bims-curels 2025-10-12 papers

Issue of 2025–10–12
seven papers selected by
Cure Mito Foundation

Science. 2025 Oct 09. 390(6769): 114-115

First approved drug for mitochondrial disease raises hopes for more.

Researchers are testing multiple treatments for the rare genetic conditions.

DOI: https://doi.org/10.1126/science.aec9018

Brain Commun. 2025 ;7(5): fcaf342

Outcomes misaligned in mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS): implications for trial design.

Renae J Stefanetti, Sarah J Charman, Jane Newman, Kate Hallsworth, Alasdair P Blain, Yi Shiau Ng, Gráinne S Gorman.

The m.3243A>G variant in the MT-TL1 gene is the most prevalent pathogenic variant in mitochondrial DNA in adults, associated with a wide clinical spectrum from asymptomatic individuals to mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome. Although pharmacological trials in mitochondrial disorders are increasing, the lack of validated endpoints remains a significant barrier to therapeutic development. This cross-sectional observational study aimed to evaluate patients with and without mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome to identify factors associated with disease burden. Seventeen individuals genetically confirmed to harbour the heteroplasmic m.3243A>G pathogenic variant were enrolled: six who met the consensus-based diagnostic criteria for mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome (median age: 30.0 (inter-quartile range: 29.3-45.0) years). Ten patients who did not have a previous history of stroke-like episodes were assigned as 'non-mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes' (age: 37.5 (32.8-48.3) years). Of these patients in the non-mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes group, seven exhibited variable features of mitochondrial disease, including hearing loss, diabetes mellitus, migraine and gastrointestinal involvement, while the remaining three were asymptomatic. One patient was excluded from analysis due to a confirmed ischaemic stroke unrelated to mitochondrial disease. Assessments included disease severity (Newcastle mitochondrial disease adult scale) and patient-reported outcomes of fatigue (fatigue impact scale), health-related quality of life (Newcastle Mitochondrial-QoL), mental well-being (Warwick-Edinburgh mental wellbeing scale), autonomic symptoms (the composite autonomic symptom) and physical activity (The International Physical Activity Questionnaire). Performance outcomes included timed-up and go, handgrip strength, cardiopulmonary exercise testing and accelerometry. Age- and sex-matched healthy controls were included for comparison of accelerometry data (age: 35.5 (28.8-50.5) years). Despite comparable age and mitochondrial DNA heteroplasmy, patients with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome had significantly higher disease burden, reduced exercise capacity and lower levels of objectively measured physical activity compared to non-mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes and controls (P < 0.05-0.001). Patient-reported outcomes did not significantly differ between mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome/non-mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes. While non-mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes patients showed expected alignment between perceived and objective measures, mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome patients demonstrated weak, absent, or paradoxical associations. This mismatch may reflect altered symptom perception, cognitive impairment, or disease-related adaptation. These findings underscore the complexity of disease expression in mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome. Regulatory agencies encourage the inclusion of patient-centred endpoints; however, this study highlights the potential limitations of relying solely on patient-reported outcomes. The divergence between subjective and objective assessments supports the need for multi-dimensional outcomes that integrate both patient perspectives and objective measures to enhance the reliability and interpretability of clinical trials in primary mitochondrial disease.

Keywords: MELAS syndrome; m.3243A>G; mitochondrial; outcome measures; stroke-like episodes

DOI: https://doi.org/10.1093/braincomms/fcaf342

BMC Med Ethics. 2025 Oct 08. 26(1): 131

Public funding for mitochondrial donation: An Australian public deliberation.

Ainsley J Newson, Jane Williams, Giuliana Fuscaldo, Ashleigh Hill, Ezra Kneebone, Karinne Ludlow, Catherine Mills, Megan Munsie, Sarah Norris, Paul Scuffham, Liz Sutton, David R Thorburn, Chris Degeling.

BACKGROUND: Mitochondrial donation (MD) is a reproductive technique that aims to allow individuals at-risk of having a child with mitochondrial DNA disease avoid this outcome. Research to inform possible clinical use of MD is underway in Australia and births following the use of this technique have been announced in the United Kingdom. However, how the availability of MD will be funded in the mid- to long-term remains uncertain. One factor impacting funding decisions is public sentiment, yet there is scant evidence globally regarding attitudes toward MD funding. We sought to discern attitudes of informed members of the Australian public to how the provision of MD should be funded.
METHODS: We held three community juries to gauge public views on how MD should be funded. A community jury involves providing a diverse group of citizens with expert testimony and facilitating deliberation to arrive at a position.
RESULTS: Forty-two jurors participated across three juries. All juries voted by majority to support public funding for MD. Each jury made slightly different funding choices: one preferred full public funding, another preferred co-payment, while the third was divided among full public funding, co-payment, and no public funding. Reasons in favour of public funding comprised value for money, equity (i.e., the fair and just distribution of MD) and promoting innovation. Reasons against were opportunity cost, that MD wasn't necessary, and ethical objections to MD. Jurors also devised conditions for future funding: external review, capped services, better funding for alternative interventions and means testing.
CONCLUSIONS: Should the current Australian MD research trial enable clinical provision, assuming that our participants' views are consistent with those of most Australians when informed of the trade-offs, benefits and costs, then it is likely that there will be strong public support for governments to fund access. However, some people may object to this expenditure.

Keywords: Bioethics; Citizens’ jury; Deliberative public engagement; Health expenditures; Mitochondrial Replacement Therapy; Public opinion

DOI: https://doi.org/10.1186/s12910-025-01284-4

Front Neuroendocrinol. 2025 Oct 03. pii: S0091-3022(25)00043-3. [Epub ahead of print] 101217

Semaglutide and the pathogenesis of progressive neurodegenerative disease: the central role of mitochondria.

George B Stefano, Pascal Büttiker, Simon Weissenberger, Jiri Raboch, Martin Anders.

While mitochondria provide critical energy resources, mitochondrial dysfunction can lead to both metabolic and neurodegenerative disorders. Primary mitochondrial disorders (e.g., Leigh syndrome) are uniformly associated with profound neurodegeneration. Recent studies have also implicated mitochondrial dysfunction as a central feature of progressive neurodegenerative diseases, notably Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, and Huntington's Disease. In addition to its profound impact on metabolic disease, the glucagon-like peptide-1 receptor agonist, semaglutide, has significant neuroprotective features and may limit the progression of one or more of these disorders. These observations might be explained at least in part by the impact of this drug on mitochondrial function and energy production. Collectively, these observations highlight disrupted energy homeostasis as a critical feature of neurodegenerative disease and suggest novel targets for the development of much-needed new neuropharmaceutical strategies.

Keywords: Alzheimer’s disease; Glucagon-like Peptide 1; Mitochondria; Neurodegenerative disease; Oxidative phosphorylation; Parkinson’s disease; Semaglutide

DOI: https://doi.org/10.1016/j.yfrne.2025.101217

GEN Biotechnol. 2023 Oct;2(5): 353-359

Developing Treatments for Rare Diseases on a Shoestring.

Ana C Puhl, Sarah Negri, Maggie A Z Hupcey, Sean Ekins.

There are thousands of rare genetic diseases lacking an approved treatment, many of which are life-limiting to children. Those caused by a missing protein may represent a target for protein replacement either by enzyme replacement therapy or gene therapy. One of the many challenges working on these types of genetic diseases is the availability of funding, as these diseases typically affect very small numbers of patients. Here we offer a novel case study of our approach to developing a treatment for one such rare disease, which has not required venture capital, angel investment or funding by foundations to date. We have instead pursued NIH small business grants to fund the early preclinical work performed by our academic collaborators and ourselves. Our approach to developing a treatment for a rare disease on a shoestring budget is unlike any of the alternative approaches to funding.

Keywords: Funding; Rare diseases; SBIR; Small business grants

DOI: https://doi.org/10.1089/genbio.2023.0033

AACE Endocrinol Diabetes. 2025 Sep-Oct;12(3):12(3): 150-152

Safe Use of Metformin in Mitochondrial Diabetes in Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes: Insights From a Patient With m.3243A>G Mutation.

Thanisha Santhosh, Prakriti Ramamurthy, Vinaya Simha.

Background/Objective: Diabetes mellitus is often seen in patients with multisystem mitochondrial disorders such as mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). Although metformin is the cornerstone of type 2 diabetes pharmacotherapy, its use in MELAS is discouraged owing to concerns of worsening lactic acidosis. The objective of this report is to present a case where metformin use in MELAS was both clinically beneficial and safely tolerated.
Case Report: A 49-year-old man, diagnosed with presumed type 2 diabetes at the age of 34 years, was started on metformin and glipizide resulting in good glucose control. Subsequent recognition of MELAS in other family members and the presence of sensorineural hearing loss prompted genetic testing, which confirmed the m.3243A>G mitochondrial sequence variant. Tapering of metformin to avoid potential lactic acidosis resulted in unacceptable hyperglycemia with fasting glucose in the range of 200 to 250 mg/dL. Metformin was then reintroduced, leading to improved glycemic control without elevation in lactate or unmasking of neurologic symptoms.
Discussion: Metformin can potentially increase lactic acidosis and neurologic manifestations in patients with mitochondrial disorders as reported previously; however, this is not a universal finding. Metformin can be safely used in select patients with MELAS under appropriate clinical supervision. Withholding metformin in all patients with mitochondrial diabetes is unnecessary and possibly disadvantageous.
Conclusion: This case highlights the importance of individualized therapeutic decisions in MELAS. Metformin, with appropriate monitoring, may represent a safe and effective treatment option for glycemic control even in mitochondrial diabetes.

Keywords: MELAS; lactic acidosis; m3243A>G mutation; metformin; mitochondrial diabetes

DOI: https://doi.org/10.1016/j.aed.2025.07.001

Mol Ther. 2025 Oct 04. pii: S1525-0016(25)00820-2. [Epub ahead of print]

Overcoming Barriers to Commercially Pre-Viable Gene and Cell Therapies for Rare and Ultra-Rare Diseases.

David Barrett, Paula M Cannon, Federico Mingozzi, Matthew Porteus, Isabelle Rivière, Terence R Flotte.

Gene and cell therapies offer transformative potential for patients with rare and ultra-rare diseases. However, many treatments stall despite demonstration of safety and efficacy in pre-clinical studies and early-stage clinical trials. This market failure creates a barrier where otherwise successful therapies are unable to reach patients due to commercial non-viability. In March 2025, ASGCT held a workshop, "Establishing and Maintaining Access to Gene and Cell Therapy for Rare and Ultrarare Diseases," focusing on developing actionable paths forward to ensure that successful gene therapies reach patients regardless of commercial viability. The field faces ongoing and deep-seated challenges; addressing them will require coordinated action across private companies, regulatory agencies, and non-profit organizations to explore non-traditional business models. During the workshop and described here, ASGCT reviewed a matrix of solutions encompassing regulatory innovations, manufacturing efficiencies, financial modeling, and patient-focused frameworks to ensure that efficacious gene and cell therapies reach the patients who need them. Strategies included the creation of a temporary repository for deprioritized gene and cell therapy programs offering support while working to identify new sponsors to continue clinical trials and the creation of a consortium of developers focused on accelerating timelines and reducing costs.

DOI: https://doi.org/10.1016/j.ymthe.2025.09.049