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

Although COVID-19 is recognized primarily as a respiratory infection and the majority of deaths from thedisease 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 thatcomplicates the identification of effective therapeutics. In particular, the central nervous system (CNS) andvasculature both seem to play a significant role in disease progression, and CNS symptoms have correlatedwith poorer outcomes in COVID-19 patients. It is hypothesized that the CNS and vasculature each influencepathological dysregulation of immune response, but very little is known about how they respond and possiblycontribute to disease progression. No single therapeutic agent has emerged that broadly neutralizes COVID-19disease progression, which strongly suggests that any effective treatment strategies will need to address notonly effects of SARS-CoV-2 infection in the lungs, but also inflammation in many organ systems, which in turnwould require therapeutic access to the CNS. Thus, understanding the interactions between the lungs and theCNS is critical to identifying treatments capable of improving the prognoses of COVID-19 patients and reducinghospitalization rates and mortality. This project will evaluate how SARS-CoV-2 infection in the lungscontributes to both the organ dysfunction in COVID-19 and potential CNS infection, and how well thecombination of anti-viral and anti-inflammatory drugs addresses CNS involvement in COVID-19. These goalsdemand a physiologically relevant in vitro platform that fully recapitulates the systemic immune and cytokinestorm responses following infection of airway epithelium associated with the most severe cases of COVID-19and that can be readily used in the Biosafety Level-3 (BSL-3) facilities required for studies of this highlyinfectious respiratory disease. This project will implement a two-organ microphysiological system (MPS) modelthat 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 perfusionfor ease of use in BSL-3 facilities. The aims are to 1) model COVID-19 infection and innate pulmonaryresponse in the Airway Chip, 2) couple the NVU and Airway Chip to evaluate how the response of the AirwayChip to COVID-19 infection affects the function of the NVU, as required to establish therapeutic benchmarksfor drug testing, and 3) screen FDA-approved drugs for efficacy in treating negative symptoms in theNVU/Airway Chip model. A comparison of infection of the separate NVU/CNS and Airway tissue chips withinfection of the coupled-chip system will help determine the infectability of each MPS model and the viralcapacity to cross the blood-brain barrier into the CNS. Candidate FDA-approved drugs will be tested for theirability to affect viral infection, replication, and cytokine production in both microphysiological systems.