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

项目总结/摘要 在患有复杂心脏病的婴儿中，迫切需要新的心脏支持技术。 最近对1987年至2016年UNOS数据库的分析显示，只有55%的婴儿被安置在 心脏移植等待名单存活到移植。机械循环支持的结果 (MCS)在婴儿中是次优的。使用MCS的婴儿的6个月存活率精算报告如下： PEDIMACS为50%，大多数有不良事件。这些结果表明，迫切需要 新的治疗模式在这个年龄组。完全植入式生物支持的潜力 对心脏移植名单上的婴儿来说将是变革性的。我们的初步数据显示 提示，如果婴儿的心脏被移植， 三重基因敲除（TKO）猪。这些猪缺乏3种酶β 1，3-半乳糖基转移酶 （产生半乳糖-β 1，3-半乳糖[GaL]，胞苷一磷酸-N-乙酰神经氨酸 羟化酶（产生Neu 5Gc）和β 1，4-乙酰半乳糖胺转移酶（添加Sda）。（见表1）。 这些猪被称为三重敲除（TKO）。我们记录了缺乏预先形成的抗体 TKO猪的红细胞（RBC），即使在复杂的心脏手术后。抗猪IgM的结合 并且IgG与野生型相比大大降低（即，未修饰的[WT]猪）。 这个R33应用程序将使我们能够瞄准使能技术，以解决一个重大的翻译问题。 临床上缺乏对婴儿危重心脏病的管理。如果成功，它 为婴儿心力衰竭的管理建立了一个变革性的平台。到 根据我们的知识，我们是唯一一个快速关注其潜在应用的研究小组 在这个病人群体中发展技术。获得最先进的GEPH （适合人类婴儿移植的心脏）表明了数据的潜力 在本研究中开发，以在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.