Genetically modified mouse models to help fight COVID-19

Gurumurthy, Channabasavaiah B.; Quadros, Rolen M.; Richardson, Guy P.; Poluektova, Larisa Y.; Mansour, Suzanne L.; Ohtsuka, Masato

doi:10.1038/s41596-020-00403-2

Cited by 28 publications

(34 citation statements)

References 77 publications

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“…Whether the different identified mutations and isoforms of ACE2 could modify its trafficking and lead to cellular retention is not tested yet. Recently, Gurumurthy et al have proposed different genetically engineered mouse models that can be used to engineer the different ACE2 identified mutations in vivo and assess their effects [ 140 ]. In addition, a combination of these mutants could also occur together leading to a further decreased ACE2 membrane expression.…”

Section: Discussionmentioning

confidence: 99%

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ACE2 Nascence, trafficking, and SARS-CoV-2 pathogenesis: the saga continues

Badawi

Ali

2021

Hum Genomics

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With the emergence of the novel coronavirus SARS-CoV-2 since December 2019, more than 65 million cases have been reported worldwide. This virus has shown high infectivity and severe symptoms in some cases, leading to over 1.5 million deaths globally. Despite the collaborative and concerted research efforts that have been made, no effective medication for COVID-19 (coronavirus disease-2019) is currently available. SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE2) as an initial mediator for viral attachment and host cell invasion. ACE2 is widely distributed in the human tissues including the cell surface of lung cells which represent the primary site of the infection. Inhibiting or reducing cell surface availability of ACE2 represents a promising therapy for tackling COVID-19. In this context, most ACE2–based therapeutic strategies have aimed to tackle the virus through the use of angiotensin-converting enzyme (ACE) inhibitors or neutralizing the virus by exogenous administration of ACE2, which does not directly aim to reduce its membrane availability. However, through this review, we present a different perspective focusing on the subcellular localization and trafficking of ACE2. Membrane targeting of ACE2, and shedding and cellular trafficking pathways including the internalization are not well elucidated in literature. Therefore, we hereby present an overview of the fate of newly synthesized ACE2, its post translational modifications, and what is known of its trafficking pathways. In addition, we highlight the possibility that some of the identified ACE2 missense variants might affect its trafficking efficiency and localization and hence may explain some of the observed variable severity of SARS-CoV-2 infections. Moreover, an extensive understanding of these processes is necessarily required to evaluate the potential use of ACE2 as a credible therapeutic target.

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Section: Discussionmentioning

confidence: 99%

“…Currently, the pilot clinical study has 200 participants and is in phase 2 clinical trial [ 18 ]. In this context, genetically modified mouse models have been proposed to enhance preclinical studies in COVID-19 research [ 140 ].…”

Section: Introductionmentioning

confidence: 99%

ACE2 Nascence, trafficking, and SARS-CoV-2 pathogenesis: the saga continues

Badawi

Ali

2021

Hum Genomics

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“…The well-characterized expression cassettes in those models can be swapped (or fused) with your GOI. A couple of examples of re-engineering model designs can be found in a recent perspective article on COVID-19 mouse models [ 78 ] .…”

Section: Questions Specific To Mouse Models Generated Using Crispr-bamentioning

confidence: 99%

Designing and generating a mouse model: frequently asked questions

Gurumurthy¹,

Saunders²,

Ohtsuka³

2021

J Biomed Res

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Genetically engineered mouse (GEM) models are commonly used in biomedical research. Generating GEMs involve complex set of experimental procedures requiring sophisticated equipment and highly skilled technical staff. Because of these reasons, most research institutes set up centralized core facilities where custom GEMs are created for research groups. Researchers, on the other hand, when they begin thinking about generating GEMs for their research, several questions arise in their minds. For example, what type of model(s) would be best useful for my research, how do I design them, what are the latest technologies and tools available for developing my model(s), and finally how to breed GEMs in my research. As there are several considerations and options in mouse designs, and as it is an expensive and time-consuming endeavor, careful planning upfront can ensure the highest chance of success. In this article, we provide brief answers to several frequently asked questions that arise when researchers begin thinking about generating mouse model(s) for their work.

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“…Wild-type or genetically modified rodents, pigs, and NHPs have been of paramount interest and provide key insights into the molecular basis of health and diseases. Notably, small animals such as hamsters, cats, ferrets, and NHPs are variably susceptible to SARS-CoV-2 infection [ 160 ]. These animals, however, are not suitable as models for SARS-CoV-2 pathogenesis and drugs and vaccine testing.…”

Section: Scnt Cloning For Biomedical and Regenerative Medicinementioning

confidence: 99%

“…On contrary, mouse ( Mus musculus ) is a well-studied laboratory animal in various pathogenesis studies and drug testing, unlike humans, the wild-type mouse strains are resistant to SARS-CoV-2. As mouse ACE-2 does not effectively bind to virus spike protein, the SARS-CoV-2 infects mice only when they are genetically modified to express human ACE2 [ 160 ].…”

Section: Scnt Cloning For Biomedical and Regenerative Medicinementioning

confidence: 99%

Stem cell therapies and benefaction of somatic cell nuclear transfer cloning in COVID-19 era

et al. 2021

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Background The global health emergency of COVID-19 has necessitated the development of multiple therapeutic modalities including vaccinations, antivirals, anti-inflammatory, and cytoimmunotherapies, etc. COVID-19 patients suffer from damage to various organs and vascular structures, so they present multiple health crises. Mesenchymal stem cells (MSCs) are of interest to treat acute respiratory distress syndrome (ARDS) caused by SARS-CoV-2 infection. Main body Stem cell-based therapies have been verified for prospective benefits in copious preclinical and clinical studies. MSCs confer potential benefits to develop various cell types and organoids for studying virus-human interaction, drug testing, regenerative medicine, and immunomodulatory effects in COVID-19 patients. Apart from paving the ways to augment stem cell research and therapies, somatic cell nuclear transfer (SCNT) holds unique ability for a wide range of health applications such as patient-specific or isogenic cells for regenerative medicine and breeding transgenic animals for biomedical applications. Being a potent cell genome-reprogramming tool, the SCNT has increased prominence of recombinant therapeutics and cellular medicine in the current era of COVID-19. As SCNT is used to generate patient-specific stem cells, it avoids dependence on embryos to obtain stem cells. Conclusions The nuclear transfer cloning, being an ideal tool to generate cloned embryos, and the embryonic stem cells will boost drug testing and cellular medicine in COVID-19.

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Genetically modified mouse models to help fight COVID-19

Cited by 28 publications

References 77 publications

ACE2 Nascence, trafficking, and SARS-CoV-2 pathogenesis: the saga continues

ACE2 Nascence, trafficking, and SARS-CoV-2 pathogenesis: the saga continues

Designing and generating a mouse model: frequently asked questions

Stem cell therapies and benefaction of somatic cell nuclear transfer cloning in COVID-19 era

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