Xenotransplantation makes a comeback

transplant waiting lists in the US in 2014, but only 29,532 transplants were performed. And that gap is widening. Even when human organs are available, recipients will have to spend the rest of their lives on immunosuppressant therapies, exposing them to such comorbidities as cancer, diabetes and osteoporosis. Xenotransplantation, says A. Joseph Tector, chief medical officer at the Indiana University Health Transplant Institute, promises a nearly limitless supply of organs. But the body swiftly attacks a porcine organ placed in a human (or other primate). The main issue is the immune response (hyperacute, acute and chronic rejection by antibody-mediated and cell-mediated responses) to a transplanted animal organ, although other incompatibilities including uncontrolled complement activation and A newly announced genome-editing experiment—the largest documented to date—is the latest in a series of advances reinvigorating the field of xenotransplantation. In October, Harvard University geneticist George Church and colleagues at Boston-based startup eGenesis described (Science 350, 1101–1104, 2015) the use of CRISPR-Cas9 to disrupt all 62 genomic copies of porcine endogenous retrovirus (PERV) in cultured pig kidney epithelial cells. That feat, which dwarfs the greatest number of simultaneous DNA changes ever recorded using genome editing, removes one potential hurdle facing use of pig xenotransplants in human patients—zoonosis. But eGenesis is not the only company actively exploring the commercial prospects of xenotransplantation; Silver Spring, Maryland– based United Therapeutics has been quietly building infrastructure and partnerships— most notably with La Jolla–based Synthetic Genomics—to bring xenotransplantation closer to reality. The recent Science paper addresses a widely perceived risk that has never been documented. “Nobody’s ever shown that PERVs could actually cause a disease in a human,” points out David Sachs, director of the Transplantation Biology Research Center Laboratories at the Massachusetts General Hospital in Boston. Yet according to Geoff MacKay, interim CEO at eGenesis, who in the 1990s was vice president of transplant immunology at Novartis, it was a major consideration leading the Basel-based pharma and other companies that had been bullish on xenotransplantation to drop those programs. At the time, MacKay says, everyone viewed immune rejection as the main barrier to using nonhuman organs for transplants. But companies expected to overcome this problem, including Novartis, which earmarked $1 billion for the effort. Other firms pursuing xenotransplantation were Edinburgh, UK– based PPL Therapeutics, the company behind Dolly, the first cloned sheep, and Cambridge, Massachusetts–based Genzyme now owned by Paris-based pharma Sanofi. When the complication of PERVs became apparent, this represented one hurdle too many, MacKay says. Today, interest is once again waxing thanks both to a better understanding of organ rejection and to the use of genome editing tools, such as CRISPRCas9, to manipulate pig genes encoding proteins that trigger immune recognition. Though regulators have yet to set definitive rules for how long xenotransplants must survive before clinical trials can begin, Muhammad Mohiuddin, chief of the transplantation section at the National Heart, Lung, and Blood Institute (NHLBI), notes that a 1999 document (http://www. fda.gov/ohrms/dockets/ ac/99/other/6_3-4mtg. doc) from the US Food and Drug Administration suggested a threshold of 90% survival at 60 days and 50% survival at 90 days for “clinical cardiac bridge transplantation,” a kind of temporary transplant designed to sustain a recipient until a suitable human donor can be found. Already, that threshold is being put to the test. Mohiuddin and his colleagues at NHLBI, working with Blacksburg, Virginia– based biotech Revivicor—then a spin-out from UK’s PPL Therapeutics, now a subsidiary of United Therapeutics—have kept a heart xenograft alive for 945 days, albeit not in a life-sustaining capacity (J. Thorac. Cardiovasc. Surg. 148, 1106–1014, 2014). And researchers at Emory University have maintained a lifesustaining kidney xenograft in a baboon for 227 days. Expanding the pool of organs for transplantation remains a major challenge. According to data from the Organ Procurement Transplant Network (http://www.organdonor.gov/about/ data.html), 123,851 individuals were on Xenotransplantation makes a comeback