Targeting ERK and mTOR for the treatment of fragile X syndrome

Lead Research Organisation: University of Edinburgh
Department Name: Centre for Discovery Brain Sciences


Neurodevelopmental disorders such as fragile X syndrome (FXS) are significantly disruptive to affected individuals and their families. Early deficits that impact attention, learning, social interaction are not only disabling in themselves, but may also preclude normal environmental experiences, thus further perturbing experience-dependent brain development. Therefore, there is growing interest in addressing not only the symptoms of these disorders but also their underlying neurobiological causes.

Our proposal is based on the observations that two well-studied signalling pathways may be involved in FXS pathogenesis: the ERK pathway and the mTOR pathway. Both of these pathways are potential drug targets and may be modulated by some commonly used drugs. Our goal is to test the potential efficacy and safety of modulating these pathways using pharmacological or genetic means in a FXS mouse model. If successful, these studies will provide fast and direct applications to clinical trials in patients and will also help select patients with neurodevelopmental disabilities that may benefit from these and related treatments.

Technical Summary

With the proposal of the metabotropic glutamate receptor (mGluR) theory of fragile X syndrome, new targeted treatment strategies are being tested for fragile X syndrome (FXS), most notably mGluR5 inhibitors. It is believed that the therapeutic benefit of mGluR5 antagonism is accomplished by normalizing synaptic protein synthesis, which is elevated in FXS. However, mGluR5 receptors activate many signaling cascades that are unrelated to protein synthesis regulation, so a serious concern is that mGluR5 inhibitors will have side effects that limit their utility. It is therefore important to know if the selective targeting of intracellular signaling pathways is a viable alternative.

Our previous work strongly suggests two pathways that control mRNA translation as potential treatment targets in FXS: the extracellular signal related kinase 1/2 (ERK) pathway and the mammalian target of rapamycin (mTOR) pathway. In the current proposal, we will test the validity of these pathways as targets for the treatment of FXS by investigating anatomical, electrophysiological, and systems level phenotypes in the FXS mouse model (Fmr1-/y). In Specific Aim 1, the effects of ERK inhibition will be assessed using lovastatin, a statin that is already in widespread clinical use for hypercholesterolemia in adults and children, which we previously showed reduces ERK activation and corrects epileptogenic phenotypes in the Fmr1-/y. In Specific Aim 2, the effects of mTOR enhacement will be tested by genetic reduction of the mTOR pathway suppressor protein TSC2. We previously showed that genetic reduction of Tsc2 resolves two hippocampal phenotypes in the Fmr1-/y, and we now propose to use the same strategy to broadly define the role of mTOR enhancement for the treatment of FXS.

Planned Impact

Fragile X syndrome (FXS) is the most prevalent heritable cause of intellectual disability (ID), one of the most common single-gene causes of autism spectrum disorder (ASD). In recent years, much has been learned about the genetics of neurodevelopmental disorders such as FXS, yet there remains a profound lack of treatments that target the underlying pathophysiology. This proposal addresses the urgent need for better pharmacological strategies for treating FXS and related neurodevelopmental disorders.

The beneficiaries of the proposed research are many. Identification of new treatment strategies for FXS and potentially other ASD/ID will relieve the burden on affected individuals and their families. Our results will be of significant value to clinical practitioners who design clinical trials, and who treat patients with FXS. The pharmaceutical industry will benefit from our findings by considering new therapies based on our results, and designing new drugs that can target the ERK and mTOR pathways. We expect that the timescale of the translation of our results will be within the realm of years, as lovastatin is already available for use in adults and children.

It is estimated that the prevalence of ASD/ID in the UK is approximately 1%, and this results in significant costs necessary to care for affected individuals. The development of new treatments will thus relieve the government of a significant financial burden. Additionally, the University will benefit from this research if it results in new patents that generate revenue. As evidence of this, my previous research has generated a patent that is partially owned by MIT (see CV). The high-impact papers based on this research will also raise the academic and scientific profile of the University and UK research. Our research will also benefit charities devoted to the treatment of FXS and ASD/ID by validating the value of the scientific research they support. Finally, the postdoctoral researcher and any Ph.D. or Masters students working on this project will benefit from training in multiple neuroscience techniques, and the exposure to cutting-edge research performed in the Edinburgh Neuroscience community.
Description FRAXA postdoctoral fellowship
Amount $90,000 (USD)
Organisation FRAXA Research Foundation 
Sector Charity/Non Profit
Country United States
Start 08/2016 
End 07/2018
Description Medical Research Scotland Vacation Scholarship
Amount £2,500 (GBP)
Organisation Medical Research Scotland 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2017 
End 07/2017
Description Muir Maxwell Epilepsy Centre Seed Corn Grant
Amount £5,000 (GBP)
Organisation University of Edinburgh 
Sector Academic/University
Country United Kingdom
Start 02/2017 
End 02/2018
Description Royal Society, Start-up Grant
Amount £15,000 (GBP)
Organisation Royal Society of Medicine 
Sector Learned Society
Country United Kingdom
Start 08/2015 
End 07/2016
Description Understanding role of the ubiquitin proteasome system in ASD/ID
Amount £146,000 (GBP)
Organisation Simons Foundation 
Department Simons Foundation Autism Research Initiative
Sector Charity/Non Profit
Country United States
Start 12/2017 
End 12/2019
Description Wellcome Trust/University of Edinburgh ISSF2
Amount £35,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2016 
End 04/2017
Title RNA seq dataset from fragile X mouse model 
Description We have generated RNA-seq datasets for Fmr1 knockout mouse model hippocampus, and also CA1 pyramidal neuron specific ribosome-bound mRNA, with matched wildtype littermate controls. 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
Impact N/A 
Description Named PI in foundation of the Simons Initiative for the Developing Brain at the University of Edinburgh 
Organisation Simons Foundation
Department Simons Foundation Autism Research Initiative
Country United States 
Sector Charity/Non Profit 
PI Contribution The University of Edinburgh was awarded £20 million from the Simons Foundation for Autism Research Initiative (SFARI) to found the Simons Centre for the Developing Brain (SIDB). My research was included in the application for this award and I am a named PI in the SIDB.
Collaborator Contribution SIDB is a newly founded Centre in the University of Edinburgh, which is devoted to performing cutting edge research on autism. Please see for full details.
Impact N/A
Start Year 2017
Description Interview for BBC Radio Scotland 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact I was interviewed on BBC Radio Scotland to discuss the lab's recently published work on fragile X syndrome and autism. This interview was broadcast throughout Scotland.
Year(s) Of Engagement Activity 2017