Every few years, a new virus outbreak occurs that affects thousands of people such as the SARS-CoV in 2003, Ebola in 2014, and now the SARS-CoV-2 since December 2019. These frequent outbreaks have proved to be specially challenging as treatment discoveries have a time constraint.
SARS-CoV-2 results in COVID-19, that has flu like symptoms ranging from mild disease to severe lung injury and multi-organ failure, eventually leading to death, especially in older patients with other co-morbidities. Since the WHO declaration of COVID-19 to be a public health emergency of pandemic proportions, researchers around the world have been racing against time to find an effective treatment.
University of British Columbia published results of a clinical trial recently that have promising findings of a potentially effective drug. According to the researchers, hrsACE2, which has already been tested in phase 1 and phase 2 clinical trials, can reduce viral growth by a factor of 1,000-5,000.
The study found the receptor binding domain (RBD) of SARS-CoV-2 to be remarkably similar to the SARS-CoV RBD, signifying a similar host cell receptor. Additionally, the researchers found ACE2 to be the functional SARS-CoV receptor by in vitro study.
A study conducted on mice found overexpression of ACE2 to enhance severity of disease in mice infected with SARS-CoV. This indicates that ACE2-dependent viral entry into cells is a critical factor for morbidity. Injecting SARS-CoV spike into mice decreased ACE2 expression levels, thereby worsening lung injury.
Recent studies have shown that SARS-CoV-2 spike protein directly binds to ACE2 and that the SARS-CoV-2 spike protein recognizes human ACE2 with even higher binding affinity than Spike from SARS-CoV.
In human lung, ACE2 is found mainly in alveolar epithelial type II cells, which can also acts as a viral storage. These cells synthesize surfactant which lessens surface tension inhibiting alveolar collapse. Therefore, they are essential to the lung’s gas exchange function. In COVID-19, the severity of illness can be attributed to the damage of the alveolar epithelial type II cells, that express ACE2.
Apart from the lungs, ACE2 is also expressed in the heart, kidneys, blood vessels, and intestine. This explains the multiorgan dysfunction seen in COVID-19 patients.
According to the researchers, clinical-grade human recombinant soluble ACE2 can reduce viral growth in COVID-19 infected cells by a factor of 1,000-5,000. The drug has already been tested in phase 1 and phase 2 clinical trials. Furthermore, hrsACE2 can inhibit the infection of human blood vessels and kidney even at the early stages of infection.
The researchers aimed to provide direct evidence that clinical-grade hrsACE2 can indeed interfere with SARS-CoV-2 infections. At first they infected cells with varying numbers of SARS-CoV-2. Next using qRT-PCR, Viral RNA was purified from cells and assayed to use it as a marker for replication.
Infection of cells in the presence of hrsACE2 during 1 hr, followed by washing and incubation without hrsACE2 significantly inhibited SARS-CoV-2 infections 15 hours post infection.
The team led by University of British Columbia researcher Dr. Josef Penninger have found hrsACE2 to effectively block the receptor SARS-CoV-2 uses to infect its hosts.
“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.
Emergency funding to combat the COVID-19 outbreak from the Canadian federal government has supported part of the research.