Expanding the MECP2 network using comparative genomics reveals potential therapeutic targets for Rett syndrome

Abstract

Inactivating mutations in the Methyl-CpG Binding Protein 2 (MECP2) gene are the main cause of Rett syndrome (RTT). Despite extensive research into MECP2 function, no treatments for RTT are currently available. Here, we used an evolutionary genomics approach to construct an unbiased MECP2 gene network, using 1028 eukaryotic genomes to prioritize proteins with strong co-evolutionary signatures with MECP2. Focusing on proteins targeted by FDA-approved drugs led to three promising targets, two of which were previously linked to MECP2 function (IRAK, KEAP1) and one that was not (EPOR). The drugs targeting these three proteins (Pacritinib, DMF, and EPO) were able to rescue different phenotypes of MECP2 inactivation in cultured human neural cell types, and appeared to converge on Nuclear Factor Kappa B (NF-κB) signaling in inflammation. This study highlights the potential of comparative genomics to accelerate drug discovery, and yields potential new avenues for the treatment of RTT.

State‐of‐the‐art therapies for Rett syndrome

“…It is also tempting to look towards new developments of bioinformatic pipelines that could shed light on new candidate drugs ameliorating RTT phenotypes. 81 We believe that such an integrative approach and the fast development of these fields will be key to finding a cure for RTT.…”

“…Although these different strategies have shown encouraging results in preclinical studies, further refinement is needed to devise the best genetic approach. It is also tempting to look towards new developments of bioinformatic pipelines that could shed light on new candidate drugs ameliorating RTT phenotypes 81 . We believe that such an integrative approach and the fast development of these fields will be key to finding a cure for RTT.…”

HDAC inhibitors rescue MeCP2T158Mspeckles in a high content screen

“…The other HDACis tested target Class I HDACs (HDAC1, 2 and 3) and HDAC8 that is evolutionary closely related 42,43 . The HDAC1, 2 and 3 inhibitors Mocetinostat and Entinostat showed similar effects in both cell lines.…”

KW-2449 and VPA exert therapeutic effects on human neurons and cerebral organoids derived from MECP2-null hESCs

“…However, BDNF cannot cross the blood brain barrier, thus there is no immediate therapeutic application for RTT patients [ 10 ]. Given that therapies aiming to restore MECP2 loss-of-function are still at an early development stage, there is a great need to develop human neuronal models for accurate and comprehensive mapping of the MECP2 network which can be used for screening interventions [ 8 , 11 ].…”

“…Although MECP2 is expressed in all cell types, the lack of neuronal MECP2 is thought to account for the majority of symptoms associated with RTT [6,7]. In RTT, BDNF signaling is impaired, and BDNF and its regulators (such as histone deacetylases HDACs) are speculated as therapeutic targets for RTT syndrome [8]. Indeed, BDNF is critical for neuronal development, maturation, and plasticity through the activation of TrkB, which in turn activates PI3K/Akt pathways that regulate protein synthesis and neural function [9].…”