Mesenchymal TNFR2 promotes the development of polyarthritis and comorbid heart valve stenosis. Maria Sakkou et al.
INFRAFRONTIER / IMPC Stakeholder Meeting - Infrafrontier
Prof Kollias concluded his presentation stating that animal research is essential for modelling and understanding human disease, and summarised key points for disease modelling using animals and characteristics of animal models in the era of Precision Medicine. These alleles in fact have great potential to inform novel biological and disease mechanisms as they reflect increasing context-dependent disease pathogenesis that integrates specific protein domain functions and interactions with differential threshold for dysfunction in specific tissues.
Moreover, the mouse model will be required for rapid testing of repurposed or new therapies. Jason Heaney reported on the extensive modeling of human disease variants by BCM-KOMP2 to create and characterize mouse models of human disease relevant mutations null alleles, 58 conditional knockout alleles, and 79 point mutation and other knock-in allele types using short and long ssODNs.
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Jason emphasized that traditional null alleles remain a valuable resource for precision disease modeling, and that variant knock-in alleles in mice present unique challenges that require close collaboration between genomic discovery and animal modeling teams. Collaborations among clinicians, human geneticists and model organism researchers facilitate diagnosis and studies of undiagnosed conditions.
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Candidate causative genes and variants identified from a patient with an undiagnosed disease can be explored in a number of genetic model organisms. Robert Burgess developed a therapeutic strategy based on eliminating the mutant Gars by a RNAi-mediated allele-specific knockdown approach. Allele specific RNAi was developed and tested in vitro. Subsequently, following scAAV9 delivery of Gars-targeting miRNA shuttles, mice were analyzed at 4 weeks of age to test efficacy and showed an ameliorated phenotype. The translational potential of the approach is now being tested on a four year old female patient with severe motor neuropathy.
Whole exome sequencing identified a d e novo 12 base pair deletion in exon 8 of GARS. Assessment if the mutation is causative using mouse models and the development of a translational allele-specific knock down approach for the human disease allele is underway. A tailored phenotyping pipeline has been established with bi-weekly body weight and neurological scoring, and at 1 year of age testing of grip strength, gait analysis, adhesive removal test, and erasmus ladder. Damian Smedley provided an overview of the Genomics England project which aims to sequence genomes with a scientific focus on cancer and rare genetic disease.
Damian highlighted then the role of clinical and model organism phenotyping and presented the Genomics England process for clinical data collection and panel assignment and protocols for automated variant prioritisation. First families are now diagnosed e. Damian Smedley concluded by stating that clinical and model organism phenotypes, as well as precision animal models, are key to achieving the vision of building the future of genomic medicine. A key area where model organisms can make significant contributions to Personalised Medicine initiatives is the interpretation of gene variants.
The versatility of genome editing technology further allows in vivo chromosal engineering to analyse structural variants. A dedicated session on the disruptive genome editing technology was held with excellent contributions from leading experts providing background information on the technology and state of the art approaches to generate conditional and insertional alleles. Genentech routinely analyzes all G0 founders for a list of potential off-targets using deep sequencing. While some correlation exists between predicted scores and off target profiles, it is also evident that existing algorithms are still lacking in their predictive power.
Based on the comprehensive data-set Genentech has generated, a list of recommendations for CRISPR project design and subsequent analysis of the resulting animals was provided. The timescale of projects could be reduced from years to 6 months, no additional minigenes and loxP sites are needed, no more ES cells work, and Crismere can be applied in rats!
Using Crismere the easy production of deletions, inversions and duplications from a few bp to 24,4 Mb are possible. Yann emphasized that the generation of structural variants is now straightforward, but the genotyping determination must be done carefully. Such Down Syndrome mouse models are invaluable tools for validating therapeutic approaches to rescue the cognitive defects in DS. European RIs are built to correspond to the long-term needs of European research communities covering all research areas. They play an important role in expediting knowledge and technology and bringing together a wide diversity of stakeholders to look for solutions to current problems the society is facing.
As stated by the European Commission, RIs are a center of the knowledge triangle of research, education and innovation, producing knowledge through research, diffusing it through education, and applying it through innovation.
The EU Member States and Associated Countries operate a diverse system of RIs ranging from sectors of Physical Sciences to Health, and in their location of single sited to those built on distributed capacity and specialty. This will imply in particular theset-up of the EurOPDX public repository of models, andfurther work on establishing standards in the field. Byrne AT et al. Nat Rev Cancer.
RD-Connect is an integrated platform connecting databases, registries, biobanks and clinical bioinformatics for rare disease research.
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To help researchers study rare diseases, RD-Connect links different data types - omics e. RD-Connect enables scientists and clinicians around the world to analyse genomics data and share them with other researchers. By making data accessible beyond the usual institutional and national boundaries, RD-Connect speeds up research, diagnosis and therapy development to improve the lives of patients with rare diseases. Thompson et al. J Gen Intern Med. ELIXIR coordinates, integrates and sustains bioinformatics resources across its member states and enables users in academia and industry to access vital data, tools, standards, compute and training services for their research.
The four use cases of ELIXIR connect the technical activities to the real needs of user communities in the life sciences: Marine metagenomics, Crop and forest plants, Human data, Rare diseases. Rapid developments in '-omics' technologies such as genomics, proteomics or metabolomics, together with advances in a number of other areas e. While Personalised Medicine presents an opportunity for the European citizens to increase their chances of a successful outcome of any disease, the implementation of PM is a challenge in Europe and beyond due to fragmented activities, lack of generic solutions and insufficient cross-sectional communication between different stakeholders involved in PM healthcare specialists, regulators, researchers, industry representatives, and patient organizations.
The Coordination and Support Action PerMed was initiated to accelerate the coordination efforts between European key stakeholders, to avoid duplication in competition and to ensure maximum transparency and openness while preparing Europe for leading the global way in Personalised Medicine. Following its mission, PerMed generated a Strategic Research and Innovation Agenda SRIA on Personalised Medicine based on analysis of recent strategic reports, interviews and consultations of all relevant operational sectors important to the implementation of PM.
SRIA also presents several prioritized recommendations that have the highest potential impact and outcome when implementing the Personalised Medicine for the benefit of citizens and society as a whole. These highlight not only the importance of patients, regulatory frameworks, ICT, and the dialogue between different stakeholders, but also the relevance of European Research Infrastructures whose outcomes and achievements can be harnessed, developed further, and applied for the needs of Personalised Medicine.
A particular strength of RIs is their dynamic nature and responsiveness to the multidisciplinary needs of PM challenges that are difficult to tackle in sectorial way. Challenge 3. Personalised Medicine PM must be supported by robust knowledge of the disease and patients through excellent basic research conducted across Europe.
Animal Models in Drug Development
In order for PM to reach its promise and anticipated impact, translation of discoveries and communication across the continuum of research are required. The IMPC dataset is of increasing interest to groups working with large biobank, phenotype and genetic datasets in human. The comparative analysis of cross-species datasets will potentially be transformed by a complete catalogue of mouse mutant phenotypes.
As a consequence, we expect IMPC to make pivotal contributions to data-driven discovery in medical research. In the UK, the genomes project will focus initially on rare disease phenotypes and prostate cancer. However, it is expected that the project will expand to incorporate other sources of phenotype information. But in either case, the catalogue of gene function being developed in the IMPC will be an important validation and extension of the gene-phenotype associations that emerge from these human genetics projects, contributing to target discovery and validation.
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For example, the development of sophisticated tools such as the Phenodigm algorithm provides the community with tools to analyse mouse phenotype data to identify new pre-clinical models for human disease. Meehan et al.
Nature Genetics. This may reflect policies of funding agencies such as in the USA, where translational research is more likely to receive funding than pure basic science, or just because of the biomedical task and because the frog has that potential to add knowledge in a substantial manner.
It is beyond the scope of this review to give a full account of activities and successes. It is worth citing a few examples, however, such as, among others, the work of Bruno Reversade at the Institute of Medical Biology in Singapore, who uses Xenopus alongside other model organisms, be it vertebrate or invertebrate, to unravel mechanisms of human diseases.
Autosomal recessive cutis laxa, for example, a syndrome associated with — among others — lax and wrinkled skin, is caused by mutations in PYCR1 , which encodes an enzyme involved in proline metabolism. Knockdown of the orthologous gene in Xenopus resulted in hypoplasia and wrinkles of the tadpole skin, i.
Mutations in the homeodomain transcription factor IRX5 impair craniofacial development and germ cell migration in humans. When the Xenopus ortholog was knocked down, migration of progenitor cells in the branchial arches and gonads was disrupted, faithfully reproducing the human disease [Bonnard et al. A last and spectacular example from the Reversade laboratory concerns mutations in SMCHD1 , which encodes an epigenetic regulator. Patients suffer from an extremely rare syndrome in which the nose is completely absent.