Superiority of intranasal over systemic administration of bioengineered soluble ACE2 for survival and brain protection against SARS-CoV-2 infection

Hassler, L.; Wysocki, J.; Ahrendsen, J. T.; Ye, M.; Gelarden, I.; Nicolaescu, V.; Tomatsidou, A.; Gula, H.; Cianfarini, C.; Khurram, N.; Kanwar, Y.; Singer, B. D.; Randall, G.; Missiakas, D. M.; Henkin, J.; Batlle, D.

doi:10.1101/2022.12.05.519032

bioRxiv · 10.1101/2022.12.05.519032

Superiority of intranasal over systemic administration of bioengineered soluble ACE2 for survival and brain protection against SARS-CoV-2 infection

Hassler, L.·Wysocki, J.·Ahrendsen, J. T.·Ye, M.·Gelarden, I.·Nicolaescu, V.·Tomatsidou, A.·Gula, H.·Cianfarini, C.·Khurram, N.·Kanwar, Y.·Singer, B. D.·Randall, G.·Missiakas, D. M.·Henkin, J.·Batlle, D.

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Abstract

The present study was designed to investigate the effects of a soluble ACE2 protein termed ACE2 618-DDC-ABD, bioengineered to have long duration of action and high binding affinity to SARS-CoV-2, when administered either intranasally (IN) or intraperitoneally (IP) and before or after SARS-CoV-2 inoculation. K18hACE2 mice permissive for SARS-CoV-2 infection were inoculated with 2x104 PFU wildtype SARS-CoV-2. In one protocol, ACE2 618-DDC-ABD was given either IN or IP, pre- and post-viral inoculation. In a second protocol, ACE2 618-DDC-ABD was given either IN, IP or IN+IP but only post-viral inoculation. In addition, A549 and Vero E6 cells were used to test neutralization of SARS-CoV-2 variants by ACE2 618-DDC-ABD at different concentrations. Survival by day 5 was 0% in infected untreated mice, and 40% in mice from the ACE2 618-DDC-ABD IP-pre treated group. By contrast, in the IN-pre group survival was 90%, histopathology of brain and kidney was essentially normal and markedly improved in the lungs. When ACE2 618-DDC-ABD was administered only post viral inoculation, survival was 30% in the IN+IP group, 20% in the IN and 0% in the IP group. Brain SARS-CoV-2 titers were high in all groups except for the IN-pre group where titers were undetectable in all mice. In cells permissive for SARS-CoV-2 infection, ACE2 618-DDC-ABD neutralized wildtype SARS-CoV-2 at high concentrations, whereas much lower concentrations neutralized omicron BA. 1. We conclude that ACE2 618-DDC-ABD provides much better survival and organ protection when administered intranasally than when given systemically or after viral inoculation and that lowering brain titers is a critical determinant of survival and organ protection.

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Hassler, L., Wysocki, J., Ahrendsen, J. T., Ye, M., Gelarden, I., Nicolaescu, V., Tomatsidou, A., Gula, H., Cianfarini, C., Khurram, N., Kanwar, Y., Singer, B. D., Randall, G., Missiakas, D. M., Henkin, J., Batlle, D.. 2022-12-06. Superiority of intranasal over systemic administration of bioengineered soluble ACE2 for survival and brain protection against SARS-CoV-2 infection. https://doi.org/10.1101/2022.12.05.519032

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