humanized ace2 mouse model for for SARS-CoV-2 drug screening, vaccine, and pathogenesis studies | Cyagen

As the leading provider of custom animal model generation services, Cyagen’s R&D team began developing mouse models for studying the novel coronavirus in the early stages of the COVID-19 outbreak. We have used both the proprietary TurboKnockout® technology and optimized CRISPR technology to carry out the development of humanized ACE2 mice base on three background strains: BALB/C, C57BL/6J and C57BL/6N. Our model generation experts have designed a variety of gene targeting and construction strategies to meet the needs of different research applications. We provide valuable animal models for SARS-CoV-2 drug screening, vaccine, and pathogenesis studies.

 

Advantages of Cyagen’s Humanized ACE2 Mice

           

  • Both TurboKnockout® technology and Rapid knockout with CRISPR technology have been used to concurrently develop a variety of ACE2 mice. Customers can select appropriate ACE2 mouse models according to different research purposes.

          

CRISPR/Cas9 has the advantages of no species limitation, simple operation, low cost, and short turnaround time - but also carries problems regarding intellectual property (IP) rights disputes. Embryonic stem cell (ESC) targeting technology can carry out various complex genetic transformation with no off-target effects - but it has the problem of species limitation.

 

For these reasons, CRISPR/Cas9 technology is suggested for the construction of standard C57BL/6 mouse models - constitutive gene knockout, gene knockin - and other species in addition to mice. However, TurboKnockout® technology - based on ESC targeting - is often recommended for complex model construction and for customers who are concerned about IP rights.

 

  • Our humanized ACE2 mice were developed across three background strains:  BALB/C, C57BL/6J, and C57BL/6N.

           

The C57BL/6 (B6) mouse strain is the preferred genetic background strain for most site-directed modification and transgenic models. B6 mice have a low incidence rate of various tumors, and is also the preferred murine model for studying diet-induced obesity and chronic experimental autoimmune encephalomyelitis (EAE) multiple sclerosis (MS).

 

BALB/c is an albino and immunodeficient mouse strain that is extremely sensitive to carcinogens. It is the most used mouse strain in the research fields of oncology, inflammation, and autoimmunity – often the first choice for experimental animals required for new drug development projects. In addition, studies have shown that BALB/c mice are more susceptible to virus infection than C57BL/6, because BALB/c mice have more neutrophils and lymphocytes that penetrate the lung tissue in the immune response. The inflammatory response is stronger over a larger affected area, so the BALB/c background are also strong candidates for SARS-CoV-2 & COVID-19 related research.

 

  • Multiple gene targeting and construction strategies:

 

In addition to a variety of humanized ACE2 mice, you can find ACE2 knockout (KO) mice and conditional knockin (cKI) mice from Cyagen's ACE2 Catalog Models. These models help to achieved ACE2 global knockout and tissue specific knockout in mice to meet the different requirements of novel coronavirus (SARS-CoV-2) research. In addition, for the same type of humanized ACE2 mouse model, Cyagen performs a variety of targeting strategies to meet the requirement form customers who have refined requirements for targeting strategy. Refer to the table below for detailed design ideas.

 

ACE2 mouse recommendation

CRISPR Technology
Project Type Background Strain Targeting Strategy Strategy Detail
Humanized ACE2 (hACE2) Mice C57BL/6J The murine signal peptide (aa.1~17) will be retained,the region from aa.18 to aa.805 of mouse Ace2 will be replaced with the region from aa.18 to aa.805 of human ACE2
  • Mouse ACE2 replaced by human ACE2;
  • Keep the murine signal peptide, in order to not affect the gene expression of corresponding pathways in the mouse to a greater extent;
  • Human ACE2 expressed under the control of mouse promoter;
  • Currently a best-selling model;
C57BL/6N
BALB/c
ACE2 Knockin Model (H11 Locus) C57BL/6J Expression of human ACE2 and CreERT2 on the mouse H11 safe site is controlled by the K18 promoter
  • Mouse model that over-expresses human ACE2 in epithelial cells;
  • l Express CreERT2, which can be used as an inducible expression tool, and can be combined with other popular targets such as TMPRSS2/ACE2 model to assist other pathway research.
ACE2 Conditional Knockin Model(Rosa26 Locus) C57BL/6J Conditionally expression of human ACE2 on mouse Rosa26 safe locus
  • Conditional over-expression of human ACE2 mouse model:
  • Both human ACE2 and murine ACE2 are expressed in this model. Strong promoters for human ACE2, so hACE2 expression level is higher;
  • According to the clinical manifestations of the disease, tissue-specific expression may be performed at the pathogenic sites and/or tissues. At the same time, we provide corresponding specific Cre tool mice, such as lung Cre, granulocyte Cre, etc.;
BALB/c
C57BL/6N
ACE2 Knockout Model C57BL/6J Knockout of Exon 3~18 of mouse ACE2 ACE2 global knockout, normally used for control experiments;
BALB/c

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TurboKnockout® Technology
Project Type Background Strain Targeting Strategy Advantages
Humanized ACE2 Mice C57BL/6N Retains the murine signal peptide, replace the extracellular domain, transmembrane domain, and intracellular domain of mouse ACE2 with the respective domains of human ACE2, and use exogenous polyA to conditionally express the human ACE2 gene Show the overview of targeting strategy
  • No off-target effects: TurboKnockout® technology is developed based on traditional ESC targeting technology. It can modify the gene accurately, with stable insertion and no off-target effects. It can be used for any complex model construction.
  • No technical patent disputes: Compared with CRISPR/Cas9 technology, TurboKnockout® technology has no IP issues or patent disputes and is a commonly used technology involving new drug research and development projects.
BALB/c
C57BL/6N Retains the murine signal peptide, replace the extracellular domain, transmembrane domain, and intracellular domain of mouse ACE2 with the extracellular domain, transmembrane domain, and intracellular domain of  human ACE2, and use endogenous polyA to conditionally express the human ACE2 gene Show the overview of targeting strategy
BALB/c
C57BL/6N Retains the murine signal peptide, replace the extracellular domain, transmembrane domain, and intracellular domain of mouse ACE2 with the extracellular domain, transmembrane domain, and intracellular domain of human ACE2, and use endogenous polyA to over-express human ACE2 and mouse ACE2 Show the overview of targeting strategy
BALB/c

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ACE2 Mice for COVID-19 Research, As Low As $500

 

 

About Cyagen

In under 15 years since its founding, Cyagen has become a leading provider of custom mouse and rat models – delivering over 50,400 models to researchers worldwide and receiving over 3,600 peer-reviewed citations. Cyagen provides researchers from around the world with transgenic, knockout, knockin, conditional knockout models and also offers a comprehensive series of stem cell products for research use, including cell lines, media, and differentiation kits. From vector and strategy design to animal model creation, cryopreservation, and breeding, Cyagen offers complete outsourcing for all animal model needs.