Abstract
Background: Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) uses full-length angiotensin converting enzyme 2 (ACE2) as a main receptor to enter target cells. The goal of this study was to demonstrate the preclinical efficacy of a novel soluble ACE2 protein with increased duration of action and binding capacity in a lethal mouse model of COVID-19. Methods: A human soluble ACE2 variant fused with an albumin binding domain (ABD) was linked via a dimerization motif hinge-like 4-cysteine dodecapeptide (DDC) to improve binding capacity to SARS-CoV-2. This novel soluble ACE2 protein (ACE2 1-618-DDC-ABD) was then administered intranasally and intraperitoneally to mice prior to intranasal inoculation of SARS-CoV-2 and then for two additional days post viral inoculation. Results: Untreated animals became severely ill and all had to be humanely euthanized by day 6/7 and had pulmonary alveolar hemorrhage with mononuclear infiltrates. In contrast, all but one mouse infected with a lethal dose of SARS-CoV-2 that received ACE2-1-618-DDCABD survived. In the animals inoculated with SARS-CoV-2 that were untreated, viral titers were high in the lungs and brain but virus was absent in the kidneys. However, some untreated animals had variable degrees of kidney proximal tubular injury with increased NGAL and TUNEL staining indicating attenuation of the proximal tubular brush border. In contrast, viral titers in the lung and brain were reduced or non-detectable in mice that received ACE2 1-618-DDC-ABD,and the animals developed only moderate disease as assessed by a near-normal clinical score, minimal weight loss, and improved lung and kidney injury. Conclusions: This study demonstrates the preclinical efficacy of a novel soluble ACE2 protein, termed ACE2 1- 618-DDC-ABD, in a lethal mouse model of SARS-CoV-2 infection that causes severe lung injury as well as variable degrees of moderate proximal tubular injury.
| Original language | English (US) |
|---|---|
| Journal | Journal of the American Society of Nephrology |
| Volume | 33 |
| Issue number | 7 |
| DOIs | |
| State | Published - Jul 2022 |
Funding
Foundation and the NIH grant 1R21 AI166940-01 (DB), and a stipend to LH from the BMEP. (NU GoKidney) supported by the award P30 DK114857 (National Institute of Diabetes and We acknowledge Dr. Benjamin Singer, from the pulmonary and critical care division of Northwestern University, Feinberg School of Medicine for advice and critical reading of the manuscript. We also acknowledge the George M. O'Brien Kidney Research Core Center (NU GoKidney) supported by the award P30 DK114857 (National Institute of Diabetes and Digestive and Kidney Disease). Funding: We acknowledge the support of a gift from the Joseph and Bessie Feinberg Funders: Joseph and Bessie Feinberg foundation, (Grant / Award Number: ) Biomedical Education Program, (Grant / Award Number: ) National Institutes of Health, (Grant / Award Number: '1R21 AI166940-01 ') Financial Disclosure: CUST_FINANCIAL_DISCLOSURE :No data available. D. Batlle and J. Wysocki are coinventors of patents entitled “Active Low Molecular Weight Variants of Angiotensin Converting Enzyme 2 (ACE2)�, “Active low molecular weight variants of Angiotensin Converting Enzyme 2 (ACE2) for the treatment of diseases and conditions of the eye� and “Soluble ACE2 Variants and Uses therefor�. D. Batlle is founder of Angiotensin Therapeutics Inc. D. Batlle has received consulting fees from AstraZeneca, Relypsa, and Tricida, all unrelated to this work. During the conduct of these studies, D. Batlle received unrelated support from National Institute of Diabetes and Digestive and Kidney Diseases grant R01DK104785, as well as from a grant from AstraZeneca; D. Batlle also reports Research Funding: Feinberg Foundation; Honoraria: Relypsa, Tricida, Astra Zeneca; and Scientific Advisor or Membership: Tricida, and Relypsa. G. Randall reports consultancy agreements with Optikira. J. Wysocki reports scientific advisor capacity for Angiotensin Therapeutics Inc. L. Hassler reports Other Interests/Relationships: Stipend from the BMEP in support of research in Chicago. Y. Kanwar reports Advisory or Leadership Role: American J. Physiology, JASN, Kidney International, and JBC. S. Pshenychnyi is employed by and Consults for COUR Pharma.
Keywords
- Angiotensin-Converting Enzyme 2
- COVID-19
- Disease Susceptibility
- Mice
- SARS-CoV-2
- acute renal failure
- kidney disease
- renal protection
- renin angiotensin system
- virology
ASJC Scopus subject areas
- General Medicine
