Human recombinant soluble ACE2 successfully used in a patient with severe COVID-19

By Dr. Tomislav Meštrović, MD, Ph.D.Sep 27 2020

A multinational research group recently published a paper in the journal Lancet Respiratory Medicine which describes the first patient with a severe form of coronavirus disease (COVID-19) that was successfully treated with human recombinant soluble ACE2.

A pandemic spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for almost one million deaths due to COVID-19. Therefore, important insights into the viral pathophysiology may facilitate the quest for an effective vaccine and treatment option.

What we already know is that angiotensin-converting enzyme 2 (ACE2) is the crucial receptor for SARS-CoV-2 that enables viral entry into the cell. However, this enzyme also protects a myriad of different tissues in the human body from injury (which includes the lungs) – primarily acting as a regulator of the renin-angiotensin system.

SARS-CoV-2 virus binding to ACE2 receptors on a human cell, the initial stage of COVID-19 infection. Illustration Credit: Kateryna Kon / Shutterstock

The researchers have shown that ACE2 is the crucial receptor in vivo for the original SARS virus and explains why both SARS-CoV and SARS-CoV-2 became highly pathogenic viruses since the downregulation of ACE2 via virus binding disrupts renin-angiotensin system tissue homeostasis. Naturally, ACE2 has become the prime focus of COVID-19 research and in many drug development efforts.

A promising recombinant compound

Among the novel compounds currently under development is human recombinant soluble ACE2 (abbreviated as hrsACE2), which exhibits two mechanisms of action that should be of benefit against COVID-19. The first one involves binding the viral spike glycoprotein and, in turn, neutralizing SARS-CoV-2.

On the other hand, the second mechanism aims to minimize injury to multiple organs – including the lungs, kidneys, and heart – because of unrelenting renin-angiotensin system hyperactivation and augmented angiotensin II concentration.

Thus far, hrsACE2 has been tested in 89 patients (either healthy volunteers or those with acute respiratory distress syndrome), revealing a good safety profile. Likewise, hrsACE2 can decrease SARS-CoV-2 load by a factor of 1000–5000 in cell-culture experiments and engineered organoids, which directly demonstrates that ACE2 can effectively neutralize the virus.

Compassionate use of hrsACE2

A research group led by Dr. Alexander Zoufaly from the Kaiser-Franz-Josef Hospital–Clinic Favoriten in Vienna (Austria) described a case of a 45-year-old woman that was admitted to hospital with a 7-day history of cough, fever, weakness, muscle pains, and difficulties breathing, as well as a 4-day history of diarrhea and nausea.

The diagnosis of SARS-CoV-2 infection was made from a nasopharyngeal swab by using RT-PCR, which resulted in the treatment with hydroxychloroquine and anticoagulation with nadroparin. Nonetheless, the patient’s clinical condition did not improve; on the contrary, she was exhausted and needed more oxygen on the nasal cannula.

Nine days after the symptom onset, treatment with hrsACE2 intravenous infusion for five minutes twice per day was introduced. This compassionate use treatment was started after consultations among attending physicians, the patient’s family, as well as external infectious disease experts.

And the results were astonishing; after the first injection of hrsACE2, a marked reduction of angiotensin II was observed. This was followed by the reduction of inflammatory cytokine levels that are critical for COVID-19 pathology, as well as ferritin and C-reactive protein levels.

Angiotensin II concentrations returned to concentrations before treatment within 48 hours after cessation of treatment, which is in line with previous data on hrsACE2 half-life in humans. Notably, this compassionate use treatment was initiated at a late stage of the disease, with elevated inflammatory parameters and markedly deteriorated respiratory function.

Quick viral elimination

Notwithstanding the limitations of this report, the data clearly demonstrate that the virus disappeared swiftly from the serum and from the nasal cavity and lungs (albeit at a later time following hrsACE2 treatment). Whether this viral load decrease mirrors the effect of hrsACE2 treatment or just the natural course of the disease remains unproven.

Importantly, the use of hrsACE2 did not impede the generation of neutralizing antibodies. The same was observed with one patient who received hrsACE2 for only one day – i.e., rapidly undetectable viral loads in the serum and generation of antiviral IgG and IgA antibodies.

Finally, considering how SARS-CoV-2 can directly infect blood vessels, intravenous delivery of hrsACE2 may have an important effect on halting the systemic spread of the virus from the lung to other organs. Further research is needed to appraise the full treatment potential of this compound.