bims-curels 2025-03-16 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2025–03–16
eleven papers selected by
Cure Mito Foundation

Genetic and reproductive strategies to prevent mitochondrial diseases.
Retinopathy associated with MELAS syndrome. A case report.
Challenges and Possible Strategies to Address Them in Rare Disease Drug Development: A Statistical Perspective.
Mitochondrial replacement techniques to resolve mitochondrial dysfunction and ooplasmic deficiencies: where are we now?
Mitochondria-based medicine.
Metabolic remodeling in hiPSC-derived myofibers carrying the m.3243A>G mutation.
Research quality and dissemination of paediatric randomised controlled trials with and without patient and family engagement: systematic review.
How a patient-led advocacy organization supports the road to diagnosis and treatment of creatine transporter deficiency.
SIMPATHIC: Accelerating drug repurposing for rare diseases by exploiting SIMilarities in clinical and molecular PATHology.
Development of MitoWizz: a Bioinformatics Solution for Mitochondrial DNA Analysis in Both Forensic and Clinical Applications.
NHS has finally agreed to share GP patient data for research-this is why.

Hum Reprod Update. 2025 Mar 14. pii: dmaf004. [Epub ahead of print]

Genetic and reproductive strategies to prevent mitochondrial diseases.

Noemi Castelluccio, Katharina Spath, Danyang Li, Irenaeus F M De Coo, Lyndsey Butterworth, Dagan Wells, Heidi Mertes, Joanna Poulton, Björn Heindryckx.

  Mitochondrial DNA (mtDNA) diseases pose unique challenges for genetic counselling and require tailored approaches to address recurrence risks and reproductive options. The intricate dynamics of mtDNA segregation and heteroplasmy shift significantly impact the chances of having affected children. In addition to natural pregnancy, oocyte donation, and adoption, IVF-based approaches can reduce the risk of disease transmission. Prenatal diagnosis (PND) and preimplantation genetic testing (PGT) remain the standard methods for women carrying pathogenic mtDNA mutations; nevertheless, they are not suitable for every patient. Germline nuclear transfer (NT) has emerged as a novel therapeutic strategy, while mitochondrial gene editing has increasingly become a promising research area in the field. However, challenges and safety concerns associated with all these techniques remain, highlighting the need for long-term follow-up studies, an improved understanding of disease mechanisms, and personalized approaches to diagnosis and treatment. Given the inherent risks of adverse maternal and child outcomes, careful consideration of the balance between potential benefits and drawbacks is also warranted. This review will provide critical insights, identify knowledge gaps, and underscore the importance of advancing mitochondrial disease research in reproductive health.

Keywords:  germline nuclear transfer (NT); mitochondrial DNA (mtDNA); mitochondrial disease; mitochondrial gene editing; preimplantation genetic testing (PGT); prenatal diagnosis (PND)

DOI:  https://doi.org/10.1093/humupd/dmaf004
Arch Soc Esp Oftalmol (Engl Ed). 2025 Mar 07. pii: S2173-5794(25)00027-1. [Epub ahead of print]

Retinopathy associated with MELAS syndrome. A case report.

A B González Escobar, E Barco Moreno, M A López-Egea Bueno, J M Galván Cano, R Luque Aranda, A González Gómez.

  MELAS syndrome (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) is an inherited disease frequently caused by a mutation in the mitochondrial DNA variant m.3243A>G in the MT-TL1 gene. The most frequent ophthalmologic finding present in 86-87% of patients with this mutation is mitochondrial retinopathy, where the clinical picture may vary from a macular and peripapillary salt-and-pepper granular pattern to chorioretinal atrophy. We present the case of a 47-year-old woman with type 1 diabetes mellitus, epilepsy, leukoencephalopathy, and deafness who was suspected of having mitochondrial disease after fundus examination. We would like to emphasize the importance of suspecting a mitochondrial disease in progressive multisystem disorders associated with neuro-ophthalmological manifestations, since early diagnosis allows for better monitoring of systemic manifestations, reducing morbidity and mortality.

Keywords:  Atrofia coriorretiniana; Chorio-retinal atrophy; Encefalopatía; Encephalopathy; M.3243A>G; MELAS; MTTL1 gen; MTTL1 gene; Mitochondrial retinopathy; Retinopatía mitocondrial

DOI:  https://doi.org/10.1016/j.oftale.2025.03.001
Clin Pharmacol Ther. 2025 Mar 13.

Challenges and Possible Strategies to Address Them in Rare Disease Drug Development: A Statistical Perspective.

Jie Chen, Lei Nie, Shiowjen Lee, Haitao Chu, Haijun Tian, Yan Wang, Weili He, Thomas Jemielita, Susan Gruber, Yang Song, Roy Tamura, Lu Tian, Yihua Zhao, Yong Chen, Mark van der Laan, Hana Lee.

Developing drugs for rare diseases presents unique challenges from a statistical perspective. These challenges may include slowly progressive diseases with unmet medical needs, poorly understood natural history, small population size, diversified phenotypes and genotypes within a disorder, and lack of appropriate surrogate endpoints to measure clinical benefits. The Real-World Evidence (RWE) Scientific Working Group of the American Statistical Association Biopharmaceutical Section has assembled a research team to assess the landscape including challenges and possible strategies to address these challenges and the role of real-world data (RWD) and RWE in rare disease drug development. This paper first reviews the current regulations by regulatory agencies worldwide and then discusses in more detail the challenges from a statistical perspective in the design, conduct, and analysis of rare disease clinical trials. After outlining an overall development pathway for rare disease drugs, corresponding strategies to address the challenges are presented. Other considerations are also discussed for generating relevant evidence for regulatory decision-making on drugs for rare diseases. The accompanying paper discusses how RWD and RWE can be used to improve the efficiency of rare disease drug development.

DOI: https://doi.org/10.1002/cpt.3631
Hum Reprod. 2025 Mar 13. pii: deaf034. [Epub ahead of print]

Mitochondrial replacement techniques to resolve mitochondrial dysfunction and ooplasmic deficiencies: where are we now?

Jessica Subirá, María José Soriano, Luis Miguel Del Castillo, María José de Los Santos.

  Mitochondria are the powerhouses of cell and play crucial roles in proper oocyte competence, fertilization, and early embryo development. Maternally inherited mitochondrial DNA (mtDNA) mutations can have serious implications for individuals, leading to life-threatening disorders and contribute to ovarian ageing and female infertility due to poor oocyte quality. Mitochondrial replacement techniques (MRTs) have emerged as a promising approach not only to replace defective maternal mitochondria in patients carrying mtDNA mutations, but also to enhance oocyte quality and optimize IVF outcomes for individuals experiencing infertility. There are two main categories of MRT based on the source of mitochondria. In the heterologous approach, mitochondria from a healthy donor are transferred to the recipient's oocyte. This approach includes several methodologies such as germinal vesicle, pronuclear, maternal spindle, and polar body transfer. However, ethical concerns have been raised regarding the potential inheritance of third-party genetic material and the development of heteroplasmy. An alternative approach to avoid these issues is the autologous method. One promising autologous technique was the autologous germline mitochondrial energy transfer (AUGMENT), which involved isolating oogonial precursor cells from the patient, extracting their mitochondria, and then injecting them during ICSI. However, the efficacy of AUGMENT has been debated following the results of a randomized clinical trial (RCT) that demonstrated no significant benefit over conventional IVF. Recent developments have focused on novel approaches based on autologous, non-invasively derived stem cells to address infertility. While these techniques show promising results, further RCTs are necessary to establish their effectiveness and safety for clinical use. Only after robust evidence becomes available could MRT potentially become a viable treatment option for overcoming infertility and enabling patients to have genetically related embryos. This review aims to provide an overview of the current state of MRTs in addressing low oocyte quality due to mitochondrial dysfunction.

Keywords:  female infertility; mitochondria; mitochondrial DNA; mitochondrial dysfunction; mitochondrial replacement; oocyte quality

DOI:  https://doi.org/10.1093/humrep/deaf034
Bol Med Hosp Infant Mex. 2025 ;82(1): 7-14

Mitochondria-based medicine.

Salvador Vázquez-Vega, José D Martínez-Ezquerro, Sergio Sánchez-García, Edwin R Marka-Castro, Fernando Minauro-Sanmiguel.

  At the balance between human health and disease (from the very first moments to the end of life), the mitochondrion is central players because of its metabolic role in adenosine triphosphate synthesis, cell signaling, immune response, and other processes of clinical interest. On the other hand, impairments at the optimal mitochondria function have important consequences in complex diseases, such as heart disease, diabetes, and cancer, among others. These mitochondrial impairments can occur at any age damaging multiple body systems, which have prompted the mitochondrial medicine development. Since mitochondrial diseases have great variability in their clinical manifestations, early studies were centered on mitochondriopathies, however nowadays, this focus has broadened to understand and encompass the mitochondrial role of in diseases development of both pediatric and adult age. The mitochondria potential to improve diagnostic, prognostic, and treatment response strategies has been revealed by experimental approaches using proteomics, genomics, and metabolomics to identify clinical biomarkers showing disease development. Thus, the perspective of mitochondria-based medicine recognizes the importance of generating scientific evidence related to mitochondria and their role in pathological conditions from a comprehensive approach.

Keywords:  Chronic non-communicable diseases; Enfermedades crónicas no transmisibles; Enfermedades metabólicas; Enfermedades mitocondriales; Metabolic diseases; Mitochondria; Mitochondrial diseases; Mitocondria

DOI:  https://doi.org/10.24875/BMHIM.24000058
Stem Cell Reports. 2025 Feb 28. pii: S2213-6711(25)00052-9. [Epub ahead of print] 102448

Metabolic remodeling in hiPSC-derived myofibers carrying the m.3243A>G mutation.

Gabriel E Valdebenito, Anitta R Chacko, Chih-Yao Chung, Preethi Sheshadri, Haoyu Chi, Benjamin O'Callaghan, Monika J Madej, Henry Houlden, Hannah Rouse, Valle Morales, Katiuscia Bianchi, Francesco Saverio Tedesco, Robert D S Pitceathly, Michael R Duchen.

  Mutations in mitochondrial DNA cause severe multisystem disease frequently associated with muscle weakness. The m.3243A>G mutation is the major cause of mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes (MELAS). Experimental models that recapitulate the disease phenotype in vitro for disease modeling or drug screening are very limited. We have therefore generated hiPSC-derived muscle fibers with variable heteroplasmic mtDNA mutation load without significantly affecting muscle differentiation potential. The cells exhibit physiological characteristics of muscle fibers and show a well-organized myofibrillar structure. In cells carrying the m.3243A>G mutation, the mitochondrial membrane potential and oxygen consumption were reduced in relation to the mutant load. We have shown through proteomic, phosphoproteomic, and metabolomic analyses that the m.3243A>G mutation variably affects the cell phenotype in relation to the mutant load. This variation is reflected by an increase in the NADH/NAD+ ratio, which in turn influences key nutrient-sensing pathways in the myofibers. This model enables a detailed study of the impact of the mutation on cellular bioenergetics and on muscle physiology with the potential to provide a platform for drug screening.

Keywords:  iPSC-derived myofibers; mitochondria; mtDNA; mtDNA mutations

DOI:  https://doi.org/10.1016/j.stemcr.2025.102448
BMJ Open. 2025 Mar 12. 15(3): e086934

Research quality and dissemination of paediatric randomised controlled trials with and without patient and family engagement: systematic review.

Cornelia M Borkhoff, Nayantara Hattangadi, Kimberly M Nurse, Tatjana Kay, Manav Bhalla, Quenby Mahood, Francine Buchanan, Monica Taljaard, Eyal Cohen, Patricia C Parkin, Colin Macarthur.

   OBJECTIVES: Authentic patient and family engagement in child health research is defined as researchers working in partnership with patients and families on all aspects of the research process, including refining the research question, tailoring the intervention, devising study procedures and disseminating study findings. While there is good evidence of a positive impact of patient engagement on the research process, on research teams and on patient partners, there are few empirical data on the impact of patient and family engagement on research quality and dissemination. We conducted a systematic review to compare research quality and dissemination metrics for paediatric randomised controlled trials (RCTs) that engaged patients and families in the research process with trials that did not.
DESIGN: Systematic review using the Cochrane Highly Sensitive Search to identify RCTs.
DATA SOURCES: Ovid MEDLINE from 1 January 2011 through to 31 December 2020.
ELIGIBILITY CRITERIA: We included RCTs involving children and youth (<18 years of age) published in The BMJ (a peer-reviewed general medical journal).
DATA EXTRACTION AND SYNTHESIS: Trials were categorised as those engaging patients and families (PE+) and those that did not (PE-). A standardised review form was used to confirm trial eligibility and extract data on study characteristics. Two reviewers independently screened and sorted RCTs into PE+ and PE- groups, extracted data and assessed research quality using the modified Cochrane Risk of Bias Tool (based on seven methodological criteria). The dissemination of RCT findings was determined using measures of academic and non-academic citation collected from Web of Science and Scopus.
RESULTS: From 2011 to 2020, The BMJ published 45 RCTs involving children and youth. Only 10/45 RCTs (22%) reported engaging patients and families in the research process. Research quality for PE+ and PE- paediatric RCTs was similar; 4/10 (40%) of PE+ trials and 13/35 (37%) of PE- trials were rated as 'fair' or 'good' (p=1.00). Academic citation frequency per year was similar for PE+ trials and PE- trials: Web of Science (median 6.6 vs 7.1, respectively; p=0.84). Non-academic dissemination measures were generally higher among PE+ trials; for example, median PlumX Social Media score per year for PE+ trials was 46.6, compared with a median score of 7.6 for PE- trials (p=0.02).
CONCLUSIONS: Despite increasing interest in patient and family engagement in child health research, this review showed that few paediatric RCTs report patient engagement activity. Research quality was similar for trials engaging patients and families compared with those that did not. Patient and family engagement in the trial, however, was associated with higher metrics for social media attention, compared with trials with no engagement.

Keywords:  Child; PAEDIATRICS; Randomized Controlled Trial; Social Media

DOI:  https://doi.org/10.1136/bmjopen-2024-086934
Front Neurosci. 2025 ;19 1548182

How a patient-led advocacy organization supports the road to diagnosis and treatment of creatine transporter deficiency.

Heidi Wallis, Sangeetha Iyer, Emily K Reinhardt.

  The current era of drug development has evolved significantly. Patient advocacy organizations are moving beyond simply supporting community members and are taking the reins to improve the speed of diagnoses, initiate therapeutic discoveries, and lay the groundwork to ensure successful clinical trials. The Association for Creatine Deficiencies (ACD) is an international parent-led patient advocacy organization focused on the three ultra-rare neurodevelopmental monogenic disorders resulting in Cerebral Creatine Deficiency Syndromes (CCDS). These include X-linked creatine transporter deficiency (CTD), guanidinoacetate methyltransferase (GAMT) deficiency, and l-arginine:glycine amidinotransferase (AGAT) deficiency. While each is rare in its own right, the unified CCDS community is effectively advancing the field of CCDS with each disorder benefiting from progress made in the other two disease areas. ACD collaborators include caregivers, academic researchers, clinicians, industry partners, and policymakers. Since its founding in 2012, the organization has evolved and achieved significant milestones. These include advancements in disease diagnosis, investments in various therapeutic modalities, creation of a collaborative research community, a unified patient community contributing essential patient data, and repositories of patient-derived specimens. The initiatives of ACD are intended to create the earliest diagnosis possible through newborn screening, to have an effective treatment, and to make disease management strategies available to all members of the CCDS community, including those diagnosed at later stages and experiencing greater effects of the diseases.

Keywords:  X-linked; creatine transporter deficiency; drug development; guanidinoacetate methyltransferase deficiency; intellectual disability; l-arginine:glycine amidinotransferase deficiency; newborn screening; patient advocacy

DOI:  https://doi.org/10.3389/fnins.2025.1548182
Mol Genet Metab. 2025 Mar 01. pii: S1096-7192(25)00064-2. [Epub ahead of print]144(4): 109073

SIMPATHIC: Accelerating drug repurposing for rare diseases by exploiting SIMilarities in clinical and molecular PATHology.

Clara D M van Karnebeek, Annelieke R Müller, Laura Benkemoun, Ibrahim Boussaad, Martina C Cornel, Joanna IntHout, Martin de Kort, Sofia de Oliveira Martins, Alessandro Prigione, Tessel Rigter, Kit C B Roes, Anna Sanchez, Raymond Schipper, Mark D Wilkinson, Peter A C 't Hoen.

  Rare diseases affect over 400 million people worldwide, with approved treatment available for less than 6 % of these diseases. Drug repurposing is a key strategy in the development of therapies for rare disease patients with large unmet medical needs. The process of repurposing drugs compared to novel drug development is a time-saving and cost-efficient method potentially resulting in higher success rates. To accelerate and ensure sustainability in therapy development for rare neurometabolic, neurological, and neuromuscular diseases, an international consortium SIMilarities in clinical and molecular PATHology (SIMPATHIC) has been established where we move away from the one drug one disease concept and move towards one drug targeting a pathomechanism shared between diseases, by applying parallel preclinical and clinical drug development. Here the consortium describes accelerators of drug repurposing pursued by the consortium, including 1) co-creation, 2) patient empowerment, 3) use of standardized induced pluripotent stem cell (iPSC)-derived disease models and cellular and molecular profiling, 4) high-throughput drug screening in neurons, 5) innovative clinical trial design, and 6) selection of appropriate exploitation and patient access models. In this way, a fast and effective drug repurposing pathway for several rare diseases will be established to reduce time from discovery to patient access.

Keywords:  Basket trial; Drug repurposing; Drug screening; Induced pluripotent stem cells; Rare diseases; Therapy development

DOI:  https://doi.org/10.1016/j.ymgme.2025.109073
Acta Inform Med. 2024 ;32(3-4): 221-224

Development of MitoWizz: a Bioinformatics Solution for Mitochondrial DNA Analysis in Both Forensic and Clinical Applications.

Nejira Handzic, Dino Pecar, Selma Durgut, Lana Salihefendic, Rijad Konjhodzic.

   Background: MitoWizz is an advanced bioinformatics tool designed for the analysis of the human mitochondrial genome, offering precise and efficient data interpretation. It enables comparisons of sequencing results obtained from various instrumental methods with the reference Andersen genome (rCRS), aiding in the identification of alterations. This capability is particularly valuable in forensic and clinical mitochondrial DNA analysis.
Objective: The primary goal of developing MitoWizz is to automate and streamline mitochondrial DNA analysis, providing researchers and forensic experts with a fast, reliable, and comprehensive tool for sequence comparison, variation detection, and data validation.
Methods: MitoWizz compares query sequences in opposed to the reference genome and allows direct comparison of two sequences to identify genetic variations. To ensure accuracy, the results are validated through the Clustal Omega W by aligning sequences with the human mitochondrial DNA reference from GenBank (NC_012920.1).
Results: The software detected genetic variations and generated a visual report, as demonstrated in an analysis where 11 mutations were identified in various genes, with an 88% sequence identity to the reference genome. The accuracy of the detected alterations was further validated using the Omega Clustal W program.
Conslusion: MitoWizz significantly reduces analysis time and enhances result reliability by integrating multiple analytical steps into a single platform. By automating mtDNA comparisons and validation, it provides forensic and research laboratories with a high-throughput, efficient solution for precise mitochondrial genome analysis.

Keywords:  SNPs; mitochondrial DNA; population; reliability; workflow

DOI:  https://doi.org/10.5455/aim.2024.32.221-224
BMJ. 2025 Mar 13. 388 r501

NHS has finally agreed to share GP patient data for research-this is why.

Stephen Armstrong.

DOI: https://doi.org/10.1136/bmj.r501