Project Abstract SARS-CoV-2 novel coronavirus has caused a pandemic, presenting us with an urgent need to develop new models to study the pathophysiology of infection and test innovative therapeutics to combat disease. This proposal aims to use chip-based microphysiological systems to establish a model of the human lung to investigate SARS-CoV-2 infection and test novel antisense oligonucleotide (ASO) therapies to reduce viral entry and replication. Using human primary and induced pluripotent stem cell (iPSC)-derived lung epithelium, we will generate both proximal and distal airway chip models, infect with live SARS-CoV-2, and test newly designed ASOs to target host cell components to prevent viral entry and conserved viral sequences to prevent replication. We have assembled an expert team of lung biologists, virologists, and pharmaceutical industry partners to complement the iPSC and organ-chip technologies our lab has been developing over the past five years. We feel that the approach presented in this proposal will yield rapid results by generating human- relevant models to better understand the pathological mechanisms of SARS-CoV-2 infection and test novel therapeutic strategies currently in development by our pharmaceutical industry partner.

Project Narrative In collaboration with UCLA and the company IONIS we will establish a new model of COVID on a chip using both primary and iPSC derived lung epithelial cells. We will then test a novel approach to treating COVID with the world’s largest antisense company – targeting both the receptor complexes the virus uses to enter the cells and the virus itself. Delivery of the ASO’s will be to the air side of the lung chip using the type of aerosol that is currently being used in clinical trials for patients with Cystic Fibrosis. These data will be used for rapid IND submission to FDA to try this approach in human patients.