Heart Xenotransplantation with Chimeric Donor Pigs

描述（由申请人提供）：心脏移植物的移植可以显着地为患有心力衰竭的接受者提供长久而富有成效的生活。典型的移植存活期超过 10 年。然而，由于人类捐赠者严重短缺，大多数人都没有收到所需的心脏移植物。尽管美国每年大约进行 2300 例移植手术，但据估计，如果有捐赠者的话，可能有 50,000 例患者受益。在发达国家，每年未满足的移植需求估计为 135,000 例。使用供体猪可以轻松解决器官捐献者的严重短缺问题。猪可以在非常清洁的条件下饲养，并且可以消除传播人类感染和肿瘤的风险。猪心脏的生理学也与人的心脏非常相似。然而，猪心脏异种移植物遭到强烈排斥。对于传统和转基因供体猪，需要增加免疫抑制来延长移植物的存活率。这引起了人们对人畜共患感染传播给接受者的担忧。问题是宿主针对多种异种抗原的多种免疫反应会破坏移植物。 Ximerex, Inc. 开发了专有技术，可以预防急性异种移植排斥，包括急性血管排斥，而无需严重的免疫抑制。通过在供体胎猪内培养受体淋巴细胞，在移植前在供体动物内实现移植目标、对猪的特异性免疫耐受和猪组织的适应。 Ximerex 将在供体猪中处理和培养患者的骨髓细胞，并向移植中心提供嵌合脾淋巴细胞和适应的供体心脏。嵌合供体猪的价值已通过猪到羊的心脏移植得到证实，包括移植到具有预先形成的抗猪抗体的致敏羊中。在适度的免疫抑制下，观察到移植物存活时间延长。此外，在没有任何移植后免疫抑制的情况下，恒河猴的猪胰岛存活时间延长（>150天）。嵌合猪的心脏外植体表现出对抗体和补体（包括新鲜人血）的保护作用。与调节相关的蛋白质的 RNA 在心脏组织中上调。 拟议的 SBIR 项目将完成 FDA 批准 I/II 期临床试验所需的临床前研究。 I 期 SBIR 提案将在试点研究中确定将嵌合供体猪心脏移植到具有隐藏或无免疫抑制的非人类灵长类动物中的功效。后续研究将确定组织调节和特异性免疫耐受对心脏异种移植物存活时间延长的相对贡献。

DESCRIPTION (provided by applicant): The transplantation of heart grafts can dramatically provide a long and productive life to recipients with heart failure. Typical transplant survivals are more than 10 years. Because of an acute shortage of human donors, however, most do not receive their needed heart graft. Whereas approximately 2300 transplants are performed annually in the United States, it has been estimated that 50,000 could benefit, if a donor were available. In the developed world, the unmet need is estimated at 135,000 transplants per year. The use of donor pigs could readily resolve this severe shortage of organ donors. Pigs can be raised under very clean conditions and would eliminate the risk of spreading human infections and tumors. The physiology of the pig heart is also very similar to human hearts. However, pig heart xenografts are vigorously rejected. With conventional and transgenic donor pigs, increased immune suppression is required to prolong graft survival. This has raised concern about transmission of zoonotic infections to the recipient. The problem is that multiple immune reactions by the host against multiple xenoantigens destroy the graft. Ximerex, Inc. has developed proprietary technology that prevents acute xenograft rejection, including acute vascular rejection, without the need for severe immune suppression. By growing the recipient lymphocytes within donor fetal pigs, the goals of transplantation, specific immune tolerance to the pig and accommodation of the pig tissues, are achieved within the donor animal, before transplantation. Ximerex would process and grow the patient's marrow cells in the donor pig and provide chimeric spleen lymphocytes and an accommodated donor heart to the transplant center. The value of chimeric donor pigs has been demonstrated with pig to sheep heart transplants, including transplants into sensitized sheep with preformed anti-pig antibodies. With modest immune suppression, prolonged graft survival was observed. Furthermore, prolonged survival of pig islets (>150 days) in rhesus macaques was achieved without any post-transplant immune suppression. Heart explants from chimeric pigs demonstrate accommodation with protection against antibodies and complement, including fresh human blood. RNA for proteins associated with accommodation is upregulated in the heart tissue. The proposed SBIR project would complete the preclinical studies required for FDA allowance of phase I/II clinical trials. The Phase I SBIR proposal would establish in pilot studies the efficacy of transplanting chimeric donor pig hearts into non-human primates with hide or no immune suppression. Follow up studies would establish the relative contribution of tissue accommodation and specific immune tolerance to the prolongation of heart xenograft survival.