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Neurodevelopmental disorders

CRISPR to the rescue

Nature Reviews Drug Discovery volume 17, pages 240–241 (2018)Cite this article

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“Fragile X is a tantalizing prospect for anyone studying epigenetics,” explains Michael Tranfaglia, CSO of the FRAXA Research Foundation, who was not involved in the study. “There is the potential for treating FXS by demethylating the promoter. This concept has been demonstrated in vitro with nonspecific demethylating agents, but these drugs are usually too toxic to give to patients with FXS, as they are not specific enough and demethylation is a universal method of regulating gene expression.”

Previously, the authors had developed a modified CRISPR–Cas9 system with a catalytic inactive enzyme Cas9 (dCas9) that was able to bind to DNA but unable to cut it, and to which they fused a demethylase enzyme (methylcytosine dioxygenase TET1, which does not require mitosis, an important feature when attempting demethylation in postmitotic neurons). In the present paper, the authors infected an induced pluripotent stem cell (iPSC) line derived from a patient with FXS with the viral vector expressing dCas9–TET1 and a second vector encoding a guide RNA (sgRNA) that binds specifically to dCas9 and to the CGG repeat, thus acting as a bridge and ensuring accurate demethylation by TET1. Infection of iPSCs with these vectors resulted in a drastic reduction of methylation of the FMR1 CGG repeat and, more importantly, in expression of FMR1 up to 90% of the level observed in wild-type cells. Off-target effects of dCas9–TET1 on DNA methylation and gene expression of other genes were minimal.

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References

  1. Liu, X. S. et al. Rescue of fragile X syndrome neurons by DNA methylation editing of the FMR1 gene. Cell 172, 979–992 (2018)

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  1. M. Teresa Villanueva
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Berry-Kravis, E. M. et al. Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome Nat. Rev. Drug Discov. (2018)

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Villanueva, M. CRISPR to the rescue. Nat Rev Drug Discov 17, 240–241 (2018). https://doi.org/10.1038/nrd.2018.39

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