Targeting ERK and mTOR for the treatment of fragile X syndrome
Lead Research Organisation:
University of Edinburgh
Department Name: Centre for Discovery Brain Sciences
Abstract
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.
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.
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.
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.
People |
ORCID iD |
Emily Osterweil (Principal Investigator) |
Publications
Muscas M
(2019)
Lovastatin, not Simvastatin, Corrects Core Phenotypes in the Fragile X Mouse Model.
in eNeuro
Till SM
(2015)
Conserved hippocampal cellular pathophysiology but distinct behavioural deficits in a new rat model of FXS.
in Human molecular genetics
Louros SR
(2016)
Perturbed proteostasis in autism spectrum disorders.
in Journal of neurochemistry
Seo SS
(2022)
Excess ribosomal protein production unbalances translation in a model of Fragile X Syndrome.
in Nature communications
Thomson SR
(2017)
Cell-Type-Specific Translation Profiling Reveals a Novel Strategy for Treating Fragile X Syndrome.
in Neuron
Hulme H
(2020)
Microbiome-derived carnitine mimics as previously unknown mediators of gut-brain axis communication.
in Science advances
Osterweil E
(2019)
Of mice, men, and NLGN4
in Science Translational Medicine
Osterweil E
(2019)
A no-nonsense treatment for autism spectrum disorder
in Science Translational Medicine
Osterweil E
(2020)
Seizing control of fragile X syndrome
in Science Translational Medicine
Description | FRAXA postdoctoral fellowship |
Amount | $90,000 (USD) |
Organisation | FRAXA Research Foundation |
Sector | Charity/Non Profit |
Country | United States |
Start | 07/2016 |
End | 07/2018 |
Description | H2020-MSCA-ITN-2017 (Marie Sklodowska-Curie Innovative Training Networks |
Amount | € 3,680,258 (EUR) |
Funding ID | Syn2Psy (813986) |
Organisation | European Commission |
Sector | Public |
Country | European Union (EU) |
Start | 03/2019 |
End | 03/2022 |
Description | Identifying mistranslating mRNAs in Fmr1-/y and Syngap+/- models of ASD/ID |
Amount | £523,742 (GBP) |
Funding ID | MR/S026312/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 07/2019 |
End | 07/2023 |
Description | Medical Research Scotland Vacation Scholarship |
Amount | £2,500 (GBP) |
Organisation | Medical Research Scotland |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 04/2017 |
End | 07/2017 |
Description | ONO Rising Star Initiative |
Amount | £98,180 (GBP) |
Organisation | Ono Pharmaceutical |
Sector | Private |
Country | Japan |
Start | 01/2019 |
End | 01/2020 |
Description | Postdoctoral Fellowship (S Thomson) |
Amount | £153,970 (GBP) |
Organisation | Tuberous Sclerosis Association |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2014 |
End | 09/2017 |
Description | Ribosome function in plasticity and neurodevelopmental disorders |
Amount | £1,884,223 (GBP) |
Funding ID | 219556/Z/19/Z |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 02/2020 |
End | 01/2025 |
Description | Royal Society, Start-up Grant |
Amount | £15,000 (GBP) |
Organisation | Royal Society of Medicine |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 07/2015 |
End | 07/2016 |
Description | Wellcome Trust/University of Edinburgh ISSF2 |
Amount | £35,000 (GBP) |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2016 |
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 |
URL | https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE101823 |
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 http://www.sidb.org.uk/ 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 |
URL | http://patrickwildcentre.com/news/dr-emily-osterweil-talks-to-bbc-radio-scotland/ |