For whole-organ transplants to become reality, a strategy is needed to deal with the troublesome sugar. That’s why companies such as Princeton, NJ-based Nextran are genetically engineering pigs to make proteins that help repress the immune reaction that the sugar causes. Nextran, owned by pharmaceutical giant Baxter, has already used the livers of such pigs to keep patients with acute liver failure alive until donor organs were found. In these early human tests, the pig livers remained outside the body, but “it’s just a prelude to going into a human,” says University of Pittsburgh transplant surgeon John Fung. The company plans to apply for permission to conduct preliminary human trials of such xenotransplants by the end of next year.Other companies, including Immerge, PPL Therapeutics and Advanced Cell Technology, are combining this strategy with efforts to completely eliminate the guilty pig sugar. To do this, they must “knock out”-disable or remove entirely-the gene for the enzyme that makes the sugar. There is some concern, however, over whether pigs can survive without the sugar. “Chances are the pigs will be healthy, but no one’s 100 percent sure,” says immunologist David Cooper of Massachusetts General Hospital’s Transplantation Biology Research Center.
Even if the pigs do survive, genetic modifications alone might not be enough to conquer transplant rejection problems, even with antirejection drugs. So PPL, Immerge and Advanced Cell Technology are pursuing additional strategies for blocking rejection. Each hopes to fool the human immune system into thinking that a new pig organ belongs in the body, usually by infusing or implanting pig bone-marrow cells into the recipient several weeks before a transplant operation. The idea is to use antirejection drugs to keep the marrow cells alive long enough for the human immune system to start thinking of the pig cells as “self”-reducing the patient’s dependence on very large doses of the powerful drugs after the organ transplant. Fung is skeptical, though: “Trying to get animal organs to be accepted using approaches that haven’t worked in human organ transplantation requires a leap of faith.”
Omaha, NE-based Ximerex is even more ambitious, trying to completely eliminate the need for antirejection drugs by “introducing” individual pigs and transplant recipients prior to surgery. A patient’s bone marrow cells would be infused into a pig fetus, educating both the pig and human immune cells to think of each other as self. After the pig’s birth, hybrid pig/human bone marrow would be put back into the patient. One drawback: patients would have to wait four to five months between bone marrow sampling and transplant operations. Ximerex president William Beschorner doesn’t think the obstacle is insurmountable: “The typical wait for a human transplant is well over a year. It would not be a major problem for most patients.”
Each of these companies hopes to begin clinical testing of heart and kidney xenotransplants in the next few years. Although Cooper is generally optimistic, he sounds a note of caution. “It’s like peeling an onion: every time you pull off one layer, you find another problem underneath.” The thousands who die each year waiting for new organs hope those problems are solved soon.