# Evaluating teratogenic risk of anti-seizure medications in single-rosette brain organoids

> **NIH NIH R21** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $117,000

## Abstract

Project Abstract
Neural tube defects (NTDs) are common malformations of the nervous system that occur during pregnancy.
NTDs are caused by genetic variants or maternal environmental exposures, and they often lead to severe
physical and/or cognitive disabilities. Pharmaceuticals can sometimes lead to NTDs in human embryos despite
screening in rodent models due to human-specific toxicity. Many anti-seizure medications (ASMs), drugs used
in the management of epilepsy increase the risk of NTDs during pregnancy but are typically not discontinued
because of danger to the mother and fetus from seizures. Therefore, it is important to compare the
neuroteratogenic risk of these compounds to choose the most appropriate ASM during pregnancy. Having a
human-specific model of early neurodevelopment should increase this screening predictiveness. Attempts to
utilize human brain organoid technology to this end are limited due to structural heterogeneity and intra-
organoid variability. Our recent development of reproducible self-organizing single rosette spheroids (SOSRS)
from human induced pluripotent stem cells has allowed us to treat SOSRS with known neuroteratogens and
observe distinct structural changes consistent with NTDs. The goal in Aim 1 is to compare the structural
consequences of all 20 commonly used ASMs in SOSRS at multiple concentrations to determine a
concentration dependent risk for each. In Aim 2, we will perform comparative transcriptomics of SOSRS
treated with 5 mechanistically distinct neuroteratogens. Transcriptomic changes shared by all 5 will be
considered a neuroteratogenic biomarker that will then be applied by targeted NGS to RNA samples from
SOSRS treated with each of the commonly used ASMs to provide further risk comparison. In Aim 3, we will
adapt the SOSRS protocol to generate lumbar spinal cord SOSRS in order to compare teratogenicity of
valproic acid between rostral (cortical SOSRS) and caudal (lumbar SOSRS) neural tube models. Our study
may also shed light on the undefined mechanisms by which ASMs cause NTDs. The platform and biomarkers
developed by this study could also allow for screening novel pharmaceuticals for NTD risk in a human-specific
system in the future.

## Key facts

- **NIH application ID:** 10315793
- **Project number:** 1R21HD106580-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Andrew M Tidball
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $117,000
- **Award type:** 1
- **Project period:** 2021-09-20 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10315793

## Citation

> US National Institutes of Health, RePORTER application 10315793, Evaluating teratogenic risk of anti-seizure medications in single-rosette brain organoids (1R21HD106580-01). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10315793. Licensed CC0.

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