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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - AIMS-2-TRIALS (Autism Innovative Medicine Studies â€“ 2 â€“ Trials)

Teaser

Summary

Currently, there are no effective medical treatments for the core features of autism and effective therapies for frequent associated features (anxiety, depression, sleep, epilepsy) are limited. Autistic individuals and families who are seeking treatment frequently use costly nonevidence based interventions. Developing effective therapies for autism has been challenging because of the considerable diversity among autistic individuals and a limited understanding of the underlying biological mechanisms. Thus, AIMS-2-TRIALS is working towards generating new treatment options for core and associated features. With this objective, we have defined the following aims: 1) To improve our understanding of the mechanisms underpinning core and associated features of autism, and to translate these findings into clinical practice 2) To identify early neurodevelopmental pathways that modify a childâ€™s clinical and behavioural outcome 3) To provide biomarkers that can identify and separate autistic individuals into more biologically similar subgroups to select specific treatment option for individuals with particular neurobiological profiles 4) To create objective outcome measures (i.e. instruments that are sensitive to change in core and associated features of autism) to measure the effectiveness of particular treatments 5) To test a variety of potential treatments in clinical trials 6) To partner with stakeholders including autistic people and families, clinicians, policymakers, regulators and payers to identify the barriers to testing and adopting new treatments 7) To create a scientific legacy to ensure that our databases, medical devices and products are open to others and sustainable after the life of the project.

Work performed

In terms of aim 1, we have analysed our data across various levels of inference: from genetic to molecular and cellular levels, to brain circuits, cognitive differences and clinical features. For example, we have sequenced all of our DNA samples using single nucleotide polymorphism (SNP) analysis (i.e. information about single genetic building block substitutions occurring between individuals) and we also calculated genetic scores, which can indicate the extent to which a specific individual is predisposed to certain autistic traits. For aim 2, we have set up protocols for our PHENOCADES study (siblings of infants that have diagnosed autism), and data-collection and preliminary analysis for this project has started. We are working towards establishing environmental likelihood/resilience factors (e.g. pre-natal factors (i.e. maternal infection and diet) through setting up a research study in South Africa (SPS-AIMS) associated with brain development, cognition and presence/severity of clinical features. For aim 3, we have analysed data at multiple levels of inference (e.g. genetic, EEG, MRI, fMRI, DTI, clinical symptomatology and, cognition). We collaborated with colleagues in the USA to submit a letter of intent to the FDA and have had our joint work accepted by the FDA into their biomarker development program. This is the first time that this has been achieved by an academic consortium in autism. We are now preparing to submit our work to the EMA. The initial results from biomarker work are: 1) Our resting state-fMRI analysis demonstrated reduced functional connectivity in sensory-motor regions, alongside increased functional connectivity in prefrontal and parietal cortices. These differences were associated with core autism features related to communication and daily living skills. Importantly, we replicated these findings in 4 separate international cohorts containing over 2000 individuals; and obtained proof of concept that differences in brain functional connectivity can be modified by specific pharmacological compounds (even in adults) 2). Another promising result is the electrophysiological responses to pictures of upright and inverted faces â€“ we found that some autistic individuals had differences in the timing of the EEG response to faces â€“ this finding is also replicated by the ABC-CT consortium. We also found proof of concept that these differences predict clinical outcome ~ 2 years later. For aim 4, we are developing remote monitoring for people with autism to assess clinical change. These include measures of language and communication skills, a working memory task, and a learning task involving cooperation with a remote agent. Through working closely with industry and autistic people we have already developed a â€˜wearableâ€™ device, and this is being incorporated into our first clinical trial. For aim 5, we are testing new medicines. To support this aim, we have established a European-wide AIMS-2-TRIALS Clinical Trials Network (CTN) which includes 118 sites across 37 countries with access to >20,000 new patients per year. In our first year we have worked closely with a charity and industry to identify and train sites for our first clinical trial, link our work to another network in North America in order to increase the study size, identified the medication to be tested (arbaclofen), showed that this drug can impact on EEG and imaging biomarkers in a dose dependant manner, and registered our clinical-trials protocol. The trial protocol (for the first time in autism) includes testing of both our novel EEG biomarkers and our new â€˜wearableâ€™ device. We have already obtained ethical approval in the UK and Spain, submitted our protocol for regulatory approval in Europe, and launched the trial in North America. For aim 6, we have successfully recruited a group of individuals from the autism community (autistic people, parents and carers) from across Europe (the Autism Representatives group, or A-Reps).

Final results

We have generated the largest database of â€œdeep-phenotypedâ€ autistic participants in the world so far, which includes information across multiple levels of inference. Based on this (and through collaborating with autistic individuals; together with colleagues in North America, charities and industry) our work has been instrumental in having an EEG biomarker accepted into the FDA development program. Also, we incorporated that biomarker into a clinical trial that employs our new objective outcome measure. This work is underpinning multiple analysis packages to submit to the EMA. We have also created a large, highly trained CTN, which ensures researcher access to many consenting autistic individuals, thereby increasing the efficiency of clinical trials. Furthermore, by establishing the A-Reps group we have attempted to ensure that our work includes collaborative efforts and incorporates what autistic people and their families feel is beneficial and needed. Finally, one of our most significant steps forward includes the stratification markers that we are identifying helping the scientific and clinical community to form more biologically similar subgroups of autistic individuals, with the knowledge that some subgroups may better benefit from more tailored treatments.