Bioengineered soluble ACE2 for brain protection against SARS-CoV-2 infection

In a recent study posted on Bio Rxiv*Preprint server, Researchers compared the efficiency of bioengineered soluble angiotensin-converting enzyme 2 (ACE-2) for brain protection during coronavirus disease 2019 (COVID-19).

Background

Studies point to the potential of the ACE2 protein in neutralizing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using human organoids. The cellular model proposed in this study includes human ACE2, a key receptor for SARS-CoV-2 entry in human cells, and transmembrane serine protease 2 (TMPRSS2), which is a key protease for the internalization of the SARS-CoV-2-ACE2 complex.

The k18-hACE2 model has proven lethal upon infection with wild-type (WT) SARS-CoV-2, mimicking the severe lung disease observed in humans. Although there is ample evidence of significant brain damage reported by models, the reason for the universal fatality is still unknown.

About research

In this study, researchers investigated the impact of ACE2 618-DDC-ABD, a bioengineered soluble ACE2 protein with a long duration of action and strong SARS-CoV-2 binding affinity.

The team compared the effects of intraperitoneal (IP) and intranasal (IN) delivery of a soluble ACE2 protein called ACE2 618-DDC-ABD in k18-human ACE2 (hACE2) mice. Animals exhibiting weight loss greater than 20% of body weight or animals exhibiting a clinical score of 3 or greater were euthanized according to the study protocol.

Four out of 9 healthy mice in the IN-pre group were euthanized on day 5 and organs were harvested for comparison with the IP-pre group, whereas the other 5 mice belonging to the IN-pre group mice survived to the final 14 days. study day. In contrast, mice that survived the IP pregroup had to be euthanized by day 7 due to worsening clinical evaluation and weight loss.

The team utilized k18-hACE2 mice that fully express human ACE2 and are susceptible to SARS-CoV-2 infection.5–9 days after infection, animals infected with viral load You will definitely fall ill. Researchers examined pre- and post-treatment effects with ACE2 618-DDC-ABD protein and compared intranasal (IN) and intraperitoneal (IP) delivery effects using different methodologies. In the pre-treatment cohort, ACE2 618-DDC-ABD was delivered IV or IP to k18-hACE2 mice 1 hour before his SARS-CoV-2 infection, after which he was dosed 3 times at 24 and 48 hours. I was. Control animals received bovine serum albumin (BSA) in phosphate-buffered saline (PBS) both IP and IN at doses and intervals similar to ACE2 618-DDC-ABD post-treated mice .

result

All infected, untreated control mice had to be euthanized on day 5, exhibited severe weight loss, and scored high clinical scores. The 5-day survival rate of control mice treated with ACE2 618-DDC-ABD before and after virus inoculation was 90% in the IN pre group and 40% in the IP pre group. The survival rate for untreated infected controls was 0% at 5 days. In addition, the pre-IN group had minimal weight loss and superior clinical scores. In contrast, the IP pregroup reported weight loss and lower clinical ratings.

In mice treated with ACE2 618-DDC-ABD after virus inoculation, the survival rate was 30% on day 5 and 20% on day 14 in the IN+IP-post group. Additionally, in the IN post cohort, day 5 survival was 20% and day 14 survival was 10%. The IP post group had 20% survival at 5 days but 0% survival at 14 days.

On day 5, the survival rate of untreated and infected mice was 0%. Most mice given ACE2 618-DDC-ABD after virus inoculation experienced significant weight loss and worsening clinical scores, but few mice recovered and survived to day 14. did.

There were no detectable brain antibodies in the IN-pre group. On the other hand, brain titers were elevated in 5 of 8 mice in the IP pre-cohort, significantly higher than in the IN pre-group. It was slightly lower, but not significantly lower. However, brain titers were undetectable on day 14 in a minority of survivors in the post-treatment group. Lung SARS-CoV-2 titers in animals treated with ACE2 618-DDC-ABC.

Conclusion

Overall, the results of this study indicate that ACE2 618-DDC-ABD provided significantly better survival and organ protection when administered IN than IP or after viral inoculation, and that decreased brain titers were associated with survival and organ protection. demonstrated to be an important predictor of protection.

*Important Notices

bioRxiv publishes non-peer-reviewed, preliminary scientific reports and should not be considered conclusive, to guide clinical practice/health-related actions, or to be treated as established information .