Deactivating, or knocking out, incompatible pig genes is one way to improve the potential of engraftment.
Human transgenes added to the pig’s genome may also improve the odds of engraftment of a pig organ.
CRISPR has made gene editing of the pig more efficient and a new generation of tools called base editors are being applied to make fine adjustments to further improve compatibility.
The successful cloning of livestock animals in the 1990’s sparked the rise in modern interest in xenotransplantation. Transplantation of organs from our primate cousins had been unsuccessful. The pig, with its similar organ size, large litters, and use as a food source proved to be clonable and genetically manipulatable.
The obvious impediment to successful pig to human xenotransplantation was high levels of preexisting antibodies in all humans for the αGal sugar that decorated the cells of nearly all non-primates. A group spearheaded by transplant legend Tom Starzl succeeded at removing the gene that manufactured αGal and the first αGal-negative pig was born in 2002.
While the hyperacute, antibody mediated rejection seen with natural pigs was eliminated, a delayed hyperacute rejection difficulty remained under immunosuppression available at that time.
Although attributed to additional non-gal antibodies in the recipient, genetic engineering techniques available proved to be too expensive to defunctionalize the genes responsible for obvious second targets such as CMAH, a gene lost in humans that remained functional in other animals.
At that time, it was economically feasible to add transgenes to a pig, and an era of adding transgenes to the pig that would provide treatments for the complications seen post xenotransplantation (e.g. coagulation, complement activation, immune activation, etc.).
CRISPR gene editing drastically reduced the cost and complexity of knocking out genes and almost immediately was applied to pigs aimed at xenotransplantation. A formula for a triple knock out pig that had a favorable crossmatch profile with 30% of more than a thousand waitlisted kidney transplant candidates tested. A favorable pre-transplant crossmatch profile is an accepted, critical predictor of successful transplants in humans.
Together with the transgenes and knockouts, one year survival was achieved in the difficult monkey model of kidney xenotransplantation.
Newer tools called base editors can make the fine tuning adjustments to other genes as they are discovered to extend the usefulness of xenotransplantation to larger and larger populations .