bims-curels Biomed News
on Leigh syndrome
Issue of 2023‒07‒09
thirteen papers selected by
Cure Mito Foundation

  1. Clin Exp Pediatr. 2023 Jun 28.
      Most rare diseases(orphan diseases) still lack approved treatments despite major advances in research providing the tools to understand their molecular basis, as well as legislation providing regulatory and economic incentives to expedite the development of specific therapies. Addressing this translational gap is a multifaceted challenge, for which a key aspect is the selection of the optimal therapeutic modality for translating advances in rare disease knowledge into potential medicines, known as orphan drugs. There are several strategies for the development of orphan drugs for rare genetic disorders including protein replacement therapies, small molecule therapies(e.g. substrate reduction therapy, chemical chaperone therapy, cofactor therapy, expression modification therapy, read through therapy), monoclonal antibodies, antisense oligonucleotide, small interfering RNA or exon skipping therapies, gene replacement and direct genome editing therapies, mRNA therapy, and cell therapy as well as drug repurposing. Each strategy has its strength and limitations for orphan drug development. Furthermore, numerous hurdles are present in clinical trials in rare genetic disease because of difficulty in patient recruitment, unknown molecular physiology and natural history of the disease, ethical concerns about pediatric patients, and regulatory challenges. To address these barriers, the rare genetic diseases community including academic institutions, industry, patient advocacy groups, foundations, payers and government regulatory and research organizations, must be engaged as a partnership in discussions about the issues.
    Keywords:  Clinical trial; Drug development; Orphan drug; Rare disease; Strategy
  2. Orphanet J Rare Dis. 2023 07 03. 18(1): 176
    BNDMR infrastructure team
      In France, all patients followed by Rare Disease (RD) expert centers have to be registered in the National Rare Disease Registry (BNDMR). This database collects a minimum data set including diagnosis coded using the Orphanet nomenclature. Overall, 753,660 patients were recorded from 2007 to March 2022 including 493,740 with at least one rare disease diagnosis. Among these rare disease diagnoses, 1,300 diagnoses gathered between 10 and 70 patients and 792 gathered more than 70 patients, corresponding to more than one patient per million inhabitants. A total of 47 rare disease diagnoses with point prevalence or incidence reported in the literature below 1/1,000,000 have more than 70 patients in the BNDMR, suggesting larger BNDMR cohorts than expected from reported literature. As a conclusion, our national RD registry is a great resource to facilitate patients' recruitment in clinical research and a better understanding of RD natural history and epidemiology.
  3. Res Involv Engagem. 2023 Jul 03. 9(1): 45
      BACKGROUND: Patient and public involvement in health economic evaluation is still relatively rare, compared to other areas of health and social care research. Developing stronger patient and public involvement in health economic evaluation will be important in the future because such evaluations can impact on the treatments and interventions that patients can access in routine care.MAIN TEXT: The Consolidated Health Economic Evaluation Reporting Standards (CHEERS) is a reporting guideline for authors publishing health economic evaluations. We established an international group of public contributors who were involved in the update of the CHEERS 2022 reporting guidance, ensuring two items (areas of reporting) specifically about public involvement were included. In this commentary we focus on the development of a guide to support public involvement in reporting, a key suggestion made by the CHEERS 2022 Public Reference Group, who advocated for greater public involvement in health economic evaluation. This need for this guide was identified during the development of CHEERS 2022 when it became apparent that the language of health economic evaluation is complex and not always accessible, creating challenges for meaningful public involvement in key deliberation and discussion. We took the first step to more meaningful dialogue by creating a guide that patient organisations could use to support their members to become more involved in discussions about health economic evaluations.
    CONCLUSIONS: CHEERS 2022 provides a new direction for health economic evaluation, encouraging researchers to undertake and report their public involvement to build the evidence base for practice and may provide some reassurance to the public that their voice has played a part in evidence development. The CHEERS 2022 guide for patient representatives and patient organisations aims to support that endeavour by enabling deliberative discussions among patient organisations and their members. We recognise it is only a first step and further discussion is needed about the best ways to involve public contributors in health economic evaluation.
    Keywords:  CHEERS 2022; Health economic evaluation; Patient and public engagement; Patient and public involvement
  4. Trials. 2023 Jul 06. 24(1): 443
      BACKGROUND: Clinical trials aim to draw conclusions about the effects of treatments, but a trial can address many different potential questions. For example, does the treatment work well for patients who take it as prescribed? Or does it work regardless of whether patients take it exactly as prescribed? Since different questions can lead to different conclusions on treatment benefit, it is important to clearly understand what treatment effect a trial aims to investigate-this is called the 'estimand'. Using estimands helps to ensure trials are designed and analysed to answer the questions of interest to different stakeholders, including patients and public. However, there is uncertainty about whether patients and public would like to be involved in defining estimands and how to do so. Public partners are patients and/or members of the public who are part of, or advise, the research team. We aimed to (i) co-develop a tool with public partners that helps explain what an estimand is and (ii) explore public partner's perspectives on the importance of discussing estimands during trial design.METHODS: An online consultation meeting was held with 5 public partners of mixed age, gender and ethnicities, from various regions of the UK. Public partner opinions were collected and a practical tool describing estimands, drafted before the meeting by the research team, was developed. Afterwards, the tool was refined, and additional feedback sought via email.
    RESULTS: Public partners want to be involved in estimand discussions. They found an introductory tool, to be presented and described to them by a researcher, helpful for starting a discussion about estimands in a trial design context. They recommended storytelling, analogies and visual aids within the tool. Four topics related to public partners' involvement in defining estimands were identified: (i) the importance of addressing questions that are relevant to patients and public in trials, (ii) involving public partners early on, (iii) a need for education and communication for all stakeholders and (iv) public partners and researchers working together.
    CONCLUSIONS: We co-developed a tool for researchers and public partners to use to facilitate the involvement of public partners in estimand discussions.
    Keywords:  Clinical trial; Estimand; Patient and public involvement
  5. Res Involv Engagem. 2023 Jul 07. 9(1): 47
      BACKGROUND: Current practices for engaging patients in patient-oriented research (POR) result in a narrow pool of patient perspectives being reflected in POR. This project aims to address gaps in methodological knowledge to foster diversity in POR, through the co-design and evaluation of a series of educational modules for health researchers in British Columbia, Canada.METHODS: Modules were co-created by a team of academic researchers and patient partners from hardly-reached communities. The modules are presented using the Tapestry Tool, an interactive, online educational platform. Our evaluation framework focused on engagement, content quality, and predicted behavior change. The User Engagement Scale short form (UES-SF) measured participants' level of engagement with the modules. Survey evaluation items assessed the content within the modules and participants' perceptions of how the modules will impact their behavior. Evaluation items modeled on the theory of planned behavior, administered before and after viewing the modules, assessed the impact of the modules on participants' perceptions of diversity in POR.
    RESULTS: Seventy-four health researchers evaluated the modules. Researchers' engagement and ratings of module content were high. Subjective behavioral control over fostering diversity in POR increased significantly after viewing the modules.
    CONCLUSIONS: Our results suggest the modules may be an engaging way to provide health researchers with tools and knowledge to increase diversity in health research. Future studies are needed to investigate best practices for engaging with communities not represented in this pilot project, such as children and youth, Indigenous Peoples, and Black communities. While educational interventions represent one route to increasing diversity in POR, individual efforts must occur in tandem with high-level changes that address systemic barriers to engagement.
    Keywords:  Diversity; Educational modules; Hardly reached; Inclusion; Methods; Patient-oriented research
  6. Healthc Pap. 2023 Apr;pii: hcpap.2023.27111. [Epub ahead of print]21(2): 11-12
      The comments provided by Rawson and Adams (2023) miss the mark of our articles (Sirrs et al. 2023a, 2023b). We agree that the patient perspective is critical and that patients with "rare diseases have a right to healthcare and have huge unmet needs …" (p. 7). However, we challenge Rawson and Adams' (2023) thesis that keeping drug prices higher in Canada than in most other countries would solve the problem of access to therapies for rare diseases that have no available treatment.
  7. Front Health Serv. 2023 ;3 1092816
      Background: Patients with genetic cancer susceptibility are presented with complex management options involving difficult decisions, for example about genetic testing, treatment, screening and risk-reducing surgery/medications. This review sought to explore the experience of patients using decision support resources in this context, and the impact on decision-making outcomes.Methods: Systematic review of quantitative, qualitative and mixed-methods studies involving adults with or without cancer who used a decision support resource pre- or post-genetic test for any cancer susceptibility. To gather a broad view of existing resources and gaps for development, digital or paper-based patient resources were included and not limited to decision aids. Narrative synthesis was used to summarise patient impact and experience.
    Results: Thirty-six publications describing 27 resources were included. Heterogeneity of resources and outcome measurements highlighted the multiple modes of resource delivery and personal tailoring acceptable to and valued by patients. Impact on cognitive, emotional, and behavioural outcomes was mixed, but mainly positive. Findings suggested clear potential for quality patient-facing resources to be acceptable and useful.
    Conclusions: Decision support resources about genetic cancer susceptibility are likely useful to support decision-making, but should be co-designed with patients according to evidence-based frameworks. More research is needed to study impact and outcomes, particularly in terms of longer term follow-up to identify whether patients follow through on decisions and whether any increased distress is transient. Innovative, streamlined resources are needed to scale up delivery of genetic cancer susceptibility testing for patients with cancer in mainstream oncology clinics. Tailored patient-facing decision aids should also be made available to patients identified as carriers of a pathogenic gene variant that increases future cancer risks, to complement traditional genetic counselling.
    Systematic Review Registration:, identifier: CRD42020220460.
    Keywords:  cancer genetics; decision support; genetic counselling; patient decision aid; shared decision-making
  8. Yearb Med Inform. 2023 Jul 06.
      OBJECTIVES: Through a scoping review, we examine in this survey what ways health equity has been promoted in clinical research informatics with patient implications and especially published in the year of 2021 (and some in 2022).METHOD: A scoping review was conducted guided by using methods described in the Joanna Briggs Institute Manual. The review process consisted of five stages: 1) development of aim and research question, 2) literature search, 3) literature screening and selection, 4) data extraction, and 5) accumulate and report results.
    RESULTS: From the 478 identified papers in 2021 on the topic of clinical research informatics with focus on health equity as a patient implication, 8 papers met our inclusion criteria. All included papers focused on artificial intelligence (AI) technology. The papers addressed health equity in clinical research informatics either through the exposure of inequity in AI-based solutions or using AI as a tool for promoting health equity in the delivery of healthcare services. While algorithmic bias poses a risk to health equity within AI-based solutions, AI has also uncovered inequity in traditional treatment and demonstrated effective complements and alternatives that promotes health equity.
    CONCLUSIONS: Clinical research informatics with implications for patients still face challenges of ethical nature and clinical value. However, used prudently-for the right purpose in the right context-clinical research informatics could bring powerful tools in advancing health equity in patient care.
  9. J Am Med Inform Assoc. 2023 Jul 06. pii: ocad122. [Epub ahead of print]
      The design, development, implementation, use, and evaluation of high-quality, patient-centered clinical decision support (PC CDS) is necessary if we are to achieve the quintuple aim in healthcare. We developed a PC CDS lifecycle framework to promote a common understanding and language for communication among researchers, patients, clinicians, and policymakers. The framework puts the patient, and/or their caregiver at the center and illustrates how they are involved in all the following stages: Computable Clinical Knowledge, Patient-specific Inference, Information Delivery, Clinical Decision, Patient Behaviors, Health Outcomes, Aggregate Data, and patient-centered outcomes research (PCOR) Evidence. Using this idealized framework reminds key stakeholders that developing, deploying, and evaluating PC-CDS is a complex, sociotechnical challenge that requires consideration of all 8 stages. In addition, we need to ensure that patients, their caregivers, and the clinicians caring for them are explicitly involved at each stage to help us achieve the quintuple aim.
    Keywords:  clinical decision support; medical informatics applications; patient-centered care; shared decision making
  10. Cardiovasc Res. 2023 Jul 03. pii: cvad101. [Epub ahead of print]
      AIMS: Mitochondrial complex I assembly is a multi-step process which necessitates the involvement of a variety of assembly factors and chaperones to ensure the final active enzyme is correctly assembled. The role of the assembly factor ECSIT was studied across various murine tissues to determine its role in this process and how this varied between tissues of varying energetic demands. We hypothesised that many of the known functions of ECSIT were unhindered by the introduction of an ENU induced mutation, whilst it's role in complex I assembly was affected on a tissue specific basis.METHODS AND RESULTS: Here we describe a mutation in the mitochondrial complex I assembly factor ECSIT which reveals tissue specific requirements for ECSIT in complex I assembly. Mitochondrial complex I assembly is a multi-step process dependent on assembly factors that organise and arrange the individual subunits, allowing for their incorporation into the complete enzyme complex. We have identified an ENU induced mutation in ECSIT (N209I) that exhibits a profound effect on complex I component expression and assembly in heart tissue, resulting in hypertrophic cardiomyopathy in the absence of other phenotypes. The dysfunction of complex I appears to be cardiac specific, leading to a loss of mitochondrial output as measured by Seahorse extracellular flux and various biochemical assays in heart tissue, whilst mitochondria from other tissues were unaffected.
    CONCLUSIONS: These data suggest that the mechanisms underlying complex I assembly and activity may have tissue specific elements tailored to the specific demands of cells and tissues. Our data suggest that tissues with high energy demands, such as the heart, may utilise assembly factors in different ways to low energy tissues in order to improve mitochondrial output. This data have implications for the diagnosis and treatment of various disorders of mitochondrial function as well as cardiac hypertrophy with no identifiable underlying genetic cause.
    TRANSLATIONAL PERSPECTIVE: Mitochondrial diseases often present as multi system disorders with far reaching implications to the health and well being of patients. Diagnoses are often undertaken by characterisation of mitochondrial function from skin or muscle biopsy, with the expectation that any affect on mitochondrial function will be recognisable in all cell types. However, this study demonstrates that mitochondrial function may differ between cell types with the involvement of tissue specific proteins or isoforms, as such, current diagnostic techniques may miss diagnoses of a more specific mitochondrial dysfunction.
  11. Digit Biomark. 2023 Jan-Dec;7(1):7(1): 45-53
      Introduction: Digital health technologies (DHTs) provide opportunities for real-time data collection and assessment of patient function. However, use of DHT-derived endpoints in clinical trials to support medical product labelling claims is limited.Methods: From November 2020 through March 2021, the Clinical Trials Transformation Initiative (CTTI) conducted a qualitative descriptive study using semi-structured interviews with sponsors of clinical trials that used DHT-derived endpoints. We aimed to learn about their experiences, including their interactions with regulators and the challenges they encountered. Using applied thematic analysis, we identified barriers to and recommendations for using DHT-derived endpoints in pivotal trials.
    Results: Sponsors identified five key challenges to incorporating DHT-derived endpoints in clinical trials. These included (1) a need for additional regulatory clarity specific to DHT-derived endpoints, (2) the official clinical outcome assessment qualification process being impractical for the biopharmaceutical industry, (3) a lack of comparator clinical endpoints, (4) a lack of validated DHTs and algorithms for concepts of interest, and (5) a lack of operational support from DHT vendors.
    Discussion/Conclusion: CTTI shared the interview findings with the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) and during a multi-stakeholder expert meeting. Based on these discussions, we provide several new and revised tools to aid sponsors in using DHT-derived endpoints in pivotal trials to support labelling claims.
    Keywords:  Clinical outcome assessment; Digital health technology; Endpoint; Regulatory trial