Division of Nephrology/Hypertension, Department of Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.
Charité Universitätsmedizin Berlin, Berlin, Germany.
Life Sci Alliance. 2023 Apr 11;6(7). doi: 10.26508/lsa.202301969. Print 2023 Jul.
A soluble ACE2 protein bioengineered for long duration of action and high affinity to SARS-CoV-2 was administered either intranasally (IN) or intraperitoneally (IP) to SARS-CoV-2-inoculated k18hACE2 mice. This decoy protein (ACE2 618-DDC-ABD) was given either IN or IP, pre- and post-inoculation, or IN, IP, or IN + IP but only post-inoculation. Survival by day 5 was 0% in untreated mice, 40% in the IP-pre, and 90% in the IN-pre group. In the IN-pre group, brain histopathology was essentially normal and lung histopathology significantly improved. Consistent with this, brain SARS-CoV-2 titers were undetectable and lung titers reduced in the IN-pre group. When ACE2 618-DDC-ABD was administered only post-inoculation, survival was 30% in the IN + IP, 20% in the IN, and 20% in the IP group. We conclude that ACE2 618-DDC-ABD results in markedly improved survival and provides organ protection when given intranasally as compared with when given either systemically or after viral inoculation, and that lowering brain titers is a critical determinant of survival and organ protection.
一种经过生物工程改造的可溶性 ACE2 蛋白，其作用持续时间长，对 SARS-CoV-2 的亲和力高，被施用于接种 SARS-CoV-2 的 k18hACE2 小鼠的鼻腔内（IN）或腹腔内（IP）。这种诱饵蛋白（ACE2 618-DDC-ABD）在接种前和接种后通过 IN 或 IP 给药，或仅在接种后通过 IN、IP 或 IN+IP 给药。未治疗的小鼠在第 5 天的存活率为 0%，IP 预给药组为 40%，IN 预给药组为 90%。在 IN 预给药组中，脑组织病理学基本正常，肺组织病理学显著改善。与此一致的是，脑 SARS-CoV-2 滴度在 IN 预给药组中无法检测到，肺滴度降低。当 ACE2 618-DDC-ABD 仅在接种后给药时，IN+IP 组的存活率为 30%，IN 组为 20%，IP 组为 20%。我们得出结论，与全身给药或接种后给药相比，鼻腔内给药 ACE2 618-DDC-ABD 可显著提高存活率并提供器官保护，降低脑内滴度是存活率和器官保护的关键决定因素。
