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

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. ### Competing Interest Statement D.A.W., D.F.C., and S.L. are full time employees of Recombinetics, Inc; S.L. and T.S.S. are employees of Acceligen, a wholly owned subsidiary of Recombinetics Inc. Recombinetics Inc. is a company that commercializes animal gene editing and associated applied technologies for biomedical research, regenerative medicine and animal agriculture. There are no patents to declare, and the interests do not alter the authors' adherence to all the journal's policies on sharing data and materials published herein.