title: Progress and Breakthrough in Preclinical and Clinical Cardiac Xenotransplantation
Creators: name: Brenner, Paolo
Publisher: name: MyCoRe Community
Year: 2024
Subjects: subject: Xenotransplantation
subject: Heterotransplantation
subject: Heart Transplantation
subject: Herztransplantation
subject: Baboons
subject: Pavian
subject: Pig Heart
subject: 610

description: Introduction: Before starting clinical cardiac xenotransplantation the International Society for Heart and Lung Transplantation (ISHLT) advisory board recommended a 90-days-survival of 60 % in a life-supporting orthotopic pigto-baboon model (oXHTx). We achieved this with a new costimulation blockade immunosuppression (CD40mAb). Problems like perioperative xenograft dysfunction (PCXD) and cardiac xenograft (over)growth (CXO) were solved with a cold perfusion preservation and anti-proliferative drugs. Methods: Eight baboons were transplanted with GalKO/hCD46/hTM transgenic pig hearts. Immunosuppression consisted of antithymocyte globulin (ATG), rituximab, mycophenolate-mofetil (MMF), cortisone and CD40mAb(2C10). To prevent PCXD we used a non-ischemic 8oC cold perfusion solution with oxygenated blood. To inhibit CXO/hypertrophy, antihypertensive drugs and temsirolimus were given. Results: With cold perfusion no PCXD occurred. After growth control 6 recipient baboons reached the end of study (90 days), two were prolonged up to day 182 / day 195. Two baboons died on day 14 / day 26 of sepsis (pCMV- positive donor hearts). No hyperacute or delayed rejection occurred. All baboons were in excellent general conditions (Längin et al. 2018). With the same immunosuppression and cold perfusion in 2021 Prof. Mohiuddin in Baltimore (MD, USA) achieved with 7- to 10-fold genetically modified donor pigs in oXHTx a maximal survival of 264 days. The second, clinical breakthrough was a worldwide first-in-man cardiac xenotransplantation (January 7th, 2022) in Baltimore: Mr. David Bennett (57 years old, non-transplantable on extracorporeal membrane oxygenation (ECMO) support) received a pig heart with 10 gene modifications as “compassionate use”. During implantation a type-A-aortic-dissection occurred as complication. During recovery next weeks, xenograft showed normal function. Bowl problems led to laparotomy and mobilization was difficult. After day 50 situation deteriorated, and after change to a palliative concept the patient died (po day 60, histologically no major signs of xenograft rejection) (Griffith et al. 2022). Despite the marginal patient (immobilized, ECMO, redo-operation, non-compliance) and the complicated operation (A-dissection), this two-months-survival can be classified as a great success. Conclusion: After 25 years of experimental research, we achieved in Munich in the last 5 years a major progress and breakthrough with a constant reproducible long-term-survival of 3 – 6 months. This was the essential milestone on the way to clinical cardiac xenotransplantation, which was started with the patient in Baltimore and pushes this new key technology also for other organs (kidney, lung, islet cells). In Munich a first clinical pilot trial is planned in the year 2024 and eventually in 2022 a compassionate use.
description: Transplantation: Ethics, Techniques, Immunology, p. 21