Drugs to treat the social symptoms of autism are getting closer
Autism spectrum disorder(opens in new window) (ASD) is a complex, lifelong condition characterised by social communication and interaction difficulties, alongside restricted or repetitive patterns of interests and behaviours. While diagnosis is based exclusively on behavioural criteria, the term ‘spectrum’ refers to how these features vary widely between individuals. ASD is typically managed through personalised behavioural and educational interventions, especially effective when started early. However, their intensity (up to 35 hours per week) makes these interventions costly (over EUR 250 billion per year(opens in new window), limiting them to families in high-income countries). “Pharmacological treatments for core ASD features, ideally combined with behavioural interventions, are urgently needed,” says Lucie Pellissier(opens in new window) (webpage in French), coordinator of the THERAUTISM project. “Yet despite significant research, no such drugs have been approved, with existing treatments only targeting co-occurring features such as irritability, anxiety or epilepsy.” Closing this gap, THERAUTISM, which was funded by the European Research Council(opens in new window), has identified new molecular targets influencing social interaction, alongside an approach which groups mouse models based on their individual behavioural difficulties.
Groundbreaking dataset leads to molecular drug targets
A major bottleneck to ASD drug development has been the lack of molecular targets identified across the ASD spectrum or within subgroups. “Previous clinical approaches were often quite narrow – looking at one model, one tissue or one broadly expressed target – likely explaining past failures,” adds Pellissier from the National Centre for Scientific Research(opens in new window), the project host. To avoid these pitfalls, THERAUTISM built ‘SOCIALOME’, the first large translatomic(opens in new window) dataset comprising 560 samples from a neuronal circuit in ASD mouse models. The dataset captured activity within neuronal cells, their distal projections, and neighbouring neurons within the same circuit. As Pellissier explains: “Within cells, DNA is transcribed into messenger RNA (or mRNA), which ribosomes then translate into proteins. Translatomics asks: Which mRNAs are actually being translated into proteins, at a given moment in specific neurons and under specific conditions?” Applying translatomics to two ASD mouse models known to be robust (Fmr1 and Shank3 KO mice) revealed key molecular pathways linked to social behaviour (which ribosome-bound mRNAs actively translate during social interaction, and whose mRNAs were dysregulated). “Because these molecular signatures were discovered in an evolutionarily conserved brain circuit shared by mice and humans, there is more likelihood that they really do represent promising drug targets for individuals with ASD,” notes Pellissier. A family of proteins known as ‘G protein-coupled receptors’ (GPCRs), were found to be especially promising. Indeed, selectively activating only the oxytocin receptor (as opposed to oxytocin or vasopressin, used in past clinical trials) can effectively restore social interaction in ASD mouse models.
For more precise ASD diagnostics and personalised treatments
While candidate drug compounds are being optimised for clinical trials, their molecular targets are being validated in a novel behavioural analysis system. The team have uniquely combined pre-existing tools: a live mouse tracking tool, with one for analysing mouse behaviours to categorise individuals by personality profile, such as ‘anxious’ or ‘asocial’. “Separating ASD mice based on behaviour rather than genotype, as was previously done, will help us identify biomarkers for behavioural subgroups. This will enable us to be very targeted in testing drugs for the control of specific traits,” adds Pellissier. With the World Health Organization estimating that in 2021 about one in 127 people were autistic(opens in new window), and with numbers rising, she says that: “Ultimately, our aim is to enhance quality of life for individuals with ASD and their families, while reducing the long-term societal and economic cost.”
