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Abstract: SA-OR04

A Novel Soluble ACE2 Protein Protects from Lethal SARS-CoV-2 Infection

Session Information

Category: Coronavirus (COVID-19)

  • 000 Coronavirus (COVID-19)

Authors

  • Hassler, Luise, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Wysocki, Jan, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Gelarden, Ian A., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Tomatsidou, Anastasia, The University of Chicago, Chicago, Illinois, United States
  • Gula, Haley, The University of Chicago, Chicago, Illinois, United States
  • Nicolaescu, Vlad I., The University of Chicago, Chicago, Illinois, United States
  • Randall, Glenn, The University of Chicago, Chicago, Illinois, United States
  • Yeldandi, Anjana, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Batlle, Daniel, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
Background

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) uses full-length angiotensin converting enzyme 2 (ACE2) as the main receptor to enter the target cells. A novel soluble ACE2 protein with increased duration of action and binding capacity to exert a decoy effect as a way to intercept SARS-CoV-2 from binding to membrane-bound ACE2 was generated. The protein was administered to a lethal mouse model of COVID-19 to examine its efficacy.

Methods

A human soluble ACE2 variant fused with a 5kD albumin binding domain (ABD) was linked via a dimerization motif hinge-like 4-cysteine dodecapeptide to improve binding capacity to the SARS-CoV-2. This novel protein (ACE2 1-618-DDC-ABD) was administered intranasally and intraperitoneally prior to viral inoculation and on the two following consecutive days. Infected animals were observed for weight, clinical score and mortality in a BSL-3 facility. Upon sacrifice, lung histopathology was evaluated, and viral loads were measured by plaque assay.

Results

Infected mice that received ACE2-1-618-DDC-ABD developed only moderate disease assessed by a clinical score, modest weight loss and lung histology. At 6 days, mortality was totally prevented in the treated group (figure), lung histopathology was markedly improved and viral lung and brain titers reduced or non-detectable. By contrast, in untreated animals, lung histology revealed extensive pulmonary alveolar hemorrhage and mononuclear infiltrates, and they all became severely ill and had to be euthanized by day 6/7 (figure).

Conclusion

This study demonstrates for the first time in vivo the preventative/ therapeutic efficacy of a soluble ACE2 protein in a preclinical animal model.

Funding

  • Private Foundation Support