Targeting ERK signalling to ameliorate intellectual disability and autism spectrum disorder associated with chromosomal rearrangements at 16p11.2

Lead Research Organisation: CARDIFF UNIVERSITY
Department Name: School of Biosciences


Human genetics has enabled us to identify specific gene variations which are associated with neurodevelopment disorders (NDD) such intellectual disability (ID) and Autism spectrum disorder (ASD). Just over 1% of the UK population are believed to be on the autism spectrum, meaning over 695,000 people in the UK may be autistic. Intellectual disability affects about 2-3% of the general population, with at least 25% of cases likely to be caused by a genetic predisposition.
There is currently no cure for ASD/ID and no medications to treat the main symptoms of these disorders. This project aims to improve the chances of developing medicines able to reverse the effects of these genetic alterations. Among the most common genetic forms of ASD/ID lie chromosomal modifications, which cause either a deletion or a duplication of a group of genes. Interestingly, there are important differences between the duplication and the deletion patients such as metabolic changes (tendency to increase weight in the deletion and decrease weight in the duplication) and craniofacial abnormalities (deletion is associated with increased head size whereas the duplication is associated with decreased size). Importantly, duplication patients may be more susceptible to psychotic symptoms in addition to ID/ASD.
In the 16p11.2 chromosomal region there are 27 distinct genes but we currently do not know their contribution to the pathological state.
We have gathered strong preliminary evidence that one of these genes, MAPK3, may play a prominent role in the development of these ASD/ID forms associated to the 16p11.2 region.
In this project, we will investigate the role of MAPK3 in both duplication and deletion patients by monitoring in the blood its activity. The goal is to be able to use MAPK3 as a tool to help both diagnosis and future treatments.
We will also generate sophisticated human cellular models and mini-brain preparations to study how MAPK3 levels can be corrected and possibly restored using novel experimental drugs.
At the end of the project we will have demonstrate whether MAPK3 is a valid therapeutic target for the diagnosis and the treatment of 16p11.2 duplication and deletion patients.

Technical Summary

Copy number variants (CNVs - deletions or duplications) in the 16p11.2 chromosomal region are associated with intellectual disability (ID) and autism spectrum disorder (ASD) and other neurodevelopmental disorders (NDD). Recently, converging evidence from human genomic studies as well from mice strongly points to a gene located within 16p11.2, MAPK3 (ERK1), as a key factor for NDD. MAPK3 regulates ERK signalling which is a central player in neurodevelopment, cognition and behaviour, thus representing a potential therapeutic target. We recently found that a short treatment with ERK signalling inhibitors in mice with the 16p11.2 deletion restored key physiological and behavioural deficits, providing a strong rationale for a stratified intervention targeting this pathway. In this multidisciplinary project, firstly patients carrying either deletions or duplications of 16p11.2 will be characterised phenotypically and screened for peripheral alterations in ERK signalling components that can be used as biomarkers to support diagnosis and treatment development for ID/ASD. Secondly, induced pluripotent stem cells (iPSCs) derived from these patients will be used to confirm a role of ERK signalling in the neuronal alterations at the cellular level also using cerebral organoids. Thirdly, functional rescue of the observed cellular phenotypes using appropriate ERK modulators will be investigated and coupled with pharmaco-transcriptomics, with the goal to identify brain-specific downstream ERK targets. Finally, efficacy of a novel ERK activator will be assessed in 16p11.2 duplication model, to validate an experimental therapy for cognitive dysfunction in vivo. At the end of the project, evidence from patients, human cellular models and mouse models will be integrated in a coherent therapeutic approach necessary to proceed to clinical intervention in genetically stratified groups of patients with ID and ASD.

Planned Impact

Immediate impact of our results will be the implications for academics studying neuroscience and neurodevelopmental disorders, and pharmaceutical companies developing new biomarkers for accurate disease diagnosis and novel therapeutic strategies. There may also be benefits to clinicians involved in managing and treating patients affected by ASD/ID and patient groups and families living with the consequences of the genetic abnormalities being studied who may have some hope for effective diagnosis and eventually therapies becoming available.
The latest prevalence studies of autism indicate that 1.1% of the population in the UK may be on the autism spectrum, meaning over 695,000 people in the UK may be autistic. Intellectual disability affects about 2-3% of the general population, with about a 25% of cases caused by a genetic disorder, and about 5% inherited. There is no cure for ASD/ID and no medications to treat these disorders. The urgent need to identify novel targets for therapeutic approaches for these neurodevelopmental conditions will exploit genomic identification of ASD/ID sufferers with 16p11.2 deletion and duplication carriers to improve the prospect of new therapeutic targets.
New disease models will accelerate the prospects of novel therapeutics for ASD/IS. The evidence from patients, human and rodent models will be integrated in a coherent therapeutic approach necessary to proceed to clinical intervention for these two highly correlated neurodevelopmental disorders. The expected impacts include:
1. Establishment of human cell-based models of 16p11.2 deletion and duplication carriers enabling more human relevant research and study of the condition and potential therapies.
2. ERK based biomarkers to enable more rapid diagnosis of 16p11.2 deletion and duplication related diseases.
3. New understanding of ERK and related pathways and potential targets in genetic based neurological conditions to inform the development of therapies for many ERK related diseases.
4. Pre-clinical assessment results on novel compounds to treat genetic based neurological conditions to inform the design of potential clinical studies.
By training researchers and students in skills widely relevant and necessary both inside and outside academia including in industry (e.g. clinical research, genomics, statistics, bioinformatics and neuroscience) we will impact a new generation of neuroscientists to further studies of neurodevelopmental disorders and development of personalised medicines.
The well characterised models for target validation will overcome a major obstacle to making progress towards the development of new treatments. ERK and related pathways represent potentially tractable targets for drug development or indeed the repurposing of existing therapeutics in stratified medicine approaches.
The research programme we are proposing will increase our basic knowledge of the molecular and cellular events and physiology of genetic based neurodevelopmental disorders and translate across scientific disciplines.


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Bernardi RE (2019) The Inhibition of RasGRF2, But Not RasGRF1, Alters Cocaine Reward in Mice. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Morella IM (2022) Emerging roles of brain metabolism in cognitive impairment and neuropsychiatric disorders. in Neuroscience and biobehavioral reviews

Description Costed extension of MR/S037667/1
Amount £276,064 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 01/2023 
End 10/2025
Description Drug Validation and Target Identification for cognitive disorders using patient-derived cortical explants
Amount £18,306 (GBP)
Organisation Cardiff University 
Sector Academic/University
Country United Kingdom
Start 03/2022 
End 12/2022
Description Collaboration between Cardiff University and University of Manchester 
Organisation University of Manchester
Country United Kingdom 
Sector Academic/University 
PI Contribution Our Award is the result of a novel partnership with the University of Manchester to characterised potential biomarkers in patients with the 16p11.2 CNVs and to establish novel iPSC lines of this neurodevelopmental disorders.
Collaborator Contribution The University of Manchester will behavioural phenotyoe part of the patient's cohort and obtain blood samples for the biomarker analysis and iPSC generation. They will also provide samples for genotyping.
Impact The study will involve behavioural, genetic, cellular and biochemical analyses.
Start Year 2019
Description The invention relates to inhibitors of MAPK3(ERK1 MAP kinase), in particular to polypeptides having the ability to stimulate the global ERK signalling pathway in the brain and their use as neuroprotective and/or cognitive enhancing agents.The invention also concerns related polynucleotides, vectors, host cells and pharmaceutical compositions able to inhibit MAPK3, causing the stimulation of the global ERK signalling pathway.Additionally, use of the afore inhibitors or stimulators in the treatment of neurodegenerative or neuropsychiatric disorders and cognitive impairment is also disclosed. 
IP Reference WO2019102201 
Protection Patent application published
Year Protection Granted 2019
Licensed No
Impact Design and validation of a cell-penetrating peptide as a positive modulator of ERK signalling. The Peptide is able to protect from neurodegeneration in animal models of diseases such as Huntington's and Alzheimer's and to enhance cognition.
Description Media and Press Release 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Our work has been presented to a range of stakeholders including; Cerebra UK charity, to MaxAppeal (22q11.2 Deletion Syndrome charity) at their Annual General Meeting, and the All Wales Medical Genetic Service's Psychiatry & Genetics multidisciplinary team meetings (clinicians from psychiatry and medical genetics) . Cardiff University did a press release covering the work,-research-suggests, which was picked up by 29 news sites, and over 40 radio and TV stations including Fox, CBS and ABC news, 4 blogs and had a twitter reach of over 60,000 people. The authors have presented to the US Autism Science Foundation. Spectrum news also covered the research ( This has helped raise awareness of issues surrounding autism diagnosis in individuals with genetic conditions, and it has opened conversations with clinicians and charities surrounding service development and provision for individuals with neurodevelopmental genetic conditions.
Year(s) Of Engagement Activity 2021