EU-AIMS Clinical Research Platform to Identify Biomarkers for Patient-Stratification

Background:  There are no effective treatments for the core symptoms of ASD because the underlying pathophysiology(ies) remain(s) poorly understood. Clinical trials are further hampered by the profound clinical and etiological heterogeneity among individuals with ASD, as any treatment is likely only effective in some biological sub-groups. Hence, large-scale multi-disciplinary studies and new biomarker stratification approaches are needed to identify more biologically homogeneous ASD subgroups. EU-AIMS capitalizes on rare monogenic forms of ASD affecting synaptic plasticity to identify new tractable treatment targets. This approach generates predictions for potential biomarkers linked to downstream effects on the excitatory-inhibitory balance and cortical-network function underpinning cognitive development. Acceptance of these biomarker approaches by regulatory authorities is crucial to maximize their usefulness for future clinical trials.

Objectives:  (1) to develop new approaches and methodologies to identify biomarkers for patient stratification; (2) to obtain qualification advice on these approaches from the European Medicines Agency (EMA);  (3) to test  candidate biomarkers tapping E/I imbalance  in patients who harbor specific synaptic gene deficits (Phelan McDermid Syndrome) and a large cohort of children and adults with ASD.

Methods:  (1) The EU-AIMS Longitudinal European Autism Project (LEAP) is carried out in 7 European centres and will include approximately 400 individuals with ASD from 6-30 years and 250 controls with typical development or diverse intellectual disabilities. All participants are comprehensively characterized in terms of clinical symptom profile, comorbidities, quality of life, neurocognitive profile, brain structure and function, biochemical biomarkers, and genomics. We use an accelerated longitudinal design so that predicted biological differences can be compared across developmental stages. This will allow us to assess, e.g., whether differences in E/I imbalance vary according to developmental stages, sex, and/ or between genetically-driven molecular subgroups. (2) The LEAP protocol was submitted to the EMA to obtain qualification advice on the biomarker approaches and methodologies used. (3) The cohort is compared to approximately 50 children and adults with PMS to establish whether biomarkers linked to specific synaptic deficits are shared by other ASD-subgroups.

Results:  (1) We developed measures suitable for a broad age and ability range, including direct and indirect proxies of E-I imbalance. For example, a pilot study demonstrates a link between glutamate concentration in the basal ganglia, functional connectivity and severity of ASD symptoms. (2) The EMA endorsed the overall design and methodologies of EU-AIMS LEAP for the identification of biomarkers. We will present a summary of key recommendations. (3) We will report preliminary results comparing children and adults with ASD and those with PMS on candidate biomarkers affecting E-I imbalance and their dimensional relationship with symptom profile.

Conclusions: The design of LEAP provides new approaches to identify biomarkers for patient stratification and to map them both to genetic-molecular and symptom profiles. Obtaining QA from the EMA represents an important first step to inform regulatory guidelines for medication trials in ASD in Europe. The comparison of biomarkers between patients with ASD and PMS will help to ascertain how far treatment targets identified using synaptic gene models may be applicable to broader ASD sub- groups.