Revivicor’s goal is to produce genetically engineered (GE) pigs to provide human compatible cells (i.e., islets) for treatment of diabetes and organs and tissues for use in transplant surgery (xenografts).
In order for xenografts to succeed for any application, it is imperative to stop the first line of immune response to cross-species transplantation; termed Hyperacute Rejection (HAR). Hyperacute rejection is a reaction to the “foreign” organ or cell by the body's normal immune system. Humans and primates differ from other animals in that they lack an enzyme, alpha 1,3 galactosyltransferase, that places a particular sugar group (Gal) on the branched sugar chains which occur on cell surfaces. Our bodies recognize its presence on grafted pig organs as a signal to attack. Revivicor's strategy is to inactivate or "knock out" the gene in pigs which makes the enzyme that normally attaches this Gal sugar group to the surface of pig cells. Without this signal, the xeno (pig) tissue will not trigger this initial Gal-mediated rejection (see Diagram 1).
Knock-out of this Gal gene required a specific targeted gene modification to pig cells, and the production of cloned pigs from these modified cells. Revivicor succeeded on both fronts and produced the world’s first alpha 1,3 galactosyltransferase (Gal) knock-out pigs (Phelps et al., 2003).
While the presence of the foreign sugar is by far the major signal for initiating an attack by the immune system, there are other mediators of immune rejection at play. Revivicor has added a human gene to the pigs to produce a protein called CD46 that moderates the action of the immune system. This gene addition strategy, combined with Gal knockout and immune suppression drugs, demonstrated encouraging results of pig hearts in primates, with survival and function for greater than 6 months.
Revivicor's combined approach of gene knockout plus immune response regulation should reduce the need for excessive amounts of immune suppression drugs which can themselves have long term undesirable side effects.
Click here for more xenotransplantation background information.