# Humanization of ACE2 and Associated Priming Proteases in New Mouse Models for Downstream Disease and Therapy Investigations of COVID-19

> **NIH NIH R43** · INGENIOUS TARGETING LABORATORY, INC. · 2021 · $297,204

## Abstract

With the initial wave of zoonotic transmission firmly established in the human population worldwide, severe
acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) poses an eminent threat to individuals, health
care systems and societies. Various degrees of disease severity (from asymptomatic to lethal) combined with
challenging infection metrics ‒ in the absence of widespread testing coverage, as well as lack of established
vaccination and treatment options ‒ have triggered massive and urgent biomedical efforts to counter the
associated human disease that is COVID-19. Founded in the complexities of virus/host interactions, it is
imperative to utilize experimental infections with virus or viral material in translational platforms with a focus on
viral and/or host modeling in order to establish preventive as well as control strategies. In this experimental
setting, animal models play a central role as in vivo hosts for evaluation purposes of antiviral drugs,
immunotherapy and vaccines ‒ foremost in preclinical, but also in parallel-to-clinical, studies. A single type of
organism, either wildtype or genetically-modified, will however likely not be sufficient for studies of all relevant
physiological mechanisms. In this project, we propose reverse genetic designs in the mouse by introducing
genetically humanized components on large and medium scales, enabling viral binding and cellular infection
with the aim to mimic human COVID-19 disease susceptibility during early stages of the SARS-CoV-2
replication cycle. Rodent species, although favorable as small animal research objects, are generally refractory
to displaying SARS and the COVID-19 pathology upon simple infection. One way to address this species
boundary so far was to create random transgenic mouse lines carrying small-scale partially humanized gene
expression units for the human ACE2 receptor. These models, however, display partial phenotypes
characterized by: (a) no terminal-lung outcomes, (b) undesired replication in the brain and (c) lack of multi-
organ failure upon infection (exemplified by SARS-CoV, with similar outcomes expected for SARS-CoV-2). In
order to enable a distinct lung and other human phenotypes, we hypothesize that extended genomic
humanization in the form of the human ACE2 receptor alone (see Spec. Aim 1) or in combination with lung-
specific human cofactors, i.e., TMPRSS2/Furin (see Spec. Aim 2) ‒ based on their human-like expression
(verified in Spec. Aim 3) ‒ will thus improve viral infection and tissue tropism measured by timely progression
of viral titers in different organs (in Spec. Aim 4). Fluorescent reporting as well as site-specific recombination
will be enabled in an alternative Cre-recombinase fusion model of ACE2, while intrinsic features of the
TMPRSS2/Furin model will provide a fluorescent signal upon expression. Our broad SARS/COVID-19 mouse
model platform utility (consisting of three individual models at the Phase I stage) will significantly support...

## Key facts

- **NIH application ID:** 10155985
- **Project number:** 1R43AI157534-01
- **Recipient organization:** INGENIOUS TARGETING LABORATORY, INC.
- **Principal Investigator:** WEI WENG
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $297,204
- **Award type:** 1
- **Project period:** 2021-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10155985

## Citation

> US National Institutes of Health, RePORTER application 10155985, Humanization of ACE2 and Associated Priming Proteases in New Mouse Models for Downstream Disease and Therapy Investigations of COVID-19 (1R43AI157534-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10155985. Licensed CC0.

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