C: Preclinical and clinical xenotransplantation: 

C: Preclinical and clinical xenotransplantation

Research Area C will continue to perform preclinical xenotransplantation experiments and to plan a clinical study with macroencapsulated islets. C1 will further refine the optimal age and maturation stage of NPIs and assess their functionality after transplantation into hyperglycaemic mice; under the kidney capsule for control of glucose homeostasis, and into the anterior ocular chambers for longitudinal in vivo imaging. C3 will test NPIs with different combinations of genetic modifications developed by Project Group B in diabetic NHPs (Macaca fascicularis), initially with an anti-CD154ab based immunosuppressive regimen. In parallel novel immunosuppressive strategies will be tested, first in immune-competent mouse models and then translated to NHPs. A pipeline for isolating NPIs that conforms to GMP standards will be established and a protocol for the first clinical study of non-encapsulated NPI xenotransplantation finalised. C4 has already submitted a clinical study protocol for porcine islets macroencapsulated in the BetaAir® device. As mentioned above, this approach was successful and safe in a diabetic NHP model, but had limited metabolic efficacy. The islet product and the device will therefore both be optimised employing cutting-edge bio-polymer technologies. C7 will extend its successful efforts to generate haemodynamically effective, immunocompatible xenogeneic pulmonary heart valves from GGTA1/CMAH/B4GALNT2-3´ko pigs using advanced decellularisation and deglycosylation techniques. These valves will be systematically investigated for remnant glycan residues and human patients screened for antibodies against such epitopes, providing the basis for (pre)clinical implantation. C8 achieved the world’s first consistent long-term success in orthotopic cardiac xenotransplantation. In six of eight experiments, recipient baboons survived for at least three postoperative months, and two for over six months. GGTA1-ko, hCD46/hTBM-2´tg hearts were perfused with cold, hyperoncotic, oxygenated preservation solution to prevent early systolic graft failure. The recipients were immunosuppressed, with chimeric anti-CD40 ab providing the mainstay, and also medicated to prevent overgrowth of the xeno-hearts. In future experiments overgrowth will be prevented by growth hormone receptor (GHR) gene knockout or the use of minipigs. Hearts from the multi-ko, multi-tg pigs developed by B1&2 will be tested in the orthotopic porcine heart-to-baboon transplantation model with improved immunosuppressive regimens, e.g. humanised co-stimulation blockade. In the last year of the coming funding period, porcine hearts should be available for clinical application.