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Selectively Targeting ERK Signaling to Treat Fragile X Syndrome and Autism

Principal Investigator:
  • Ning Cheng, University of Calgary
  • Kids Brain Health Network

Project Overview

Autism is one of the most prevalent neurodevelopmental disorders in Canada. It has a profound impact on the health, wellness and socioeconomic wellbeing of the patients and their families. The etiology of autism is multifaceted but Extracellular signal-Regulated Kinase (ERK) pathway in the brain is a critical convergent node in the development of autism and Fragile X Syndrome (FXS). FXS is caused by mutations in the fmr1 gene and is the leading monogenic cause of autism and intellectual disability. So far, pharmacological treatments in animal models and clinical trials have used drugs that non-selectively inhibit ERK signalling and mainly affect other pathways. Thus, it is critical to determine whether directly and selectively targeting ERK pathway is beneficial in these diseases. Furthermore, a translational biomarker that tracks treatment response is urgently needed.

Recently, a selective ERK signalling inhibitor, PD325901(PD), has been found to penetrate blood-brain barrier and has strong safety data in clinical trials for neurofibromatosis type-1. We hypothesize that PD will exert beneficial effects in mouse models of FXS and idiopathic autism. We have collected strong preliminary data on acute and sub-chronic treatment with PD. Our results indicated that the treatment dose-dependently reversed certain core disease-modelling deficits in the behavioural domain in mouse models of FXS and idiopathic autism without side effects. In addition, the treatment reduced abnormally increased power of high gamma band in EEG in both models. Here, we will determine: 1. the efficacy time window, optimal dosage, and potential side effects of chronic inhibitor treatment; 2. whether EEG signal tracks behavioural improvement as a potential non-invasive biomarker. The proposed study will provide necessary groundwork and directly translatable insights toward applying PD in clinical trials for FXS and autism.