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

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.

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.

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.