New molecular targets and proof-of-concept therapies for Autism Spectrum Disorders

Project Information

THERAUTISM

Grant agreement ID: 851231

DOI

10.3030/851231

Project closed

EC signature date 7 October 2019

Start date 1 March 2020

End date 31 August 2025

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 499 025,00

EU contribution

€ 1 499 025,00

Coordinated by

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
France

Periodic Reporting for period 4 - THERAUTISM (New molecular targets and proof-of-concept therapies for Autism Spectrum Disorders)

Reporting period: 2024-09-01 to 2025-08-31

Summary of the context and overall objectives of the project

Autism spectrum disorder (ASD) is a complex, polygenic neurodevelopmental and lifelong condition. It is characterized by impairments in social communication and interaction, as well as repetitive and stereotyped behaviors. The prevalence of ASD has increased, now affecting 1% of children worldwide. The major gap in ASD remains the absence of effective drugs for managing core features of ASD. Behavioral interventions have shown some efficacy in addressing social impairments, but they are costly (€258 billion/year), highly intensive (35h/week) and effective when applied in young children with ASD. Despite extensive efforts, no drug capable of benefiting larger numbers of individuals independently of their age has been approved for core symptoms of ASD. Currently, only the antipsychotics risperidone and aripiprazole are approved to treat co-occurring features. This highlights the urgent need to develop effective drugs that directly target the core features of the condition. To achieve this goal, it requires the identification of new and promising therapeutic targets.
The EU-funded THERAUTISM project aimed to overcome this research gap, from the identification of new molecular targets to the initial step of therapeutic development. Its first objective was to identify all the molecular substrates within a small, highly conserved brain circuit implicated in social interaction deficits. The second objective of the project was to investigate two of these substrates—after characterizing the function of a newly discovered protein—with the aim of improving social deficits in several preclinical mouse models of ASD.
Overall, the THERAUTISM project aimed to identify novel therapeutic targets and innovative therapies for ASD. The project was divided into two parts:
1) identification of new molecular targets involved in social interaction deficits.
2) investigation of two specific substrates to determine the most effective therapeutic approaches to restore their function.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Since the launch of the project in March 2020, we have successfully identified the most suitable and robust preclinical mouse models of ASD, implemented all required techniques, and set up the experimental conditions in the laboratory.
Part 1 focused on identifying novel molecular substrates within a conserved brain circuit linked to social interaction deficits. We generated a substantial database containing 560 samples, enabling comprehensive mapping of these substrates. Through this effort, we already identified promising and highly druggable targets, including some unexpected ones within this neuronal circuit.
Part 2 aimed to investigate two specific substrates of social interactions. Our studies revealed that only one of these two targets was differentially dysregulated, but only in a subset of preclinical models of ASD (1 published article). In contrast, the second target was not specifically involved in social interaction deficits (1 published article, 1 under revision). Importantly, we identified a selective pharmacological compound capable of improving social interaction, which could represent a new strategic therapeutic option for individuals with ASD.
The THERAUTISM project resulted in 2 published research articles, 2 published reviews, 3 currently under revision, 1 database and 4 research articles in preparation, and the work was presented in 8 national and 8 international meetings.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The identification of new therapeutical targets and the development of treatments to improve the core social features of ASD have long remained major research gaps. The THERAUTISM project addressed these gaps, by providing a substantial database of molecular substrates underlying social interaction deficits and by advancing new pharmacological compounds for ASD. As a result, the project provides valuable resources for the scientific community and paves the way for the development of innovative therapeutic options. Ultimately, the outcomes of the THERAUTISM project offer new therapeutical options for individuals with ASD.

outline of the project