Kaufmann, Markus, Schuffenhauer, Ansgar, Fruh, Isabelle, Klein, Jessica, Thiemeyer, Anke, Rigo, Pierre, Gomez-Mancilla, Baltazar, Heidinger-Millot, Valerie, Schopfer, Ulrich, Mueller, Matthias, Fodor, Barna and Cobos-Correa, Amanda (2015) High Throughput Screening using iPSC-derived neuronal progenitors to identify compounds counteracting epigenetic gene silencing in Fragile X Syndrome. Journal of Biomolecular Screening, 20 (9). pp. 1101-1111. ISSN 1087-05711552-454X

Abstract

Fragile X Syndrome (FXS) is the most common form of inherited mental retardation. The underlying cause of the disease is the lack of Fragile X mental retardation protein (FMRP) which regulates synapsis. Its absence is caused in the majority of cases by epigenetic silencing of the FMR1 gene by DNA methylation triggered by an abnormal CGG repeat expansion (>200) in the untranslated 5’UTR. Today, no specific therapy exists for FXS and current treatments are only directed to improve behavioral symptoms. Neuronal progenitors derived from FXS patient-induced pluripotent stem cells (iPSCs) represent a unique model to study the disease and develop assays for large scale drug discovery screens since they conserve the FMR1 gene silenced within the disease context. We have established a high content imaging assay to run the first large-scale phenotypic screen aimed to identify compounds that reactivate the silenced FMR1 gene. A set of 50000 compounds was tested including modulators of several epigenetic targets. We describe an integrated drug discovery model comprising iPS generation, culture scale-up and quality control and screening with a very sensitive high content imaging assay assisted by single cell image analysis and multi-parametric data analysis based on machine learning algorithms. The screening identified several compounds that induced a weak expression of FMRP and thus, sets the basis for further large scale screens to find candidate drugs or targets tackling the underlying mechanism of FXS with potential for therapeutic intervention.

Item Type:	Article
Date Deposited:	26 Apr 2016 23:45
Last Modified:	04 Jul 2016 23:45
URI:	https://oak.novartis.com/id/eprint/24652