Developing therapeutics for treating Rett syndrome by correcting neuronal long-gene misregulation – Lead compound optimization and in vivo validation

Disruption of X-linked methyl CpG-binding protein 2 (MECP2) causes Rett syndrome (RTT) - a devastating neurodevelopmental disorder leading to nonsyndromic mental retardation, learning disability, and autism. Currently there is no cure. We recently identified a molecular defect that is a likely cause of RTT – the mis-regulation of long highly methylated genes through MECP2 dysfunction. Notably, many of the mis-regulated highly methylated long genes are required for proper neuronal functions including synapses that underlie learning and memory. We hypothesize that restoring the expression of mis-regulated long genes and synaptic development may be key to treating RTT. A score of hits were identified and the majority were successfully validated by a series of in vitro experiments. Moreover, structural, pharmacokinetic (PK) and blood-brain-barrier (BBB) permeability analyses suggest favorable chemistry for therapeutics. In the next phase of study, we plan to further the drug development by focusing on behavioral testing while starting to investigate potential drug targets and mechanism of action (MOA).