20384
Province of Ontario Neurodevelopmental Disorders Network: Integrated Discovery from Genes to Treatment
Emerging data from human and animal studies have been producing several potential molecular targets, yet there still exists a large gap between the time at which a potential target is identified and the first phase III trial, due to either (1) a target that is not relevant to the disease or not amenable to pharmacological intervention or (2) difficulty in stratifying patients into those most likely to respond to the intervention and/or identifying appropriate clinical end-points or biomarkers. While autism is highly heritable, over 450 genes have been implicated, and no single gene accounts for more than 1% of cases. In areas of other biomarkers, such as imaging, there is also great variability in findings. The observed heterogeneity in ASD suggests that a single treatment is unlikely be effective for most individuals and that in addition to novel targets, we need biologically informed ways of predicting treatment response.
Objectives: To develop an integrated discovery system that will facilitate the translation of genomic and epigenomic findings into treatments by accelerating the discovery of new molecular targets and stratification strategies.
Methods:
With funding from the Ontario Brain Institute and several industry partners, we developed an ICH—GCP compliant clinical trials network dedicated to neurodevelopmental disorders, which we embedded in a multiplatform , multisite biomarker core. Children recruited contribute a genomic sample, extensive phenotypic behavioral and cognitive data, some specific to their diagnosis and some quantifying cognition and behavioral deficits irrespectively of diagnosis (e.g. empathic accuracy, inhibition, attention, social function) as well structural and functional imaging and electrophysiological data. Classification algorithms are used within heterogeneous data to allow for new clustering techniques, in an effort to identify biologically homogeneous subgroups. Children recruited in the clinical trials already have contributed all of the above to allow for prediction of treatment response. In addition, we develop biological models of neurodevelopmental disorders, including mouse models as well as induced pluripotent stem cell (iPS) lines derived from skin or blood of research participants, based on knowledge of mutations in patients. We use cutting-edge technologies, including induced pluripotent stem-cells, and high-throughput imaging and behavioural phenotyping in genetically altered mice to identify mechanisms of disease and the effectiveness of therapeutics.
Results:
At the time of submission, more than 1000 children ages 18 months to 18 years have been recruited and characterized across four sites. More than 45 mouse models of ASD related mutations have been characterized and imaged. This presentation will use empathic accuracy to demonstrate the translational paradigm from genomics and epigenomics to imaging and ultimately to treatment. The rest of the pNEL will highlight novel findings in genomics, epigenomics and imaging in children across the platforms, as well as, cross species data within the POND platforms.
Conclusions:
We present the rational, methods and feasibility of an integrated discovery system aimed at exploring the biological heterogeneity of ASD and related disorders, using cross species genomic, phenotypic and imaging data, with the ultimate goal of predicting treatment response. Early data demonstrates the effectiveness of this approach