University of Maryland School of Medicine, Baltimore, Maryland, USA.
Revivicor Inc, Blacksburg, Virginia, USA.
Xenotransplantation. 2022 Sep;29(5):e12776. doi: 10.1111/xen.12776. Epub 2022 Sep 20.
We have been testing genetically engineered (GE) pig hearts and optimizing immunosuppression (IS) in non-human primates (NHPs) since 2005. We demonstrate how we translated this preclinical investigation into a US Food and Drug Administration (FDA)-approved clinical cardiac xenotransplantation. First, genetically engineered (GE) pig hearts were transplanted into the abdomen of NHP along with IS, which included anti-CD20 and anti-CD40-based co-stimulation blockade antibodies. We reported 945 days of survival of three gene GE pig hearts in NHPs. Building on this proof-of-concept, we tested 3-10 gene-modified GE pig hearts (in order to improve the immunocompatibility of the xenograft further) in a life-supporting orthotopic model, but had limited success due to perioperative cardiac xenograft dysfunction (PCXD). With novel non-ischemic continuous perfusion preservation (NICP), using the XVIVO Heart solution (XHS), life-supporting survival was extended to 9 months. We approached the FDA under an application for "Expanded Access" (EA), to transplant a GE pig heart in a patient with end-stage non-ischemic cardiomyopathy. He was without other therapeutic options and dependent on VA-ECMO. A team of FDA reviewers reviewed our preclinical research experience and data and allowed us to proceed. This clinical cardiac xenotransplantation was performed, and the patient survived for 60 days, demonstrating the translational preclinical investigation of cardiac xenotransplantation from bench to bedside. The ultimate etiology of graft failure is currently a topic of investigation and lessons learned will progress the field forward.
自 2005 年以来，我们一直在对基因工程（GE）猪心进行测试，并优化非人类灵长类动物（NHP）的免疫抑制（IS）。我们展示了如何将这项临床前研究转化为美国食品和药物管理局（FDA）批准的临床心脏异种移植。首先，将基因工程（GE）猪心与 IS 一起移植到 NHP 的腹部，IS 包括抗 CD20 和抗 CD40 的共刺激阻断抗体。我们报告了三只有基因 GE 猪心在 NHP 中存活了 945 天。在此概念验证的基础上，我们在生命支持的原位模型中测试了 3-10 个基因修饰的 GE 猪心（以进一步提高异种移植物的免疫相容性），但由于围手术期心脏异种移植物功能障碍（PCXD），我们的尝试受到限制。使用 XVIVO 心脏溶液（XHS）进行新型非缺血性连续灌注保存（NICP）后，生命支持的存活时间延长至 9 个月。我们根据“扩大准入”（EA）的申请向 FDA 提出申请，在一名终末期非缺血性心肌病患者中移植 GE 猪心。他没有其他治疗选择，依赖于 VA-ECMO。一组 FDA 审查员审查了我们的临床前研究经验和数据，并允许我们继续进行。进行了这项临床心脏异种移植，患者存活了 60 天，证明了心脏异种移植从实验室到临床的转化。目前，移植物衰竭的最终病因是一个研究课题，所吸取的经验教训将推动该领域的发展。
