Preclinical committee

Aims

Writing

The Committee for Preclinical Research strives to establish common protocols for (pre)clinical research, thereby harmonizing and standardizing the worldwide efforts to investigate Down syndrome, thus enabling better comparisons between studies across the globe.

The Committee is pursuing its objectives to help standardise high quality preclinical research into Down syndrome, including by facilitating access to important resources, and helping provide essential robust data for those resources including controls.

Preclinical Committee

Activities

  • Human cell lines

    Committee member Anita Bhattacharyya has been diligently pursuing different possible repositories for human induced pluripotent stem cells (iPSCs) and for human fibroblast cell lines. Ideally, we would like to have one ‘go to’ repository for DS resources internationally. Factors to consider are what each repository is prepared to bank, and cost to researchers. We would like to include unpublished data if possible, and protocols. We aim to have some preliminary recommendations for discussion by the wider T21RS community later in 2021. Also, for discussion are options to help fund such a DS and control cell line bank.

  • Mouse models

    The 2018 spreadsheet of all published chromosomal models is available to all T21RS members and this includes simplified ‘lab names’ that can be used in papers after stating the full correct name as held by the Mouse Nomenclature Committee (see Downloads).

    We will review updates likely in late 2021, noting new rodent strains may be published later in 2020/2021.

    Establishing common protocols for preclinical research: behavioural analysis, cellular characterisation, breeding schemes and rigorous reporting of genetic and environmental details for Down syndrome models.

    The preclinical committee has recommendations for how papers should report mouse experiments on DS research. These include:

    1. T21RS members will have information available about the ARRIVE (Animal Research: Reporting of In Vivo Experiments) guidelines to improve the reporting of research using animals – maximizing information published and minimizing unnecessary studies.
    2. defining each mouse strain by its official MGI (Mouse Genome Informatics) name, which is unique and available from the MGI website (www.informatics.jax.org).

    Randall Roper, Mara Dierssen, Yann Herault created a checklist specifically for reporting DS mouse model research; these are based on the ARRIVE guidelines with extras important specifically for DS research. We will circulate these ‘rules’ to T21RS for discussion in 2021 and then to finalise and publish.

  • Training the next generation of DS researchers

    We wish to bring early stage researchers onto the T21RS Preclinical Committee, in order to gain ‘managerial’ experience of working with the T21RS community. We have issued the invitations for junior PIs/postdocs to apply to us for a one-year membership of the committee. So far, we have welcomed the following junior members:

    • Antonella Tramutola (Alzheimer-Down Unit, Hospital de la Santa Creu i Sant, Spain)
    • Sujay Ghosh (University of Calcutta Ballygunge Science College Campus, India)
    • Florencia Iulita (Alzheimer-Down Unit, Hospital de la Santa Creu i Sant, Spain)
    • Hiruy Sibhatu Meharena (Massachusetts Institute of Technology, US)

    The next invitation will be issued in late 2021.

Events

Preconference meeting (3rd International T21RS Conference)

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International meetings

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Training the next generation of DS researchers

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Publications

2021

Mouse models of aneuploidy to understand chromosome disorders. An organism or cell carrying a number of chromosomes that is not a multiple of the haploid count is in a state of aneuploidy. This condition results in signifcant changes in the level of expression of genes that are gained or lost from the aneuploid chromosome(s) and most cases in humans are not compatible with life. However, a few aneuploidies can lead to live births, typically associated with deleterious phenotypes. We do not understand why phenotypes arise from aneuploid syndromes in humans. Animal models have the potential to provide great insight, but less than a handful of mouse models of aneuploidy have been made, and no ideal system exists in which to study the efects of aneuploidy per se versus those of raised genedosage. Here, we give an overview of human aneuploid syndromes, the efects on physiology of having an altered number of chromosomes and we present the currently available mouse models of aneuploidy, focusing on models of trisomy 21 (which causes Down syndrome) because this is the most common, and therefore, the most studied autosomal aneuploidy. Finally,we discuss the potential role of carrying an extra chromosome on aneuploid phenotypes, independent of changes in gene dosage, and methods by which this could be investigated further. Click here to see the article    

2021

Comprehensive phenotypic analysis of the Dp1Tyb mouse strain reveals a broad range of Down syndrome-related phenotypes (2021). Down syndrome (DS), trisomy 21, results in many complex phenotypes including cognitive deficits, heart defects and craniofacial alterations. Phenotypes arise from an extra copy of human chromosome 21 (Hsa21) genes. However, these dosagesensitive causative genes remain unknown. Animal models enable identification of genes and pathological mechanisms. The Dp1Tyb mouse model of DS has an extra copy of 63% of Hsa21-orthologous mouse genes. In order to establish whether this model recapitulates DS phenotypes, we comprehensively phenotyped Dp1Tyb mice using 28 tests of different physiological systems and found that 468 out of 1800 parameters were significantly altered. We show that Dp1Tyb mice have wide-ranging DS-like phenotypes, including aberrant erythropoiesis and megakaryopoiesis, reduced bone density, craniofacial changes, altered cardiac function, a prediabetic state, and deficits in memory, locomotion, hearing and sleep. Thus, Dp1Tyb mice are an excellent model for investigating complex DS phenotype-genotype relationships for this common disorder. Click here to see the article    

2021

Specific Susceptibility to COVID-19 in Adults with Down Syndrome (2021). This review lead by Dr E. Okun provides a biological overview with regard to specific susceptibility of individuals with Down syndrome to SARS-CoV-2 infection as well as data from a recent survey on the prevalence of COVID-19 among them. Authors see an urgent need to protect people with DS, especially those with Alzheimer's disease from COVID-19 and future pandemics and focus on developing protective measures, which also include interventions by health systems worldwide for reducing the negative social effects of long-term isolation and increased periods of hospitalization. Click here to see the article

2020

Down syndrome:  Progress in Brain Research, Volume 251, Preclinical Research in Down syndrome: insights for pathophysiology and treatments, (2020) Editor: Mara Dierssen. A comprehensive new book has just been published (2020) that describes in detail important aspects of preclinical research into Down syndrome: Progress in Brain Research, Volume 251, Preclinical Research in Down syndrome: insights for pathophysiology and treatments. The book is edited by Mara Dierssen as part of the activities of the T21RS Pre-Clinical Committee to serve our members. Members will have 30% discount.

2019

Treatment outcomes in mouse models (2019), an updated Table has been loaded onto the Preclinical section of the T21RS website by Jean Delabar which contains comprehensive information on treatments in DS mouse models with a range of regimes.

Article may be downloaded from T21RS Downloads for Preclinical Research.

2018

Overview of DS mouse models (2018) Created by Yann Herault with input from other members of the T21RS Preclinical Committee.

Article may be downloaded from T21RS Downloads for Preclinical Research.

2015

Treatment outcomes in mouse models (2015), Table of comprehensive information on treatments in DS mouse models with a range of regimes.