Singh Avneesh K, Goerlich Corbin E, Zhang Tianshu, Lewis Billeta, Hershfeld Alena, Braileanu Gheorghe, Kurvi Kasinath, Rice Kathryn, Sentz Faith, Mudd Sarah, Odonkor Patrick, Strauss Erik, Williams Brittney, Burke Allen, Gupta Anuj, Drachenberg Cinthia B, Ayares David, Griffith Bartley P, Mohiuddin Muhammad M
Department of Surgery, The University of Maryland School of Medicine, Baltimore, MD, USA.
Department of Surgery, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Commun Med (Lond). 2025 Jan 7;5(1):6. doi: 10.1038/s43856-025-00731-y.
Improvement in gene modifications of donor pigs has led to the prevention of early cardiac xenograft rejection and significantly prolonged cardiac xenograft survival in both heterotopic and orthotopic preclinical non-human primate (NHP) models. This progress formed the basis for FDA approval for compassionate use transplants in two patients.
Based on our earlier report of 9-month survival of seven gene-edited (7-GE) hearts transplanted (life-supporting orthotopic) in baboons, we transplanted 10 gene-edited pig hearts into baboons (n = 4) using non-ischemic continuous perfusion preservation (NICP) and immunosuppression regimen based on co-stimulation blockade by anti-CD40 monoclonal antibody. This pivotal study expands on the 7-GE backbone, with 3 additional gene edits, using 10-GE pigs as donors to baboon recipients.
10 GE cardiac xenografts provide life-supporting function up to 225 days (mean 128 ± 36 days) in a non-human primate model. Undetectable or latent porcine cytomegalovirus (PCMV) does not influence cardiac xenograft survival in this study but still needs more exploration with a larger cohort. Xenograft histology demonstrates adipose (Fat) deposition (n = 1), chronic vasculopathy (n = 1), micro and macro thrombosis, and acute cellular rejection (n = 1).
These data demonstrate that 10 GE cardiac xenografts have variable cardiac xenograft survival in NHP due to perhaps presence of 4th antigen and require further study. However, these 10GE organs may be suitable for clinical cardiac xenotransplantation and have already been utilized in two human cases.
供体猪基因修饰的改进已使早期心脏异种移植排斥反应得到预防，并在临床前非人类灵长类动物（NHP）的异位和原位模型中显著延长了心脏异种移植的存活时间。这一进展为美国食品药品监督管理局（FDA）批准在两名患者中进行同情使用移植奠定了基础。
基于我们之前关于七颗基因编辑（7-GE）心脏在狒狒体内进行支持生命的原位移植并存活9个月的报告，我们使用非缺血连续灌注保存（NICP）以及基于抗CD40单克隆抗体共刺激阻断的免疫抑制方案，将10颗基因编辑猪心脏移植到狒狒体内（n = 4）。这项关键研究在7-GE基础上进行扩展，增加了3项额外的基因编辑，使用10-GE猪作为狒狒受体的供体。
在非人类灵长类动物模型中，10个基因编辑的心脏异种移植提供了长达225天（平均128±36天）的支持生命功能。在本研究中，无法检测到或潜伏的猪巨细胞病毒（PCMV）不影响心脏异种移植的存活，但仍需要更大样本队列进行更多探索。异种移植组织学显示脂肪（Fat）沉积（n = 1）、慢性血管病变（n = 1）、微血栓和大血栓形成以及急性细胞排斥反应（n = 1）。
这些数据表明，由于可能存在第四种抗原，10-GE心脏异种移植在NHP中的存活时间存在差异，需要进一步研究。然而，这些10-GE器官可能适用于临床心脏异种移植，并且已经在两例人类病例中得到应用。
