bims-curels Biomed News
on Leigh syndrome
Issue of 2024–02–25
nine papers selected by
Cure Mito Foundation
  1. Decoding the mitochondria without a code: mechanistic insights into mitochondrial DNA depletion syndromes.
  2. Orphan drug development: Challenges, regulation, and success stories.
  3. Rare genetic diseases in India: Steps toward a nationwide mission program.
  4. Mitochondrial replacement techniques for treating infertility.
  5. Bridging the clinical-research gap: Harnessing an electronic data capture, integration, and visualization platform to systematically assess prospective patient-reported outcomes in mitochondrial medicine.
  6. The NAD+ Precursor Nicotinamide Riboside Rescues Mitochondrial Defects and Neuronal Loss in iPSC derived Cortical Organoid of Alpers' Disease.
  7. Mitochondrial Chronic Progressive External Ophthalmoplegia.
  8. Mitochondrial Transportation, Transplantation, and Subsequent Immune Response in Alzheimer's Disease: An Update.
  9. What Do Rights Have to Do with It?
  1. J Biosci. 2024 ;pii: 32. [Epub ahead of print]49
    Decoding the mitochondria without a code: mechanistic insights into mitochondrial DNA depletion syndromes.
    Ritoprova Sen, Cuckoo Teresa Jetto, Ravi Manjithaya.
      Mitochondrial DNA depletion syndromes (MDS) encompass a wide spectrum of rare genetic disorders caused by severe reduction in mitochondrial DNA (mtDNA), and exhibit heterogenous phenotypes classified as myopathic, encephalomyopathic, hepatocerebral, and neurogastrointestinal. Prognosis for such a spectrum of diseases is poor and is majorly dependent on symptomatic treatment and nutritional supplementation. Understanding the mechanistic aspect of mtDNA depletion can help bring forth a new era of medicine, moving beyond symptomatic treatment and focusing more on organelle-targeted therapies. In this review, we highlight some of the proposed mechanistic bases of mtDNA depletion and the latest therapeutic measures used to treat MDS.
  2. J Biosci. 2024 ;pii: 30. [Epub ahead of print]49
    Orphan drug development: Challenges, regulation, and success stories.
    Narendra Chirmule, Huije Feng, Esha Cyril, Vihang Vivek Ghalsasi, Mohua Chakraborty Choudhury.
      Rare diseases, also known as orphan diseases, are diseases with low occurrence in the population. Developing orphan drugs is challenging because of inadequate financial and scientific resources and insufficient subjects to run clinical trials. With advances in genome sequencing technologies, emergence of cell and gene therapies, and the latest developments in regulatory pathways, some orphan drugs that have curative potential have been approved. In India, due to its large population and resource crunch, developing orphan drugs is phenomenally challenging. After adopting the Orphan Drug Act, the US-FDA has continuously made advances in regulatory pathways for orphan drugs. Particularly, n-of-one clinical trials have been successful in some cases. India has recently adopted policies that have impacted the long-neglected rare-disease ecosystem; however, there is no clear regulatory path for orphan drug development in India. We have proposed a multi-pronged approach involving close collaboration between the government, regulatory bodies, industries, and patient advocacy groups to boost orphan drug development in India. We believe that rapidly evolving technologies and business models can enable better and faster development of novel orphan drugs in India and other resource-constrained countries.
  3. J Biosci. 2024 ;pii: 34. [Epub ahead of print]49
    Rare genetic diseases in India: Steps toward a nationwide mission program.
    Anjana Kar, Sundaravadivel P, Ashwin Dalal.
      Rare genetic diseases are rare by themselves with prevalence of 1 in 25,000, but collectively they are a significant cause of morbidity and mortality. Till date, collectively there are more than 9,000 rare diseases documented, which impose a devastating impact on patients, their families, and the healthcare system, including enormous societal burden. Obtaining a conclusive diagnosis for a patient with a rare genetic disease can be long and gruelling. For some patients it takes months or years to receive a definite diagnosis, and around 50% of the patients remain undiagnosed even with expert clinical and advanced high-end laboratory investigations. Owing to the large population and practice of consanguinity the Indian population is a pool of indigenous variants and unreported phenotypes or diseases. A mission program on pediatric rare diseases is an unparalleled initiative to study unique clinical conditions via the use of latest state-of-art technologies and with the combination of a mulit-omics approach. Our initiative will not only provide diagnosis to patients with rare disease but also build a platform for translational research for rare disease screening, management, and treatment.
  4. J Med Ethics. 2024 Feb 21. pii: jme-2023-109660. [Epub ahead of print]
    Mitochondrial replacement techniques for treating infertility.
    Esther Braun.
      Mitochondrial replacement techniques (MRTs) usually aim to prevent the genetic transmission of maternally inherited mitochondrial diseases. Until now, only the UK and Australia have implemented specific legal regulations of MRTs. In both countries, clinical trials on these techniques are only permissible for cases with a high risk of severe mitochondrial disease in the offspring. However, these techniques can also be applied to treat infertility, especially for older women with impaired oocyte quality. In some countries without legal regulation of these techniques, MRTs are already offered for this purpose. Yet, this application of MRTs has received insufficient attention in the bioethical literature so far.In this paper, I examine whether there are ethical reasons to prohibit trials on MRTs in the context of infertility when they are permitted for preventing mitochondrial disease. Allowing MRTs in one context but not the other might be justified either because their application in the context of mitochondrial disease (1) is supported by a more convincing evidence base, (2) has a higher potential benefit or (3) has a lower risk. I compare both applications of MRTs with respect to these three factors. I conclude that there is no convincing reason to prohibit clinical trials on MRTs for infertility when they are permitted in the context of mitochondrial disease.
    Keywords:  Embryos and Fetuses; Ethics- Medical; Fertilization in Vitro; Genetic Engineering; Reproductive Medicine
    DOI:  https://doi.org/10.1136/jme-2023-109660
  5. Mol Genet Metab. 2024 Feb 16. pii: S1096-7192(24)00233-6. [Epub ahead of print]142(1): 108348
    Bridging the clinical-research gap: Harnessing an electronic data capture, integration, and visualization platform to systematically assess prospective patient-reported outcomes in mitochondrial medicine.
    Laura E MacMullen, Ibrahim George-Sankoh, Katelynn Stanley, Elizabeth M McCormick, Colleen C Muraresku, Amy Goldstein, Zarazuela Zolkipli-Cunningham, Marni J Falk.
       PURPOSE: Optimizing individualized clinical care in heterogeneous rare disorders, such as primary mitochondrial disease (PMD), will require gaining more comprehensive and objective understanding of the patient experience by longitudinally tracking quantifiable patient-specific outcomes and integrating subjective data with clinical data to monitor disease progression and targeted therapeutic effects.
    METHODS: Electronic surveys of patient (and caregiver) reported outcome (PRO) measures were administered in REDCap within clinical domains commonly impaired in patients with PMD in the context of their ongoing routine care, including quality of life, fatigue, and functional performance. Descriptive statistics, group comparisons, and inter-measure correlations were used to evaluate system feasibility, utility of PRO results, and consistency across outcome measure domains. Real-time tracking and visualization of longitudinal individual-level and cohort-level data were facilitated by a customized data integration and visualization system, MMFP-Tableau.
    RESULTS: An efficient PRO electronic capture and analysis system was successfully implemented within a clinically and genetically heterogeneous rare disease clinical population spanning all ages. Preliminary data analyses demonstrated the flexibility of this approach for a range of PROs, as well as the value of selected PRO scales to objectively capture qualitative functional impairment in four key clinical domains. High inter-measure reliability and correlation were observed. Between-group analyses revealed that adults with PMD reported significantly worse quality of life and greater fatigue than did affected children, while PMD patients with nuclear gene disorders reported lower functioning relative to those with an mtDNA gene disorder in several clinical domains.
    CONCLUSION: Incorporation of routine electronic data collection, integration, visualization, and analysis of relevant PROs for rare disease patients seen in the clinical setting was demonstrated to be feasible, providing prospective and quantitative data on key clinical domains relevant to the patient experience. Further work is needed to validate specific PROs in diverse PMD patients and cohorts, and to formally evaluate the clinical impact and utility of harnessing integrated data systems to objectively track and integrate quantifiable PROs in the context of rare disease patient clinical care.
    Keywords:  Data integration; Data visualization; Fatigue; Function; Mitochondrial diseases; Patient reported outcome measures; Personalized medicine; Quality of life
    DOI:  https://doi.org/10.1016/j.ymgme.2024.108348
  6. Int J Biol Sci. 2024 ;20(4): 1194-1217
    The NAD+ Precursor Nicotinamide Riboside Rescues Mitochondrial Defects and Neuronal Loss in iPSC derived Cortical Organoid of Alpers' Disease.
    Yu Hong, Zhuoyuan Zhang, Tsering Yangzom, Anbin Chen, Bjørn Christian Lundberg, Evandro Fei Fang, Richard Siller, Gareth John Sullivan, Jiri Zeman, Charalampos Tzoulis, Laurence A Bindoff, Kristina Xiao Liang.
      Alpers' syndrome is an early-onset neurodegenerative disorder usually caused by biallelic pathogenic variants in the gene encoding the catalytic subunit of polymerase-gamma (POLG), which is essential for mitochondrial DNA (mtDNA) replication. The disease is progressive, incurable, and inevitably it leads to death from drug-resistant status epilepticus. The neurological features of Alpers' syndrome are intractable epilepsy and developmental regression, with no effective treatment; the underlying mechanisms are still elusive, partially due to lack of good experimental models. Here, we generated the patient derived induced pluripotent stem cells (iPSCs) from one Alpers' patient carrying the compound heterozygous mutations of A467T (c.1399G>A) and P589L (c.1766C>T), and further differentiated them into cortical organoids and neural stem cells (NSCs) for mechanistic studies of neural dysfunction in Alpers' syndrome. Patient cortical organoids exhibited a phenotype that faithfully replicated the molecular changes found in patient postmortem brain tissue, as evidenced by cortical neuronal loss and depletion of mtDNA and complex I (CI). Patient NSCs showed mitochondrial dysfunction leading to ROS overproduction and downregulation of the NADH pathway. More importantly, the NAD+ precursor nicotinamide riboside (NR) significantly ameliorated mitochondrial defects in patient brain organoids. Our findings demonstrate that the iPSC model and brain organoids are good in vitro models of Alpers' disease; this first-in-its-kind stem cell platform for Alpers' syndrome enables therapeutic exploration and has identified NR as a viable drug candidate for Alpers' disease and, potentially, other mitochondrial diseases with similar causes.
    Keywords:  Alpers' disease; NAD+; NR; cortical organoids; induced pluripotent stem cells; mitochondrial function
    DOI:  https://doi.org/10.7150/ijbs.91624
  7. Brain Sci. 2024 Jan 27. pii: 135. [Epub ahead of print]14(2):
    Mitochondrial Chronic Progressive External Ophthalmoplegia.
    Ali Ali, Ali Esmaeil, Raed Behbehani.
       BACKGROUND: Chronic progressive external ophthalmoplegia (CPEO) is a rare disorder that can be at the forefront of several mitochondrial diseases. This review overviews mitochondrial CPEO encephalomyopathies to enhance accurate recognition and diagnosis for proper management.
    METHODS: This study is conducted based on publications and guidelines obtained by selective review in PubMed. Randomized, double-blind, placebo-controlled trials, Cochrane reviews, and literature meta-analyses were particularly sought.
    DISCUSSION: CPEO is a common presentation of mitochondrial encephalomyopathies, which can result from alterations in mitochondrial or nuclear DNA. Genetic sequencing is the gold standard for diagnosing mitochondrial encephalomyopathies, preceded by non-invasive tests such as fibroblast growth factor-21 and growth differentiation factor-15. More invasive options include a muscle biopsy, which can be carried out after uncertain diagnostic testing. No definitive treatment option is available for mitochondrial diseases, and management is mainly focused on lifestyle risk modification and supplementation to reduce mitochondrial load and symptomatic relief, such as ptosis repair in the case of CPEO. Nevertheless, various clinical trials and endeavors are still at large for achieving beneficial therapeutic outcomes for mitochondrial encephalomyopathies.
    KEY MESSAGES: Understanding the varying presentations and genetic aspects of mitochondrial CPEO is crucial for accurate diagnosis and management.
    Keywords:  CPEO; chronic progressive external ophthalmoplegia; mitochondrial diseases
    DOI:  https://doi.org/10.3390/brainsci14020135
  8. Mol Neurobiol. 2024 Feb 17.
    Mitochondrial Transportation, Transplantation, and Subsequent Immune Response in Alzheimer's Disease: An Update.
    Pegah Javadpour, Fatemeh Abbaszadeh, Abolhassan Ahmadiani, Mohsen Rezaei, Rasoul Ghasemi.
      Alzheimer's disease (AD) is a devastating neurodegenerative disease characterized by memory impairment and a progressive decline in cognitive function. Mitochondrial dysfunction has been identified as an important contributor to the development of AD, leading to oxidative stress and energy deficits within the brain. While current treatments for AD aim to alleviate symptoms, there is an urgent need to target the underlying mechanisms. The emerging field of mitotherapy, which involves the transplantation of healthy mitochondria into damaged cells, has gained substantial attention and has shown promising results. However, research in the context of AD remains limited, necessitating further investigations. In this review, we summarize the mitochondrial pathways that contribute to the progression of AD. Additionally, we discuss mitochondrial transfer among brain cells and mitotherapy, with a focus on different administration routes, various sources of mitochondria, and potential modifications to enhance transplantation efficacy. Finally, we review the limited available evidence regarding the immune system's response to mitochondrial transplantation in damaged brain regions.
    Keywords:  Alzheimer’s disease; Energy metabolism; Mitochondria; Mitochondrial transplantation; Neurodegenerative diseases
    DOI:  https://doi.org/10.1007/s12035-024-04009-7
  9. Am J Bioeth. 2024 Mar;24(3): 31-33
    What Do Rights Have to Do with It?
    Eric Scarffe, Amber Polk.
      
    DOI:  https://doi.org/10.1080/15265161.2024.2303111
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