bims-curels Biomed News
on Leigh syndrome
Issue of 2024–06–23
twelve papers selected by
Cure Mito Foundation
  1. Evaluating the efficacy of vatiquinone in preclinical models of mitochondrial disease.
  2. Beyond the membrane: Exploring non-viral methods for mitochondrial gene delivery.
  3. Case report: Late-onset MELAS syndrome with mtDNA 5783G>A mutation diagnosed by urinary sediment genetic testing.
  4. Fetal bradycardia as the initial symptom of mitochondrial disease: A case report.
  5. Recurrent mitochondrial disease caused by the "m.3243A> G″ mutation: A case report.
  6. Mitochondrial therapeutics and mitochondrial transfer for neurodegenerative diseases and aging.
  7. Activation of Neurotoxic Astrocytes Due to Mitochondrial Dysfunction Triggered by POLG Mutation.
  8. The economic impact of living with a rare disease for children and their families: a scoping review protocol.
  9. Relationship between Cellular Oxygen Consumption and Atherosclerosis-Associated Mitochondrial Mutations (Variants of the Mitochondrial Genome).
  10. The Role of Mitochondrial Copy Number in Neurodegenerative Diseases: Present Insights and Future Directions.
  11. Spectrum of rare and common mitochondrial DNA variations from 1029 whole genomes of self-declared healthy individuals from India.
  12. Enhancing pediatric access to cell and gene therapies.
  1. Res Sq. 2024 Jun 03. pii: rs.3.rs-4202689. [Epub ahead of print]
    Evaluating the efficacy of vatiquinone in preclinical models of mitochondrial disease.
    Ernst-Bernhard Kayser, Yihan Chen, Michael Mulholland, Vivian Truong, Katerina James, Allison Hanaford, Simon Johnson.
      Background Genetic mitochondrial diseases are a major challenge in modern medicine, impacting around 1:4,000 individuals. Leigh syndrome is the most common pediatric presentation of mitochondrial disease. There are currently no effective clinical treatments for mitochondrial disease. In humans, patients are often treated with antioxidants, vitamins, and strategies targeting energetics. The vitamin-E related compound vatiquinone (EPI-743, α-tocotrienol quinone) has been the subject of at least 19 clinical trials in the US since 2012, but the effects of vatiquinone on an animal model of mitochondrial disease have not yet been reported. Here, assessed the impact of vatiquinone on disease progression and in two animal models of mitochondrial disease. Methods The efficacy of vatiquinone in vitro was assessed using human fibroblasts treated with the general mitochondrial oxidative stress inducer paraquat, the GPX4 inhibitor RSL3, or the glutathione synthase inhibitor BSO in combination with excess iron. The therapeutic potential of vatiquinone in vivo was assessed using tamoxifen-induced mouse model for GPX4 deficiency and the Ndufs4 knockout mouse model of Leigh syndrome. In both models, animals were treated daily with vatiquinone or vehicle and relevant disease endpoints were assessed. Results Vatiquinone robustly prevented death in cultured cells induced by RSL3 or BSO/iron, but had no effect on paraquat induced cell death. Vatiquinone had no impact on disease onset, progression, or survival in either the tamoxifen-inducible GPX4 deficient model or the Ndufs4 (-/-) mouse model, though the drug may have reduced seizure risk. Conclusions Vatiquinone provided no benefit to survival in two mouse models of disease, but may prevent seizures in the Ndufs4 (-/-) model. Our findings are consistent with recent press statements regarding clinical trial results and have implications for drug trial design and reporting in patients with rare diseases.
    DOI:  https://doi.org/10.21203/rs.3.rs-4202689/v1
  2. Mitochondrion. 2024 Jun 17. pii: S1567-7249(24)00080-1. [Epub ahead of print]78 101922
    Beyond the membrane: Exploring non-viral methods for mitochondrial gene delivery.
    Dilpreet Singh.
      Mitochondrial disorders, stemming from mutations in mitochondrial DNA (mtDNA), present a significant therapeutic challenge due to their complex pathophysiology and broad spectrum of clinical manifestations. Traditional gene therapy approaches, primarily reliant on viral vectors, face obstacles such as potential immunogenicity, insertional mutagenesis, and the specificity of targeting mtDNA. This review delves into non-viral methods for mitochondrial gene delivery, emerging as a promising alternative to overcome these limitations. Focusing on lipid-based nanoparticles, polymer-based vectors, and mitochondrial-targeted peptides, the mechanisms of action, advantages, and current applications in treating mitochondrial diseases was well elucidated. Non-viral vectors offer several benefits, including reduced immunogenicity, enhanced safety profiles, and the flexibility to carry a wide range of genetic material. We examine case studies where these methods have been applied, highlighting their potential in correcting pathogenic mtDNA mutations and mitigating disease phenotypes. Despite their promise, challenges such as delivery efficiency, specificity, and long-term expression stability persist. The review underscores the need for ongoing research to refine these delivery systems carry a wide range of genetic material. We examine case studies where these methods settings. As we advance our understanding of mitochondrial biology and gene delivery technologies, non-viral methods hold the potential to revolutionize the treatment of mitochondrial disorders, offering hope for therapies that can precisely target and correct the underlying genetic defects.
    Keywords:  Gene therapy; Lipid-based nanoparticles; Mitochondrial disorders; Mitochondrial gene delivery; Mitochondrial-targeted peptides; Non-viral vectors; Polymer-based vectors; Precision medicine
    DOI:  https://doi.org/10.1016/j.mito.2024.101922
  3. Front Genet. 2024 ;15 1367716
    Case report: Late-onset MELAS syndrome with mtDNA 5783G>A mutation diagnosed by urinary sediment genetic testing.
    Hao Cai, Li-Min Li, Miao Zhang, Yuying Zhou, Pan Li.
       Background: Patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) usually present with multisystemic dysfunction with a wide range of clinical manifestations. When the tests for common mitochondrial DNA (mtDNA) point mutations are negative and the mtDNA defects hypothesis remains, urine epithelial cells can be used to screen the mitochondrial genome for unknown mutations to confirm the diagnosis.
    Case presentation: A 66-year-old Chinese woman presented with symptoms of MELAS and was initially misdiagnosed with acute encephalitis at another institution. Although genetic analysis of blood lymphocyte DNA was negative, brain imaging, including magnetic resonance imaging, magnetic resonance spectroscopy, and clinical and laboratory findings, were all suggestive of MELAS. Finally, the patient was eventually diagnosed with MELAS with the mtDNA 5783G>A mutation in the MT-TC gene with a urinary sediment genetic test.
    Conclusion: This case report expands the genetic repertoire associated with MELAS syndrome and highlights the importance that full mtDNA sequencing should be warranted beside the analysis of classical variants when a mitochondrial disorder is highly suspected. Furthermore, urine sediment genetic testing has played a crucial role in the diagnosis of MELAS.
    Keywords:  MELAS; MT-TC; late-onset; m.5783G>A; urinary sediment
    DOI:  https://doi.org/10.3389/fgene.2024.1367716
  4. Pediatr Int. 2024 Jan-Dec;66(1):66(1): e15771
    Fetal bradycardia as the initial symptom of mitochondrial disease: A case report.
    Ryutaro Shinkai, Takashi Honda, Rumi Watanabe, Mari Ooka, Kazuteru Kitsuda, Yoichiro Hirata, Kenji Ishikura.
      
    Keywords:  fetal bradycardia; hypertrophic cardiomyopathy; lactic acidosis; mitochondrial disease
    DOI:  https://doi.org/10.1111/ped.15771
  5. Asian J Surg. 2024 Jun 17. pii: S1015-9584(24)01160-6. [Epub ahead of print]
    Recurrent mitochondrial disease caused by the "m.3243A> G″ mutation: A case report.
    Ning Zhai, Jing Hu, Hong Yan.
      
    DOI:  https://doi.org/10.1016/j.asjsur.2024.05.251
  6. Neural Regen Res. 2025 Mar 01. 20(3): 794-796
    Mitochondrial therapeutics and mitochondrial transfer for neurodegenerative diseases and aging.
    Neville Ng, Michelle Newbery, Nicole Miles, Lezanne Ooi.
      
    DOI:  https://doi.org/10.4103/NRR.NRR-D-23-02106
  7. Int J Biol Sci. 2024 ;20(8): 2860-2880
    Activation of Neurotoxic Astrocytes Due to Mitochondrial Dysfunction Triggered by POLG Mutation.
    Kristina Xiao Liang, Anbin Chen, Atefeh Kianian, Cecilie Katrin Kristiansen, Tsering Yangzom, Jessica Furriol, Lena Elise Høyland, Mathias Ziegler, Torbjørn Kråkenes, Charalampos Tzoulis, Evandro Fei Fang, Gareth John Sullivan, Laurence A Bindoff.
      Mitochondrial diseases are associated with neuronal death and mtDNA depletion. Astrocytes respond to injury or stimuli and damage to the central nervous system. Neurodegeneration can cause astrocytes to activate and acquire toxic functions that induce neuronal death. However, astrocyte activation and its impact on neuronal homeostasis in mitochondrial disease remain to be explored. Using patient cells carrying POLG mutations, we generated iPSCs and then differentiated these into astrocytes. POLG astrocytes exhibited mitochondrial dysfunction including loss of mitochondrial membrane potential, energy failure, loss of complex I and IV, disturbed NAD+/NADH metabolism, and mtDNA depletion. Further, POLG derived astrocytes presented an A1-like reactive phenotype with increased proliferation, invasion, upregulation of pathways involved in response to stimulus, immune system process, cell proliferation and cell killing. Under direct and indirect co-culture with neurons, POLG astrocytes manifested a toxic effect leading to the death of neurons. We demonstrate that mitochondrial dysfunction caused by POLG mutations leads not only to intrinsic defects in energy metabolism affecting both neurons and astrocytes, but also to neurotoxic damage driven by astrocytes. These findings reveal a novel role for dysfunctional astrocytes that contribute to the pathogenesis of POLG diseases.
    DOI:  https://doi.org/10.7150/ijbs.93445
  8. HRB Open Res. 2023 ;6 41
    The economic impact of living with a rare disease for children and their families: a scoping review protocol.
    Niamh Buckle, Orla Doyle, Naonori Kodate, Suja Somanadhan.
       Background: Rare diseases are an often chronic, progressive and life-limiting group of conditions affecting more than 30 million people in Europe. These diseases are associated with significant direct and indirect costs to a spectrum of stakeholders, ranging from individuals and their families to society overall. Further quantitative research on the economic cost for children and their families living with a rare disease is required as there is little known on this topic. This scoping review aims to document the extent and type of evidence on the economic impacts of living with a rare disease for children and their families.
    Methods: This scoping review will follow the PRISMA-ScR and Joanna Briggs Institute guidelines and follow the six-stage methodology for scoping reviews: (1) identifying the research question, (2) identifying relevant studies, (3) study selection, (4) charting the data, (5) collating, summarising and reporting results and (6) knowledge user consultation. Key inclusion criteria have been developed according to the Population-Concept-Context (PCC) framework. The databases EconLit, ABI/Inform, MEDLINE, PubMed, CINAHL, and Scopus will be searched for possible articles for inclusion. Two independent reviewers will screen titles and abstracts of potential articles using a dual review process to ensure all relevant studies are included. All included articles will be assessed using a validated quality appraisal tool. A panel of patient and public involvement representatives experiencing rare diseases and knowledge users will validate the review results.
    Conclusions: This scoping review will map the current literature on the economic impact of paediatric rare diseases to understand how these impacts affect children living with rare diseases and their families. This evidence has the potential to influence policy and future research in this area and will support further research on the economic impact of rare diseases on families.
    Keywords:  Child; cost-of-illness; economic evaluation; family; financial hardship; orphan diseases; rare diseases; ultra-rare diseases
    DOI:  https://doi.org/10.12688/hrbopenres.13765.2
  9. Curr Med Chem. 2024 Jun 14.
    Relationship between Cellular Oxygen Consumption and Atherosclerosis-Associated Mitochondrial Mutations (Variants of the Mitochondrial Genome).
    Alexander N Orekhov, Vasily V Sinyov, Mikhail Y Vyssokikh, Ludmila Manukhova, Maria V Marey, Plamena R Angelova, Andrey V Omelchenko, Andrey Y Vinokurov, Zukhra B Khasanova, Igor A Sobenin.
       BACKGROUND: Mitochondria are the main sites of cellular aerobic energy production through conjugation of respiration and oxidative phosphorylation. We have recently discovered mutations (genome variants) of mitochondrial DNA (mtDNA) associated with atherosclerosis. We have then investigated the possible mechanisms underlying such association and the role of mitochondrial mutations in atherogenesis. Mitochondrial dysfunction is a known component of the pathogenesis of chronic human diseases, including atherosclerosis.
    OBJECTIVE: The aim of the study was to explore whether there is a relationship between cellular oxygen consumption and atherosclerosis-associated mitochondrial mutations. The study of mitochondrial respiration abnormalities can help to understand the role of mtDNA mutations in pathology.
    METHOD: By using the polarographic method with Clark electrode, we tested the possibility of respiration impairment in permeabilized cells carrying the tested mtDNA variants using the cybrid (cytoplasmic hybrid) lines. Mitochondria introduced in the cybrid lines were obtained from atherosclerotic patients that differed in the profile of mtDNA mutations, which made it possible to compare the degree of mtDNA mutation load with the rate of oxygen consumption by cybrid cells.
    RESULTS: It was found that three of the studied mutations were individually associated with impaired respiration. Besides, some combinations of two specific mutations have a high probability of being associated with altered oxygen consumption. As a result, eight mutations were identified, individually or paired combinations of which were associated with high or low rates of cellular respiration, significantly different from control cells.
    CONCLUSION: The observed effect may be involved in the pathogenesis of atherosclerosis. The study of mtDNA mutations associated with atherosclerosis can help reveal pharmacological targets for the development of novel therapies.
    Keywords:  Atherosclerosis; Mitochondria; Mitochondrial Dysfunction; Respiration; mtDNA Mmutation
    DOI:  https://doi.org/10.2174/0109298673302002240605092523
  10. Int J Mol Sci. 2024 May 31. pii: 6062. [Epub ahead of print]25(11):
    The Role of Mitochondrial Copy Number in Neurodegenerative Diseases: Present Insights and Future Directions.
    Annamaria Cerantonio, Luigi Citrigno, Beatrice Maria Greco, Selene De Benedittis, Giuseppe Passarino, Raffaele Maletta, Antonio Qualtieri, Alberto Montesanto, Patrizia Spadafora, Francesca Cavalcanti.
      Neurodegenerative diseases are progressive disorders that affect the central nervous system (CNS) and represent the major cause of premature death in the elderly. One of the possible determinants of neurodegeneration is the change in mitochondrial function and content. Altered levels of mitochondrial DNA copy number (mtDNA-CN) in biological fluids have been reported during both the early stages and progression of the diseases. In patients affected by neurodegenerative diseases, changes in mtDNA-CN levels appear to correlate with mitochondrial dysfunction, cognitive decline, disease progression, and ultimately therapeutic interventions. In this review, we report the main results published up to April 2024, regarding the evaluation of mtDNA-CN levels in blood samples from patients affected by Alzheimer's (AD), Parkinson's (PD), and Huntington's diseases (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). The aim is to show a probable link between mtDNA-CN changes and neurodegenerative disorders. Understanding the causes underlying this association could provide useful information on the molecular mechanisms involved in neurodegeneration and offer the development of new diagnostic approaches and therapeutic interventions.
    Keywords:  mitochondrial DNA copy number; mitochondrial function; neurodegenerative diseases
    DOI:  https://doi.org/10.3390/ijms25116062
  11. Comput Biol Chem. 2024 Jun 10. pii: S1476-9271(24)00106-3. [Epub ahead of print]112 108118
    Spectrum of rare and common mitochondrial DNA variations from 1029 whole genomes of self-declared healthy individuals from India.
    Vishu Gupta, Bani Jolly, Rahul C Bhoyar, Mohit Kumar Divakar, Abhinav Jain, Anushree Mishra, Vigneshwar Senthivel, Mohamed Imran, Vinod Scaria, Sridhar Sivasubbu.
      Mitochondrial disorders are a class of heterogeneous disorders caused by genetic variations in the mitochondrial genome (mtDNA) as well as the nuclear genome. The spectrum of mtDNA variants remains unexplored in the Indian population. In the present study, we have cataloged 2689 high confidence single nucleotide variants, small insertions and deletions in mtDNA in 1029 healthy Indian individuals. We found a major proportion (76.5 %) of the variants being rare (AF<=0.005) in the studied population. Intriguingly, we found two 'confirmed' pathogenic variants (m.1555 A>G and m.14484 T>C) with a frequency of ∼1 in 250 individuals in our dataset. The high carrier frequency underscores the need for screening of the mtDNA pathogenic mutations in newborns in India. Interestingly, our analysis also revealed 202 variants in our dataset which have been 'reported' in disease cases as per the MITOMAP database. Additionally, we found the frequency of haplogroup M (52.2 %) to be the highest among all the 18 top-level haplogroups found in our dataset. In comparison to the global population datasets, 20 unique mtDNA variants are found in the Indian population. We hope the whole genome sequencing based compendium of mtDNA variants along with their allele frequencies and heteroplasmy levels in the Indian population will drive additional genome scale studies for mtDNA. Furthermore, the identification of clinically relevant variants in our dataset will aid in better clinical interpretation of the variants in mitochondrial disorders.
    Keywords:  Allele frequencies; Haplogroups; Heteroplasmy; Indian population; Mitochondrial DNA; Mitochondrial Disorders
    DOI:  https://doi.org/10.1016/j.compbiolchem.2024.108118
  12. Nat Med. 2024 Jun 17.
    Enhancing pediatric access to cell and gene therapies.
    Crystal L Mackall, Catherine M Bollard, Nancy Goodman, Casey Carr, Rebecca Gardner, Rayne Rouce, Elena Sotillo, Rich Stoner, Fyodor D Urnov, Alan S Wayne, Julie Park, Donald B Kohn.
      Increasing numbers of cell and gene therapies (CGTs) are emerging to treat and cure pediatric diseases. However, small market sizes limit the potential return on investment within the traditional biopharmaceutical drug development model, leading to a market failure. In this Perspective, we discuss major factors contributing to this failure, including high manufacturing costs, regulatory challenges, and licensing practices that do not incorporate pediatric development milestones, as well as potential solutions. We propose the creation of a new entity, the Pediatric Advanced Medicines Biotech, to lead late-stage development and commercialize pediatric CGTs outside the traditional biopharmaceutical model in the United States-where organized efforts to solve this problem have been lacking. The Pediatric Advanced Medicines Biotech would partner with the academic ecosystem, manufacture products in academic good manufacturing practice facilities and work closely with regulatory bodies, to ferry CGTs across the drug development 'valley of death' and, ultimately, increase access to lifesaving treatments for children in need.
    DOI:  https://doi.org/10.1038/s41591-024-03035-1
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