New therapeutic targets identified for Rett syndrome

Written by Naamah Maundrell

A study published in the Proceedings of the National Academy of Sciences, has described the potential for reversing the genetic neurodevelopmental disorder, Rett syndrome, by targeting specific genes. Researchers from the Fred Hutchinson Cancer Research Center (WA, USA) have identified 30 genes that could be utilized to reactivate the inactive X chromosome that is silenced in the disorder.
Rett syndrome affects approximately 15,000 girls in the USA and 350,000 across the globe. Currently, there is no treatment for the rare autism spectrum disorder, which causes a backsliding in development.

Lead scientist on this new study Antonio Bedalov (Fred Hutchinson Cancer Research Center) commented: “They have this period of normal development, and then it’s taken away from them…it’s devastating for the families.” 

Girls with Rett syndrome are heterozygous for a mutation in the X-linked MeCP2 gene.  As cells in affected girls will only be missing functioning MeCP2 when the wild-type copy of the gene is on the inactive X, the researchers investigated how reactivation of the silenced copy of MeCP2 could be exploited to reverse Rett syndrome.

The team carried out a genetic screen for genes that, when downregulated, led to reactivation of a MeCP2 reporter on the inactive X chromosome. 30 genes were identified that revealed a mechanism involved in the maintenance of X-chromosome inactivation in differentiated cells, plus a number of potential therapeutic targets. These findings are in the preclinical stage but the team hopes ultimately to apply their approach to other disorders involving the X chromosome.

Sources: Sripathy S, Leko V, Adrianse RL et al. Screen for reactivation of MeCP2 on the inactive X chromosome identifies the BMP/TGF-β superfamily as a regulator of XIST expression. Proceedings of the National Academy of Sciences. doi:10.1073/pnas.1621356114 (2017) (Epub ahead of print); www.fredhutch.org/en/news/releases/2017/scientists-uncover-possible-therapeutic-targets-for-rare-autism-spectrum-disorder.html