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

Dan Vershkov, Nina Fainstein, Sapir Suissa, Tamar Golan-Lev, Tamir Ben-Hur*, Nissim Benvenisty

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

27 Scopus citations


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.

Original languageAmerican English
Pages (from-to)2531-2539.e4
JournalCell Reports
Issue number10
StatePublished - 5 Mar 2019

Bibliographical note

Publisher Copyright:
© 2019 The Author(s)


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


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