小柯机器人

美国eGenesis公司Wenning Qin等研究人员合作完成人源化猪异种移植供体的设计与试验。相关论发表在2023年10月11日出版的《自然》杂志上。

研究人员描述了从基因工程猪供体移植到食蟹猴模型中的肾脏移植的设计、制造和长期维持生命的功能。对猪供体进行了工程改造，使其携带69个基因组编辑，消除了聚糖抗原，过表达了人类转基因基因，并灭活了猪内源性逆转录病毒。体外功能分析表明，经过编辑的肾内皮细胞对炎症的调节程度与人类内皮细胞没有区别，这表明这些经过编辑的细胞获得了高度的人类免疫相容性。

当移植到食蟹猴体内时，单独敲除三种聚糖抗原的肾脏存活时间较差，而敲除三种聚糖抗原并表达人转基因的肾脏存活时间明显更长，这表明人转基因在体内表达的益处。这些结果表明，异种肾移植的临床前研究可以成功地在非人灵长类动物中进行，并使其更接近于基因工程猪肾移植的临床试验。

据介绍，最近的人类死亡模型研究和异种移植的使用探索了猪器官用于人类移植的前景。为了进行人体研究，必须对临床准备好的猪供体进行改造，并在非人灵长类动物身上成功地进行异种移植试验。

附：英文原文

Title: Design and testing of a humanized porcine donor for xenotransplantation

Author: Anand, Ranjith P., Layer, Jacob V., Heja, David, Hirose, Takayuki, Lassiter, Grace, Firl, Daniel J., Paragas, Violette B., Akkad, Adam, Chhangawala, Sagar, Colvin, Robert B., Ernst, Russell J., Esch, Nicholas, Getchell, Kristen, Griffin, Alexandra K., Guo, Xiaoyun, Hall, Katherine C., Hamilton, Paula, Kalekar, Lokesh A., Kan, Yinan, Karadagi, Ahmad, Li, Feng, Low, Susan C., Matheson, Rudy, Nehring, Claudia, Otsuka, Ryo, Pandelakis, Matthew, Policastro, Robert A., Pols, Rebecca, Queiroz, Luis, Rosales, Ivy A., Serkin, William T., Stiede, Kathryn, Tomosugi, Toshihide, Xue, Yongqiang, Zentner, Gabriel E., Angeles-Albores, David, Chris Chao, J., Crabtree, Juliet N., Harken, Sierra, Hinkle, Nicole, Lemos, Tania, Li, Mailin, Pantano, Lorena, Stevens, Denise, Subedar, Omar D., Tan, Xiaoqing, Yin, Shiyi, Anwar, Imran J., Aufhauser, David, Capuano, Saverio, Kaufman, Dixon B., Knechtle, Stuart J., Kwun, Jean, Shanmuganayagam, Dhanansayan, Markmann, James F., Church, George M., Curtis, Mike, Kawai, Tatsuo, Youd, Michele E., Qin, Wenning

Issue&Volume: 2023-10-11

Abstract: Recent human decedent model studies1,2 and compassionate xenograft use3 have explored the promise of porcine organs for human transplantation. To proceed to human studies, a clinically ready porcine donor must be engineered and its xenograft successfully tested in nonhuman primates. Here we describe the design, creation and long-term life-supporting function of kidney grafts from a genetically engineered porcine donor transplanted into a cynomolgus monkey model. The porcine donor was engineered to carry 69 genomic edits, eliminating glycan antigens, overexpressing human transgenes and inactivating porcine endogenous retroviruses. In vitro functional analyses showed that the edited kidney endothelial cells modulated inflammation to an extent that was indistinguishable from that of human endothelial cells, suggesting that these edited cells acquired a high level of human immune compatibility. When transplanted into cynomolgus monkeys, the kidneys with three glycan antigen knockouts alone experienced poor graft survival, whereas those with glycan antigen knockouts and human transgene expression demonstrated significantly longer survival time, suggesting the benefit of human transgene expression in vivo. These results show that preclinical studies of renal xenotransplantation could be successfully conducted in nonhuman primates and bring us closer to clinical trials of genetically engineered porcine renal grafts.

DOI: 10.1038/s41586-023-06594-4

Source: https://www.nature.com/articles/s41586-023-06594-4

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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