Physiological basis for xenotransplantation from genetically modified pigs to humans.

The collective efforts of scientists over multiple decades have led to advancements in molecular and cellular biology-based technologies including genetic engineering and animal cloning that are now being harnessed to enhance the suitability of pig organs for xenotransplantation into humans. Using organs sourced from pigs with multiple gene deletions and human transgene insertions, investigators have overcome formidable immunological and physiological barriers in pig-to-nonhuman primate (NHP) xenotransplantation and achieved prolonged pig xenograft survival. These studies informed the design of Revivicor's (Revivicor Inc, Blacksburg, VA) genetically engineered pigs with 10 genetic modifications (10 GE) (including the inactivation of 4 endogenous porcine genes and insertion of 6 human transgenes), whose hearts and kidneys have now been studied in preclinical human xenotransplantation models with brain-dead recipients. Additionally, the first two clinical cases of pig-to-human heart xenotransplantation were recently performed with hearts from this 10 GE pig at the University of Maryland. Although this review focuses on xenotransplantation of hearts and kidneys, multiple organs, tissues, and cell types from genetically engineered pigs will provide much-needed therapeutic interventions in the future.

Genetically Modified Porcine-to-Human Cardiac Xenotransplantation.

A 57-year-old man with nonischemic cardiomyopathy who was dependent on venoarterial extracorporeal membrane oxygenation (ECMO) and was not a candidate for standard therapeutics, including a traditional allograft, received a heart from a genetically modified pig source animal that had 10 individual gene edits. Immunosuppression was based on CD40 blockade. The patient was weaned from ECMO, and the xenograft functioned normally without apparent rejection. Sudden diastolic thickening and failure of the xenograft occurred on day 49 after transplantation, and life support was withdrawn on day 60. On autopsy, the xenograft was found to be edematous, having nearly doubled in weight. Histologic examination revealed scattered myocyte necrosis, interstitial edema, and red-cell extravasation, without evidence of microvascular thrombosis - findings that were not consistent with typical rejection. Studies are under way to identify the mechanisms responsible for these changes. (Funded by the University of Maryland Medical Center and School of Medicine.).

Commentary on achievement of first life-saving xenoheart transplant.

Two months of post-transplant survival were achieved in an end-stage heart disease patient with a porcine heart from a pig whose genome had been modified in 10 of its genes. This first-ever life-saving cardiac xenotransplantation was the result of decades of work and close coordination by researchers in genetic engineering, animal cloning, immunology, ex vivo organ perfusion, and thoracic surgery.

The role of industry in advancing xenotransplantation.

PURPOSE OF REVIEW: Xenotransplantation offers the opportunity to alleviate the imbalance between the demand of patients with end stage organ failure and the supply of organs available for transplantation but remains aspirational. This review highlights how collaboration between academia and industry are essential for success. RECENT FINDINGS: The science of xenotransplantation has accelerated in recent years with key discoveries in genetic engineering, enabling disruption of genes facilitating rejection, and transgenic expression of desired human genes. Combined with similar progress directed toward induction of transplant tolerance, the stage has been set for meaningful progress. These advances are reviewed in detail elsewhere in this volume and argue that the breakthroughs needed to deliver substantial cross-species organ survival have largely been achieved, heralding a liminal stage of human xenotransplantation. However, xenotransplantation as a meaningful therapy for medically refractory end organ failure will not be realized through scientific innovation alone. The advent of broadly available, therapeutic xenogeneic tissues requires extensive development and regulatory expertise; the biotechnology/pharmaceutical industry can provide extensive resources and expertise in those essential areas. SUMMARY: Successful delivery of xenotransplantation as an available therapy for curing end stage organ failure is best accomplished through partnership and collaboration between academia and industry.

A personal perspective on the science, ethics, and commercialization of xenotransplantation.

A parent of a child with a fatal lung disease decides to try to save her first with improved pharmaceuticals to hold the disease at bay, and then with an unlimited supply of transplantable lungs to cure the disease and manage the consequences of eventual organ rejection. The parent needs to surmount science, ethics, and commercialization issues for organ transplantation to be a practical cure, and several of those issues are particularly difficult for xenotransplanation. After half-a-decade of effort, the parent's personal journey has resulted in a 100-fold increase in the number of hours that pulmonary xenografts are viable, but still remains significantly shy of commercial viability and still leaves some ethical issues open.

The promise of organ and tissue preservation to transform medicine.

The ability to replace organs and tissues on demand could save or improve millions of lives each year globally and create public health benefits on par with curing cancer. Unmet needs for organ and tissue preservation place enormous logistical limitations on transplantation, regenerative medicine, drug discovery, and a variety of rapidly advancing areas spanning biomedicine. A growing coalition of researchers, clinicians, advocacy organizations, academic institutions, and other stakeholders has assembled to address the unmet need for preservation advances, outlining remaining challenges and identifying areas of underinvestment and untapped opportunities. Meanwhile, recent discoveries provide proofs of principle for breakthroughs in a family of research areas surrounding biopreservation. These developments indicate that a new paradigm, integrating multiple existing preservation approaches and new technologies that have flourished in the past 10 years, could transform preservation research. Capitalizing on these opportunities will require engagement across many research areas and stakeholder groups. A coordinated effort is needed to expedite preservation advances that can transform several areas of medicine and medical science.