# Elucidating pathogenic mechanisms in STRADA-related brain malformation and epilepsy

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $420,070

## Abstract

PROJECT SUMMARY
Epilepsy is a major cause of morbidity, mortality, disability, and expense, and affects over 470,000 children in
the U.S. While many medications to control seizures have been developed, about 30% of patients do not
respond to medications, and to date, there are no medications that can prevent or halt the progression of
epilepsy. Recently, many genetic causes of epilepsy have been identified, providing insights into pathways
involved in epileptogenesis. Mutations causing hyperactivity of the mTOR pathway (so-called “mTORpathies”)
have emerged as an important cause of cerebral malformations and epilepsy, including tuberous sclerosis
complex, focal cortical dysplasia, and polyhydramnios, megalencephaly, and symptomatic epilepsy (PMSE)
syndrome, which is associated with severe epilepsy and intellectual disability and is caused by a loss-of-
function in the STRADA gene. Inhibition of the mTOR pathway with rapamycin or its analogs can help in
mTORopathies, but many individuals still have seizures that do not respond. Prior studies generated stem cells
from individuals with PMSE and differentiated them into excitatory neurons in 2-D culture and dorsally-fated
human cerebral organoids, 3-D neural structures that resemble the developing cortex and predominantly
contain excitatory neurons. The PMSE organoids demonstrated mTOR hyperactivity, increased size, abnormal
morphology, delayed neuronal differentiation, and an increase in outer radial glia, a progenitor cell that is
responsible for the expanded size of the human brain. These findings explain megalencephaly in PMSE, but
the intermediate mechanisms by which STRADA loss-of-function results in these observed phenotypes is not
known. Furthermore, the effect of STRADA loss-of-function on inhibitory interneurons that originate from
ventral forebrain structures is not known. Abnormal inhibitory interneurons are a major cause of epilepsy and
autism, both prominent features of mTORopathies. This proposal will test the central hypothesis that loss of
STRADA causes cortical malformation by mTOR complex 1 hyperactivity, and that inhibitory interneuron
development is also impaired, resulting in epilepsy. This innovative proposal will use dorsally-fated organoids
to identify which signaling pathway alterations downstream of STRADA result in altered cortical development,
and will determine whether compensatory feedback signals hinder the effectiveness of rapamycin treatment
(Aim 1). We will also generate fusions between ventrally-fated and dorsally-fated organoids to study
interneuron development, interneuron migration, cell-type specific transcriptional alterations (Aim 2), as well as
neuronal network hyperexcitability that can result in epilepsy (Aim 3). The proposed study will have significant
impact because understanding the signaling pathways and cell types responsible for pathogenesis in PMSE
will provide a platform to develop mechanistically driven therapies that can halt or reverse epileptog...

## Key facts

- **NIH application ID:** 10867413
- **Project number:** 5R01NS127829-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Louis Tuong Chinh Dang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $420,070
- **Award type:** 5
- **Project period:** 2022-08-15 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10867413

## Citation

> US National Institutes of Health, RePORTER application 10867413, Elucidating pathogenic mechanisms in STRADA-related brain malformation and epilepsy (5R01NS127829-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10867413. Licensed CC0.

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