Liver Xenotransplantation using CRISPR-modified Porcine Organs

使用 CRISPR 修饰的猪器官进行肝脏异种移植

基本信息

  • 批准号:
    9974026
  • 负责人:
  • 金额:
    $ 77.19万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-02-01 至 2025-01-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY / ABSTRACT Liver transplantation has failed to reach its full potential for saving lives due to the inadequate organ supply. Every year thousands of potentially salvageable patients die awaiting an allograft, hundreds of others receive a `marginal” donor organ, often in desperate circumstances, and a many times this number of potential recipients are never offered listing for lifesaving organs due to the need to ration this precious but limited resource. Liver xenotransplantation offers a potential solution to the organ shortage but clinical application has been stymied by four principle hurdles: 1) risk of zoonotic infection of humans, 2) the vigorous immune response mounted to xenogeneic tissues, and 3) physiologic incompatibilities due to species divergence arising in a rarity of protein: protein interactions, and if these obstacles can be consistently overcome, the 4) need to identify a clinically applicable IS regimen. A new tool with unprecedented potential to address these barriers to widespread application of xenotransplantation is found in technology such as CRISPR-Cas9 that dramatically increases gene editing specificity and efficiency. A powerful example is found in recent work by our industry partner, eGenesis, who used CRISPR-Cas9 to rid the pig genome of 62 copies of functional porcine endogenous retroviruses (PERVs), essentially eliminating the risk of PERV transmission to an organ recipient. In the current proposal, we explore the ability of advanced gene editing to address immunologic and physiologic barriers that cause immediate graft dysfunction of liver xenografts when transplanted into a translational baboon model. With the general goal preventing initial xenograft dysfunction (IXD) to gain long term survival of pig liver xenografts in baboon recipients, studies in Aim I will focus on two recently identified potential impediments to xenograft survival: 1) ischemia reperfusion injury, and 2) platelet consumption. Recent findings in cardiac xenotransplantation studies have exposed the critical contribution of IR injury to early heart xenograft demise. Our wealth of experience with ex vivo liver perfusion and also xeno liver perfusion with human blood and the recently reported technique for ischemia free liver transplants should yield a definitive answer to this question. Aim II will focus on understanding the impact of gene edits that: 1) eliminate expression of the three major antibody targets of preformed human anti-pig antibodies, 2) gain expression of human proteins designed to address complement and coagulation dysregulation occurring with porcine liver xenotransplants in NHP, and 3) mitigate innate and cell-mediated immunity and inflammation. To accomplish this, we will take advantage of liver transplant, ex vivo liver perfusion with human blood and in vitro assays well established in our lab and a panel of CRISPR modified pigs with varied expression of genetic edits.
项目摘要/摘要 由于器官供应不足,肝移植未能充分发挥其挽救生命的潜力。 每年,数以千计的潜在可挽救的患者在等待同种异体移植时死亡,数百人接受了 “边缘”捐献器官,通常在绝望的情况下,潜在的接受者人数是这个数字的数倍 由于需要对这一宝贵但有限的资源进行配给,从未提供救生器官的名单。肝 异种移植为器官短缺提供了一种潜在的解决方案,但临床应用受到阻碍。 通过四个主要障碍:1)人畜共患传染病的风险,2)强烈的免疫反应上升到 异种组织,以及3)稀有蛋白质引起的物种差异引起的生理不亲和性: 蛋白质的相互作用,如果这些障碍能够持续克服,就需要在临床上找出 适用的是养生法。 一种具有前所未有的潜力的新工具,可以解决这些阻碍广泛应用的障碍 异种移植被发现在CRISPR-Cas9等技术中显著增加了基因编辑 特异性和有效性。在我们的行业合作伙伴eGenesis最近的工作中发现了一个强有力的例子,他 用CRISPR-Cas9去除猪基因组中62份功能性猪内源性逆转录病毒 (PERV),基本上消除了PERV传播给器官接受者的风险。在目前的提案中, 我们探索高级基因编辑的能力,以解决免疫和生理障碍导致 将异种肝脏移植到平移的狒狒模型中时的即刻移植物功能障碍。 总的目标是预防初始异种移植功能障碍(IxD)以获得猪肝脏的长期存活 AIM I中的研究将集中在最近发现的两个潜在障碍上 异种移植存活:1)缺血再灌注损伤,2)血小板消耗。心脏疾病的最新发现 异种移植研究揭示了IR损伤在异种心脏移植早期死亡中的关键作用。 我们在体外肝脏灌流和人血异种肝脏灌流方面的丰富经验 最近报道的无缺血肝移植技术应该会给出这个问题的明确答案。 AIM II将重点了解基因编辑的影响,这些编辑:1)消除三个主要基因的表达 预制的人抗猪抗体的抗体靶标,2)获得设计用于 解决NHP猪肝脏异种移植中出现的补体和凝血失调问题,以及 3)减轻先天和细胞介导的免疫和炎症。为了实现这一目标,我们将利用 肝移植、体外人血肝脏灌流和体外检测已在我们的实验室和 CRISPR转基因猪的小组具有不同的基因编辑表达。

项目成果

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JAMES FRANCIS MARKMANN其他文献

JAMES FRANCIS MARKMANN的其他文献

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{{ truncateString('JAMES FRANCIS MARKMANN', 18)}}的其他基金

Liver Xenotransplantation using CRISPR-modified Porcine Organs
使用 CRISPR 修饰的猪器官进行肝脏异种移植
  • 批准号:
    10333323
  • 财政年份:
    2020
  • 资助金额:
    $ 77.19万
  • 项目类别:
Liver Xenotransplantation using CRISPR-modified Porcine Organs
使用 CRISPR 修饰的猪器官进行肝脏异种移植
  • 批准号:
    10089398
  • 财政年份:
    2020
  • 资助金额:
    $ 77.19万
  • 项目类别:
Liver Xenotransplantation using CRISPR-modified Porcine Organs
使用 CRISPR 修饰的猪器官进行肝脏异种移植
  • 批准号:
    10561616
  • 财政年份:
    2020
  • 资助金额:
    $ 77.19万
  • 项目类别:
Expanding the Liver Transplant Organ Pool through Ex Vivo Liver Perfusion
通过离体肝脏灌注扩大肝移植器官库
  • 批准号:
    9310237
  • 财政年份:
    2016
  • 资助金额:
    $ 77.19万
  • 项目类别:
Mechanisms of B Cell-Dependent Transplantation Tolerance
B 细胞依赖性移植耐受的机制
  • 批准号:
    8608994
  • 财政年份:
    2006
  • 资助金额:
    $ 77.19万
  • 项目类别:
Mechanisms of B Cell-Dependent Transplantation Tolerance
B 细胞依赖性移植耐受的机制
  • 批准号:
    8811397
  • 财政年份:
    2006
  • 资助金额:
    $ 77.19万
  • 项目类别:
Mechanism of anti-CD45 induced transplantation tolerance
抗CD45诱导移植耐受的机制
  • 批准号:
    7599695
  • 财政年份:
    2006
  • 资助金额:
    $ 77.19万
  • 项目类别:
Mechanism of anti-CD45 induced transplantation tolerance
抗CD45诱导移植耐受的机制
  • 批准号:
    7557931
  • 财政年份:
    2006
  • 资助金额:
    $ 77.19万
  • 项目类别:
Mechanisms of B cell-Dependent Transplantation Tolerance
B 细胞依赖性移植耐受的机制
  • 批准号:
    10062841
  • 财政年份:
    2006
  • 资助金额:
    $ 77.19万
  • 项目类别:
Mechanisms of B cell-Dependent Transplantation Tolerance
B 细胞依赖性移植耐受的机制
  • 批准号:
    10308033
  • 财政年份:
    2006
  • 资助金额:
    $ 77.19万
  • 项目类别:

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