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

项目摘要/摘要 对于患有复杂心脏病的婴儿，迫切需要新的心脏支持技术。 最近对1987年至2016年联合国儿童基金会数据库的分析记录显示，只有55%的婴儿被放置在 心脏移植等待名单存活到移植。机械循环支持的效果 (MCS)在婴儿中是次佳的。接受MCS治疗的婴儿的精算六个月存活率由 PEDIMAC为50%，大多数有不良反应。这些结果表明迫切需要一种 这一年龄段的新治疗模式。一种完全可植入的生物支架的潜力 对于心脏移植名单上的婴儿来说，这将是变革性的。我们的初步数据显示 提示抗猪抗体不会成为婴儿GEPH移植的障碍，如果心脏 取自‘三重击倒’(TKO)猪。这些猪缺乏1，3-半乳糖基转移酶的3种酶 (生产半乳糖-1，3半乳糖[GAL]，胞苷一磷酸-N-乙酰神经氨酸 羟基酶(产生Neu5Gc)和1，4-乙酰半乳糖胺转移酶(增加sda)。(表1)。 这些猪被称为三重击倒(TKO)。我们发现没有预先形成的抗体 即使在复杂的心脏手术后，对TKO猪的红细胞(RBC)也是如此。抗猪免疫球蛋白M的结合 与野生型(即未改良的[WT]猪)相比，免疫球蛋白大大降低。 此R33应用程序将使我们能够瞄准支持技术，以解决主要的 危重心脏病婴儿救治中的临床缺陷。如果成功，它将 为婴幼儿心力衰竭的管理建立了一个变革性的平台。至 我们的知识，我们是唯一一个专注于这一潜在应用的快速研究小组 在这群患者中开发技术。获取可用的最先进的GEPH (适合在人类婴儿身上移植的心脏)表明了数据的潜力 本研究开发的五年内为临床应用提供支持。

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.