Studies in pig-to-primate cardiac xenotransplantation

猪到灵长类动物心脏异种移植的研究

• 批准号: 8097350
• 负责人: CHRISTOPHER G.A. MCGREGOR
• 金额: $ 104.96万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8097350
• 关键词: Achievement; Antibodies; Antibody Formation; Antigen Targeting; Antigens; Binding; Biochemical; Biochemical Markers; Biopsy; Blood Circulation; Bortezomib; Carbohydrates; Cardiac; Cell Transplantation; Chronic; Clinical; Development; Diagnosis; Dissection; Echocardiography; Effectiveness; Electrocardiogram; Endothelial Cells; Engineering; Family suidae; Flow Cytometry; Functional disorder; Funding; Future; Gene Expression; Grant; Heart; Heart Transplantation; Histologic; Histology; Immune response; Immunosuppression; Immunosuppressive Agents; In Situ; Individual; Injury; Intervention; Lasers; Life; Measurement; Mediating; Methods; Modality; Modeling; Monitor; Neoadjuvant Therapy; Organ Donor; Outcome; Patients; Perioperative; Pharmaceutical Preparations; Physiologic Monitoring; Plasma Cells; Plasmapheresis; Primates; Principal Investigator; Procedures; Proteasome Inhibitor; Proteins; Pulmonary Vascular Resistance; RNA; Recombinant Proteins; Recovery; Sampling; Solutions; Surgical Models; Survivors; T-Lymphocyte; Techniques; Testing; Time; Tissues; Transgenic Organisms; Transplantation; Variant; Xenograft procedure; base; cariporide; clinical application; glycosyltransferase; heart preservation; heart xenograft; improved; method development; mycophenolate mofetil; novel; preclinical study; prevent; treatment effect

DESCRIPTION (provided by applicant): The objective of this application is to achieve 90-day median survival of life-supporting cardiac xenotransplantation (CXTx) in the pig-to-primate model using genetically-engineered donors, clinical immunosuppression (IS) and modalities to diagnose and treat delayed xenograft rejection (DXR) leading to preclinical studies of CXTx. Prolonged xenograft survival is now limited by non-Gal antibody-mediated DXR (NGDXR). With improved outcomes for orthotopic (OCXTx), it has emerged that early xenograft function is compromised in up to 50% of cases. We have termed this perioperative cardiac xenograft dysfunction (PCXD). For potential future clinical application of CXTx, it is essential to understand the mechanisms and improve the outcomes of both NGDXR and PCXD. All transplants for Specific Aims (SA) 1-3 will use donors transgenic for CD55 with inactivation of the GGTA-1 glycosyltransferase locus (GTKO:CD55+). In SA 1, to better understand PCXD, plasmapheresis will be used to remove preformed non-Gal antibody (PNGA) and the proteasome inhibitor Bortezomib given to delete plasma cells prior to OCXTx. This therapy will also be combined with cariporide cardiac preservation to mitigate preoperative injury. The impact of PNGA depletion and cariporide treatment on PCXD will be assessed by measurement of cardiac function by echocardiography (ECHO), biochemical markers of cardiac injury, recipient antibody and plasma cell levels, and will be correlated with cardiac gene expression in interim biopsies and explanted hearts. In SA 2, to prevent DXR optimal IS based on induction therapy for B- and T-cells, triple drug IS and Bortezomib will be used to control NGA in OCXTx recipients surviving SA 1. We will further study the mechanism(s) of NGDXR through analysis of antibody responses to GTKO PAECs and novel individual non-Gal carbohydrate and protein target antigens we have identified. Changes in cardiac gene expression will be correlated with DXR. In SA 3, we utilize life-supporting intrathoracic heterotopic CXTx, a currently clinically used heart transplant variant which, as well as being a potential technique for initial clinical application of CXTx, will uniquely allow a) observation of recovery of PCXD by ECHO and b) development of methods for the diagnosis and treatment of DXR without loss of the recipient as the native heart supports the circulation during these periods of xenograft dysfunction. In this aim, plasmapheresis and Bortezomib will be used to treat DXR. The objective of this application, to achieve 3-month median survival of circulation-bearing CXTx, if successful, will lay the groundwork for preclinical studies during this grant period to support clinical application of CXTx. RELEVANCE: Successful xenotransplantation offers a potential clinical solution to alleviate the chronic and increasing shortage of donor organs and cells for transplantation. Our previous studies over 12 years have achieved the longest median survival of heterotopic cardiac xenotransplants and the longest survivors of life-supporting orthotopic cardiac xenotransplants. Achievement of the specific aims of this proposal will bring cardiac xenotransplantation to the threshold of clinical application.

描述（由申请人提供）： 该应用的目标是使用基因工程供体、临床免疫抑制 (IS) 和诊断和治疗迟发性异种移植排斥的方法，在猪到灵长类动物模型中实现生命支持心脏异种移植 (CXTx) 的 90 天中位生存期(DXR) 导致 CXTx 的临床前研究。现在，异种移植物存活时间的延长受到非 Gal 抗体介导的 DXR (NGDXR) 的限制。随着原位 (OCXTx) 结果的改善，高达 50% 的病例中早期异种移植功能受到损害。我们将这种围手术期心脏异种移植功能障碍（PCXD）称为。对于 CXTx 未来潜在的临床应用，了解 NGDXR 和 PCXD 的机制并改善其结果至关重要。所有针对特定目标 (SA) 1-3 的移植都将使用 CD55 转基因供体，且 GGTA-1 糖基转移酶基因座 (GTKO:CD55+) 失活。在 SA 1 中，为了更好地了解 PCXD，将在 OCXTx 之前使用血浆去除术去除预先形成的非 Gal 抗体 (PNGA) 和蛋白酶体抑制剂硼替佐米 (Bortezomib) 以消除浆细胞。该疗法还将与卡立波利心脏保存相结合，以减轻术前损伤。 PNGA 消耗和卡立波利治疗对 PCXD 的影响将通过超声心动图 (ECHO) 测量心脏功能、心脏损伤的生化标志物、受体抗体和浆细胞水平进行评估，并将与临时活检和移植中的心脏基因表达相关联心。在 SA 2 中，为了防止基于 B 细胞和 T 细胞诱导治疗的 DXR 最佳 IS，三联药物 IS 和硼替佐米将用于控制 SA 1 幸存的 OCXTx 接受者中的 NGA。我们将进一步研究 NGDXR 的机制通过分析 GTKO PAEC 的抗体反应以及我们确定的新型个体非 Gal 碳水化合物和蛋白质靶抗原。心脏基因表达的变化将与 DXR 相关。在 SA 3 中，我们利用了支持生命的胸腔内异位 CXTx，这是一种目前临床上使用的心脏移植变体，它也是 CXTx 初始临床应用的潜在技术，将独特地允许 a) 通过 ECHO 观察 PCXD 的恢复，b) ）开发 DXR 的诊断和治疗方法，而不会失去受体，因为在异种移植功能障碍期间，原生心脏支持循环。为此，血浆置换和硼替佐米将用于治疗 DXR。本申请的目标是实现循环 CXTx 的 3 个月中位生存期，如果成功，将为本资助期内的临床前研究奠定基础，以支持 CXTx 的临床应用。 相关性：成功的异种移植为缓解移植供体器官和细胞的长期且日益短缺的问题提供了潜在的临床解决方案。我们之前超过 12 年的研究已经实现了异位心脏异种移植中最长的中位存活率和原位心脏异种移植中维持生命的最长存活率。该提案具体目标的实现将使心脏异种移植迈入临床应用的门槛。