# Drug development for tuberous sclerosis complex and other pediatric epileptogenic diseases using neurovascular and cardiac microphysiological models

> **NIH NIH UH3** · VANDERBILT UNIVERSITY · 2021 · $1,149,180

## Abstract

The goal of this proposal is to establish in vitro tissue chip models of the closely related neurological disorders
tuberous sclerosis complex (TSC) epilepsy, DEPDC5-associated epilepsy, and their associated cardiac
dysfunction. The proposed research leverages emerging bioengineering technology for microphysiological
systems developed at the Vanderbilt Institute for Integrative Biosystems Research and Education (VIIBRE)
with human induced pluripotent stem cell tools in regular use at Vanderbilt University Medical Center to ask
probing questions about genetic disorders that afflict the heart and brain and about the drugs to treat them.
The VIIBRE neurovascular unit (NVU)/blood-brain barrier and cardiac I-Wire organ-on-chip models will test the
hypothesis that mTORC1 and mTORC2 signaling differentially affect neural and cardiac dysfunction in TSC-
and DEPDC5-associated epilepsy. The primary and shared abnormality in patients with TSC and DEPDC5-
associated epilepsy is dysregulation of the mTOR kinase complex 1 (mTORC1) signaling pathway. TSC also
has abnormalities in mTORC2 signaling not seen in DEPDC5-associated epilepsy. A focus on mTOR signaling
in these human mTORopathies has several advantages. First, rapamycin and related compounds are FDA-
approved mTORC1 inhibitors and have been shown to have efficacy in some aspects of the disease
manifestations of TSC. Second, TSC- and DEPDC5-associated epilepsy are both associated with neural and
cardiac dysfunction. Third, the role for compensatory or differential mTORC2 activity is unclear and
controversial. For patients with TSC, drugs targeting the mTORC1 signaling pathway have been associated
with shrinkage of brain tumors, reduced seizures, and improved cardiac function. Thus, drug development for
this group of diseases is well suited for study using both the NVU and I-Wire cardiac-tissue chips. In its first two
years, the project will develop the NVU and I-Wire disease models, aimed at refining the TSC and DEPDC5
NVU model; applying the I-Wire model to TSC and DEPDC5 cardiomyocytes; and validating outcome
methodologies in control and patient-derived NVU and I-Wire chips. The next three years aim to evaluate, for
biomarker identification in control, TSC, and DEPDC5 NVU and I-Wire chips, changes in mTORC1 and
mTORC2 signaling, protein markers of cellular health and toxicity, metabolites, functional measures and
electrophysiological activity; and, use ion mobility-mass spectrometry to evaluate NVU and I-Wire outcome
measures plus drug metabolites after treatment with mTORC1 inhibitor rapamycin, the seizure drug vigabatrin,
and novel pre-clinical mTOR drug candidates. The NVU and I-Wire will assess the efficacy and toxicity of these
agents and define TSC/DEPDC5 shared vs disease-specific effects. With this organ-on-chip/human induced
pluripotent stem cell platform, it will be possible to address currently confounding mechanisms of
pathogenesis, identify new disease biomarkers, quantify how drugs cross...

## Key facts

- **NIH application ID:** 10240589
- **Project number:** 5UH3TR002097-05
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** KEVIN C ESS
- **Activity code:** UH3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,149,180
- **Award type:** 5
- **Project period:** 2017-07-21 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10240589

## Citation

> US National Institutes of Health, RePORTER application 10240589, Drug development for tuberous sclerosis complex and other pediatric epileptogenic diseases using neurovascular and cardiac microphysiological models (5UH3TR002097-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10240589. Licensed CC0.

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