Progress in producing knockout models for xenotransplantation by nuclear transfer

Abstract

The pig is thought to be the most suitable non-human organ source for xenotransplantation. However, one of the major constraints to using pig organs for xenotransplantation is human natural antibody-mediated hyperacute rejection (HAR). Elimination of α(1, 3) galactosyltransferase (GGTA1) from the pig is expected to be a solution to the problem of hyperacute and delayed vascular rejection. Based on the extensive efforts made in characterization of GGTA1 in structure and function, improvement in the technique of DNA transfection of somatic cells and optimization of the pig nuclear transfer (NT) procedures, a specific modification has been made to one copy of the GGTA1 gene thus rendering it non-functional. When homozygosity of the genetic modification is achieved, this will allow concentrated efforts to address the role of galα(1, 3) gal specific natural antibody in HAR, acute vascular rejection and to examine the efficacy of xenotransplantation in a non-human primate model without HAR confounding the experiments. Since swine are widely used as models of human disease, the ability to make specific genetic modifications to swine as described here is predicted to have a large impact not only on production agriculture but also on biomedicine.