Use of Zebrafish Models to Boost Research in Rare Genetic Diseases.
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ABSTRACT:
SUBMITTER: Crouzier L
PROVIDER: S-EPMC8706563 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Recent advances in sequencing technologies have made it significantly easier to find the genetic roots of rare hereditary pediatric diseases. These novel methods are not panaceas, however, and they often give ambiguous results, highlighting multiple possible causative mutations in affected patients. Furthermore, even when the mapping results are unambiguous, the affected gene might be of unknown function. In these cases, understanding how a particular genotype can result in a phenotype also needs carefully designed experimental work. Model organism genetics can offer a straightforward experimental setup for hypothesis testing. Containing orthologs for over 80% of the genes involved in human diseases, zebrafish (Danio rerio) has emerged as one of the top disease models over the past decade. A plethora of genetic tools makes it easy to create mutations in almost any gene of the zebrafish genome and these mutant strains can be used in high-throughput preclinical screens for active molecules. As this small vertebrate species offers several other advantages as well, its popularity in biomedical research is bound to increase, with "aquarium to bedside" drug development pipelines taking a more prevalent role in the near future.
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Project description:The structural and functional similarity of the larval zebrafish pronephros to the human nephron, together with the recent development of easier and more precise techniques to manipulate the zebrafish genome have motivated many researchers to model human renal diseases in the zebrafish. Over the last few years, great advances have been made, not only in the modeling techniques of genetic diseases in the zebrafish, but also in how to validate and exploit these models, crossing the bridge towards more informative explanations of disease pathophysiology and better designed therapeutic interventions in a cost-effective in vivo system. Here, we review the significant progress in these areas giving special attention to the renal phenotype evaluation techniques. We further discuss the future applications of such models, particularly their role in revealing new genetic diseases of the kidney and their potential use in personalized medicine.
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Project description:Several examples have always illustrated how access to large numbers of biospecimens and associated data plays a pivotal role in the identification of disease genes and the development of pharmaceuticals. Hence, allowing researchers to access to significant numbers of quality samples and data, genetic biobanks are a powerful tool in basic, translational and clinical research into rare diseases. Recently demand for well-annotated and properly-preserved specimens is growing at a high rate, and is expected to grow for years to come. The best effective solution to this issue is to enhance the potentialities of well-managed biobanks by building a network.Here we report a 5-year experience of the Telethon Network of Genetic Biobanks (TNGB), a non-profit association of Italian repositories created in 2008 to form a virtually unique catalogue of biospecimens and associated data, which presently lists more than 750 rare genetic defects. The process of TNGB harmonisation has been mainly achieved through the adoption of a unique, centrally coordinated, IT infrastructure, which has enabled (i) standardisation of all the TNGB procedures and activities; (ii) creation of an updated TNGB online catalogue, based on minimal data set and controlled terminologies; (iii) sample access policy managed via a shared request control panel at web portal. TNGB has been engaged in disseminating information on its services into both scientific/biomedical - national and international - contexts, as well as associations of patients and families. Indeed, during the last 5-years national and international scientists extensively used the TNGB with different purposes resulting in more than 250 scientific publications. In addition, since its inception the TNGB is an associated member of the Biobanking and Biomolecular Resources Research Infrastructure and recently joined the EuroBioBank network. Moreover, the involvement of patients and families, leading to the formalization of various agreements between TNGB and Patients' Associations, has demonstrated how promoting Biobank services can be instrumental in gaining a critical mass of samples essential for research, as well as, raising awareness, trust and interest of the general public in Biobanks. This article focuses on some fundamental aspects of networking and demonstrates how the translational research benefits from a sustained infrastructure.
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Project description:Atherosclerotic cardiovascular disease is the leading cause of death. Elevated circulating concentrations of lipids are a central pathogenetic driver of atherosclerosis. While numerous effective therapies for this condition have been developed, there is substantial unmet need for this pandemic illness. Here, I will review nutritional, physiological, genetic, and pathological discoveries in the emerging zebrafish model for studying dyslipidemia and atherosclerosis. The technical and physiological advantages and the pharmacological potential of this organism for discovery and validation of dyslipidemia and atherosclerosis targets are stressed through summary of recent findings. An emerging literature shows that zebrafish, through retention of a cetp ortholog gene and high sensitivity to ingestion of excess cholesterol, rapidly develops hypercholesterolemia, with a pattern of distribution of lipid species in lipoprotein particles similar to humans. Furthermore, recent studies leveraging the optical transparency of zebrafish larvae to monitor the fate of these ingested lipids have provided exciting insights to the development of dyslipidemia and atherosclerosis. Future directions for investigation are considered, with particular attention to the potential for in vivo cell biological study of atherosclerotic plaques.
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Project description:Background: The Rare Disease Research Partnership (RAinDRoP) was established in 2018 to bring together a wide variety of diverse voices in the rare disease community in Ireland and form a research partnership. This approach enabled clinicians, patients, carers and researchers to work together to identify top research priorities for rare diseases, which focused on a life-course perspective rather than a disease-specific need. Methods: A participatory multiple phase approach was used to identify research priorities for rare diseases. The research process involved three main phases: Phase I, Public Consultation Survey on Research in Rare Diseases in Ireland (PCSRRDI); Phase II, Research Prioritisation Workshop (RPW); Phase III, Follow-up Public Consultation and Prioritisation Survey (FWPCPS). Results: In total, 240 individuals completed the phase I PCSRRDI, which comprised of a cross-section of health care professionals, researchers and people living with rare diseases. One thousand and fifteen statements were collected, reflecting issues and shared challenges in rare diseases. A shortlisting step by step was used to identify any statements that had received a total score of above 50% into 10-12 researchable questions or statements per the theme for the phase II workshop. Phase II was focused on three main themes: (1) Route to Diagnosis, (2) Living with Rare Disease, (3) Integrated and Palliative Care. In total, 62 individuals attended the overall workshop; 42 participated in the prioritisation sessions. A cross-section of health care professionals, researchers and people living with rare diseases were engaged at each workshop. Seventy-five individuals completed the final phase III public ranking by priority responses, and they ranked the top 15 research priorities defined by the multi-stakeholders at the phase II consensus meeting. Conclusions: This study identified priorities for rare diseases research aimed at improving the health and wellbeing of people living with rare diseases.
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Project description:Zebrafish (Danio rerio) is an excellent model to study a wide diversity of human cancers. In this review, we provide an overview of the genetic and reverse genetic toolbox allowing the generation of zebrafish lines that develop tumors. The large spectrum of genetic tools enables the engineering of zebrafish lines harboring precise genetic alterations found in human patients, the generation of zebrafish carrying somatic or germline inheritable mutations or zebrafish showing conditional expression of the oncogenic mutations. Comparative transcriptomics demonstrate that many of the zebrafish tumors share molecular signatures similar to those found in human cancers. Thus, zebrafish cancer models provide a unique in vivo platform to investigate cancer initiation and progression at the molecular and cellular levels, to identify novel genes involved in tumorigenesis as well as to contemplate new therapeutic strategies.
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Project description:Rare diseases pose a global challenge, in that their collective impact on health systems is considerable, whereas their individually rare occurrence impedes research and development of efficient therapies. In consequence, patients and their families are often unable to find an expert for their affliction, let alone a cure. The tide is turning as pharmaceutical companies embrace gene therapy development and as serviceable tools for the repair of primary mutations separate the ability to create cures from underlying disease expertise. Whereas gene therapy by gene addition took decades to reach the clinic by incremental disease-specific refinements of vectors and methods, gene therapy by genome editing in its basic form merely requires certainty about the causative mutation. Suddenly we move from concept to trial in 3 years instead of 30: therapy development in the fast lane, with all the positive and negative implications of the phrase. Since their first application to eukaryotic cells in 2013, the proliferation and refinement in particular of tools based on clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (Cas) prokaryotic RNA-guided nucleases has prompted a landslide of therapy-development studies for rare diseases. An estimated thousands of orphan diseases are up for adoption, and legislative, entrepreneurial, and research initiatives may finally conspire to find many of them a good home. Here we summarize the most significant recent achievements and remaining hurdles in the application of CRISPR/Cas technology to rare diseases and take a glimpse at the exciting road ahead.
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Project description:Established in 2003 by the Office of Rare Diseases Research (ORDR), in collaboration with several National Institutes of Health (NIH) Institutes/Centers, the Rare Diseases Clinical Research Network (RDCRN) consists of multiple clinical consortia conducting research in more than 200 rare diseases. The RDCRN supports longitudinal or natural history, pilot, Phase I, II, and III, case-control, cross-sectional, chart review, physician survey, bio-repository, and RDCRN Contact Registry (CR) studies. To date, there have been 24,684 participants enrolled on 120 studies from 446 sites worldwide. An additional 11,533 individuals participate in the CR. Through a central data management and coordinating center (DMCC), the RDCRN's platform for the conduct of observational research encompasses electronic case report forms, federated databases, and an online CR for epidemiological and survey research. An ORDR-governed data repository (through dbGaP, a database for genotype and phenotype information from the National Library of Medicine) has been created. DMCC coordinates with ORDR to register and upload study data to dbGaP for data sharing with the scientific community. The platform provided by the RDCRN DMCC has supported 128 studies, six of which were successfully conducted through the online CR, with 2,352 individuals accrued and a median enrollment time of just 2 months. The RDCRN has built a powerful suite of web-based tools that provide for integration of federated and online database support that can accommodate a large number of rare diseases on a global scale. RDCRN studies have made important advances in the diagnosis and treatment of rare diseases.
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Project description:Home to a culturally heterogeneous population, India is also a melting pot of genetic diversity. The population architecture characterized by multiple endogamous groups with specific marriage patterns, including the widely prevalent practice of consanguinity, not only makes the Indian population distinct from rest of the world but also provides a unique advantage and niche to understand genetic diseases. Centuries of genetic isolation of population groups have amplified the founder effects, contributing to high prevalence of recessive alleles, which translates into genetic diseases, including rare genetic diseases in India.Rare genetic diseases are becoming a public health concern in India because a large population size of close to a billion people would essentially translate to a huge disease burden for even the rarest of the rare diseases. Genomics-based approaches have been demonstrated to accelerate the diagnosis of rare genetic diseases and reduce the socio-economic burden. The Genomics for Understanding Rare Diseases: India Alliance Network (GUaRDIAN) stands for providing genomic solutions for rare diseases in India. The consortium aims to establish a unique collaborative framework in health care planning, implementation, and delivery in the specific area of rare genetic diseases. It is a nation-wide collaborative research initiative catering to rare diseases across multiple cohorts, with over 240 clinician/scientist collaborators across 70 major medical/research centers. Within the GUaRDIAN framework, clinicians refer rare disease patients, generate whole genome or exome datasets followed by computational analysis of the data for identifying the causal pathogenic variations. The outcomes of GUaRDIAN are being translated as community services through a suitable platform providing low-cost diagnostic assays in India. In addition to GUaRDIAN, several genomic investigations for diseased and healthy population are being undertaken in the country to solve the rare disease dilemma.In summary, rare diseases contribute to a significant disease burden in India. Genomics-based solutions can enable accelerated diagnosis and management of rare diseases. We discuss how a collaborative research initiative such as GUaRDIAN can provide a nation-wide framework to cater to the rare disease community of India.
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Project description:Introduction: Genetic skeletal diseases (GSDs) are a diverse and complex group of rare genetic conditions that affect the development and homeostasis of the skeleton. Although individually rare, as a group of related diseases, GSDs have an overall prevalence of at least 1 per 4,000 children. There are currently very few specific therapeutic interventions to prevent, halt or modify skeletal disease progression and therefore the generation of new and effective treatments requires novel and innovative research that can identify tractable therapeutic targets and biomarkers of these diseases. Areas covered: Remarkable progress has been made in identifying the genetic basis of the majority of GSDs and in developing relevant model systems that have delivered new knowledge on disease mechanisms and are now starting to identify novel therapeutic targets. This review will provide an overview of disease mechanisms that are shared amongst groups of different GSDs and describe potential therapeutic approaches that are under investigation. Expert opinion: The extensive clinical variability and genetic heterogeneity of GSDs renders this broad group of rare diseases a bench to bedside challenge. However, the evolving hypothesis that clinically different diseases might share common disease mechanisms is a powerful concept that will generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.
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