SEATTLE, WASHINGTON.
Trans Am Clin Climatol Assoc. 2020;131:270-285.
Since the first report of a successful liver transplant in 1968, access to this operation has dramatically improved. In 2018, 8,250 patients underwent liver transplantation in the United States. Despite this remarkable advance, a persistent shortage of donor organs remains the primary obstacle to optimal utilization of this life-saving operation. Over the past two decades, transplant professionals have pursued two broad strategies to overcome this roadblock: increasing the number of donor organs and decreasing the number of patients requiring transplantation through advances in medical interventions. Despite these efforts, more than 13,500 patients remained on liver transplant waiting lists at the end of 2018. Almost 1,200 died while waiting, and 1,350 were removed from wait lists because they had become too sick to survive the operation. Clearly, a dramatic new approach to the donor organ shortage is needed. One effort, first attempted by surgeons in the 1960s, was to utilize donor organs from other species (xenotransplantation). The major obstacle to xenotransplantation acceptance has been the fear of transmitting new infectious diseases from animals to humans. As the twentieth century came to a close, national moratoria on xenotransplantation ended both research and clinical activities in this field. The recent discoveries that modern gene-editing techniques can be used to eliminate the retrovirus that is ubiquitous in pigs and that retrovirus-free pigs can be cloned has reopened the possibility that xenotransplantation may be a potentially game-changing approach to eliminating the donor shortage for liver and other solid organ transplant recipients. In response to these advances, the FDA has released comprehensive industry guidelines regarding all aspects of xenotransplantation. This release has resulted in numerous preclinical studies in which organs from genetically modified pigs are transplanted into various nonhuman primates (NHPs). Use of a variety of gene-editing and immunosuppressive techniques has greatly increased the survival of recipient animals in the past few years. Survival of NHP renal transplant recipients has been extended to 435 days, functional cardiac transplant recipients to 195 days, and liver transplant recipients to 29 days. Current research studies using various gene modification strategies combined with newer immunosuppressive protocols are attempting to further extend the survival of these experimental animals. These encouraging results have raised the possibility that clinical xenotransplantation in humans is just beyond the horizon. The most likely candidates for initial clinical studies probably will be kidney transplant recipients who are difficult to crossmatch for human organs, neonates with severe congenital heart disease, and liver transplant candidates with acute liver failure.
自 1968 年首例成功的肝移植报告以来，接受这种手术的机会显著增加。2018 年，美国有 8250 名患者接受了肝移植。尽管取得了这一显著进展，但供体器官的持续短缺仍然是充分利用这种救命手术的主要障碍。在过去的二十年中，移植专业人员通过两种广泛的策略来克服这一障碍：增加供体器官的数量，并通过医疗干预的进步减少需要移植的患者数量。尽管做出了这些努力，但到 2018 年底，仍有超过 13500 名患者在肝移植等待名单上。几乎有 1200 人在等待过程中死亡，1350 人因病情恶化无法接受手术而被从等待名单中删除。显然，需要采取一种全新的方法来解决供体器官短缺问题。早在 20 世纪 60 年代，外科医生就尝试过利用来自其他物种的供体器官（异种移植）。异种移植接受的主要障碍是担心从动物传播新的传染病到人类。随着 20 世纪接近尾声，对异种移植的国家禁令结束了这一领域的研究和临床活动。最近的发现表明，现代基因编辑技术可用于消除普遍存在于猪体内的逆转录病毒，并且无逆转录病毒的猪可以克隆，这重新开启了异种移植可能是消除肝和其他实体器官移植受者供体短缺的潜在变革性方法的可能性。针对这些进展，FDA 发布了有关异种移植各个方面的全面行业指南。这导致了大量的临床前研究，其中来自基因改良猪的器官被移植到各种非人类灵长类动物（NHPs）中。在过去几年中，使用各种基因编辑和免疫抑制技术大大提高了受体动物的存活率。NHPs 肾移植受者的存活时间延长到 435 天，功能心脏移植受者的存活时间延长到 195 天，肝移植受者的存活时间延长到 29 天。目前正在使用各种基因修饰策略和较新的免疫抑制方案进行研究，以进一步延长这些实验动物的存活时间。这些令人鼓舞的结果提出了异种临床移植在人类中即将出现的可能性。最初的临床研究最有可能是难以与人源器官配型的肾移植受者、患有严重先天性心脏病的新生儿和急性肝衰竭的肝移植候选者。
