High-Throughput Screening Using iPSC-Derived Neuronal Progenitors to Identify Compounds Counteracting Epigenetic Gene Silencing in Fragile X Syndrome

Kaufmann, Markus; Schuffenhauer, Ansgar; Fruh, Isabelle; Klein, Jessica; Thiemeyer, Anke; Rigo, Pierre; Gomez‐Mancilla, Baltazar; Heidinger-Millot, Valerie; Bouwmeester, Tewis; Schopfer, Ulrich; Müeller, Matthias; Fodor, Barna D.; Cobos-Correa, Amanda

doi:10.1177/1087057115588287

Cited by 80 publications

(72 citation statements)

References 29 publications

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“…Interestingly these findings imply early neurodedevelopmental alterations, prior to synaptogenesis, although more studies are needed to understand in depth the pathophysiology of these defects. Four groups have used FXS 107–109110 patient-derived hiPSCs to create proof of concept high-throughput drug discovery systems, though unfortunately the sensitivity and robustness of these screens is still poor and will require significant work. Promisingly though, Park et al 111 used a genomic engineering technique known as CRISPR/Cas (Box 3) to ablate CGG repeats in FXS patient-derived hiPSCs and thus restore expression of FMR1 mRNA and consequently FMRP protein.…”

Section: Induced-pluripotent Stem Cell Models Of Neurodevelopmentamentioning

confidence: 99%

Human induced pluripotent stem cells for modelling neurodevelopmental disorders

et al. 2017

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Currently, we have a poor understanding of the pathogenesis of neurodevelopmental disorders, owing to the fact that post-mortem and imaging studies are only capable of measuring the postnatal status quo and offer little insight into the processes that give rise to the observed outcomes. Human induced pluripotent stem cells (hiPSCs) in principle should prove powerful in elucidating the pathways that give rise to neurodevelopmental disorders. HiPSCs are embryonic stem cell-like cells that can be derived from somatic cells. They retain the unique genetic signature of the individual from whom they were derived from, and thus allow researchers to recapitulate that individual’s idiosyncratic neural development in a dish. In the case of diseased individuals, we can reenact the disease-altered trajectory of brain development and examine how and why phenotypic and molecular abnormalities arise in these diseased brains. In this paper, we review various aspects of hiPSC biology and experimental design as well as discuss existing hiPSC models of neurodevelopmental disorders. As already shown by some studies discussed in this review, our hope is that iPSCs will illuminate the pathophysiology of developmental disorders of the CNS and lead to therapeutic avenues for the millions that today suffer from neurodevelopmental disorders.

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Section: Induced-pluripotent Stem Cell Models Of Neurodevelopmentamentioning

confidence: 99%

Human induced pluripotent stem cells for modelling neurodevelopmental disorders

et al. 2017

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“…Such a high-content screening assay for FMRP has been used to carry out a phenotypic screen of a library of 50,000 compounds (Kaufmann et al 2015). Multiparametric data analysis coupled to machine learning made it possible to identify several new compounds that weakly induced FMRP production in FM cells and to examine the heterogeneous response of cells in the population to these compounds (Kaufmann et al 2015). In principle, such assays could be applied to quantifying FMRP directly from patient cells.…”

Section: Fmrp Protein Assaysmentioning

confidence: 99%

Recent advances in assays for the fragile X-related disorders

2017

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The Fragile X-related disorders are a group of 3 clinical conditions resulting from the instability of a CGG-repeat tract at the 5’ end of the FMR1 transcript. Fragile X-associated tremor/ataxia syndrome (FXTAS) and Fragile X-associated primary ovarian insufficiency (FXPOI) are disorders seen in carriers of FMR1 alleles with 55–200 repeats. Female carriers of these premutation (PM) alleles are also at risk of having a child who has an FMR1 allele with >200 repeats. Most of these full mutation (FM) alleles are epigenetically silenced resulting in a deficit of the FMR1 gene product, FMRP. This results in Fragile X Syndrome (FXS), the most common heritable cause of intellectual disability and autism. The diagnosis and study of these disorders is challenging in part because the detection of alleles with large repeat numbers has, until recently, been either time-consuming or unreliable. This problem is compounded by the mosaicism for repeat length and/or DNA methylation that is frequently seen in PM and FM carriers. Furthermore, since AGG interruptions in the repeat tract affect the risk that a FM allele will be maternally transmitted, the ability to accurately detect these interruptions in female PM carriers is an additional challenge that must be met. This review will discuss some of the pros and cons of some recently described assays for these disorders, including those that detect FMRP levels directly, as well as emerging technologies that promise to improve the diagnosis of these conditions and to be useful in both basic and translational research settings.

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“…Fragile X Syndrome (FXS), an intellectual disability disorder, is another disease where low levels of the mutated protein, in this case FMRP, lead to a pathological effect. A high-content imaging based screen to measure FMRP levels in the cytoplasm, as well as other subcellular compartments has been performed on more than 50,000 compounds in neural progenitor cells derived from FXS patient iPSCs (Kaufmann et al, 2015). …”

Section: Disease Model In a Dish Considerations For Phenotypic Assaymentioning

confidence: 99%

Studying human disease using human neurons

2017

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Utilizing patient derived cells has enormous promise for discovering new drugs for diseases of the nervous system, a goal that has been historically quite challenging. In this review, we will outline the potential of human stem cell derived neuron models for assessing therapeutics and high-throughput screening and compare to more traditional drug discovery strategies. We summarize recent successes of the approach and discuss special considerations for developing human stem cell based assays. New technologies, such as genome editing, offer improvements to help overcome the challenges that remain. Finally, human neurons derived from patient cells have advantages for translational research beyond drug screening as they can also be used to identify individual efficacy and safety prior to clinical testing and for dissecting disease mechanisms.

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High-Throughput Screening Using iPSC-Derived Neuronal Progenitors to Identify Compounds Counteracting Epigenetic Gene Silencing in Fragile X Syndrome

Cited by 80 publications

References 29 publications

Human induced pluripotent stem cells for modelling neurodevelopmental disorders

Human induced pluripotent stem cells for modelling neurodevelopmental disorders

Recent advances in assays for the fragile X-related disorders

Studying human disease using human neurons

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