First gene-edited calf with reduced susceptibility to a major viral pathogen

Workman, A. M.; Heaton, M. P.; Vander Ley, B. L.; Webster, D. A.; Sherry, L.; Larson, S.; Kalbfleisch, T.; Harhay, G. P.; Jobman, E. E.; Carlson, D. F.; Sonstegard, T. S.

doi:10.1101/2022.12.08.519336

bioRxiv · 10.1101/2022.12.08.519336

First gene-edited calf with reduced susceptibility to a major viral pathogen

Workman, A. M.·Heaton, M. P.·Vander Ley, B. L.·Webster, D. A.·Sherry, L.·Larson, S.·Kalbfleisch, T.·Harhay, G. P.·Jobman, E. E.·Carlson, D. F.·Sonstegard, T. S.

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Abstract

Bovine viral diarrhea virus (BVDV) is one of the most important viruses affecting the health and well-being of bovine species throughout the world. Here we used CRISPR-mediated homology-directed repair and somatic cell nuclear transfer to produce a live calf with a six amino acid substitution in the BVDV binding domain of bovine CD46. The result was a gene-edited calf with dramatically reduced susceptibility to infection as measured by clinical signs and the lack of viral infection in white blood cells. The edited calf has no off-target edits and appears normal and healthy at 16 months of age without obvious adverse effects from the on-target edit. This precision bred, proof-of-concept animal provides the first evidence that intentional genome alterations in CD46 may reduce the burden of BVDV-associated diseases in cattle, and is consistent with our stepwise, in vitro and ex vivo experiments with cell lines and matched fetal clones.

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Workman, A. M., Heaton, M. P., Vander Ley, B. L., Webster, D. A., Sherry, L., Larson, S., Kalbfleisch, T., Harhay, G. P., Jobman, E. E., Carlson, D. F., Sonstegard, T. S.. 2022-12-08. First gene-edited calf with reduced susceptibility to a major viral pathogen. https://doi.org/10.1101/2022.12.08.519336

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