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Josef Penninger : Trial drug
can significantly block early stages of COVID-19 in engineered human tissues


In cell cultures
analyzed in the current study, hrsACE2 inhibited the coronavirus load by a
factor of 1,000-5,000. Credit: IMBA/Tibor Kulcsar

‘There is hope for this horrible pandemic,’
says UBC scientist Dr. Josef Penninger


An international team led by University of
British Columbia researcher Dr. Josef Penninger 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 that, as of April 2, has affected more than 981,000 people and
claimed the lives of 50,000 people worldwide.


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 Penninger, professor in UBC’s faculty of
medicine, director of the Life Sciences Institute and the Canada 150 Research
Chair in Functional Genetics at UBC.


“This work stems from an amazing
collaboration among academic researchers and companies, including Dr. Ryan
Conder’s gastrointestinal group at STEMCELL
Technologies
in Vancouver, Nuria Montserrat in Spain, Drs. Haibo Zhang and
Art Slutsky from Toronto and especially 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 breakthrough
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, 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
struggling to treat 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,” says 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.


“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,” says Núria Montserrat, ICREA professor at the Institute for
Bioengineering of Catalonia in Spain.


“The virus causing COVID-19 is a close
sibling to the first 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. There is hope for this horrible
pandemic.”


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.


Editors/journalists:
Click here
to see more illustrations of engineered replicas of human blood vessels and
kidneys grown from stem cells being treated with hrsACE2. Image credit:
IMBA/Tibor Kulcsar


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