TOWARD THE PHARMACOLOGICAL REACTIVATION OF MECP2: DEVELOPING NEW PRE-CLINICAL TOOLS FOR THE RETT SYNDROME (DSB.AD006.285)

Thematic area

Biomedical sciences

Project area

Structure responsible for the research project

Institute of genetics and biophysics "Adriano Buzzati Traverso" (IGB)

Project manager

MARCELLA VACCA
Phone number: +390816132702
Email: marcella.vacca@igb.cnr.it

Abstract

Rett syndrome (RTT), a severe neurodevelopmental disorder mainly affecting girls, is caused by mutation in the MECP2 gene (95% of cases with RTT). The gene maps on the X chromosome and is mono-allelically expressed in somatic cells (mostly neurons), because of the X-chromosome inactivation (XCI) epigenetic process. The epigenetic reactivation of the MECP2 WT allele harbored by inactive Xi could compensate for MECP2 deficiency within the mutant cells of patients with classic RTT, as a neuroprotective strategy.
The current proposal aims to identify small molecules able to unsilenced the inactive Mecp2 allele by exploiting the ability of self-renewal and differentiation of Pluripotent Stem cells, both from mouse and human origin, as a cell source of somatic progeny, namely neural cells. Specifically, we propose to run automated screen of epidrugs to link selective inhibition/antagonism of specific epi-regulator targets with a biological and disease phenotype in neural cell-based assays. Compounds will be primarily assayed for initial target validation in murine cells then transferred to patient-derived samples for phenotypic profiling studies in vitro. [...]

Start date of activity

15/06/2020

Keywords

Mecp-2 reactivation, X-chromosome inactivation (XCI);, morphological and functional biomarkers

Last update: 26/08/2025