bims-curels 2026-03-15 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2026–03–15
twelve papers selected by
Cure Mito Foundation

Revisiting the promise and pitfalls of mitochondrial replacement therapies.
From disease prevention to fertility treatment: rethinking the use of mitochondrial donation for oocyte-related infertility in the light of safety and efficacy.
The goal attainment scale in primary mitochondrial disease: Construct validity and lessons learned from a randomized controlled trial.
Pluripotent stem-cell-based screening uncovers sildenafil as a mitochondrial disease therapy.
From Prohibition to Prudent Opening : Exploring the Legalization of Human Germline Gene Editing for Correcting Genetic Diseases.
"I've Never Really Thought about This…" - The Complexity of Patient Involvement in Education from the Teachers' Point of View.
Energy Compensation Strategy: The Frontier of Neurodegenerative Disease Treatment.
[Understand, integrate, decide].
Let's do it together! Co-creating a supportive tool to enhance patient involvement in agenda setting in healthcare communication.
Deferring to Expertise whilst Maintaining Autonomy.
Advancing cell and gene therapy: Application of AI/ML in clinical development and patient management.
The Essential Role of Bedside Training in Undergraduate Medical Education: A Systematic Review.

Hum Reprod. 2026 Mar 08. pii: deag020. [Epub ahead of print]

Revisiting the promise and pitfalls of mitochondrial replacement therapies.

Nuno Costa-Borges, Dagan Wells.

  Mitochondrial replacement therapies (MRTs) have been proposed as a means of avoiding the transmission of pathogenic mitochondrial DNA (mtDNA) mutations from mother to child. While clinical cases using this groundbreaking strategy have now been reported for the two principal MRT methods-pronuclear transfer and maternal spindle transfer-recent data continues to raise questions about the reliability of these approaches for disease prevention.

Keywords:  female infertility; maternal spindle transfer; mitochondrial diseases; mitochondrial replacement therapies; mitochondrial reversal; oocyte quality; pronuclear transfer

DOI:  https://doi.org/10.1093/humrep/deag020
Hum Reprod. 2026 Mar 13. pii: deag027. [Epub ahead of print]

From disease prevention to fertility treatment: rethinking the use of mitochondrial donation for oocyte-related infertility in the light of safety and efficacy.

Flor Pasturino, Guido M W R De Wert, Cathy Herbrand, Hubert J M Smeets.

  Maternal spindle transfer (MST) and pronuclear transfer (PNT) raise a number of important ethical and regulatory issues. These IVF procedures that transfer nuclear DNA to enucleated oocytes or zygotes aim to prevent transmitting mitochondrial disease by female carriers of mitochondrial DNA (mtDNA) mutations and enable them to have healthy genetically related children. MST/PNT might also prove effective in treating oocyte-related infertility, but are not permitted in the UK and Australia, unlike MST/PNT for mtDNA disorders. The paper discusses the regulation of MST/PNT for both applications in relation to their risks and efficacy, highlighting the scarcity of clinical data. Based on risk reduction, it has even been proposed to treat oocyte-related infertility first before moving to mtDNA disorders. We argue that a prohibition of MST/PNT for infertility is not justified, neither should it initially be applied only for infertility because of the little evidence yet available regarding its efficacy and potential risks. We propose a staged approach to identify MST/PNT-treatable causes of oocyte-related infertility first, followed by a preclinical study and clinical trial and, if positive, wider application. Importantly, we call for transparency in publishing regular trial results, deeper ethical reflection, and more consistent policies that consider comparable uncertainties in mtDNA disorders and oocyte-related infertility.

Keywords:  assisted reproduction; ethics; maternal spindle transfer; mitochondria; mitochondrial DNA disorders; mitochondrial donation; nuclear transfer; oocyte-related infertility; pronuclear transfer; translational research

DOI:  https://doi.org/10.1093/humrep/deag027
Mol Genet Metab. 2026 Mar 03. pii: S1096-7192(26)00158-7. [Epub ahead of print]148(2): 109875

The goal attainment scale in primary mitochondrial disease: Construct validity and lessons learned from a randomized controlled trial.

Kristofoor E Leeuwenberg, Joanna IntHout, Jan T Groothuis, Edith Cup, Jan Smeitink, Karlien Mul, Mirian C H Janssen.

   BACKGROUND: Primary mitochondrial diseases (PMD) are rare heterogeneous disorders caused by defective oxidative phosphorylation, with symptoms varying widely between individuals with PMD. Despite extensive research, no consensus exists on outcome measures that adequately reflect function, activities, and participation for adults with mitochondrial diseases. The Goal Attainment Scale (GAS) offers a personalized, patient-centered way to capture these outcomes. However, its validity and standardized use in trials remain unclear. This study assessed GAS construct validity in a PMD trial, including comparison with the Canadian Occupational Performance Measure (COPM), and provides guidance for future application.
METHODS: Data from a double-blind, randomized, placebo-controlled, exploratory Phase IIA cross-over trial on the safety and efficacy of sonlicromanol (KH176) in 18 adult m.3243 A>G patients, were retrospectively analyzed. GAS goals were categorized using the World Health Organization International Classification of Functioning, Disability and Health. Additional outcome measures with overlapping content were selected to evaluate GAS validity. Implementation quality was evaluated using 17 GAS appraisal criteria.
RESULTS: Most goals addressed fatigue or lack of energy (85%, 22/26). GAS showed weak to moderate negative correlations with the Checklist Individual Strength (CC = -0.40) and Beck Depression Inventory-II scores (CC = -0.37), indicating higher GAS scores were associated with reductions in fatigue and depressive symptoms. Moderate correlations were observed between GAS and COPM scores (CC = 0.50-0.55). No significant correlations were found with the 6-min walk test, 36-item Short Form Health Survey or Newcastle Mitochondrial Disease Scale for Adults. Only 6 out of 17 (35%) implementation criteria were fully met.
CONCLUSIONS: GAS demonstrated some construct validity in relation to fatigue and depressive symptoms, showed limited overlap with conventional outcome measures and suffered from suboptimal implementation. Although exploratory, these findings suggest GAS may capture patient-relevant change in individuals with PMD. To realize its potential, standardized methodology and further validation are essential for its use as a robust outcome measure in future PMD trials.

Keywords:  Construct validity; Goal attainment scale; Mitochondrial disease; Outcome measure

DOI:  https://doi.org/10.1016/j.ymgme.2026.109875
Cell. 2026 Mar 11. pii: S0092-8674(26)00173-X. [Epub ahead of print]

Pluripotent stem-cell-based screening uncovers sildenafil as a mitochondrial disease therapy.

Annika Zink, Dao-Fu Dai, Annika Wittich, Marie-Thérèse Henke, Giulia Pedrotti, Sonja Heiduschka, Guillem Santamaria, Tancredi Massimo Pentimalli, Christian Brueser, Sofia Notopoulou, Abdul Rahim Umar, Aleksandra Zhaivoron, Laura Petersilie, Caleb Jerred, Jesper Bergmans, Louis Anton Neu, Fabian Schumacher, Jan Keller-Findeisen, Agnieszka Rybak-Wolf, Daniel Stach, Jeanette Reinshagen, Undine Haferkamp, Kim Krieg, Andrea Zaliani, Liliya Euro, Alessia Di Donfrancesco, Chiara Santanatoglia, Enrica Cappellozza, Marta Suarez Cubero, Mario Pavez-Giani, Oleh Bakumenko, David Meierhofer, Alan Foley, Susanne Morales-Gonzalez, Isabella Tolle, Diran Herebian, Daniele Bonesso, Giulia Cecchetto, Sakurako Nagumo Wong, Monica Moresco, Alessandra Maresca, Ilaria Decimo, Francesco De Sanctis, Annalisa Adamo, Merel J W Adjobo-Hermans, Roberto Duchi, Maria Barandalla, Marco Scaglia, Andrea Perota, Cesare Galli, Burkhard Kleuser, Lukas Cyganek, Chris Mühlhausen, Lars Schlotawa, Valeria Tiranti, Ertan Mayatepek, Ildiko Szabo, Chiara La Morgia, Thomas Klopstock, Valerio Carelli, Felix Distelmaier, Andrea Rossi, Nikolaus Rajewsky, Ghanim Ullah, Stefan Jakobs, Christine R Rose, Spyros Petrakis, Frank Edenhofer, Werner J H Koopman, Pawel Lisowski, Anu Suomalainen, Dario Brunetti, Antonio Del Sol, Emanuela Bottani, Ole Pless, Markus Schuelke, Alessandro Prigione.

  Mitochondrial disease encompasses inherited disorders affecting mitochondrial function. A severe and untreatable form of mitochondrial disease is Leigh syndrome (LS), causing psychomotor regression and metabolic crises. To accelerate drug discovery for LS, we screen a library of 5,632 repurposable compounds in neural cells from LS-patient-derived induced pluripotent stem cells (iPSCs). We identify phosphodiesterase type 5 (PDE5) inhibitors as leads and prioritize sildenafil for its clinical safety. Sildenafil corrects mitochondrial membrane potential defects, restores neurodevelopmental pathways, and normalizes calcium responses in LS brain organoids. In small and large mammalian models of LS, sildenafil extends lifespan and ameliorates disease phenotypes. Off-label treatment on an individual basis with sildenafil in six LS patients improves their motor function and resistance to metabolic crises. Collectively, the findings highlight the potential of iPSC-driven drug discovery and position sildenafil as a promising drug candidate for mitochondrial disease.

Keywords:  Leigh syndrome; PDE5 inhibitors; PRKG1; brain organoids; drug repurposing; drug screening; high-content analysis; iPSCs; mitochondrial diseases; sildenafil

DOI:  https://doi.org/10.1016/j.cell.2026.02.008
J Bioeth Inq. 2026 Mar 13.

From Prohibition to Prudent Opening : Exploring the Legalization of Human Germline Gene Editing for Correcting Genetic Diseases.

Lijie Wang, Shunbin Zhang, Wei Zhong, Kainan Zhu, Quan Yang, Zichuan Ma, Jianzhen Li.

  The rapid advancement of human germline gene editing (HGGE) technology has brought opportunities for gene therapy in patients with rare diseases. However, due to risks related to technical safety, ethics, and societal concerns, some countries have explicitly prohibited the application of germline gene editing. In reality, the use of HGGE for correcting genetic diseases contributes to safeguarding the fundamental rights of patients with rare genetic disorders and their offspring. The off-target effects of CRISPR/Cas9 gene editing technology are controllable, and preliminary clinical successes have been achieved, with a low probability of substantial harm. Moreover, the expected number of actual applications is minimal, meaning it will not significantly alter the human gene pool in the short term. When applied reasonably, HGGE for correcting genetic diseases does not pose the aforementioned ethical or social risks. Its application is ethically justified, and by implementing matching safety safeguards and regulatory frameworks, the legalization of HGGE for genetic disease correction can be achieved, thereby balancing technological innovation with human rights protection.

Keywords:  Genetic diseases; Human germline gene editing; Legalization; Prudent opening

DOI:  https://doi.org/10.1007/s11673-025-10521-9
Perspect Med Educ. 2026 ;15(1): 200-211

"I've Never Really Thought about This…" - The Complexity of Patient Involvement in Education from the Teachers' Point of View.

Elias Schriwer, Agnes Elmberger, Anders Sondén, Terese Stenfors.

Introduction: Patient involvement in health professions education (HPE) often takes the form of isolated, small-scale activities, where teachers' initiatives largely determine whether and how patients are included. Understanding how teachers make sense of patient involvement is therefore crucial for strengthening and sustaining this practice in HPE. Using a phenomenographic approach, our aim was to explore how teachers understand patient involvement in HPE and visualize these interrelated understandings in an outcome space.
Methods: We conducted semi-structured interviews with 20 teachers experienced in working with patient involvement across eight different HPE programs at one university. The interview guide was developed within the research group, in dialogue with a patient representative.
Results: We identified four qualitatively different ways in which teachers understand patient involvement: as a way to 1) create variation in education, 2) improve education, 3) improve health care or 4) improve society. These four categories were comprised of seven themes of expanding awareness: the role of the patient, the role of the student, the role of the teacher, role of education, interaction between patient and student, view of workplace learning and teachers' perceived agency.
Discussion and conclusion: Our findings suggest that there is considerable complexity in how teachers understand the purpose and value of patient involvement in education. These differences will influence why, how, and to what extent patients are involved in HPE. Striving towards a more complex understanding may support more beneficial, sustainable and meaningful patient involvement. Further research should explore how different stakeholders' understandings influence the practice of patient involvement in HPE.

DOI: https://doi.org/10.5334/pme.1875
ACS Chem Neurosci. 2026 Mar 12.

Energy Compensation Strategy: The Frontier of Neurodegenerative Disease Treatment.

Junyue Tang, Yuning Sun, Xingyu Lin, Xinhui Zhao, Chun Mao, Mimi Wan, Jianying Li, Ya Guan.

  Neurodegenerative diseases are a major threat to global public health. Recent studies have revealed that mitochondrial DNA damage and the imbalance of protein homeostasis during aging constitute the core pathological basis of neurodegeneration. The resulting energy metabolism disorders are the common pathogenic hubs of multiple neurodegenerative diseases. In this review, we focus on representative neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, and Huntington's disease, and systematically discuss their pathology related to metabolic disorders. We introduce various energy compensation strategies: (1) rebuilding the energy supply by enhancing mitochondrial function; (2) implementing systemic metabolic remodeling; (3) supplementing alternative energy substrates; (4) utilizing direct energy delivery technology. This review also highlights the technical bottlenecks of existing energy compensation strategies, guiding future research on neurodegenerative diseases.

Keywords:  eirect energy delivery; energy compensation; energy substrate supplementation; metabolic reprogramming; mitochondria-targeted therapies; neurodegenerative diseases

DOI:  https://doi.org/10.1021/acschemneuro.5c00964
Rev Med Liege. 2026 Mar;81(3): 127-128

[Understand, integrate, decide].

Patrizio Lancellotti.

This issue highlights the growing complexity of modern medicine through diverse clinical situations, ranging from rare diseases to everyday practice challenges. It emphasizes the central role of clinical reasoning in data integration and medical decision-making.

Keywords: Clinical practice; Clinical reasoning; Decision-making; Medical complexity
Patient Educ Couns. 2026 Feb 16. pii: S0738-3991(26)00066-2. [Epub ahead of print]148 109533

Let's do it together! Co-creating a supportive tool to enhance patient involvement in agenda setting in healthcare communication.

Connie Timmermann, Trine Ammentorp Gregersen, Elna Leth Pedersen, Mona Engdal Larsen, Tina Faaborg Linaa, Jette Ammentorp.

   OBJECTIVE: Communication training improves healthcare professionals' person-centered skills, yet patients are less often supported in taking an active role. This paper describes the development of an explainer film to enhance patient empowerment and involvement in clinical interactions.
METHOD: The study was conducted at a Danish university hospital. Through participatory workshops, the project actively involved patients with diabetes, clinicians, and researchers in a co-reflective, collaborative process. Data collection included written field notes and videotaped documentation.
DISCUSSION AND INNOVATION: Individuals with diabetes identified key challenges in actively participating in healthcare conversations. Patients expressed a desire for greater involvement in setting consultation agendas but often struggled to assert their needs within fixed clinical structures. To co-develop an explainer film, a participatory, iterative process involving patients, clinicians, and researchers was employed. This approach ensured a supportive tool that aligns with patients' real-world needs, enhancing its relevance and effectiveness in fostering communication skills and self-advocacy in clinical encounters.
CONCLUSION: Developing supportive tools such as explainer films may enhance patient engagement and communication. Future efforts should focus on creating accessible, user-friendly resources to better align clinical communication with patients' needs.

Keywords:  Diabetes; Participatory methods; Patient and public involvement; Patient partnership; Person-centered communication; Workshops

DOI:  https://doi.org/10.1016/j.pec.2026.109533
Episteme (Edinb). 2025 Jun 01. 22(2): 472-491

Deferring to Expertise whilst Maintaining Autonomy.

Rebecca C H Brown.

  This paper will consider the extent to which patients' dependence on clinical expertise when making medical decisions threatens patient autonomy. I start by discussing whether or not dependence on experts is prima facie troubling for autonomy and suggest that it is not. I then go on to consider doctors' and other healthcare professionals' status as 'medical experts' of the relevant sort and highlight a number of ways in which their expertise is likely to be deficient. I then consider how this revised picture of medical expertise should lead us to view the potential threat to patient autonomy that results from depending on such 'experts'. I argue that, whether or not patients are aware of the limitations of medical expertise, in practice it is difficult to do other than defer to medical advice, and this presents a threat to patient autonomy that should be addressed. I conclude by suggesting some ways in which this threat to autonomy might be mitigated.

Keywords:  Expertise; autonomy; epistemic authority; epistemic autonomy; medical ethics; social epistemology

DOI:  https://doi.org/10.1017/epi.2024.3
J Biopharm Stat. 2026 Mar 12. 1-19

Advancing cell and gene therapy: Application of AI/ML in clinical development and patient management.

Kelly Speth, Sanhita Sengupta, Md Shamsuzzaman, James Whitmore, Daniel Li, Alan Y Chiang, Zhenzhen Xu, Qinghua Song.

  This article explores the transformative potential of artificial intelligence (AI) and machine learning (ML) in advancing cell and gene therapy (CGT) development, with an emphasis on chimeric antigen receptor (CAR) T-cell therapy. We examine how AI/ML advanced analytics can enhance CGT clinical development by optimizing patient selection with robust eligibility criteria, facilitating clinical trial site and patient recruitment, and informing study design through risk profiling and biomarker development. Furthermore, we discuss the application of AI/ML for improving patient management, focusing on personalized dosing strategies, as well as post-treatment monitoring using wearable technology and mobile health. Opportunities and challenges presented by AI/ML in addressing the complexities of CGT, and a brief review of legislation and regulatory agency policy as it relates to AI/ML, are discussed. Overall, the integration of AI/ML offers promising avenues to enhance the efficiency, quality, and equity of CGT development and patient care.

Keywords:  Artificial intelligence (AI); cell and gene therapy (CGT); chimeric antigen receptor (CAR) T-cell therapy; clinical development; real-world patient journey

DOI:  https://doi.org/10.1080/10543406.2026.2629434
J Assoc Physicians India. 2026 Mar;74(3): 99-102

The Essential Role of Bedside Training in Undergraduate Medical Education: A Systematic Review.

Christopher Mathew, John C Mathew, Sumana S Philip.

This systematic review examined the role of bedside teaching (BST) in undergraduate medical education, focusing on its impact on clinical competence and professional growth. The review included 15 studies that investigated the effects of BST on physical examination skills, diagnostic abilities, communication skills, and confidence among medical students. The results showed that BST significantly improved physical examination skills, diagnostic abilities, and communication skills, and increased confidence among students. BST was also found to enhance empathy and professionalism among students. However, the review highlighted several challenges in implementing BST, including time constraints, lack of trained faculty, and declining opportunities for BST. To address these challenges, the review recommended integrating BST into the medical curriculum, providing faculty development programs, and utilizing technology-enhanced learning tools. The findings of this systematic review underscore the importance of BST in undergraduate medical education, emphasizing its potential to enhance clinical competence and professional growth among future healthcare professionals.

DOI: https://doi.org/10.59556/japi.74.1063