bims-curels Biomed News
on Leigh syndrome
Issue of 2023–05–07
eleven papers selected by
Cure Mito Foundation



  1. J Pharmacokinet Pharmacodyn. 2023 May 02.
      Rare disease drug development is wrought with challenges not the least of which is access to the limited data currently available throughout the rare disease ecosystem where sharing of the available data is not guaranteed. Most pharmaceutical sponsors seeking to develop agents to treat rare diseases will initiate data landscaping efforts to identify various data sources that might be informative with respect to disease prevalence, patient selection and identification, disease progression and any data projecting likelihood of patient response to therapy including any genetic data. Such data are often difficult to come by for highly prevalent, mainstream disease populations let alone for the 8000 rare disease that make up the pooled patient population of rare disease patients. The future of rare disease drug development will hopefully rely on increased data sharing and collaboration among the entire rare disease ecosystem. One path to achieving this outcome has been the development of the rare disease cures accelerator, data analytics platform (RDCA-DAP) funded by the US FDA and operationalized by the Critical Path Institute. FDA intentions were clearly focused on improving the quality of rare disease regulatory applications by sponsors seeking to develop treatment options for various rare disease populations. As this initiative moves into its second year of operations it is envisioned that the increased connectivity to new and diverse data streams and tools will result in solutions that benefit the entire rare disease ecosystem and that the platform becomes a Collaboratory for engagement of this ecosystem that also includes patients and caregivers.
    Keywords:  Data analytics; Digital research environment (DRE); Drug development; MIDD; Rare diseases
    DOI:  https://doi.org/10.1007/s10928-023-09859-7
  2. Exp Mol Med. 2023 May 01.
      Mitochondria are of fundamental importance in programmed cell death, cellular metabolism, and intracellular calcium concentration modulation, and inheritable mitochondrial disorders via mitochondrial DNA (mtDNA) mutation cause several diseases in various organs and systems. Nevertheless, mtDNA editing, which plays an essential role in the treatment of mitochondrial disorders, still faces several challenges. Recently, programmable editing tools for mtDNA base editing, such as cytosine base editors derived from DddA (DdCBEs), transcription activator-like effector (TALE)-linked deaminase (TALED), and zinc finger deaminase (ZFD), have emerged with considerable potential for correcting pathogenic mtDNA variants. In this review, we depict recent advances in the field, including structural biology and repair mechanisms, and discuss the prospects of using base editing tools on mtDNA to broaden insight into their medical applicability for treating mitochondrial diseases.
    DOI:  https://doi.org/10.1038/s12276-023-00973-7
  3. J Med Ethics. 2023 May 02. pii: jme-2022-108659. [Epub ahead of print]
      Mitochondrial replacement techniques (MRTs) are a new group of biotechnologies that aim to aid women whose eggs have disease-causing deleteriously mutated mitochondria to have genetically related healthy children. These techniques have also been used to aid women with poor oocyte quality and poor embryonic development, to have genetically related children. Remarkably, MRTs create humans with DNA from three sources: nuclear DNA from the intending mother and father, and mitochondrial DNA from the egg donor. In a recent publication Françoise Baylis argued that MRTs are detrimental for genealogical research via mitochondrial DNA because they would obscure the lines of individual descent. In this paper, I argue that MRTs do not obscure genealogical research, but rather that MRT-conceived children can have two mitochondrial lineages. I argue for this position by showing that MRTs are reproductive in nature and, thus, they create genealogy.
    Keywords:  fertilization in vitro; gene transfer techniques; genetic engineering; genetic therapy; in vitro techniques
    DOI:  https://doi.org/10.1136/jme-2022-108659
  4. Mutagenesis. 2023 May 05. pii: gead010. [Epub ahead of print]
      Mitochondrial DNA mutation and toxicity have been linked to several inherited and acquired diseases; however, these are challenging to diagnose and characterise due to clinical and genetic heterogeneity. This review investigates current techniques for the analysis of mitochondrial perturbations, and novel, emerging endpoints for routine application within the clinical setting. Particular focus is given to the biochemistry of the mitochondria influencing each endpoint and the relation of these to toxicity. Current approaches such as the use of metabolic markers (e.g., lactate production), and muscle biopsies to measure mitochondrial proteins were found to lack specificity. Newly emerging identified endpoints were: fibroblast growth factor-21, glucose uptake, mitochondrial membrane potential, mitochondrial morphology, mtDNA heteroplasmy, and mutation of mtDNA and nuclear DNA. Owed to the advancement in genetic analysis techniques, it is suggested by this review that genotypic endpoints of mtDNA mutation and heteroplasmy show particular promise as indicators of mitochondrial disease. It is, however, acknowledged that any single endpoint in isolation offers limited information; therefore, it is recommended that analysis of several endpoints simultaneously will offer the greatest benefit in terms of disease diagnosis and study. It is hoped that this review further highlights the need for advancement in understanding mitochondrial disease.
    DOI:  https://doi.org/10.1093/mutage/gead010
  5. Orphanet J Rare Dis. 2023 May 05. 18(1): 106
      Patient registries serve to overcome the research limitations inherent in the study of rare diseases, where patient numbers are typically small. Despite the value of real-world data collected through registries, adequate design and maintenance are integral to data quality. We aimed to describe an overview of the challenges in design, quality management, and maintenance of rare disease registries.A systematic search of English articles was conducted in PubMed, Ovid Medline/Embase, and Cochrane Library. Search terms included "rare diseases, patient registries, common data elements, quality, hospital information systems, and datasets". Inclusion criteria were any manuscript type focused upon rare disease patient registries describing design, quality monitoring or maintenance. Biobanks and drug surveillances were excluded.A total of 37 articles, published between 2001 and 2021, met the inclusion criteria. Patient registries covered a wide range of disease areas and covered multiple geographical locations, with a predisposition for Europe. Most articles were methodological reports and described the design and setup of a registry. Most registries recruited clinical patients (92%) with informed consent (81%) and protected the collected data (76%). Whilst the majority (57%) collected patient-reported outcome measures, only few (38%) consulted PAGs during the registry design process. Few reports described details regarding quality management (51%) and maintenance (46%).Rare disease patient registries are valuable for research and evaluation of clinical care, and an increasing number have emerged. However, registries need to be continuously evaluated for data quality and long-term sustainability to remain relevant for future use.
    Keywords:  Data quality; Design; Maintenance; Patient registry; Rare disease
    DOI:  https://doi.org/10.1186/s13023-023-02719-0
  6. Pharmaceut Med. 2023 May 04.
      What is patient-centricity? In some contexts, it has been associated with targeting therapies based on biomarkers or enabling healthcare access. There has been a surge in patient-centricity publications, and in many cases for the biopharmaceutical industry, patient engagement is used to endorse pre-held assumptions at a specific moment in time. Rarely is patient engagement used to drive business decisions. Here we describe an innovative partnership between Alexion, AstraZeneca Rare Disease and patients that allowed a deeper understanding of the biopharmaceutical stakeholder ecosystem and an empathic understanding of each patient's and caregiver's lived experience. Alexion's decision to build patient-centricity frameworks resulted in the formation of two unique organisation design platforms: STAR (Solutions To Accelerate Results for patients) and LEAP (Learn, Evolve, Activate and deliver for Patients) Immersive Simulations. These interconnected programmes required cultural, global, and organisational shifts. STAR generates global patient insights that are embedded in drug candidate and product strategies while helping to establish enterprise foundational alignment and external stakeholder engagement plans. LEAP Immersive Simulations produce detailed country-level patient and stakeholder insights that contribute to an empathetic understanding of each patient's lived experience, support country medicine launches and provide ideas to have a positive impact along the patient journey. Combined, they deliver integrated, cross-functional insights, patient-centric decision making, an aligned patient journey, and 360° stakeholder activation. Throughout these processes, the patient is empowered to dictate their needs and validate the proposed solutions. This is not a patient engagement survey. This is a partnership where the patient co-authors strategies and solutions.
    DOI:  https://doi.org/10.1007/s40290-023-00474-y
  7. J Med Ethics. 2023 May 02. pii: jme-2022-108741. [Epub ahead of print]
      Count Me In (CMI) was launched in 2015 as a patient-driven research initiative aimed at accelerating the study of cancer genomics through direct participant engagement, electronic consent and open-access data sharing. It is an example of a large-scale direct-to-patient (DTP) research project which has since enrolled thousands of individuals. Within the broad scope of 'citizen science', DTP genomics research is defined here as a specific form of 'top-down' research endeavour developed and overseen by institutions within the traditional human subjects research context; in novel ways, it engages and recruits patients with defined diseases, consents them for medical information and biospecimens sharing, and stores and disseminates genomic information. Importantly, these projects simultaneously aim to empower participants in the research process while increasing sample size, particularly in rare disease states. Using CMI as a case study, this paper discusses how DTP genomics research raises new questions in the context of traditional human subjects research ethics, including issues surrounding participant selection, remote consent, privacy and return of results. It aims to demonstrate how current research ethics frameworks may be insufficient in this context, and that institutions, institutional review boards and investigators should be aware of these gaps and their role in ensuring the conduct of ethical, novel forms of research together with participants. Ultimately, a broader question is raised of whether the rhetoric of participatory genomics research advocates for an ethic of personal and social duty for contributing to the advancement of generalisable knowledge about health and disease.
    Keywords:  Databases- Genetic; Ethics- Research; Genetic Privacy; Informed Consent
    DOI:  https://doi.org/10.1136/jme-2022-108741
  8. Hepatology. 2023 May 05.
       BACKGROUND AND AIMS: Clinical trials have been a central driver of change and have provided the evidence base necessary to advance new therapies for liver diseases. This review provides a perspective on the status of trials in hepatology, and a vantage point into the emerging capabilities and external forces that will shape the conduct of clinical trials in the future.
    APPROACHES: The adaptations to clinical trials operations in response to the disruptions by the COVID-19 pandemic, and opportunities for innovation in hepatology trials are emphasized. Future trials in hepatology will be driven by unmet therapeutic needs and fueled by technological advances incorporating digital capabilities with expanded participant derived data collection, computing, and analytics. Their design will embrace innovative trial designs adapted to these advances and that emphasize broader and more inclusive participant engagement. Their conduct will be further shaped by evolving regulatory needs and the emergence of new stakeholders in the clinical trials ecosystem.
    CONCLUSIONS: The evolution of clinical trials will offer unique opportunities to advance new therapeutics that will ultimately improve the lives of patients with liver diseases.
    DOI:  https://doi.org/10.1097/HEP.0000000000000436
  9. Innov Clin Neurosci. 2023 Jan-Mar;20(1-3):20(1-3): 25-31
      This article expands on a session, titled "Patient Centricity: Design and Conduct of Clinical Trials in Orphan Diseases," that was presented as part of a two-day meeting on Pediatric Drug Development at the International Society for Central Nervous System (CNS) Clinical Trials and Methodology (ISCTM) Autumn Conference in Boston, Massachusetts, in October 2020. Speakers from various areas of pediatric drug development addressed a variety of implications of including children in drug development programs, including implications for rare/orphan diseases. The speakers have written summaries of their talks. The session's lead Chair was Dr. Joan Busner, who wrote introductory and closing comments. Dr. Simon Day, regulatory consultant, outlined some of the past mistakes that have plagued trials that did not consult with patient groups in the early design phase. Dr. Atul Mahableshwarkar provided an industry perspective of a recent trial that benefited from the inclusion of patient input. Drs. Lucas Kempf and Maria Sheean provided regulatory input from the perspectives of the United States (US) Food and Drug Administration (FDA) and European Medicines Agency (EMA), respectively. Dr. Judith Dunn outlined a novel approach for assessing and rank ordering patient and clinician clinical meaningfulness and the disconnect that may occur. Dr. Busner provided closing comments, tied together the presented issues, and provided a synopsis of the lively discussion that followed the session. In addition to the speakers above, the discussion included two representatives from patient advocacy groups, as well as an additional speaker who described the challenges of conducting a pediatric trial in the US and European Union (EU), given the often competing regulatory requirements. This article should serve as an expert-informed reference to those interested and involved in CNS drug development programs that are aimed at children and rare diseases and seek to ensure a patient-centric approach.
    Keywords:  CNS orphan drug development; CNS pediatric drug development; CNS rare disease drug development; Patient centricity
  10. J Transl Med. 2023 Apr 30. 21(1): 292
      The recent paper by Kariampuzha et al. describes an exciting application of artificial intelligence to rare disease epidemiology. The authors' AI model appears to offer a major leap over Orphanet, the resource which is often a "first stop" for basic epidemiological data on rare diseases. To ensure appropriate use of this exciting tool, it is important to consider its strengths and weaknesses in context. The tool currently incorporates only PubMed abstracts, so key information located in the full text of articles is absent. Such missing information may include incidence and prevalence values, as well as important elements of study design and context. Additionally, results from the public version of the tool differ from those described in the original article, including obsolete values for prevalence and the use of non-prevalence studies in place of those listed in the article. At present, it would be appropriate to utilize the AI tool much like Orphanet: a helpful "first stop" which should be manually checked for completeness and accuracy. Users should understand the benefits of this exciting technology, and that it is not yet a panacea for the challenges of analyzing rare disease epidemiology.
    Keywords:  Artificial intelligence; Epidemiology; Incidence; Orphan drugs; Prevalence; Rare diseases
    DOI:  https://doi.org/10.1186/s12967-023-04152-0