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Animal Models

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Division of Comparative Medicine

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Preclinical Safety and Biodistribution of CRISPR Targeting SIV in Non-Human Primates

Burdo et al., Gene Therapy. 2024.

https://pmc.ncbi.nlm.nih.gov/articles/PMC11090835/

Nonhuman primates have served as a valuable resource for evaluating novel eradication and cure strategies for HIV infection. Using a male rhesus macaque model, researchers demonstrated the safety and utility of CRISPR gene-editing technology for targeting integrated simian immunodeficiency virus (SIV). Their work suggests that a single intravenous inoculation for HIV gene editing can be utilized to reach viral reservoirs throughout the body. Additionally, no off-target effects or abnormal pathology were observed. Together, these findings support the continued development of HIV eradicative cure strategies using CRISPR technology in humans. Supported by ORIP (P40OD012217, U42OD021458).

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).

Thresholds for Post-Rebound SHIV Control after CCR5 Gene-Edited Autologous Hematopoietic Cell Transplantation

Cardozo-Ojeda et al., eLife. 2021.

https://elifesciences.org/articles/57646

Investigators developed a mathematical model to project the minimum threshold of C-C chemokine receptor type 5 (CCR5) gene-edited cells necessary for a functional cure from HIV. This was based on blood T cell reconstitution and plasma simian-HIV (SHIV) dynamics from SHIV-1157ipd3N4-infected juvenile pig-tailed macaques that underwent autologous transplantation with CCR5 gene editing. The model predicts that viral control can be obtained following analytical treatment interruption (ATI) when: (1) transplanted hematopoietic stem and progenitor cells (HSPCs) are at least fivefold higher than residual endogenous HSPCs after total body irradiation and (2) the fraction of protected HSPCs in the transplant achieves a threshold (76–94%) sufficient to overcome transplantation-dependent loss of SHIV immunity. Under these conditions, if ATI is withheld until transplanted gene-modified cells engraft and reconstitute to a steady state, spontaneous viral control is projected to occur. Supported by ORIP (P51OD010425), NCATS and NIAID.