SSRP Abstract

Board 34: Identifying Early Developmental Neurotoxicity Modeled in a Cerebral Organoid System

Student Scientist: Trey Theobald ’25
Research Mentors: Ethan Lippman (Departments of Biomedical Engineering and Chemical & Biomolecular Engineering, Vanderbilt University) and Andrew Kjar (Department of Chemical & Biomolecular Engineering, Vanderbilt University)

In drug development, human clinical trials are used to screen for toxicity and side effects in patient populations. Due to the uncertainty of these side effects as well as their severity, pregnant individuals are generally excluded from such trials to prevent injury to the developing fetus. In this project, human brain cells are grown in a pattern that mimics the development of the fetus thereby providing a way to test medication safety without endangering an infant’s life.

Pregnant individuals are typically excluded from traditional clinical trials due to ethical and safety concerns for the fetus. This lack of data leads to challenges in managing the health concerns of the expectant patient while also protecting the developing fetus from neurologically damaging medications. To be able to effectively understand how certain medications impact fetal neurodevelopment, alternative screening methods for neurotoxicity are essential. Here, we provide a scalable, human specific model for neurological drug toxicity screening using human induced pluripotent stem cell derived cerebral organoids that model the growth and layering of the developing fetal brain. In control organoids, neural progenitors (SOX2⁺/PAX6⁺) comprised the center of the tissue while mature neurons (ßIIIT⁺/TBR1⁺) formed the outer surface. We tested gabapentin for neurotoxicity using folic acid and valproic acid as controls to verify the sensitivity of our system. Size and shape characterization over 30 days revealed that folic acid and gabapentin drug concentration did not affect the growth kinetics of organoids while organoids dosed with valproic acid exhibited a decreased growth rate at a concentration of 10 mM. Secondary cell titer assays revealed decreased viability in organoids with high concentrations of valproic acid, confirming the size characterization. Preliminary spinning disc confocal imaging indicated that organoids dosed with 10mM valproic acid exhibited few ßIIIT⁺ cells. Future development of our high throughput screening organoid model will provide an ethical and efficient method of evaluating neurotoxicity for early developmental and fetal populations.