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Animal Models

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Proof-of-Concept Studies With a Computationally Designed Mpro Inhibitor as a Synergistic Combination Regimen Alternative to Paxlovid

Papini et al., PNAS. 2024.

https://www.pnas.org/doi/abs/10.1073/pnas.2320713121?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%20%200pubmed

As the spread and evolution of SARS-CoV-2 continues, it is important to continue to not only work to prevent transmission but to develop improved antiviral treatments as well. The SARS-CoV-2 main protease (Mpro) has been established as a prominent druggable target. In the current study, investigators evaluate Mpro61 as a lead compound, utilizing structural studies, in vitro pharmacological profiling to examine possible off-target effects and toxicity, cellular studies, and testing in a male and female mouse model for SARS-CoV-2 infection. Results indicate favorable pharmacological properties, efficacy, and drug synergy, as well as complete recovery from subsequent challenge by SARS-CoV-2, establishing Mpro61 as a promising potential preclinical candidate. Supported by ORIP (R24OD026440, S10OD021527), NIAID, and NIGMS.

Nonhuman Primate Models for SARS-CoV-2 Research: Cryopreservation as a Means to Maintain Critical Models and Enhance the Genetic Diversity of Colonies

Arnegard and Hild et al., Lab Animal. 2021.

https://doi.org/10.1038/s41684-021-00792-1

This commentary, written by ORIP staff, addresses the need for improved cryopreservation methods and resources for nonhuman primate (NHP) gametes and embryos to safeguard newly developed NHP models and enhance the genetic diversity of NHP colonies without reliance on animal importations. Cryopreservation also plays critical roles in medical approaches to preserve the fertility of patients who must undergo potentially gonadotoxic treatments, as well as nascent genome editing efforts to develop new NHP models for human diseases. Given these diverse benefits to research progress, ORIP continues to fund the development of cryopreservation tools and approaches for NHPs and other animal models.

Sensitive Tracking of Circulating Viral RNA Through All Stages of SARS-CoV-2 Infection

Huang  et al., Journal of Clinical Investigation. 2021.

https://www.jci.org/articles/view/146031

Circulating SARS-CoV-2 RNA could represent a more reliable indicator of infection than nasal RNA, but quantitative reverse transcription PCR (RT-qPCR) lacks diagnostic sensitivity for blood samples. Researchers developed a CRISPR-amplified, blood-based COVID-19 (CRISPR-ABC) assay to detect SARS-CoV-2 in plasma. They evaluated the assay using samples from SARS-CoV-2-infected African green monkeys and rhesus macaques, as well as from COVID-19 patients. CRISPR-ABC consistently detected viral RNA in the plasma of the experimentally infected primates from 1 to 28 days after infection. The increases in plasma SARS-CoV-2 RNA in the monkeys preceded rectal swab viral RNA increases. In the patient cohort, the new assay demonstrated 91.2% sensitivity and 99.2% specificity versus RT-qPCR nasopharyngeal testing, and it also detected COVID-19 cases with transient or negative nasal swab RT-qPCR results. These findings suggest that detection of SARS-CoV-2 RNA in blood by CRISPR-augmented RT-PCR could improve COVID-19 diagnosis, facilitate the evaluation of SARS-CoV-2 infection clearance, and help predict the severity of infection. Supported by ORIP (P51OD011104).