DEPI v3: A systems biology and artificial intelligence based patient stratification and drug positioning platform for neurodevelopmental disorders

Abstract

Neurodevelopmental disorders (NDDs) are a group of highly heterogenous and prevalent disorders characterized by abnormal brain development. These disorders remain an area of high unmet medical need due to the lack of specific pharmacological treatments addressing the core symptoms, especially social communication deficits. Most clinical trials in NDDs over the past decades have failed to show efficacy across patients recruited using behavior-based diagnosis despite bearing unrelated molecular pathophysiology. Here, we present the DEPI platform, STALICLA’s data-driven solution to meet the biological stratification needs in complex NDD populations. DEPI is the first systems biology and multi-omics based, AI module driven platform in the NDD space for the development of precision medicine-based treatments. It uses curated NDD-risk catalogs to identify pathway-level perturbations associated to clinical observations. Furthermore, it combines supervised and unsupervised machine learning methods to characterize molecular signatures (genetic, transcriptomic and metabolomic) across individuals through mechanistic endophenotyping. Importantly, the platform facilitates matching of the right treatments to the right patients with NDDs. The platform has been proven clinically successful by: i) identifying a first clinically actionable subgroup of patients with Autism Spectrum Disorder (ASD Phenotype 1), and the corresponding tailored treatment, STP1, with outstanding and unprecedented target engagement results in a Phase 1b clinical trial; and ii) blindly recalling known drug responder patients with sensitivity and specificity values ~80% for patients with fragile X syndrome.