Biology subjects

LaCroix, A. S.

Publications and source records attributed to LaCroix, A. S..

3 recordsLinked to original sources

bioRxiv2026

Human CNS-3D organoids predict clinical seizure liability from calcium network activity

Drug-induced seizures remain a major safety concern in drug development, yet human seizure liability is difficult to predict using conventional preclinical models. Here, we evaluated whether spontaneous calcium network activity in human induced pluripotent stem cell-derived CNS-3D Brain Organoids could predict clinically observed seizure risk across a pharmacokinetically anchored drug set. CNS-3D organoids contained neuronal and astrocytic populations, expressed neuroactive receptor and ion-channel gene programs that aligned with human cortical tissue, and exhibited reproducible spontaneous calcium oscillations across production batches. A retrospective drug panel of 66 small-molecule drugs was assembled from human clinical evidence, including 30 seizure-associated drugs and 36 comparator drugs without documented clinical seizure liability. Drugs were tested across concentration ranges anchored to reported clinical Cmax, and calcium time-series responses were integrated with chemical structure features using a machine-learning workflow. The final model predicted clinical seizure liability with an AUROC of 0.872, achieving 83.3% sensitivity and 88.9% specificity in drug-level cross-validation. Model scores also stratified seizure-associated drugs by clinical context and prevalence, suggesting that CNS-3D activity profiles capture clinically meaningful differences in seizure risk. Compared with published in vitro and preclinical seizure-liability models, CNS-3D organoid-based predictions showed improved balanced sensitivity and specificity. These findings support high-throughput calcium profiling in human CNS-3D organoids as a scalable, exposure-aware platform for predicting human seizure liability and contributing functional human data to neuro-safety assessment.

pharmacology and toxicology↗

bioRxiv2025

Long-Term Potentiation and Closed-Loop Learning in Paired Brain Organoids for CNS Drug Discovery

Learning and memory, central to cognitive function and critical targets for drug discovery in neurological disorders, fundamentally rely on synaptic plasticity, such as long-term potentiation (LTP). We developed an embedded electrode array (EEA) capable of supporting paired CNS-3D brain organoids, derived from human, induced pluripotent stem cells (iPSCs), that were interconnected via guided axonal growth, as a novel functional biomarker model for probing learning-related plasticity in vitro. Using open-loop stimulation protocols, a robust, network-level LTP in trained organoids was demonstrated that was not observed in untrained organoids. Importantly, LTP was enhanced in the presence of elevated levels of brain-derived neurotrophic factor (BDNF), and it was prevented by the NMDA receptor antagonist AP5. Furthermore, a closed-loop "maze-game", inspired by Pac-Man(R), demonstrated that paired brain organoids could learn to perform better in the game when given reinforcement feedback, and that this effect depended on BDNF. This integrated platform provides a human-relevant in vitro model of synaptic plasticity and cognitive function, establishing a functional biomarker platform for central nervous system (CNS) drug discovery and linking game performance as a measurable readout of learning-related plasticity to the emerging field of organoid intelligence.

bioengineering↗

bioRxiv2018

Tunable molecular tension sensors reveal extension-based control of vinculin loading

Molecular tension sensors have contributed to a growing understanding of mechanobiology. However, the limited dynamic range and inability to specify the mechanical sensitivity of these sensors has hindered their widespread use in diverse contexts. Here, we systematically examine the components of tension sensors that can be altered to improve their functionality. Guided by the development of a first principles model describing the mechanical behavior of these sensors, we create a collection of sensors that exhibit predictable sensitivities and significantly improved performance in cellulo. Utilized in the context of vinculin mechanobiology, a trio of these new biosensors with distinct force- and extension- sensitivities reveal that an extension-based control paradigm regulates vinculin loading. To enable the rational design of molecular tension sensors appropriate for diverse applications, we predict the mechanical behavior, in terms of force and extension, of additional 1020 distinct designs.

biophysics↗