Cardiac xenotransplantation: from concept to clinic.

For many patients with terminal/advanced cardiac failure, heart transplantation is the most effective, durable treatment option, and offers the best prospects for a high quality of life. The number of potentially life-saving donated human organs is far fewer than the population who could benefit from a new heart, resulting in increasing numbers of patients awaiting replacement of their failing heart, high waitlist mortality, and frequent reliance on interim mechanical support for many of those deemed among the best candidates but who are deteriorating as they wait. Currently, mechanical assist devices supporting left ventricular or biventricular heart function are the only alternative to heart transplant that is in clinical use. Unfortunately, the complication rate with mechanical assistance remains high despite advances in device design and patient selection and management, and the quality of life of the patients even with good outcomes is only moderately improved. Cardiac xenotransplantation from genetically multi-modified (GM) organ-source pigs is an emerging new option as demonstrated by the consistent long-term success of heterotopic (non-life-supporting) abdominal and life-supporting orthotopic porcine heart transplantation in baboons, and by a recent 'compassionate use' transplant of the heart from a GM pig with 10 modifications into a terminally ill patient who survived for 2 months. In this review, we discuss pig heart xenotransplantation as a concept, including pathobiological aspects related to immune rejection, coagulation dysregulation, and detrimental overgrowth of the heart, as well as GM strategies in pigs to prevent or minimize these problems. Additional topics discussed include relevant results of heterotopic and orthotopic heart transplantation experiments in the pig-to-baboon model, microbiological and virologic safety concepts, and efficacy requirements for initiating formal clinical trials. An adequate regulatory and ethical framework as well as stringent criteria for the selection of patients will be critical for the safe clinical development of cardiac xenotransplantation, which we expect will be clinically tested during the next few years.

Renal xenotransplantation: experimental progress and clinical prospects.

There are >100,000 patients waiting for kidney transplants in the United States and a vast need worldwide. Xenotransplantation, in the form of the transplantation of kidneys from genetically engineered pigs, offers the possibility of overcoming the chronic shortage of deceased and living human donors. These genetic manipulations can take the form of (i) knockout of pig genes that are responsible for the expression of antigens against which the primate (human or nonhuman primate) has natural "preformed" antibodies that bind and initiate complement-mediated destruction or (ii) the insertion of human transgenes that provide protection against the human complement, coagulation, or inflammatory responses. Between 1989 and 2015, pig kidney graft survival in nonhuman primates increased from 23 days to almost 10 months. There appear to be no clinically significant physiological incompatibilities in renal function between pigs and primates. The organ-source pigs will be housed in a biosecure environment, and thus the risk of transferring an exogenous potentially pathogenic microorganism will be less than that after allotransplantation. Although the risk associated with porcine endogenous retroviruses is considered small, techniques are now available whereby they could potentially be excluded from the pig. The US Food and Drug Administration suggests that xenotransplantation should be restricted to "patients with serious or life-threatening diseases for whom adequately safe and effective alternative therapies are not available." These might include those with (i) a high degree of allosensitization to human leukocyte antigens or (ii) rapid recurrence of primary disease in previous allografts. The potential psychosocial, regulatory, and legal aspects of clinical xenotransplantation are briefly discussed.

[Immunology in clinical practice. XXIII. Xenotransplantation]. / Immunologie in de medische praktijk. XXIII. Xenotransplantatie.

Currently xenotransplantation is being discussed on national and international levels as a possible solution to tranplantation waiting lists, in view of the lack of alternative therapies. In recent years, enormous progress has been made in the area of immunology, especially concerning hyperacute rejection. However, long-term survival is still fiction due to relatively unknown, sequential rejection processes. Moreover, it remains questionable if xenogeneic organs will function physiologically, especially if they are metabolically complex. A third problem is the possible infectious risk of xenotransplantation to the patient and the population. Regarding this hazard, various committees and policy reports demand clarity first before the initial clinical transplantations become fact. In the Netherlands, the government largely adopted an identical advice by the Health Council. Artificial organs and cloning developments indicate that xenotransplantation might merely be an intermediate station in the route to develop adequate treatment for patients with organ failure.