional drug discovery, leveraging already known safety profiles, shortened development and financial costs. Current advances in computational biology, artificial intelligence and big-data analytics have expanded the range of opportunities for systematic repurposing, but the successful translation of these opportunities is increasingly dependent on the holistic input of medicinal chemistry. The therapeutic relevance of medicinal chemistry-guided repurposing is being investigated over a range of unmet medical conditions, such as complicated diseases, rare diseases and new health crises, such as the COVID-19 pandemic. In this review, we underscore the critical importance of medicinal chemistry, including structure-activity relationship analysis, molecular optimization, target engagement assay, and ADMET refinement, in supporting the efficacy and safety of repurposed candidates. We further discuss the co-existence of these strategies with in silico predictions of the target, virtual screening, and phenotypic assays to narrow down lead compounds and improve translational success. Additionally, the role of medicinal chemistry in personalized medicine is also taken into account, where special attention is paid to the possibility of modifying pharmacological characteristics to patient-specific molecular and biological phenotypes. The study aims to encourage researchers and clinicians to adopt the revolutionary potential of drug repurposing to enhance treatment decisions and overall health outcomes among a large number of patients. Moreover, in a medical landscape that is becoming more complex, drug repurposing can transform the pharmaceutical industry, accelerate the process of making viable therapy available, and facilitate the delivery of quality healthcare.

Keywords:  Drug development; Drug discovery; Drug repurposing; Medicinal chemistry; Therapeutic

DOI:  https://doi.org/10.1007/s43441-026-01013-y
Nanoscale. 2026 Jul 08.

Restoring the powerhouse: mitochondrial transplantation in regenerative medicine and cancer therapy.

Ngoc-Tri Tran, Hsiu-Ching Liu, Der-Yang Cho, Ming-You Shie, Shang-Hsiu Hu.

Mitochondrial dysfunction acts as a central contributor to diverse pathologies, ranging from neurodegenerative disorders to cancer, yet traditional pharmacotherapy often fails to restore organelle bioenergetics. Building on the discovery of natural intercellular mitochondrial transfer, Mitochondrial Transplantation (MtT) has emerged as a groundbreaking strategy to replace damaged organelles with healthy exogenous mitochondria. The present review synthesizes the recent progress in MtT, highlighting the intervention's dual therapeutic role: restoring metabolic homeostasis in regenerative medicine and reversing metabolic reprogramming to sensitize tumors in oncology. The text critically assesses current isolation techniques and innovative delivery strategies designed to overcome stability and uptake challenges. By evaluating biological mechanisms and translational barriers of "mitotherapy", the article provides a comprehensive theoretical foundation for advancing precision organelle-centered medicine.

DOI: https://doi.org/10.1039/d6nr00488a
Psychol Health. 2026 Jul 08. 1-21

The experiences of partners of individuals with pre-symptomatic Huntington's disease: a reflexive thematic analysis.

Lewis Pares, Fiona Eccles, Maria Dale, Jane Simpson.

   OBJECTIVE: Individuals with the Huntington disease gene can often remain symptom free until their mid-40s. While the experiences of partners of individuals at the symptomatic stage of Huntington's disease have been explored, the experiences of the partner in this pre-symptomatic stage have been largely ignored. This qualitative study explores the experiences of partners of individuals with pre-symptomatic Huntington's disease to provide new insights into the perspectives of and challenges to partners during this stage.
METHODS AND MEASURES: Eight partners (five women and three men) of individuals (four women, four men) with pre-symptomatic Huntington's disease from three different countries (UK, US and Canada) took part in individual, semi-structured interviews. Reflexive thematic analysis was used to create themes.
RESULTS: The analysis resulted in three themes: (1) Partners' navigation of time and uncertainty during the pre-symptomatic stage;(2) Immersion in the research: a road to hope; (3) Us versus the world: how the shared experience of HD strengthened relationships.
CONCLUSION: Partners were affected by Huntington's disease even before symptoms appeared and developed proactive strategies to manage uncertainty and future planning. Couples often navigated these challenges together, strengthening their relationship through communication and shared decision-making. The study highlights implications for supporting partners' psychological well-being in both research and clinical practice.

Keywords:  Huntington’s Disease; chronic illness; experience; partner; qualitative

DOI:  https://doi.org/10.1080/08870446.2026.2697157
Probl Sotsialnoi Gig Zdravookhranenniiai Istor Med. 2026 Dec 15. 34(3): 585-591

[THE BLOGOSPHERE AS SPACE OF PHYSICIAN-PATIENT COMMUNICATION].

E V Moreeva.

  The article analyses the medical blogosphere as a special digital space where new models of communication between physician and patient are formed. The relevance of research is conditioned by increasing role of digital media in health care, spreading of practices of independent search of medical information by patients and intensification of influence of social platforms on confidence and reputation of physician and decision-making regarding health. It is demonstrated that medical blogosphere performs simultaneously informational, educational, navigational and reputational functions. At the same time, the given space is associated with significant risks: dissemination of unreliable information, blurring of professional boundaries, threats to confidentiality and decreasing of quality of medical communication under absence of professional moderation. The thesis is substantiated that blogosphere does not replace clinical interaction, but becomes an important communicative contour that precedes, accompanies and continues full-time reception. The conclusion is made about necessity of institutionalization of professional presence of physicians in digital sphere, development of digital and media literacy in patients and elaboration of ethical standards of medical blogging.

Keywords:  confidence; digital communication; medical blogging; medical blogosphere; medical information.; patient; physician; social media

DOI:  https://doi.org/10.32687/0869-866X-2026-34-3-585-591
Trials. 2026 Jul 11. pii: 488. [Epub ahead of print]27(1):

Vulnerability, protection and fairness: ethical and regulatory limits in small-N gene therapy trials.

Margaux Reckelbus, Eva Van Steijvoort, Isabelle Huys, Pascal Borry.

   BACKGROUND: International ethics frameworks emphasize both the protection of vulnerable participants and the importance of equitable inclusion in research. In ultra-rare gene therapy trials, extensive safety monitoring, long-term follow-up requirements, and specialized treatment infrastructure are necessary to ensure participant protection and scientific validity. However, these requirements operate within healthcare systems characterized by geographic, financial, and social inequalities, raising concerns about whether all eligible patients have a fair opportunity to participate. Recent regulatory reforms in the European Union (EU), United Kingdom (UK), and United States (US) increasingly promote methodological flexibility for small patient populations through adaptive trial designs, risk proportionate oversight, and alternative evidentiary approaches.
MAIN BODY: This commentary examines the extent to which existing clinical trial guidance for gene therapy promotes fair inclusion while safeguarding participants. We analyze binding and non-binding guidance from the European Medicines Agency (EMA), United States Food and Drug Administration (FDA), Medicines and Healthcare products Regulatory Agency (MHRA), International Council for Harmonisation (ICH), Council for International Organizations of Medical Sciences (CIOMS), and United Nations Educational, Scientific and Cultural Organization (UNESCO), alongside illustrative examples from Zolgensma®, Roctavian®, and Hemgenix®. Current frameworks provide substantial methodological flexibility with natural history data, external controls, decentralized approaches, and proportionate evidence requirements. Emerging initiatives such as FDA Diversity Action Plans, the UK Inclusion and Diversity Plan, and recent EU regulatory reforms further reflect growing attention to procedural fairness. Nevertheless, operational barriers remain. Long-term follow-up obligations, geographic concentration of expertise, financial burdens, and reliance on patient advocacy networks continue to shape who can realistically participate in research. While regulators increasingly recognize these challenges, guidance rarely requires concrete measures to mitigate them.
CONCLUSION: Current gene therapy trial frameworks largely succeed in supporting methodological flexibility for ultra-rare conditions but insufficiently operationalize fair inclusion. Ethical concerns arise not because participant protections are excessive, but because the burdens associated with necessary scientific and regulatory requirements may disproportionately affect patients facing structural disadvantages. Ensuring justice in ultra-rare gene therapy research requires extending proportionate, risk-based approaches beyond evidence generation to include the identification and mitigation of foreseeable barriers to participation.

Keywords:  Clinical trial; Fair inclusion; Gene therapy; Procedural fairness; Rare diseases; Vulnerability

DOI:  https://doi.org/10.1186/s13063-026-09896-w
Res Involv Engagem. 2026 Jul 06. pii: 107. [Epub ahead of print]12(1):

Beyond the ethics deflection: Why patient burden is a scientific review question, not just an IRB concern.

Srdjan Stakic.

  Patient advocates increasingly serve as voting members of Scientific Review Committees (SRCs) charged with evaluating the scientific merit and feasibility of clinical trial protocols. In principle, this gives advocates a seat at the table when the scientific architecture of a trial is most malleable. In practice, a recurring pattern undermines that promise. When advocates raise concerns about visit frequency, procedural invasiveness, or restrictive eligibility criteria, those concerns are often deflected on the grounds that they are ethical rather than scientific, and therefore properly the province of the Institutional Review Board. This Comment names that pattern jurisdictional dismissal and argues that it rests on a category error. Patient burden is a primary determinant of accrual, retention, data completeness, and generalizability. These are scientific concerns by any reasonable definition. When SRCs decline to engage with them, they let an unsuccessful trial proceed to ethics review with a fixed design that the IRB cannot meaningfully alter. I describe how jurisdictional dismissal operates, distinguish the scientific feasibility question that belongs to the SRC from the ethical acceptability question that belongs to the IRB, and propose four concrete changes to SRC practice that recognize feasibility as a scientific criterion in its own right.

Keywords:  Clinical trial design; Co-production; Institutional review board; Patient and public involvement; Patient burden; Research ethics; Scientific review; Trial feasibility

DOI:  https://doi.org/10.1186/s40900-026-00927-z