PT  - JOURNAL ARTICLE
AU  - Yuling Han
AU  - Liuliu Yang
AU  - Xiaohua Duan
AU  - Fuyu Duan
AU  - Benjamin E. Nilsson-Payant
AU  - Tomer M. Yaron
AU  - Pengfei Wang
AU  - Xuming Tang
AU  - Tuo Zhang
AU  - Zeping Zhao
AU  - Yaron Bram
AU  - David Redmond
AU  - Sean Houghton
AU  - Duc Nguyen
AU  - Dong Xu
AU  - Xing Wang
AU  - Skyler Uhl
AU  - Yaoxing Huang
AU  - Jared L. Johnson
AU  - Jenny Xiang
AU  - Hui Wang
AU  - Fong Cheng Pan
AU  - Lewis C. Cantley
AU  - Benjamin R. tenOever
AU  - David D. Ho
AU  - Todd Evans
AU  - Robert E. Schwartz
AU  - Huanhuan Joyce Chen
AU  - Shuibing Chen
TI  - Identification of Candidate COVID-19 Therapeutics using hPSC-derived Lung Organoids
AID  - 10.1101/2020.05.05.079095
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.05.05.079095
4099  - http://biorxiv.org/content/early/2020/05/05/2020.05.05.079095.short
4100  - http://biorxiv.org/content/early/2020/05/05/2020.05.05.079095.full
AB  - The SARS-CoV-2 virus has caused already over 3.5 million COVID-19 cases and 250,000 deaths globally. There is an urgent need to create novel models to study SARS-CoV-2 using human disease-relevant cells to understand key features of virus biology and facilitate drug screening. As primary SARS-CoV-2 infection is respiratory-based, we developed a lung organoid model using human pluripotent stem cells (hPSCs) that could be adapted for drug screens. The lung organoids, particularly aveolar type II cells, express ACE2 and are permissive to SARS-CoV-2 infection. Transcriptomic analysis following SARS-CoV-2 infection revealed a robust induction of chemokines and cytokines with little type I/III interferon signaling, similar to that observed amongst human COVID-19 pulmonary infections. We performed a high throughput screen using hPSC-derived lung organoids and identified FDA-approved drug candidates, including imatinib and mycophenolic acid, as inhibitors of SARS-CoV-2 entry. Pre- or post-treatment with these drugs at physiologically relevant levels decreased SARS-CoV-2 infection of hPSC-derived lung organoids. Together, these data demonstrate that hPSC-derived lung cells infected by SARS-CoV-2 can model human COVID-19 disease and provide a valuable resource to screen for FDA-approved drugs that might be repurposed and should be considered for COVID-19 clinical trials.Competing Interest StatementR.E.S. is on the scientific advisory board of Miromatrix Inc. The authors have no conflict of interest. L.C.C. is a founder and member of the board of directors of Agios Pharmaceuticals and is a founder and receives research support from Petra Pharmaceuticals. L.C.C. is an inventor on patents (pending) for Combination Therapy for PI3K-associated Disease or Disorder, and The Identification of Therapeutic Interventions to Improve Response to PI3K Inhibitors for Cancer Treatment. L.C.C. is a co-founder and shareholder in Faeth Therapeutics. T.M.Y. is a stockholder and on the board of directors of DESTROKE, Inc., an early-stage start-up developing mobile technology for automated clinical stroke detection.