DROIDp – Drug Research Organoid-Integrated Development Platform: a Combinatorial NAM for Assessment of in vitro Learning and Memory in Drug and Chemical Testing

About This Grant

The rates of neurodevelopmental disorders and Alzheimer’s disease are rising, yet success in drug development and public health interventions remains limited. Developmental neurotoxicity testing is hindered by reliance on animal models, creating a backlog of untested chemicals. The proposal outlines a Drug Research Organoid-Integrated Development platform (DROIDp) – an in vitro neural system that combines human iPSCderived 3D brain organoids with advanced sensors in form of 2D and 3D microelectrode arrays, and AI-driven analytics – to develop a combinatorial New Approach Methodologies (NAMs) of learning and memory. This approach is a novel combinatorial NAMs, serving as a human-based alternative to traditional animal behavior studies in neuropharmacology and (developmental) neurotoxicology. In DROIDp, organoids will be stimulated using open- and closed-loop paradigms, measuring neural activity, synaptic plasticity, and network dynamics in response to stimuli to develop a set of neural learning metrics, which can assess neural function in disease settings or in response to neuroactive compounds. The study will evaluate organoids derived from both healthy individuals and patients with SYNGAP1-related disorders and Alzheimer’s disease, testing their neural responses and sensitivity to pharmacological interventions. Data from electrophysiology, transcriptomics, and extracellular vesicle (EV) profiling will be analyzed using self-supervised learning and explainable AI (xAI) to correlate the in vitro data to clinical data to develop robust biomarkers for function. By enabling measurement of learning and memory processes in human neural tissue, the platform addresses a critical gap: current in vitro assays cannot capture higher-order neural responses, and evaluations of neurotoxicity or drug efficacy still rely on animal behavioral tests. This interdisciplinary project led by a team with a well-established history of collaboration, fostering a cohesive and productive working environment. The team’s expertise spans neuroscience, toxicology, engineering, data science and neuroethics to drive a paradigm shift in drug development and chemical safety testing. DROIDp will advance neuroscience by enabling human-based models of neurodevelopmental and neurodegenerative disorders for studying disease mechanisms and evaluating candidate therapeutics. It will offer a more predictive tool for developmental neurotoxicity testing, capturing complex neural functions to improve risk assessment. Expected outcomes include a fully developed, standardized organoid platform demonstrating reliable readouts of learning and memory on the cellular level, reproducibility across batches and cell lines across many individuals, and responsiveness to known neuroactive compounds, yielding performance benchmarks ready for formal validation by the NIH Complement-ARIE network or regulatory agencies. Successful completion will deliver a combinatorial NAMs in neuroscience – a critical need identified by the Complement-ARIE program’s consortium. This outcome is expected to significantly improve the predictive accuracy, efficiency, and ethical standards of preclinical drug discovery and toxicity screening.