The Applications of Genome Editing in Xenotransplantation

Higher living standards and better medical care are increasing the lifespan of people around the world. Aging populations, however, have an increased incidence of loss of function or failure of cell, tissue or organ. This has led to the development of new medical disciplines, such as organ transplantation and more recently regenerative medicine. Organ transplantation using human donors (allotransplantation) has made enormous progress thanks to the discovery of novel immunosuppressive drugs. However, the growing demand for organs far exceeds the number of organs potentially available from human donors. Xenotransplantation, namely transplantation between animal donors and man, offers the opportunity to use healthy and highly specialized cells, tissues or solid organs readily available for immediate transfer to patients requiring replacement therapy (Ekser et al., 2012). The therapeutic potential of xenotransplantation is wide, some already in clinical use like bioprosthetic heart valves, decellularized pig tissues (skin, ligaments, bone and cartilage), polyclonal antisera, and pancreatic islet, or in a pre-clinical phase like kidney, heart, liver, lung, cornea, and dopaminergic neurons. The pig is a very suitable species for xenotransplantation for reasons that are well documented in the literature, including physiological and anatomical features, and the availability of a high resolution map of the genome. Moreover, the use of pigs for clinical purposes raises little concern from the wider public, because they are already bred by the millions for meat production worldwide. At present, the use of bioprosthetic heart valves of animal origin is a well established xenotransplantation procedure in clinical practice; however, pig islet xenotransplantation has just entered clinical trials (http://www.lctglobal.com/products/ diabecell/about-type-1-diabetes), and life supporting solid organs transplanted into nonhuman primates still do not survive long enough to warrant implementation of clinical trials (Le Bas-Bernardet et al., 2011) although heterotopic heart transplantation in a primate model has resulted in the remarkable survival of almost three years (Mohiuddin et al., 2015). Therefore, several issues still need to be addressed from the safety point of view, and a number of immunological hurdles have been identified (Table 1) and are currently being addressed at multiple levels (Griesemer et al., 2014). It is expected that the development of novel immunosuppressive strategies for allotransplantation and xenotransplantation, the modification of the immunogenicity of the donor pig through genetic engineering and, possibly the induction of immune tolerance, a phenomenon occasionally observed in allotransplantation, will all contribute to bringing xenotransplantation closer to the clinic (Ekser et al., 2012).