By Ana Gajic
An international team of researchers led by University of British Columbia and in collaboration with St. Michael’s Hospital has found a trial drug that effectively blocks the cellular door SARS-CoV-2 uses to infect its hosts.
The findings, published today in Cell, hold promise as a treatment capable of stopping early infection of the novel coronavirus. The study provides new insights into key aspects of SARS-CoV-2, the virus that causes COVID-19, and its interactions on a cellular level, as well as how the virus can infect blood vessels and kidneys.
“We are hopeful our results have implications for the development of a novel drug for the treatment of this unprecedented pandemic,” says Dr. Josef Penninger, Professor in UBC’s Faculty of Medicine and Director of the Life Sciences Institute at UBC.
“This work stems from an amazing collaboration among academic researchers and companies, including STEMCELL Technologies in Vancouver, Dr. Nuria Montserrat in Spain, Drs. Haibo Zhang and Art Slutsky from Toronto and Dr. Ali Mirazimi’s infectious biology team in Sweden, who have been working tirelessly day and night for weeks to better understand the pathology of this disease and to provide therapeutic options.”
ACE2 — a protein on the surface of the cell membrane — is now at centre-stage in this outbreak as the key receptor for the spike glycoprotein of SARS-CoV-2. In earlier work, Dr. Penninger and colleagues at the University of Toronto and the Institute of Molecular Biology in Vienna first identified ACE2, and found that in living organisms, ACE2 is the key receptor for SARS, the viral respiratory illness recognized as a global threat in 2003. His laboratory also went on to link the protein to both cardiovascular disease and lung failure.
While the COVID-19 outbreak continues to spread around the globe, the absence of a clinically proven antiviral therapy or a treatment specifically targeting the critical SARS-CoV-2 receptor ACE2 on a molecular level has meant an empty arsenal for health-care providers treating severe cases of COVID-19.
“Our new study provides very much needed direct evidence that a drug — called APN01 (human recombinant soluble angiotensin-converting enzyme 2 – hrsACE2) — soon to be tested in clinical trials by the European biotech company Apeiron Biologics, is useful as an antiviral therapy for COVID-19,” adds Dr. Art Slutsky, a Scientist at the Keenan Research Centre for Biomedical Science of St. Michael’s Hospital and Professor at the University of Toronto who is a collaborator on the study.
In cell cultures analyzed in the current study, hrsACE2 inhibited the coronavirus load by a factor of 1,000-5,000. In engineered replicas of human blood vessel and kidneys — organoids grown from human stem cells — the researchers demonstrated that the virus can directly infect and duplicate itself in these tissues. This provides important information on the development of the disease and the fact that severe cases of COVID-19 present with multi-organ failure and evidence of cardiovascular damage. Clinical grade hrsACE2 also reduced the SARS-CoV-2 infection in these engineered human tissues.
“These research findings demonstrated in human-engineered organoids not only establish a novel drug screening platform, but more importantly, also provide a direct link to the clinical features and mechanistic insights of multiple organ failure associated with COVID-19.” says Dr. Haibo Zhang, a Scientist at the Keenan Research Centre for Biomedical Science of St. Michael’s Hospital and Professor at the University of Toronto who is another collaborator on the study.
“Using organoids allows us to test in a very agile way treatments that are already being used for other diseases, or that are close to being validated. In these moments in which time is short, human organoids save the time that we would spend to test a new drug in the human setting.” states Dr. Núria Montserrat, ICREA Professor at the Institute for Bioengineering of Catalonia (IBEC) in Spain.
“The virus causing the COVID-19 is a close sibling to the SARS virus,” adds Penninger. “Our previous work has helped to rapidly identify ACE2 as the entry gate for SARS-CoV-2, which explains a lot about the disease. Now we know that a soluble form of ACE2 that catches the virus away, could be indeed a very rational therapy that specifically targets the gate the virus must take to infect us.”
This research was supported in part by the Canadian federal government through emergency funding focused on accelerating the development, testing, and implementation of measures to deal with the COVID-19 outbreak.
About St. Michael’s Hospital
St. Michael’s Hospital provides compassionate care to all who enter its doors. The hospital also provides outstanding medical education to future health care professionals in more than 27 academic disciplines. Critical care and trauma, heart disease, neurosurgery, diabetes, cancer care, care of the homeless and global health are among the Hospital’s recognized areas of expertise. Through the Keenan Research Centre and the Li Ka Shing International Healthcare Education Centre, which make up the Li Ka Shing Knowledge Institute, research and education at St. Michael’s Hospital are recognized and make an impact around the world. Founded in 1892, the hospital is fully affiliated with the University of Toronto.
About Unity Health Toronto
Unity Health Toronto, comprised of Providence Healthcare, St. Joseph’s Health Centre and St. Michael’s Hospital, works to advance the health of everyone in our urban communities and beyond. Our health network serves patients, residents and clients across the full spectrum of care, spanning primary care, secondary community care, tertiary and quaternary care services to post-acute through rehabilitation, palliative care and long-term care, while investing in world-class research and education. For more information, visit www.unityhealth.to.