Reactivation of MECP2 with Epigenome Editing Tools to Rescue Rett Syndrome

Rudolf Jaenisch, MD | Whitehead Institute

$600,000 AWARDED

Rett Syndrome is a devastating disorder caused by the loss-of-function mutation of the MECP2 gene located on the X chromosome. Girls with Rett have a mutated copy of the gene and a healthy copy but silenced by the inactive X chromosome. Reactivation of this silenced gene is an attractive strategy for curing the disorder as it addresses the root cause of this disease. One approach to reactivation is to screen for compounds that can unsilence the healthy copy of this gene. RSRT’s Reactivation Consortium is currently pursuing this approach.

The Jaenisch lab will pursue a different approach, one that leverages a novel technology that has taken the scientific world by storm, CRISPR. In this instance CRISPR will not be used to edit the genome but rather to deliver certain epigenetic molecules to the inactive MECP2. The epigenome controls when genes are turned on or off by adding or removing certain chemical tags. One can think of the genome (DNA) as a charm bracelet and the epigenome as charms that can be added and removed. Methyl tags on DNA keep genes silent and acetyl tags keep genes active. In this experiment the goal will be to activate the healthy MECP2 copy by synergistically removing methyl tags and adding acetyl tags.

These experiments will be done in cells derived from individuals with Rett Syndrome.

Looking ahead, it’s important to note that the CRISPR guides and epigenetic molecules will need to be delivered to patients via vectors in much the same way as gene therapy. Any valuable insights learned from our gene therapy work will be applicable to this strategy as well.

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