Abstract: SA-OR21
A Soluble ACE2 Protein Improves Survival and Lowers Viral Titers in a Lethal Mouse Model of SARS-CoV-2 Infection with the Delta Variant
Session Information
- COVID-19: A New Understanding and Lessons Learned
November 04, 2023 | Location: Room 107, Pennsylvania Convention Center
Abstract Time: 04:30 PM - 04:39 PM
Category: Coronavirus (COVID-19)
- 000 Coronavirus (COVID-19)
Authors
- Cianfarini, Cosimo L., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
- Wysocki, Jan, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
- Ismail, Ahmed Kamal, 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) utilizes Angiotensin Converting Enzyme 2 (ACE2) as its main receptor for cell entry. We have previously shown that a bioengineered soluble ACE2 protein designed to have increased binding to the SARS-CoV-2 spike protein and with extended duration of action can neutralize SARS-CoV-2 in the k18hACE2 mouse model infected with the ancestral SARS-CoV-2 strain (Washington isolate). Here we investigated the preventative/therapeutic potential of intranasally administering this soluble ACE2 protein in the same lethal mouse model infected with the SARS-CoV-2 delta variant which causes severe disease in humans.
Methods
k18hACE2 mice were inoculated with SARS-CoV-2 delta variant (2x104 PFU) and followed for up to 14 days in a BSL-3 facility. ACE2-618-ABD-DDC or PBS as vehicle control (n=10 per group) were administered intranasally 6h prior as well as 24 and 48hrs after viral inoculation. Infected animals were observed for weight loss, a clinical score, and mortality. Viral load was assessed by plaque assay in brain, lung, and kidney tissue.
Results
All untreated animals had succumbed to the disease at day 6, whereas survival at day 14 was 90% in mice receiving ACE2-618-ABD-DDC (Fig, left panel). Brain and lung viral titers were markedly reduced in mice receiving ACE2-618-ABD-DDC (Fig, middle panels). Despite uniform lethality of the disease in untreated animals, infected mice showed absence of kidney viral titers in all groups (Fig, right panel).
Conclusion
This study demonstrates the protective effect of ACE2-618-ABD-DDC in a lethal mouse model of SARS-CoV-2 infection with the delta variant. This soluble ACE2 protein markedly improved survival in the otherwise lethal model and reduced viral titers in lungs and brains to almost undetectable levels. It also shows a consistent lack of replicating virus in the kidney of animals infected with the delta variant. Taken together with our previously published experiments, the data supports a universal protective effect of our soluble ACE2 protein against infections with different SARS-CoV-2 variants.
Funding
- Private Foundation Support