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Natural enzyme in the body as a starting point for Covid-19 treatments

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(Vienna, 01 March 2021 ) Normally, ACE2, an enzyme in the membrane of somatic cells, plays a role in regulating blood pressure and protecting against cardiovascular disease. The SARS-CoV-2 coronavirus uses it to dock onto body cells in order to infect them. It was hitherto assumed that the concentration of the enzyme falls in the presence of Covid-19 infection in the body, which is why a newly developed drug (genetically engineered ACE2) aims to elevate it. However, a recent study conducted by MedUni Vienna shows that, rather than falling, the concentration can even rise in the presence of an infection.

ACE2 is part of the renin-angiotensin system (RAS), which influences the body's fluid balance and blood pressure. This involves the interaction of two enzymes, ACE and ACE2, which work together or antagonistically. Whereas ACE is responsible for raising blood pressure in response to stress, for example, ACE2 counteracts this stress and, as well as expanding blood vessels to lower blood pressure, also performs other functions, such as e.g., inhibiting inflammation. As in the RAS, this interaction occurs in many physiological systems.

It was expected that the concentration of ACE2 in the body would change in the presence of a coronavirus infection, given its role in the infection process. In fact, even at the start of the pandemic, previous data showed that the ACE2 concentration could drop over the course of a disease. On the basis of animal experiments with SARS-CoV(-1), it was assumed that these data would also be valid for humans infected with SARS-CoV-2. Hence, the supposed drop in ACE2 was held responsible for the tissue damage in severe courses of the infection.

Administration of ACE2 as a medication
A therapeutic approach for this assumption is to administer ACE2. One of the thoughts behind this is to allow the virus to bind to the injected ACE2, thereby reducing the number of infected cells in the body. Although there is already a published "Case Report" describing how the condition of a severely affected patient improved significantly following administration of ACE2, more detailed studies about the effects of the novel coronavirus (SARS-CoV-2) on the RAS in humans are still lacking. Nonetheless, the newly developed medication is aimed at administering ACE2.

Elevated ACE2 concentration in coronavirus infection
In a large-scale clinical study, a team led by Manfred Hecking and Roman Reindl-Schwaighofer from the Division of Nephrology and Dialysis of the Department of Medicine III of MedUni Vienna and Vienna General Hospital has now shown that the ACE2 concentration does not fall in Covid-19. In the study, blood samples were taken from 126 people during an acute coronavirus infection and analysed by mass spectrometry.

Although this confirmed the assumption that the RAS is knocked off course by a coronavirus infection, the direction this took was surprising: "Not only does the concentration of ACE2 not fall in Covid-19, in severe courses of the disease, in which patients with severe breathing difficulties had to be ventilated on the ICU, the concentration rose by more than seven-fold," explain Principal Investigators Manfred Hecking and Roman Reindl-Schwaighofer. The researchers assume that this effect could be directly attributable to the lung damage. "The fact that ACE2 rises following a SARS infection could also be due to the pneumonia itself." Therefore, where possible, severely inflamed lungs produce more ACE2.

According to Hecking and Reindl-Schwaighofer, the new data are not inconsistent with administering ACE2 as a medication. However, the body itself is obviously capable of producing more ACE2 in severe Covid-19. "Early administration of high doses of ACE2 can therefore be helpful, particularly since the body takes some time to increase ACE2, so that it is not initially present in clinically relevant dosages."

The researchers intend to conduct further studies to investigate regulation of the RAS directly in the lung tissue. The ongoing clinical study is part of a research project entitled "Covid-19 and RAS Blockade" that was given fast-track approval by the FWF (Austrian Science Fund) in May 2020, because of its relevance in the coronavirus pandemic. Some of the people who were studied came from the largest clinical coronavirus study in Austria, ACOVACT, which is looking at the clinical efficacy of therapeutics to combat a coronavirus disease.

Service: American journal of respiratory and critical care medicine
Angiotensin-Converting Enzyme 2 (ACE2) Elevation in Severe COVID-19
Roman Reindl-Schwaighofer, Sebastian Hödlmoser, Farsad Eskandary, Marko Poglitsch, Diana Bonderman, Robert Strassl, Judith H Aberle, Rainer Oberbauer, Alexander Zoufaly, Manfred Hecking.
Am J Respir Crit Care Med. 2021 Feb 18., doi: 10.1164/rccm.202101-0142LE.

Online ahead of print. pubmed.ncbi.nlm.nih.gov/33600742/