Article by Nadia Boachie

Graphic design by Ingrid Barany

In March 2020, the World Health Organization (WHO) declared COVID-19 a global pandemic. Researchers immediately began collaborating in efforts to develop a vaccine, find treatments, and better analyze the trajectory of the virus to help prepare for current and future outbreaks. In Toronto, a number of brilliant scientists have demonstrated their ability to perform quality research when the stakes are at their highest. Now, more than ever, there is immense pressure to yield useful scientific results. 

The IMS Magazine had the pleasure of sitting down with one of these researchers, Professor Haibo Zhang, to discuss his ongoing studies on COVID-19. Dr. Zhang is a staff scientist in the Keenan Research Centre for Biomedical Science at St. Michael’s Hospital. He is a professor in the Anesthesia, Medicine, and Physiology Departments at the University of Toronto. His work is currently looking at a potential drug to treat COVID-19. Together with his team of researchers, students, and several collaborators, he is making great strides to uncover treatments that can be used globally in human patients. 

Before COVID-19, Dr. Zhang’s translational research program focused on the mechanisms and therapy of acute lung injury and sepsis. “My research has been lung infection and stem cell therapy. I have been doing this for almost 20 years since I started my faculty appointment with the University of Toronto,” he recalls.

Dr. Zhang has published over 250 peer-reviewed articles and is the recipient of several large research grants, the latest being a one-million-dollar grant from CIHR for COVID-19 related research. His two-year study is one of 99 COVID-19 research projects that are funded by the Canadian federal government¹.

Almost 20 years ago, the world faced a similar outbreak of Severe Acute Respiratory Syndrome (SARS)—the viral respiratory illness recognized as a global threat in 2003. Researchers identified a cell membrane protein called angiotensin-converting enzyme 2 (ACE2) that is a host cell receptor for SARS coronavirus (SARS-CoV) infections. Researchers quickly realized that ACE2 has even higher binding affinity to SARS-CoV-2, which causes COVID-19.

ACE2 is currently an important target for COVID-19 treatments due to its key involvement in the mechanism behind the infection. It can be considered the cellular door in which SARS-CoV-2 infects its host. Dr. Zhang describes the process by which COVID-19 infections occur, “there is receptor-ligand interaction between ACE2 on host cells and the surface spike protein on SARS-CoV-2 virus that allows the virus to penetrate into the host. The virus then replicates and causes injury to different organs through the blood stream.”

In collaboration with Professor Penninger of University of British Columbia, who co-founded a company called Apeiron Biologics located in Vienna, they produced a soluble form of ACE2 named APN01. Dr. Zhang hopes that if a soluble form of ACE2 is administered in the infected sites, it can act as a decoy and competitively bond with the virus so that it can no longer enter cells. The immune system will then be able to tackle the already infected virus while it remains at manageable levels.

In a paper published earlier this year, Dr. Zhang and his group discussed the rationale for targeting ACE2 receptors as a specific target to treat COVID-19. This paper was published in Intensive Care Medicine and was cited over 1,150 times in less than 10 months.²  

Currently, Dr. Zhang and international collaborators are on track to complete clinical trials that are assessing the efficacy of the soluble form of ACE2. “We have a Phase IIb trial ongoing to treat 200 severely infected COVID-19 patients. The randomized, double-blind, controlled trial will compare APN01 to a placebo at different clinical centres in Austria, Denmark, Sweden, Germany and Russia.“We have just recruited the last patient a couple of weeks ago,” he shares.

The research group has also published a case report of a patient with a severe COVID-19 infection. They saw some promising effects, however, they “cannot make any affirmative conclusions because it is a case report,” Dr. Zhang explains. The patient described in the report is a 45-year-old woman who was diagnosed with a SARS-CoV-2 infection and 9 days after she had symptoms was treated with APN01 intravenous infusions for 5 min twice daily. The data shows that the virus disappeared rapidly. They concluded that it remains speculative whether this decrease in viral load reflects the effect of APN01 treatment or the of the virus’ natural progression, but the results were promising overall.³

Dr. Zhang expressed his excitement to get results from the upcoming clinical trials, “we cannot do any analysis now because we are not yet finished data collection, so we are anxious to see our results,” he clarifies.

Although there is a lot of focus and excitement on clinical trials, Dr. Zhang’s group is conducting a lot of pre-clinical work on COVID-19 in a CL3 lab – a Level 3 containment lab that maintains secure facilities for work with Risk Group 3 pathogens such as emerging infectious diseases.⁵ “For clinical trials, you can only look at the outcome and you do not know exactly what the mechanisms are. The pre-clinical trials tell us what key cell signaling sources are responsible for these changes.” Prior to working at the CL3 lab of the Temerty Faculty of Medicine Dr. Zhang,in collaboration with an international team, found that the soluble human ACE2 can significantly inhibit the virus in human-engineered tissue. This earlier pre-clinical work was published in the journal Cell. The paper also demonstrated that the virus can directly infect and replicate itself in human blood vessel and kidney organoids.⁵

“The University of Toronto was pretty well known in the lung research field before COVID-19,” Dr. Zhang tells IMS Magazine. “However, through our analysis of the mechanism of COVID-19 and potential drugs for treatment, people have been far more connected with us,” he explains. Dr. Zhang elaborated how he had panel meetings every day at the beginning of the pandemic in order to figure out how to contain this virus. A lot of companies and physicians contacted his team when there were major outbreaks in countries like Italy.

Dr. Haibo Zhang is collaborating on COVID-19 related projects with several research groups and companies in and out of the Toronto community. Collaborators include team members at Stanford University, Southern California University, Columbia University, Medicago and Tailed Genes Inc., and yet Dr. Zhang seamlessly manages it all. When asked how he keeps up with everything, Dr. Zhang’s response was “you just keep going and, in the lab, we fortunately have a very strong senior research associate, research coordinator, physician-scientist fellows, PhD and master’s students, a great team. For all the different collaborations with different companies and groups I have to keep track of progress daily. It is pretty intense, but it is going well, so we keep going to fight the terrible COVID-19.”

References

1. Canadian Institutes of Health Research. Government of Canada [Internet]. Government of Canada funds 49 additional COVID-19 research projects – Details of the funded projects. Updated April 2020. [cited 2020 Dec 4]. Available from: https://www.canada.ca/en/institutes-health-research/news/2020/03/government-of-canada-funds-49-additional-covid-19-research-projects-details-of-the-funded-projects.html.
2. Zhang H, Penninger JM, Li Y, et al. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Medicine. 2020;46(4):586-90.
3. ClinicalTrials.gov [Internet]. NIH: US National Library of Medicine (US). Identifier NCT04335136. Recombinant Human Angiotensin-converting Enzyme 2 (rhACE2) as a Treatment for Patients With COVID-19 (APN01-COVID-19). 2020 Apr 6. [cited 2020 Dec 4]. Available from: https://clinicaltrials.gov/ct2/show/NCT04335136
4. Zoufaly A, Poglitsch M, Aberle JH, et al. Human recombinant soluble ACE2 in severe COVID-19. The Lancet Respiratory Medicine. 2020;8(11):1154-8.
5. Temerty Faculty of Medicine. [Internet]. [cited 2021 Jan 4]. Available from: https://medicine.utoronto.ca/combined-containment-level-3-unit