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

> **NIH NIH UH3** · VANDERBILT UNIVERSITY · 2020 · $1,142,940

## Abstract

Although COVID-19 is recognized primarily as a respiratory infection and the majority of deaths from the
disease are attributed to pulmonary failure, it has become increasingly apparent that the SARS-CoV-2 virus,
either directly or indirectly, affects all major organ systems with a confounding degree of variability that
complicates the identification of effective therapeutics. In particular, the central nervous system (CNS) and
vasculature both seem to play a significant role in disease progression, and CNS symptoms have correlated
with poorer outcomes in COVID-19 patients. It is hypothesized that the CNS and vasculature each influence
pathological dysregulation of immune response, but very little is known about how they respond and possibly
contribute to disease progression. No single therapeutic agent has emerged that broadly neutralizes COVID-19
disease progression, which strongly suggests that any effective treatment strategies will need to address not
only effects of SARS-CoV-2 infection in the lungs, but also inflammation in many organ systems, which in turn
would require therapeutic access to the CNS. Thus, understanding the interactions between the lungs and the
CNS is critical to identifying treatments capable of improving the prognoses of COVID-19 patients and reducing
hospitalization rates and mortality. This project will evaluate how SARS-CoV-2 infection in the lungs
contributes to both the organ dysfunction in COVID-19 and potential CNS infection, and how well the
combination of anti-viral and anti-inflammatory drugs addresses CNS involvement in COVID-19. These goals
demand a physiologically relevant in vitro platform that fully recapitulates the systemic immune and cytokine
storm responses following infection of airway epithelium associated with the most severe cases of COVID-19
and that can be readily used in the Biosafety Level-3 (BSL-3) facilities required for studies of this highly
infectious respiratory disease. This project will implement a two-organ microphysiological system (MPS) model
that uses an existing NeuroVascular Unit (NVU)/blood-brain barrier tissue chip for the CNS component,
repurposes the NVU as an Airway Chip for the lung component, and converts both chips to gravity perfusion
for ease of use in BSL-3 facilities. The aims are to 1) model COVID-19 infection and innate pulmonary
response in the Airway Chip, 2) couple the NVU and Airway Chip to evaluate how the response of the Airway
Chip to COVID-19 infection affects the function of the NVU, as required to establish therapeutic benchmarks
for drug testing, and 3) screen FDA-approved drugs for efficacy in treating negative symptoms in the
NVU/Airway Chip model. A comparison of infection of the separate NVU/CNS and Airway tissue chips with
infection of the coupled-chip system will help determine the infectability of each MPS model and the viral
capacity to cross the blood-brain barrier into the CNS. Candidate FDA-approved drugs will be tested for their
ability to af...

## Key facts

- **NIH application ID:** 10174287
- **Project number:** 3UH3TR002097-04S1
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** KEVIN C ESS
- **Activity code:** UH3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,142,940
- **Award type:** 3
- **Project period:** 2020-09-19 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10174287

## Citation

> US National Institutes of Health, RePORTER application 10174287, Drug development for tuberous sclerosis complex and other pediatric epileptogenic diseases using neurovascular and cardiac microphysiological models (3UH3TR002097-04S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10174287. Licensed CC0.

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