bims-curels 2024-07-14 papers

Issue of 2024–07–14
six papers selected by
Cure Mito Foundation

Pharmaceut Med. 2024 Jul 09.

Increasing Diversity, Equity, Inclusion, and Accessibility in Rare Disease Clinical Trials.

Gareth Baynam, Simeón Baker, Charles Steward, Marshall Summar, Meghan Halley, Anne Pariser.

Diversity, equity, inclusion, and accessibility (DEIA) are foundational principles for clinical trials and medical research. In rare diseases clinical research, where numbers of participants are already challenged by rarity itself, maximizing inclusion is of particular importance to clinical trial success, as well as ensuring the generalizability and relevance of the trial results to the people affected by these diseases. In this article, we review the medical and gray literature and cite case examples to provide insights into how DEIA can be proactively integrated into rare diseases clinical research. Here, we particularly focus on genetic diversity. While the rare diseases DEIA literature is nascent, it is accelerating as many patient advocacy groups, professional societies, training and educational organizations, researcher groups, and funders are setting intentional strategies to attain DEIA goals moving forward, and to establish metrics to ensure continued improvement. Successful examples in underserved and underrepresented populations are available that can serve as case studies upon which rare diseases clinical research programs can be built. Rare diseases have historically been innovation drivers in basic, translational, and clinical research, and ultimately, all populations benefit from data diversity in rare diseases populations that deliver novel insights and approaches to how clinical research can be performed.

DOI: https://doi.org/10.1007/s40290-024-00529-8

Front Cell Neurosci. 2024 ;18 1403734

Brain organoid as a model to study the role of mitochondria in neurodevelopmental disorders: achievements and weaknesses.

Raquel Coronel, Enrique García-Moreno, Emilio Siendones, Maria J Barrero, Beatriz Martínez-Delgado, Carlos Santos-Ocaña, Isabel Liste, M V Cascajo-Almenara.

Mitochondrial diseases are a group of severe pathologies that cause complex neurodegenerative disorders for which, in most cases, no therapy or treatment is available. These organelles are critical regulators of both neurogenesis and homeostasis of the neurological system. Consequently, mitochondrial damage or dysfunction can occur as a cause or consequence of neurodevelopmental or neurodegenerative diseases. As genetic knowledge of neurodevelopmental disorders advances, associations have been identified between genes that encode mitochondrial proteins and neurological symptoms, such as neuropathy, encephalomyopathy, ataxia, seizures, and developmental delays, among others. Understanding how mitochondrial dysfunction can alter these processes is essential in researching rare diseases. Three-dimensional (3D) cell cultures, which self-assemble to form specialized structures composed of different cell types, represent an accessible manner to model organogenesis and neurodevelopmental disorders. In particular, brain organoids are revolutionizing the study of mitochondrial-based neurological diseases since they are organ-specific and model-generated from a patient's cell, thereby overcoming some of the limitations of traditional animal and cell models. In this review, we have collected which neurological structures and functions recapitulate in the different types of reported brain organoids, focusing on those generated as models of mitochondrial diseases. In addition to advancements in the generation of brain organoids, techniques, and approaches for studying neuronal structures and physiology, drug screening and drug repositioning studies performed in brain organoids with mitochondrial damage and neurodevelopmental disorders have also been reviewed. This scope review will summarize the evidence on limitations in studying the function and dynamics of mitochondria in brain organoids.

Keywords: 3D cultures; drug repurposing; high-throughput screening; mitochondrial diseases; neurodevelopmental disorders; organoid; spheroids

DOI: https://doi.org/10.3389/fncel.2024.1403734

BMJ Open. 2024 Jul 08. 14(7): e082502

Patient engagement in a Canadian health research funding institute: implementation and impact.

Dawn P Richards, Rosie Twomey, Trudy Flynn, Linda Hunter, Eunice Lui, Allan Stordy, Christine Thomas, Karim Khan.

BACKGROUND: Patient engagement (PE) or involvement in research is when patient partners are integrated onto teams and initiatives (not participants in research). A number of health research funding organisations have PE frameworks or rubrics but we are unaware of them applying and reporting on their own internal PE efforts. We describe our work at the Canadian Institutes of Health Research's Institute of Musculoskeletal Health and Arthritis (CIHR IMHA) to implement, evaluate and understand the impact of its internal PE strategy.
METHODS: A co-production model was used involving patient partners, a PE specialist and staff from IMHA. A logic model was co-developed to guide implementing and evaluating IMHA's PE strategy. Some of evaluating the PE strategy and understanding its impact was a collaboration between the Public and Patient Engagement Collaborative (McMaster University) and IMHA.
RESULTS: IMHA convened a PE Research Ambassador (PERA) group which co-led this work with the support of a PE specialist. In doing so, PERA had a number of meetings since 2020, set its own priorities and co-produced a number of outputs (video, publications, webinars, blog and modules called the How-to Guide for PE in Research). This work to evaluate and measure impacts of IMHA's PE strategy revealed positive results, for example, on PERA members, Institute Advisory Board members and staff, as well as beyond the institute based on uptake and use of the modules. Areas for improvement are mainly related to increasing the diversity of PERA and to improving accessibility of the PE outputs (more languages and formats).
CONCLUSIONS: Implementing a PE strategy within CIHR IMHA resulted in several PE activities and outputs with impacts within and beyond the institute. We provide templates and outputs related to this work that may inform the efforts of other health research funding organisations. We encourage health research funders to move beyond encouraging or requiring PE in funded projects to fully 'walk the talk' of PE by implementing and evaluating their own PE strategies.

Keywords: Community Participation; Community-Based Participatory Research; Implementation Science; Patient Participation

DOI: https://doi.org/10.1136/bmjopen-2023-082502

Orphanet J Rare Dis. 2024 Jul 10. 19(1): 262

A rare partnership: patient community and industry collaboration to shape the impact of real-world evidence on the rare disease ecosystem.

T L Klein, J Bender, S Bolton, T Collin-Histed, A Daher, L De Baere, D Dong, J Hopkin, J Johnson, T Lai, M Pavlou, T Schaller, I Žnidar.

People with rare lysosomal storage diseases face challenges in their care that arise from disease complexity and heterogeneity, compounded by many healthcare professionals being unfamiliar with these diseases. These challenges can result in long diagnostic journeys and inadequate care. Over 30 years ago, the Rare Disease Registries for Gaucher, Fabry, Mucopolysaccharidosis type I and Pompe diseases were established to address knowledge gaps in disease natural history, clinical manifestations of disease and treatment outcomes. Evidence generated from the real-world data collected in these registries supports multiple stakeholders, including patients, healthcare providers, drug developers, researchers and regulators. To maximise the impact of real-world evidence from these registries, engagement and collaboration with the patient communities is essential. To this end, the Rare Disease Registries Patient Council was established in 2019 as a partnership between the Rare Disease Registries and global and local patient advocacy groups to share perspectives on how registry data are used and disseminated. The Patient Council has resulted in a number of patient initiatives including patient representation at Rare Disease Registries advisory boards; development of plain language summaries of registry publications to increase availability of real-world evidence to patient communities; and implementation of digital innovations such as electronic patient-reported outcomes, and patient-facing registry reports and electronic consent (in development), all to enhance patient engagement. The Patient Council is building on the foundations of industry-patient advocacy group collaboration to fully integrate patient communities in decision-making and co-create solutions for the rare disease community.

Keywords: Fabry disease; Gaucher disease; Lysosomal storage diseases; MPS I; Patient communities; Pompe disease; Real-world data; Real-world evidence; Registries

DOI: https://doi.org/10.1186/s13023-024-03262-2

Eur J Neurol. 2024 Jul 08. e16405

Adult presentation of a rare mitochondrial tRNA Val gene mutation-an expanding clinical phenotype.

Eimear Joyce, Mohib Ali, Georgia Richard, Siobhan Kelly, Fiachra Martin, Peter J Conlon, Anna Whelehan, Yi Shiau Ng, Stela Lefter.

BACKGROUND AND PURPOSE: Late-onset mitochondrial disorders are diagnostically challenging with significant heterogeneity in disease presentation. A case is reported of a 67-year-old gentleman who presented with a 3-month history of seizures, recurrent encephalopathy, ataxia and weight loss, preceded by recent initiation of haemodialysis for end-stage chronic kidney disease.
METHODS: Extensive work-up including serological, cerebrospinal fluid, magnetic resonance imaging and electroencephalography was performed. Whole exome sequencing and muscle biopsy confirmed the diagnosis.
RESULTS: Magnetic resonance imaging brain demonstrated a single non-enhancing T2 fluid attenuated inversion recovery hyperintense cortical/subcortical signal change in the right temporal lobe and cerebellar atrophy. Given the subacute presentation of uncertain aetiology, he was empirically treated for autoimmune/paraneoplastic encephalitis. Despite radiological resolution of the cortical abnormality 2 weeks later, there was no clinical improvement. Further collateral history unveiled a mildly ataxic gait and longstanding hearing loss suggestive of a genetic cause. Whole exome sequencing revealed a likely pathogenic, heteroplasmic mitochondrial DNA variant in the MT-TV gene, m.1659T>C, present at higher levels of heteroplasmy in muscle (91%) compared to other mitotic tissues. A high fat/protein diet and multivitamins including co-enzyme Q10 were commenced. Treatment of the nutritional deficiency and avoidance of intermittent fasting due to unreliable oral intake secondary to encephalopathy probably contributed to the clinical improvement seen over the ensuing few months, with resolution of his encephalopathy and return to his baseline gait and weight.
CONCLUSION: An adult case is reported with an acute neurological presentation mimicking encephalitis, caused by a heteroplasmic m.1659T>C MT-TV variant, previously reported once in a child who displayed a different clinical phenotype.

Keywords: MT‐TV gene variant; late onset mitochondrial disorder; m.1659T>C

DOI: https://doi.org/10.1111/ene.16405

Fam Pract Manag. 2024 Jul;31(4): 44

Why I Almost Fired a Patient.

Sanford J Brown.