The genetically engineered pig heart as a bridge to allotransplantation in infants

基因工程猪心脏作为婴儿同种异体移植的桥梁

• 批准号: 10815486
• 负责人: David C Cleveland
• 金额: $ 50.13万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10815486
• 关键词: Address; Adverse event; Allografting; Antibodies; Antigens; Aorta; B-Lymphocytes; Binding; Biological; Blood Transfusion; Blood typing procedure; Cardiac; Cattle; Clinical; Clinical Trials; Complex; Cytidine Monophosphate N-Acetylneuraminic Acid; Data; Databases; Documentation; Enzymes; Erythrocytes; Family suidae; Focus Groups; Functional disorder; Galactose; Galactosyltransferases; Genes; Genetic Engineering; Heart; Heart Diseases; Heart Transplantation; Heart failure; Hour; Human; Immune response; Immune system; Immunoglobulin G; Immunoglobulin M; Implant; Infant; Infant Mortality; Knock-out; Knowledge; Length; Life; Lung; Maintenance; Mixed Function Oxygenases; Modeling; Operative Surgical Procedures; Papio; Patients; Pericardial body location; Peripheral Blood Mononuclear Cell; Population; Postoperative Period; Probability; Procedures; Reporting; Research; T-Lymphocyte; Techniques; Technology; Testing; Therapeutic immunosuppression; Thymectomy; Time; Transplantation; United Network for Organ Sharing; Waiting Lists; age group; allotransplant; blood group; clinical application; clinical translation; cross reactivity; graft failure; heart xenograft; improved; in vivo; mechanical circulatory support; natural antibodies; novel; palliation; patient population; pericardial sac; preclinical study; prevent; success; transplant model

PROJECT SUMMARY/ABSTRACT There is a critical need for novel cardiac support techniques in infants with complex cardiac disease. A recent analysis of UNOS database from 1987 to 2016 documented only 55% of infants placed on cardiac transplant wait list survived to transplantation. The results of mechanical circulatory support (MCS) in infants is suboptimal. Actuarial six month survival of infants placed on MCS is reported by PEDIMACS to be 50% and most have adverse events. These results establish a pressing need for a new treatment paradigm in this age group. The potential of a completely implantable biologic support for infants on the cardiac transplant list would be transformative. Our preliminary data strongly suggest that anti-pig antibodies will not be a barrier to GEPH transplantation in infants if hearts are taken from `triple-knockout' (TKO) pigs. These pigs lack the 3 enzymes 1,3-galactosyltransferase (produces galactose-1,3galactose [GaL], cytidine monophosphate-N-acetylneuraminic acid hydroxylase (produces Neu5Gc), and 1,4-acetylgalactosaminyltrnsferase (adds Sda). (Table 1). These pigs are referred to as triple knockouts (TKO). We documented a lack of pre-formed antibodies to red blood cells (RBCs) of TKO pigs even after complex cardiac procedures. Binding of anti-pig IgM and IgG is greatly reduced compared with that to wild-type (i.e., unmodified [WT] pigs). This R33 application will allow us to target enabling technology to address a major translational clinical deficiency in the management of infants with critical cardiac disease. If successful, it establishes a transformative platform for the management of heart failure in the infant population. To our knowledge, we are the only research group focused on the potential application of this rapidly developing technology in this patient population. Access to the most advanced GEPHs available (hearts that would be suitable for transplantation in human infants) indicates the potential for data developed in this study to provide support for clinical application within five years.

项目摘要/摘要 在患有复杂心脏疾病的婴儿中，需要新颖的心脏支持技术。 对1987年至2016年UNOS数据库的最新分析仅记录了55％的基础设施 心脏移植等待名单幸存为移植。机械电路支持的结果 （MC）婴儿次优。据报道，放置在MCS上的婴儿的六个月生存。 Pedimacs为50％，大多数都有不良事件。这些结果确定了对 该年龄段的新治疗范式。完全可植入的生物学支持的潜力 对于心脏移植清单上的婴儿，将是有变革的。我们的初步数据 表明，如果心脏是抗猪抗体，则不会成为GEPH移植的障碍 取自“三重敲打”（TKO）猪。这些猪缺乏3种酶1,3-半乳糖基转移酶 （产生半乳糖-1,3galactos [GAL]，胞苷单磷酸-N-乙酰神经酰胺酸 羟化酶（产生neu5GC）和1,4-乙酰基乳糖酰氨基氨基植物酶（添加SDA）。 （表1）。 这些猪被称为三重敲除（TKO）。我们记录了缺乏预制的抗体 即使经过复杂的心脏手术，也要对TKO猪的红细胞（RBC）。抗铅IgM的结合 与野生型（即未修饰的[wt]猪）相比，IgG大大降低了。 该R33应用程序将使我们能够针对启用技术来解决主要的翻译 患有危急心脏病的婴儿治疗的临床缺乏。如果成功的话，它 建立一个用于管理婴儿人群心力衰竭的变革平台。到 我们的知识，我们是唯一关注这一潜在应用的研究小组 在该患者人群中开发技术。访问最先进的Gephs （适合在人类婴儿中移植的心脏）表明数据的潜力 在这项研究中开发的旨在在五年内为临床应用提供支持。