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Cell Rep. 2019 Mar 5;26(10):2531-2539.e4. doi: 10.1016/j.celrep.2019.02.026.

FMR1 Reactivating Treatments in Fragile X iPSC-Derived Neural Progenitors In Vitro and In Vivo.

Author information

1
The Azrieli Center for Stem Cells and Genetic Research, Department of Genetics, Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram, Jerusalem 91904, Israel; Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah - Hebrew University Medical Center, Jerusalem 91120, Israel.
2
Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah - Hebrew University Medical Center, Jerusalem 91120, Israel.
3
The Azrieli Center for Stem Cells and Genetic Research, Department of Genetics, Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram, Jerusalem 91904, Israel.
4
Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah - Hebrew University Medical Center, Jerusalem 91120, Israel. Electronic address: tamir@hadassah.org.il.
5
The Azrieli Center for Stem Cells and Genetic Research, Department of Genetics, Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram, Jerusalem 91904, Israel. Electronic address: nissimb@mail.huji.ac.il.

Abstract

Fragile X syndrome (FXS) is caused primarily by a CGG repeat expansion in the FMR1 gene that triggers its transcriptional silencing. In order to investigate the regulatory layers involved in FMR1 inactivation, we tested a collection of chromatin modulators for the ability to reactivate the FMR1 locus. Although inhibitors of DNA methyltransferase (DNMT) induced the highest levels of FMR1 expression, a combination of a DNMT inhibitor and another compound potentiated the effect of reactivating treatment. To better assess the rescue effect following direct demethylation, we characterized the long-term and genome-wide effects of FMR1 reactivation and established an in vivo system to analyze FMR1-reactivating therapies. Systemic treatment with a DNMT inhibitor in mice carrying FXS induced pluripotent stem cell (iPSC)-derived transplants robustly induced FMR1 expression in the affected tissue, which was maintained for a prolonged period of time. Finally, we show a proof of principle for FMR1-reactivating therapy in the context of the CNS.

KEYWORDS:

disease modeling; drug screening; fragile X syndrome; neurodevelopmental disorders; pluripotent stem cells

PMID:
30840878
DOI:
10.1016/j.celrep.2019.02.026
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