Using Phylogenetic Profiling to Guide Drug Repurposing for Rett Syndrome

Rett syndrome is a rare genetic disorder caused by mutations in the MECP2 gene. It is characterized by typical early development followed by regression, loss of purposeful hand movements, and intellectual disability. The mechanism of action of MECP2 is not yet fully understood, limiting mechanism-based drug design and repurposing. We aimed to characterize MECP2 based on its evolutionary profile, to shed light on its genetic interactions and identify compounds that target them. To achieve this, we examined the conservation levels of MECP2 across 1000 organisms and identified its top co-evolved genes. We and others have shown that co-evolved genes are functionally associated. We constructed a network of MECP2 interacting genes and used publicly available drug-gene interaction databases (e.g. DGIDB and Drug Target Commons) to prioritize compounds that can influence this network. We integrated pharmacological and medical data such as drug permeability and safety information to arrive at the final drug candidate list. We tested these drugs in human MECP2 knock-out cells and identified compounds that can reverse some of the effects of Rett syndrome in-vitro.

This innovative computational pipeline for drug repurposing has tremendous potential to advance Rett research at both the basic and translational levels. We hope to gain significant insights into MECP2’s mode of action and find therapies to alleviate Rett syndrome symptoms.