bims-curels 2023-07-16 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2023‒07‒16
ten papers selected by
Cure Mito Foundation

Therapeutic potential of engineering the mitochondrial genome.
Modeling-based prediction tools for preimplantation genetic testing of mitochondrial DNA diseases: estimating symptomatic thresholds, risk, and chance of success.
Positioning patients to partner: exploring ways to better integrate patient involvement in the learning health systems.
Recent advances in small molecules for improving mitochondrial disorders.
Assessment highlights need for improvement in standards of development for rare genetic diseases core outcome sets.
Drug Drop Test: How to Quickly Identify Potential Therapeutic Compounds for Mitochondrial Diseases Using Yeast Saccharomyces cerevisiae.
Quantitative systems pharmacology for rare disease drug development.
Patient and public involvement in health research in Norway: a survey among researchers and patient organisations.
Mitochondrial encephalopathy with lactic-acidosis and stroke-like episodes syndrome presenting as progressive supranuclear palsy.
Does value-based healthcare support patient-centred care? A scoping review of the evidence.

Biochim Biophys Acta Mol Basis Dis. 2023 Jul 08. pii: S0925-4439(23)00170-9. [Epub ahead of print] 166804

Therapeutic potential of engineering the mitochondrial genome.

Mengmeng Liu, Wei Ji, Xin Zhao, Xiaoliang Liu, Ji-Fan Hu, Jiuwei Cui.

  Mitochondrial diseases are a group of clinical disorders caused by mutations in the genes encoded by either the nuclear or the mitochondrial genome involved in mitochondrial oxidative phosphorylation. Disorders become evident when mitochondrial dysfunction reaches a cell-specific threshold. Similarly, the severity of disorders is related to the degree of gene mutation. Clinical treatments for mitochondrial diseases mainly rely on symptomatic management. Theoretically, replacing or repairing dysfunctional mitochondria to acquire and preserve normal physiological functions should be effective. Significant advances have been made in gene therapies, including mitochondrial replacement therapy, mitochondrial genome manipulation, nuclease programming, mitochondrial DNA editing, and mitochondrial RNA interference. In this paper, we review the recent progress in these technologies by focusing on advancements that overcome limitations.

Keywords:  Embryonic stem cell; Mitochondrial disorders; Mitochondrial replacement therapy; Programmable nucleases; mtDNA editing; mtDNA mutation

DOI:  https://doi.org/10.1016/j.bbadis.2023.166804
J Assist Reprod Genet. 2023 Jul 13.

Modeling-based prediction tools for preimplantation genetic testing of mitochondrial DNA diseases: estimating symptomatic thresholds, risk, and chance of success.

Dongmei Ji, Ning Zhang, Weiwei Zou, Zhikang Zhang, Jordan Lee Marley, Zhuoli Liu, Chunmei Liang, Lingchao Shen, Yajing Liu, Dan Liang, Tianhong Su, Yinan Du, Yunxia Cao.

  PURPOSE: Preimplantation genetic testing (PGT) has become a reliable tool for preventing the germline transmission of mitochondrial DNA (mtDNA) variants. However, procedures are not standardized across mtDNA variants. In this study, we aim to estimate symptomatic thresholds, risk, and chance of success for PGT for mtDNA pathogenic variant carriers.METHODS: We performed a systematic analysis of heteroplasmy data including 455 individuals from 187 familial pedigrees with the common m.3243A>G, m.8344A>G, or m.8993T>G pathogenic variants. We applied binary logistic regression for estimating symptomatic thresholds of heteroplasmy, simplified Sewell-Wright formula and Kimura equations for predicting the risk of disease transmission, and binomial distribution for predicting minimum oocyte numbers.
RESULTS: We estimated the symptomatic thresholds of m.8993T>G and m.8344A>G as 29.86% and 16.15%, respectively. We could not determine a threshold for m.3243A>G. We established models for mothers harboring common and rare mtDNA pathogenic variants to predict the risk of disease transmission and the number of oocytes required to produce an embryo with sufficiently low variant load. In addition, we provide a table allowing the prediction of transmission risk and the minimum required oocytes for PGT patients with different variant levels.
CONCLUSION: We have established models that can determine the symptomatic thresholds of common mtDNA pathogenic variants. We also constructed universal models applicable to nearly all mtDNA pathogenic variants which can predict risk and minimum numbers for PGT patients. These models have advanced our understanding of mtDNA disease pathogenesis and will enable more effective prevention of disease transmission using PGT.

Keywords:  Genetic counseling; Heteroplasmy; Mitochondrial DNA variants; Mitochondrial diseases; PGT

DOI:  https://doi.org/10.1007/s10815-023-02880-2
Res Involv Engagem. 2023 Jul 10. 9(1): 51

Positioning patients to partner: exploring ways to better integrate patient involvement in the learning health systems.

Nakia K Lee-Foon, Maureen Smith, Sarah M Greene, Kerry Kuluski, Robert J Reid.

  Globally, health systems are increasingly striving to deliver evidence based care that improves patients', caregivers' and communities' health outcomes. To deliver this care, more systems are engaging these groups to help inform healthcare service design and delivery. Their lived experiences-experiences accessing and/or supporting someone who accesses healthcare services-are now viewed by many systems as expertise and an important part of understanding and improving care quality. Patients', caregivers' and communities' participation in health systems can range from healthcare organizational design to being members of research teams. Unfortunately, this involvement greatly varies and these groups are often sidelined to the start of research projects, with little to no role in later project stages. Additionally, some systems may forgo direct engagement, focusing solely on patient data collection and analysis. Given the benefits of active patient, caregiver and community participation in health systems on patient health outcomes, systems have begun identifying different approaches to studying and applying findings of patient, caregiver and community informed care initiatives in a rapid and consistent fashion. The learning health system (LHS) is one approach that can foster deeper and continuous engagement of these groups in health systems change. This approach embeds research into health systems, continuously learning from data and translating findings into healthcare practices in real time. Here, ongoing patient, caregiver and community involvement is considered vital for a well functioning LHS. Despite their importance, great variability exists as to what their involvement means in practice. This commentary examines the current state of patient, caregiver and community participation in the LHS. In particular, gaps in and need for resources to support their knowledge of the LHS are discussed. We conclude by recommending several factors health systems must consider in order to increase participation in their LHS. Systems must: (1) assess patients', caregivers and community understanding of how their feedback are used in the LHS and how collected data are used to inform patient care; (2) review the level and extent of these groups' participation in health system improvement activities; and (3) examine whether health systems have the workforce, capacity and infrastructure to nurture continuous and impactful engagement.

Keywords:  Community based; Learning health system; Patient engagement; Patient involvement; Patient partners; Research communities of practice; Stakeholder engagement

DOI:  https://doi.org/10.1186/s40900-023-00459-w
RSC Adv. 2023 Jul 07. 13(30): 20476-20485

Recent advances in small molecules for improving mitochondrial disorders.

Liying Meng, Guanzhao Wu.

Mitochondrial disorders are observed in various human diseases, including rare genetic disorders and complex acquired pathologies. Recent advances in molecular biological techniques have dramatically expanded the understanding of multiple pathomechanisms involving mitochondrial disorders. However, the therapeutic methods for mitochondrial disorders are limited. For this reason, there is increasing interest in identifying safe and effective strategies to mitigate mitochondrial impairments. Small-molecule therapies hold promise for improving mitochondrial performance. This review focuses on the latest advances in developing bioactive compounds for treating mitochondrial disease, aiming to provide a broader perspective of fundamental studies that have been carried out to evaluate the effects of small molecules in regulating mitochondrial function. Novel-designed small molecules ameliorating mitochondrial functions are urgent for further research.

DOI: https://doi.org/10.1039/d3ra03313a
J Clin Epidemiol. 2023 Jul 07. pii: S0895-4356(23)00172-5. [Epub ahead of print]

Assessment highlights need for improvement in standards of development for rare genetic diseases core outcome sets.

Andrada Ciucă, Siddharth Banka, William G Newman, Ramona Moldovan, Jamie J Kirkham.

  OBJECTIVE: A rare disease is classified as such if it affects less than 1 persons in 2,000. The Core Outcome Set STandards for Development (COS-STAD) is a set of standards that represent the minimum recommendations to be considered in the process of COS development. The aim of this study was to provide a baseline assessment of COS development standards for rare genetic diseases.STUDY DESIGN AND SETTING: Core Outcome Measures in Effectiveness Trials (COMET) database contains 447 published COS studies. Studies focusing on COS development for rare genetic diseases were eligible for inclusion and were assessed by two independent evaluators.
RESULTS: Nine COS studies were included in the analysis. Eight different rare genetic diseases were investigated. None of the studies met all standards for development. The number of standards met ranged from 6 to 10 and the median was 7.
CONCLUSION: This study is the first assessment of COS-STAD for rare genetic diseases COS studies and it highlights a great need for improvement. First in terms of numbers of rare diseases considered for COS developments, second in methodology, particularly regarding the consensus process and third in reporting of the COS development studies.

Keywords:  COS; core outcome sets; minimum standards; rare diseases; research methodology

DOI:  https://doi.org/10.1016/j.jclinepi.2023.07.002
Int J Mol Sci. 2023 Jun 27. pii: 10696. [Epub ahead of print]24(13):

Drug Drop Test: How to Quickly Identify Potential Therapeutic Compounds for Mitochondrial Diseases Using Yeast Saccharomyces cerevisiae.

Martina Magistrati, Alexandru Ionut Gilea, Maria Carla Gerra, Enrico Baruffini, Cristina Dallabona.

  Mitochondrial diseases (MDs) refer to a group of clinically and genetically heterogeneous pathologies characterized by defective mitochondrial function and energy production. Unfortunately, there is no effective treatment for most MDs, and current therapeutic management is limited to relieving symptoms. The yeast Saccharomyces cerevisiae has been efficiently used as a model organism to study mitochondria-related disorders thanks to its easy manipulation and well-known mitochondrial biogenesis and metabolism. It has been successfully exploited both to validate alleged pathogenic variants identified in patients and to discover potential beneficial molecules for their treatment. The so-called "drug drop test", a phenotype-based high-throughput screening, especially if coupled with a drug repurposing approach, allows the identification of molecules with high translational potential in a cost-effective and time-saving manner. In addition to drug identification, S. cerevisiae can be used to point out the drug's target or pathway. To date, drug drop tests have been successfully carried out for a variety of disease models, leading to very promising results. The most relevant aspect is that studies on more complex model organisms confirmed the effectiveness of the drugs, strengthening the results obtained in yeast and demonstrating the usefulness of this screening as a novel approach to revealing new therapeutic molecules for MDs.

Keywords:  Saccharomyces cerevisiae; drug drop test; drug repurposing; mitochondrial diseases; yeast model

DOI:  https://doi.org/10.3390/ijms241310696
J Pharm Sci. 2023 Jul 06. pii: S0022-3549(23)00274-5. [Epub ahead of print]

Quantitative systems pharmacology for rare disease drug development.

Jane Pf Bai, Jie Wang, Yifei Zhang, Lingshan Wang, Xiling Jiang.

  Though hundreds of drugs have been approved by the US Food and Drug Administration (FDA) for treating various rare diseases, most rare diseases still lack FDA-approved therapeutics. To identify the opportunities for developing therapies for these diseases, the challenges of demonstrating the efficacy and safety of a drug for treating a rare disease are highlighted herein. Quantitative systems pharmacology (QSP) has increasingly been used to inform drug development; our analysis of QSP submissions received by FDA showed that there were 121 submissions as of 2022, for informing rare disease drug development across development phases and therapeutic areas. Examples of published models for inborn errors of metabolism, non-malignant hematological disorders, and hematological malignancies were briefly reviewed to shed light on use of QSP in drug discovery and development for rare diseases. Advances in biomedical research and computational technologies can potentially enable QSP simulation of the natural history of a rare disease in the context of its clinical presentation and genetic heterogeneity. With this function, QSP may be used to conduct in-silico trials to overcome some of the challenges in rare disease drug development. QSP may play an increasingly important role in facilitating development of safe and effective drugs for treating rare diseases with unmet medical needs.

Keywords:  Dose optimization; Quantitative systems pharmacology; Rare disease drug development

DOI:  https://doi.org/10.1016/j.xphs.2023.06.019
Res Involv Engagem. 2023 Jul 08. 9(1): 48

Patient and public involvement in health research in Norway: a survey among researchers and patient organisations.

Sigve Nyvik Aas, Marita Borg Distefano, Ingvild Pettersen, Berit Gravrok, Laila Yvonne Nordvoll, Jon Fauskanger Bjaastad, Sameline Grimsgaard.

  BACKGROUND: Patient and public involvement (PPI) in health research may improve both the relevance and quality of the research. There is however a lack of research investigating the experiences, attitudes and barriers towards PPI in clinical research in Norway. The Norwegian Clinical Research Infrastructure Network therefore conducted a survey among researchers and PPI contributors aiming to investigate experiences with PPI and identify current challenges for successful involvement.METHODS: Two survey questionnaires were developed and distributed in October and November 2021. The survey targeting 1185 researchers was distributed from the research administrative system in the Regional Health Trusts. The survey targeting PPI contributors was distributed through Norwegian patient organisations, regional and national competence centers.
RESULTS: The response rate was 30% among researchers and was unobtainable from PPI contributors due to the survey distribution strategy. PPI was most frequently used in the planning and conduct of the studies, and less utilized in dissemination and implementation of results. Both researchers and user representatives were generally positive to PPI, and agreed that PPI might be more useful in clinical research than in underpinning research. Researchers and PPI contributors who reported that roles and expectations were clarified in advance, were more likely to experience a common understanding of roles and responsibilities in the research project. Both groups pointed to the importance of earmarked funding for PPI activities. There was a demand for a closer collaboration between researchers and patient organisations to develop accessible tools and effective models for PPI in health research.
CONCLUSIONS: Surveys among clinical researchers and PPI contributors indicate overall positive attitudes towards PPI in clinical research. However, more resources, such as budget, time, and accessible tools, are needed. Clarifying roles and expectations, and creating new PPI models under resource constraints can enhance its effectiveness. PPI is underutilized in disseminating and implementing research results, presenting an opportunity for improving healthcare outcomes.

Keywords:  Health research; Patient and public involvement; User representatives

DOI:  https://doi.org/10.1186/s40900-023-00458-x
Parkinsonism Relat Disord. 2023 Jul 07. pii: S1353-8020(23)00239-0. [Epub ahead of print]113 105516

Mitochondrial encephalopathy with lactic-acidosis and stroke-like episodes syndrome presenting as progressive supranuclear palsy.

Reece M Hass, Jennifer L Whitwell, Elizabeth A Coon, Keith A Josephs, Farwa Ali.



Keywords:  MELAS; Mitochondrial disorders; Movement disorders; PSP; Progressive supranuclear palsy

DOI:  https://doi.org/10.1016/j.parkreldis.2023.105516
BMJ Open. 2023 07 10. 13(7): e070193

Does value-based healthcare support patient-centred care? A scoping review of the evidence.

Martha Kidanemariam, Arwen H Pieterse, Dorine J van Staalduinen, Willem Jan W Bos, Anne M Stiggelbout.

  BACKGROUND: Standardisation of outcome measures is integral to value-based healthcare (VBHC), which may conflict with patient-centred care, focusing on personalisation.OBJECTIVES: We aimed to provide an overview of measures used to assess the effect of VBHC implementation and to examine to what extent the evidence indicates that VBHC supports patient-centred care.
DESIGN: A scoping review guided by the Joanna Briggs Institute methodology.
SOURCES OF EVIDENCE: We searched the following databases on 18 February 2021: Cochrane Library, EMBASE, MEDLINE and Web of Science.
ELIGIBILITY CRITERIA: We included empirical papers assessing the effect of the implementation of VBHC, published after introduction of VBHC in 2006.
DATA EXTRACTION AND SYNTHESIS: Two independent reviewers double-screened papers and data were extracted by one reviewer and checked by the other. We classified the study measures used in included papers into six categories: process indicator, cost measure, clinical outcome, patient-reported outcome, patient-reported experience or clinician-reported experience. We then assessed the patient-centredness of the study measures used.
RESULTS: We included 39 studies using 94 unique study measures. The most frequently used study measures (n=72) were process indicators, cost measures and clinical outcomes, which rarely were patient-centred. The less frequently used (n=20) patient-reported outcome and experience measures often measured a dimension of patient-centred care.
CONCLUSION: Our study shows that the evidence on VBHC supporting patient-centred care is limited, exposing a knowledge gap in VBHC research. The most frequently used study measures in VBHC research are not patient-centred. The major focus seems to be on measures of quality of care defined from a provider, institution or payer perspective.

Keywords:  health policy; health services administration & management; organisation of health services; patient-centered care

DOI:  https://doi.org/10.1136/bmjopen-2022-070193