AWARDEES

Christine Bear

Senior Scientist, Programme in Molecular Medicine - Hospital for Sick Children 

Development of a platform for SARS-CoV-2 therapy testing and development using primary nasal epithelial cultures

There is an urgent need to define the pathogenesis of COVID-19 disease and to find therapies that ameliorate the consequences of COVID-19 infection while vaccines are being developed.  This is particularly relevant for those with pre-existing respiratory diseases. However, progress in therapy development is limited by the need for Level 3 biosafety containment in order to study the replicating virus and the paucity of relevant cell-based models of SARS-CoV-2 infection. A pseudo-virus containing the SARS-CoV-2 spike (S) gene is relatively safe (requiring level 2 biosafety containment) and has been shown to model the initial stages of infection using generic cell lines.  Recent transcriptomic studies revealed that primary nasal epithelial cells harbor high levels of the SARS-CoV-2 receptor gene, ACE2, suggesting that the lining of the upper respiratory tract is a primary determinant of disease pathogenesis.  Therefore, we will use  the pseudo-virus of SARS-CoV-2 to infect primary nasal epithelial cultures from our bioresource at the Hospital for Sick Children in order to produce a high-fidelity infection model suitable for understanding disease mechanisms and testing emerging therapies.  

Parastoo Khoshakhlagh

Co-founder, President and CEO, GC Therapeutics, Inc.

Investigating the effects of hypertension drugs on the Infectivity of SARS-CoV-2 in synthetically accelerated vascularized type II pneumocyte-containing pulmonary organoids

The SARS-CoV-2 virus, which is responsible for the COVID-19 pandemic, is known to enter type II pneumocytes in the lung by binding to the angiotensin-converting enzyme 2 (ACE2) membrane protein. COVID-19 patients with hypertension and cardiovascular disease seem to have a 3x higher mortality rate. It has been suggested that commonly prescribed drug classes for these conditions, ACE inhibitors and angiotensin-receptor blockers (ARBs), may alter ACE2 expression and augment disease prognosis and mortality in COVID-19 patients. Given the common use of these drugs, there is an urgent need to better understand their potential effect on ACE2 expression in the lungs and their role in SARS-CoV-2 infectivity. Currently, there is a lack of reliable in vitro models to accurately study the effects of ACE inhibitors and ARBs on human lungs. Here, we propose using our genetic-programming technology, the TFome, to rapidly differentiate human induced pluripotent stem cells (hiPSCs) into vascularized type II pneumocyte-containing pulmonary organoids. We have previously built the first most comprehensive library of human transcription factors (TFs; 1564 genes, “TFome”) and developed reproducible protocols to differentiate hiPSCs into multiple cell types with >95% efficiency in <4 days6. These cells have been shared with >48 academic labs for basic science, drug screening and regenerative medicine studies. By developing physiologically-relevant lung organoids we hope to provide alternatives to animal testing and provide the field with an accurate model to screen potential therapeutics and study the pathogenesis of current and future SARS-CoV-2.