Autism is a spectrum of neurodevelopmental conditions. It is heterogeneous, which means that every autistic person is different and has a unique set of strengths and challenges. Some autistic people are able to live and work independently while others may have learning differences and need more or specialist support. Some co-occurring physical and mental health conditions are more common in autism, such as epilepsy, anxiety and depression.
Autism is highly heritable, and its underlying genetic mechanisms are complex and varied. It is clear that both genetics and environmental factors influence the development of autism, but the relative contributions from and interactions between genetic and environmental factors are not yet known.
EU-AIMS – meeting the research challenges head-on
The heterogeneity of autism creates a challenge for the development of effective clinical trials for medicines and non-medical interventions. For a number of reasons, prior clinical trials have been less definitive than researchers would have hoped. To address some of these reasons, EU-AIMS contributed to the development of specific tools and methods and created a European network of specialised and skilled centres for diagnosis and running of clinical studies and trials.
Another complicating factor for clinical trials is that autistic people can be extremely different from one another, so that no single treatment could hope to help all of them. Clinical trials working with subgroups of autistic people who share similar characteristics are more likely to find successful treatments than trials working with large, diverse groups of autistic people. The EU-AIMS project therefore aimed to learn more about the diversity of autism. This work will aid the development of personalised therapies by improving understanding of the mechanisms underpinning core features and differences in individual needs.
EU-AIMS has considerably advanced our knowledge of the variability within the biology and behavioural characteristics of autistic people, identified areas for medical intervention and successfully demonstrated that medicines can modulate biological differences associated with autism. In order to conduct this work, the EU-AIMS project brought together over 150 leading psychiatrists, psychologists, cognitive developmental neuroscientists, basic neuroscientists, neurobiologists, geneticists and others from over 16 academic institutions, 6 industry partners, and 3 small-to-medium size enterprises (SMEs).
Identifying biomarkers for autism on an unprecedented scale
A key focus of EU-AIMS was the identification of biomarkers, short for biological markers. These are any objective measures such as patterns of brain activity, a cognitive test score, or particular genetic variants that may, for example, predict how a person responds to interventions.
Biomarkers could, for example, be used during the diagnostic process to predict whether symptoms will change during development, and/ or to select the best interventions, support or treatment for any given person. Biomarkers have the potential for supporting research into personalised profiles and thereby addressing the challenges of the diversity seen in autism.
To aid in the search for autism biomarkers, EU-AIMS conducted three longitudinal studies with over 1,200 participants across the lifespan, at a scale and complexity that was previously unprecedented anywhere in the world.
Data was collected from the cohorts below using the highest research standards, then analysed with newly developed methods, leading to significant progress in the understanding of the relationship of brain structure and signs of autism:
- Eurosibs: a study of infants with an autistic sibling. These siblings, who have an increased genetic likelihood of developing autism, were followed up from 4 months to 3 years with the aim of better understanding early signs of autism.
- Longitudinal European Autism Project (LEAP): the largest study of its type to identify biological markers for autism from childhood to adulthood, this study included autistic and non-autistic children, adolescents and adults and volunteers with mild intellectual disabilities aged 6-30 years.
- SynaG study: this aimed to better understand the relationship between genes and symptoms in individuals with genetic syndromes associated with autism, such as variations in genes called SHANK3 and NRXN (Neurexin).
Some of the EU-AIMS research findings from these studies include:
- Brain ‘over-connectivity’ at 14 months predicted more repetitive behaviours later in childhood.
- Six-month-old babies that show little interest in faces went on to show more social-communication difficulties later in development.
- Biological sex, whether you are genetically male or female, is associated with significant variation in the brain phenotype of autism (phenotype means a person’s observable characteristics or traits).
- Differences in cortical connectivity and ‘shiftability’ (changes) in brain function following a one-time dose of a serotonergic or glutamatergic medication are associated with aspects of clinical symptomatology.
- Lastly and importantly, researchers identified potential candidate biomarkers that could be further developed for use in clinical trials.
Animal and cellular studies – translating findings into humans
Animal models and new non-invasive techniques, such as induced pluripotent stem cells (iPSC), were used to identify causal links from genes and environmental factors to molecular changes and biological pathways. Using iPSC methods, researchers can reprogramme cells from, for example, a human hair root to stem cells so they can be turned (induced) into any cells (pluripotent) that researchers are interested in studying. In this case researchers were interested in brain cells such as neurons.
Various EU-AIMS animal and cellular studies have focused on conditions associated with autism that are caused by changes in a single gene, to identify associated biological and behavioural characteristics.
A key task was to ‘translate’ findings from animal models to humans to identify comparable underlying mechanisms characteristic of autism. This can be achieved by using measures that are safe to use in humans such as high-tech magnetic resonance spectroscopy (MRS), electroencephalogram (EEG), and structural and functional magnetic resonance imaging (sMRI and fMRI). It is important to understand how mechanisms describing certain types of behaviour in animal studies relate and compare to mechanisms described in humans.
For example, researchers tested whether certain medicines or related pharmacological compounds were effective in rodent and cellular models, thereby identifying potential new treatments for humans based on an improved understanding of underlying biological mechanisms across animals and humans at cellular and behavioural levels.
Creating trained networks for future research
EU-AIMS established the first European Clinical Trials Network for autism including over 118 clinical and research sites across 37 European countries. This network provides a platform for training, research, biomarker identification and to facilitate clinical trials for medical and non-medical approaches. This network has so far supported three industry-sponsored clinical trials for autism. It will continue to accelerate information exchange, critical discourse, and collaboration between leaders of the European autism community, having a long-lasting impact on the competitiveness and quality of autism research in Europe as part of AIMS-2-TRIALS, the follow-up project that began in 2018.
EU-AIMS was the first academic/industry group to submit a proposal for potential autism biomarkers and obtain ‘qualification advice’ from the European Medicines Agency (EMA). This is key to clarifying the research standards required for identifying biomarkers for subsequent approval by the EMA. This crucial step improved understanding between regulatory authorities, academics and industry; and helps to ensure that measures used in and developed for research and clinical trials are safe and reliable. This work led to a joint publication between EU-AIMS researchers and the EMA in Nature Reviews Drug Discovery (‘Identification and validation of biomarkers for autism spectrum disorders’). The EMA quoted the work of the project when they developed new EU policies on medicine testing in autism, and as such, EU-AIMS contributed significantly to the progress in regulatory science to support the development of medical/ non-medical interventions.
Creating a secure and sustainable central database
EU-AIMS research efforts were underpinned by a central database to efficiently and safely store the research data collected, conduct quality control steps, pre-process and download data from each study for registered analysis projects. This anonymised and harmonised data has been made available via a custom-built infrastructure called the EU-AIMS DataSharingSystems. Institute Pasteur agreed to host the central database from the project.