Rett syndrome (RTT) is a severe neurodevelopmental disorder almost exclusively occurring in young girls with the incidence of one in 8,000 to 10,000 births. Apparently normal early childhood development for 6-18 months is followed by a rather sudden loss of acquired language, cognitive, social and motor skills. Typical RTT symptoms include stereotypical hand wringing and clapping, seizures, and breathing abnormalities.
RTT is caused by mutations in Mecp2, an X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2). MeCP2 is a transcriptional repressor that selectively binds to methylated CpG dinucleotides on genomic DNA and recruits corepressor complexes. Mecp2-knockout mice have been generated by several groups, and all recapitulate well human disease symptoms. Since MeCP2 re-expression in knock-out mice leads to significant improvement of disease symptoms, it is thought that restoring of MeCP2 wildtype activity in affected RTT individuals may be a promising therapeutic approach. MeCP2 mutations occur only on one allele of the X-chromosome, with the other allele being wildtype MeCP2. One way to accomplish normal MECP2 expression would be to transcriptionally activate the silenced copy of wildtype MeCP2.
The Philpot lab aims to identify small molecules that are capable of unsilencing the dormant copy of wildtype MeCP2.
We apply high-throughput and high-content screening approaches with different cell-based models in partnership with the Rett Syndrome Research Trust and collaborators in the pharmaceutical industry, which allows us access to large small molecule libraries. We work closely with our colleagues across the US as members of the “Reactivating MECP2 Consortium”.
Katz DM, Bird A, Coenraads M, Gray SJ, Menon DU, Philpot BD, Tarquinio DC. Rett Syndrome: Crossing the Threshold to Clinical Translation. Trends Neurosci. 2016 Feb;39(2):100-13. doi: 10.1016/j.tins.2015.12.008. Review.