Abstract
Background There is an urgent need for approaches to prevent and treat SARS-CoV-2 infection. Administration of soluble ACE2 protein acting as a decoy to bind to SARS-CoV-2 should limit viral uptake mediated by binding to membrane-bound full-length ACE2, and further therapeutic benefit should result from ensuring enzymatic ACE2 activity to affected organs in patients with COVID-19. Methods A short variant of human soluble ACE2 protein consisting of 618 amino acids (hACE2 1–618) was generated and fused with an albumin binding domain (ABD) using an artificial gene encoding ABDCon, with improved albumin binding affinity. Human kidney organoids were used for infectivity studies of SARS-CoV-2 in a BSL-3 facility to examine the neutralizing effect of these novel ACE2 variants. Results Whereas plasma ACE2 activity of the naked ACE2 1–618 and ACE2 1–740 lasted about 8 hours, the ACE2 1–618-ABD resulted in substantial activity at 96 hours, and it was still biologically active 3 days after injection. Human kidney organoids express ACE2 and TMPRSS2, and when infected with SARS-CoV-2, our modified long-acting ACE2 variant neutralized infection. Conclusions This novel ACE2 1–618-ABD can neutralize SARS-CoV-2 infectivity in human kidney organoids, and its prolonged duration of action should ensure improved efficacy to prevent viral escape and dosing convenience.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 795-803 |
| Number of pages | 9 |
| Journal | Journal of the American Society of Nephrology |
| Volume | 32 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 2021 |
Funding
D. Batlle was funded by National Institute of Diabetes and Digestive and Kidney Diseases grant RO1DK104785 and by a gift to Northwestern University by the Joseph and Bessie Feinberg Foundation. D. Batlle and J. Wysocki are coinventors of the issued patent “Active Low Molecular Weight Variants of Angiotensin Converting Enzyme 2” and provisional patents “Active low molecular weight variants of Angiotensin Converting Enzyme 2 (ACE2) for the treatment of diseases and conditions of the eye” and “Shorter soluble forms of Angiotensin Converting Enzyme 2 (ACE2) for treating and preventing coronavirus infection.” D. Batlle is founder/owner 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 AstraZeneca and Fein-berg Foundation; received honoraria from Astra-Zeneca, Relypsa, and Tricida; and was a scientific advisor member with Relypsa and Tricida. G. Randall reports consultancy agreements with Optikira. J.A. Wertheim reports consultancy agreements with Miromatrix Medical; ownership interest in Bristol-Myers Squib and Merk & Co.; honoraria from Ann and Robert H. Lurie Children’s Hospital of Chicago, Dartmouth College, Miromatrix Medical, National Institutes of Health, Springer Publishing Company, and Taylor and Francis; patents and inventions via a patent that is not receiving any royalties; and being a scientific advisor or member with Standards Co-ordinating Body, Organogenesis, Alliance for Regenerative Medicine. J. Wysocki reports scientific advisor capacity for Angiotensin Therapeutics Inc. All remaining authors have nothing to disclose.
ASJC Scopus subject areas
- General Medicine
