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-kB) 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.
| Original language | English |
|---|---|
| Article number | e67085 |
| Journal | eLife |
| Volume | 10 |
| DOIs | |
| State | Published - 6 Aug 2021 |
Bibliographical note
Funding Information:We thank Dr. Yaron Daniely and the Yissum team for being a major driving force for this project. We thank Dr. Liana Patt and the Integra Holdings team for their support. We thank Dr. Hae Kyung Lee and Susan Finniss for their technical support. Figures include vector images designed by Freepik. We thank Dr. Amir Eden and Prof. Yinon Ben Neriah for their insight and comments. Funding: This project was supported by an Israel Science Foundation grant 1591/19 to YT and by Integra Holdings. Additional support to BPB and IU came from a grant from the Beethoven Foundation.
Publisher Copyright:
© Unterman et al.