走向临床的异种器官移植

孙圣坤; 杨树军; 卫浩; 杨海宏; 卢静; 彭江

doi:10.3969/j.issn.1674-7445.2023234

走向临床的异种器官移植

doi: 10.3969/j.issn.1674-7445.2023234

孙圣坤^1, ,,
杨树军³,
卫浩⁴,
杨海宏³,
卢静²,
彭江^5, ,

11.
100000　北京，中国人民解放军总医院第三医学中心泌尿外科
2.
卫勤部
3.
兰州大学第二医院泌尿外科
4.
青岛大学附属医院泌尿外科
5.
中国人民解放军总医院第四医学中心骨科医学部骨科研究所

基金项目: 国家重点研发计划（2019YFA0110704）

详细信息

作者简介:

通讯作者:
孙圣坤（ORCID 0000-0002-6463-6425），Email：sunshengkun@301hospital.com.cn；彭江（ORCID 0000-0003-4662-9288），主任医师，教授，博士研究生导师，研究方向为股骨头坏死保髋治疗、关节软骨损失修复、周围神经损失修复及骨科康复治疗，Email: pengjiang301@126.com

中图分类号: R617, Q78
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出版历程
- 收稿日期: 2023-11-05
- 网络出版日期: 2023-12-25
- 刊出日期: 2024-03-15

Application of xenotransplantation in clinical practice

Sun Shengkun^{1
, ,},
Yang Shujun³,
Wei Hao⁴,
Yang Haihong³,
Lu Jing²,
Peng Jiang^{5
, ,}

11.
Department of Urology, the Third Medical Center of Chinese People's Liberation Army General Hospital, Beijing 100000, China

More Information

Corresponding author: Sun Shengkun, Email:sunshengkun@301hospital.com.cn; Peng Jiang, Email: pengjiang301@126.com

摘要

摘要: 器官移植是治疗终末期器官衰竭的最佳方案，但器官短缺是全球性的问题，限制了器官移植的进一步发展。最新的研究表明，基因修饰猪可能很快成为临床器官移植供体的现实替代来源。异种移植可能是解决器官短缺问题的有效途径之一。2021年以来，全世界完成了2例活体异种器官移植、6例脑死亡异种器官移植，并启动了异种肾移植的Ⅰ期临床试验，取得了超出预期的结果。因此，本文在回顾、分析近几年活体及脑死亡受者异种移植临床试验结果的基础上，讨论与异种移植临床研究相关的科学、技术和伦理问题，希望为我国异种器官移植临床研究提供借鉴，促进临床异种移植的发展。
- 异种移植 /
- 器官移植 /
- 基因修饰猪 /
- 非人灵长类动物 /
- 免疫抑制 /
- 生理性匹配 /
- 跨物种感染 /
- 伦理
Abstract: Organ transplantation is the optimal treatment for end-stage organ failure. Nevertheless, organ shortage is a global problem, which limits further development of organ transplantation. Recent research shows that genetically modified pig may become a realistic alternative source of clinical organ transplantation donor. Xenotransplantation may serve as one of the effective measures to resolve the problem of organ shortage. Since 2021, 2 cases of living xenotransplantation and 6 cases of xenotransplantation in brain death recipients have been performed worldwide, and phase Ⅰ clinical trial of xenotransplantation has been launched, and the results have exceeded expectations. Therefore, in this article, recent clinical trial results of xenotransplantation in living and brain death recipients were retrospectively analyzed, and scientific, technical and ethical issues related to clinical research of xenotransplantation were illustrated, hoping to provide reference for clinical research of xenotransplantation in China and promote the development of xenotransplantation in clinical practice.
- Xenotransplantation /
- Organ transplantation /
- Genetically modified pig /
- Non-human primate /
- Immunosuppression /
- Physiological matching /
- Cross species infection /
- Ethic

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FIG. 2989. FIG. 2989.

FIG. 2989.. FIG. 2989.

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表 1 过去3年的活体及脑死亡受者异种移植临床试验

Table 1. Clinical trial of xenotransplantations in living and brain death recipients in the past 3 years

研究单位	手术时间	供体猪基因编辑方案	移植器官	受者	免疫调节方案	预后结果
马里兰大学医学院^[3-4]	2023年 9月20日	10基因编辑	心脏	男性，58岁，晚期心力衰竭患者	抗CD154抗体+常规抗排斥药物	术后第1个月无任何排斥反应，术后40 d因排斥反应死亡
纽约大学朗格尼移植研究所^[5]	2023年 7月14日	GGTA1^①单基因敲除	肾脏	男性，58岁，脑死亡，死亡原因为脑肿瘤	_^②	观察61 d后切除肾脏，尽管出现短暂的排斥反应，但移植肾正常工作
纽约大学朗格尼移植研究所^[6]	2022年 7月6日	10基因编辑	心脏	女性，64岁，脑死亡，既往2次器官移植病史（肾、胰腺）	诱导：ATG^③+甲泼尼龙+依库珠单抗；维持：甲泼尼龙+吗替麦考酚酯	术后监测66 h。移植后立即表现出良好的心功能，并在研究期间功能良好。心内膜心肌活组织检查未发现细胞或抗体介导的排斥反应，无人畜共患病传播的证据
纽约大学朗格尼移植研究所^[6]	2022年 6月16日	10基因编辑	心脏	男性，72岁，脑死亡	诱导：ATG+甲泼尼龙+依库珠单抗；维持：甲泼尼龙+吗替麦考酚酯	术后监测66 h。供体猪和受者尺寸不匹配，术后心功能下降
阿拉巴马大学^[7]	2022年4月22日首次公布，2023年9月1日更新	10基因编辑	肾脏	尚无入选	诱导：ATG+甲泼尼龙+依库珠单抗；维持：他克莫司+吗替麦考酚酯+泼尼松+依库珠单抗	Ⅰ期临床试验。2023年9月1日还未招募，预计2024年1月开始，2028年6月初步完成，2029年6月研究结束
马里兰大学医学院^[8-10]	2022年 1月7日	10基因编辑	心脏	男性，57岁，活体，非缺血性心肌病，依赖体外膜肺氧合生存	利妥昔单抗+ATG+补体C1抑制剂+KPL-404+吗替麦考酚酯（最终因中性粒细胞减少而改为他克莫司）	术后49 d移植心脏开始膨胀并逐渐衰竭。术后60 d因移植失败死亡。无明显排斥反应。尸检所有受者器官均检测到猪巨细胞病毒或猪玫瑰病毒DNA和猪细胞DNA
阿拉巴马大学^[11]	2021年	10基因编辑	肾脏	男性，57岁，外伤后脑死亡，移植前双肾切除，植入猪的双肾	诱导：甲泼尼龙+ATG+抗CD20单抗；维持：吗替麦考酚酯+他克莫司+泼尼松	肾脏存活74 h，产生尿液但血清肌酐未下降。未检测到猪病毒。术后1 d出现弥漫性血栓性微血管病，但术后3 d没有证据显示出现皮质坏死或间质出血
纽约大学朗格尼移植研究所^[12-13]	2021年 11月22日、2021年 9月25日	GGTA1单基因敲除	肾脏接入股动静脉	2例脑死亡患者，肾脏未切除	吗替麦考酚酯+甲泼尼龙	观察54 h，期间持续产生尿液，估算肾小球滤过率增加，血清肌酐下降，活组织检查未发生超急性排斥反应及抗体介导的排斥反应，移植肾每小时产生尿量是自体肾脏的2倍。受体未检测到猪内源性逆转录病毒。但2023年9月30日，该团队在Lancet发文，多模态深度表型分析显示，早期存在抗体介导的排斥反应
注：①GGTA1为α-1, 3-半乳糖基转移酶。　　　　②为原文未提及。　　　　③ATG为抗胸腺细胞球蛋白。

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参考文献(41)

[1]	许艺红, 肖义军. 猪作为人类器官移植供体的研究进展[J]. 生物学通报, 2022, 57(11): 1-4. DOI: 10.3969/j.issn.0006-3193.2022.11.001. XU YH, XIAO YJ. Research progress on pigs as human organ transplant donors[J]. Bull Biol, 2022, 57(11): 1-4. DOI: 10.3969/j.issn.0006-3193.2022.11.001.
[2]	窦科峰, 张玄. 临床异种器官移植十大问题的思考[J]. 器官移植, 2022, 13(4): 411-416. DOI: 10.3969/j.issn.1674-7445.2022.04.001. DOU KF, ZHANG X. Reflection on 10 problems of clinical xenotransplantation[J]. Organ Transplant, 2022, 13(4): 411-416. DOI: 10.3969/j.issn.1674-7445.2022.04.001.
[3]	Um medicine faculty-scientists and clinicians perform second historic transplant of pig heart into patient with end-stage cardiovascular disease[EB/OL]. [2023-11-01].https://www.umms.org/ummc/news/2023/um-medicine-clinicians-perform-second-historic-transplant-of-pig-heart-into-patient.
[4]	In memoriam: xenotransplant patient lawrence faucette[EB/OL]. [2023-11-01]. https://www.umms.org/ummc/news/2023/announcing-the-passing-of-lawrence-faucette.
[5]	Two-month study of pig kidney xenotransplantation gives new hope to the future of the organ supply[EB/OL]. [2023-11-01]. https://nyulangone.org/news/two-month-study-pig-kidney-xenotransplantation-gives-new-hope-future-organ-supply.
[6]	MOAZAMI N, STERN JM, KHALIL K, et al. Pig-to-human heart xenotransplantation in two recently deceased human recipients[J]. Nat Med, 2023, 29(8): 1989-1997. DOI: 10.1038/s41591-023-02471-9.
[7]	Porcine kidney xenotransplantation in patients with end-stage kidney disease[EB/OL]. [2023-11-01]. https://clinicaltrials.gov/study/NCT05340426?term=Porcine%20Kidney%20Xenotransplantation%20in%20Patients%20With%20End-Stage%20Kidney%20Disease&rank=1.
[8]	HAWTHORNE WJ. World first pig-to-human cardiac xenotransplantation[J]. Xenotransplantation, 2022, 29(1): e12733. DOI: 10.1111/xen.12733.
[9]	MOHIUDDIN MM, SINGH AK, SCOBIE L, et al. Graft dysfunction in compassionate use of genetically engineered pig-to-human cardiac xenotransplantation: a case report[J]. Lancet, 2023, 402(10399): 397-410. DOI: 10.1016/S0140-6736(23)00775-4.
[10]	GRIFFITH BP, GOERLICH CE, SINGH AK, et al. Genetically modified porcine-to-human cardiac xenotransplantation[J]. N Engl J Med, 2022, 387(1): 35-44. DOI: 10.1056/NEJMoa2201422.
[11]	PORRETT PM, ORANDI BJ, KUMAR V, et al. First clinical-grade porcine kidney xenotransplant using a human decedent model[J]. Am J Transplant, 2022, 22(4): 1037-1053. DOI: 10.1111/ajt.16930.
[12]	MONTGOMERY RA, STERN JM, LONZE BE, et al. Results of two cases of pig-to-human kidney xenotransplantation[J]. N Engl J Med, 2022, 386(20): 1889-1898. DOI: 10.1056/NEJMoa2120238.
[13]	LOUPY A, GOUTAUDIER V, GIARRAPUTO A, et al. Immune response after pig-to-human kidney xenotransplantation: a multimodal phenotyping study[J]. Lancet, 2023, 402(10408): 1158-1169. DOI: 10.1016/S0140-6736(23)01349-1.
[14]	GAO M, ZHANG J, WANG R, et al. Pig-to-human xenotransplantation: moving toward organ customization[J]. Precis Clin Med, 2023, 6(2): pbad013. DOI: 10.1093/pcmedi/pbad013.
[15]	SINGH AK, CHAN JL, SEAVEY CN, et al. CD4⁺CD25^HiFoxP3⁺ regulatory T cells in long-term cardiac xenotransplantation[J]. Xenotransplantation, 2018, 25(2): e12379. DOI: 10.1111/xen.12379.
[16]	ANAND RP, LAYER JV, HEJA D, et al. Design and testing of a humanized porcine donor for xenotransplantation[J]. Nature, 2023, 622(7982): 393-401. DOI: 10.1038/s41586-023-06594-4.
[17]	DENNER J, LÄNGIN M, REICHART B, et al. Impact of porcine cytomegalovirus on long-term orthotopic cardiac xenotransplant survival[J]. Sci Rep, 2020, 10(1): 17531. DOI: 10.1038/s41598-020-73150-9.
[18]	NIU D, WEI HJ, LIN L, et al. Inactivation of porcine endogenous retrovirus in pigs using CRISPR-Cas9[J]. Science, 2017, 357(6357): 1303-1307. DOI: 10.1126/science.aan4187.
[19]	LÄNGIN M, MAYR T, REICHART B, et al. Consistent success in life-supporting porcine cardiac xenotransplantation[J]. Nature, 2018, 564(7736): 430-433. DOI: 10.1038/s41586-018-0765-z.
[20]	BIKHET M, IWASE H, YAMAMOTO T, et al. What therapeutic regimen will be optimal for initial clinical trials of pig organ transplantation?[J]. Transplantation, 2021, 105(6): 1143-1155. DOI: 10.1097/TP.0000000000003622.
[21]	HANSEN-ESTRUCH C, COOPER DKC, JUDD E. Physiological aspects of pig kidney xenotransplantation and implications for management following transplantation[J]. Xenotransplantation, 2022, 29(3): e12743. DOI: 10.1111/xen.12743.
[22]	HINRICHS A, RIEDEL EO, KLYMIUK N, et al. Growth hormone receptor knockout to reduce the size of donor pigs for preclinical xenotransplantation studies[J]. Xenotransplantation, 2021, 28(2): e12664. DOI: 10.1111/xen.12664.
[23]	ADAMS A, CENDALES LC, COOPER DKC, et al. American Society of Transplant Surgeons-American Society of Transplantation report of FDA meeting on regulatory expectations for xenotransplantation products[J]. Am J Transplant, 2023, 23(9): 1290-1299. DOI: 10.1016/j.ajt.2023.05.010.
[24]	IWASE H, HARA H, EZZELARAB M, et al. Immunological and physiological observations in baboons with life-supporting genetically engineered pig kidney grafts[J]. Xenotransplantation, 2017, 24(2): e12293. DOI: 10.1111/xen.12293.
[25]	COOPER DKC, HARA H, IWASE H, et al. Pig kidney xenotransplantation: progress toward clinical trials[J]. Clin Transplant, 2021, 35(1): e14139. DOI: 10.1111/ctr.14139.
[26]	IWASE H, YAMAMOTO T, COOPER DKC. Episodes of hypovolemia/dehydration in baboons with pig kidney transplants: a new syndrome of clinical importance?[J]. Xenotransplantation, 2019, 26(2): e12472. DOI: 10.1111/xen.12472.
[27]	ADAMS AB, KIM SC, MARTENS GR, et al. Xenoantigen deletion and chemical immunosuppression can prolong renal xenograft survival[J]. Ann Surg, 2018, 268(4): 564-573. DOI: 10.1097/SLA.0000000000002977.
[28]	GOLDSTONE AB, BACHA EA, SYKES M. On cardiac xenotransplantation and the role of xenogeneic tolerance[J]. J Thorac Cardiovasc Surg, 2023, 166(3): 968-972. DOI: 10.1016/j.jtcvs.2022.11.036.
[29]	MOHIUDDIN MM, GOERLICH CE, SINGH AK, et al. Progressive genetic modifications of porcine cardiac xenografts extend survival to 9 months[J]. Xenotransplantation, 2022, 29(3): e12744. DOI: 10.1111/xen.12744.
[30]	YAMAMOTO T, LADOWSKI JM, BIKHET M, et al. Efficacy of ATG and rituximab in capuchin monkeys (a new world monkey)-an in vitro study relevant to xenotransplantation[J]. Xenotransplantation, 2020, 27(6): e12627. DOI: 10.1111/xen.12627.
[31]	YAMAMOTO T, HARA H, FOOTE J, et al. Life-supporting kidney xenotransplantation from genetically engineered pigs in baboons: a comparison of two immunosuppressive regimens[J]. Transplantation, 2019, 103(10): 2090-2104. DOI: 10.1097/TP.000000000000 2796.
[32]	BÜHLER L, AWWAD M, BASKER M, et al. High-dose porcine hematopoietic cell transplantation combined with CD40 ligand blockade in baboons prevents an induced anti-pig humoral response[J]. Transplantation, 2000, 69(11): 2296-2304. DOI: 10.1097/00007890-200006150-00013.
[33]	TUCK N. Animals in moral limbo: how literary pigs may help lab-generated ones[J]. Animals (Basel), 2020, 10(4): 629. DOI: 10.3390/ani10040629.
[34]	EL MASRI J, AFYOUNI A, GHAZI M, et al. Current state of clinical trials on xenograft[J]. Xenotransplantation, 2023, 30(3): e12801. DOI: 10.1111/xen.12801.
[35]	For physicians: how to request single patient expanded access (“compassionate use”) [EB/OL]. [2023-11-01]https://www.fda.gov/drugs/investigational-new-drug-ind-application/physicians-how-request-single-patient-expanded-access-compassionate-use.
[36]	SADE RM, MUKHERJEE R. Ethical issues in xenotransplantation: the first pig-to-human heart transplant[J]. Ann Thorac Surg, 2022, 113(3): 712-714. DOI: 10.1016/j.athoracsur.2022.01.006.
[37]	SPILLMAN MA, SADE RM. Clinical trials of xenotransplantation: waiver of the right to withdraw from a clinical trial should be required[J]. J Law Med Ethics, 2007, 35(2): 265-272. DOI: 10.1111/j.1748-720X.2007.00135.x.
[38]	杨树军,卫浩,彭江,等. 中国公众对异种肾移植接受度的预测模型构建及验证 [J]. 器官移植, 2024,15(1):102-111. DOI: 10.3969/j.issn.1674-7445.2023164. YANG SJ, WEI H, PENG J, et al. Construction and validation of a prediction model for public acceptance of kidney xenotransplantation in China[J]. Organ Transplant, 2024,15(1):102-111. DOI: 10.3969/j.issn.1674-7445.2023164.
[39]	DAS S, KOYANO-NAKAGAWA N, GAFNI O, et al. Generation of human endothelium in pig embryos deficient in ETV2[J]. Nat Biotechnol, 2020, 38(3): 297-302. DOI: 10.1038/s41587-019-0373-y.
[40]	WANG J, XIE W, LI N, et al. Generation of a humanized mesonephros in pigs from induced pluripotent stem cells via embryo complementation[J]. Cell Stem Cell, 2023, 30(9): 1235-1245. DOI: 10.1016/j.stem.2023.08.003.
[41]	COOPER DKC, HARA H. "You cannot stay in the laboratory forever"*: taking pig kidney xenotransplantation from the laboratory to the clinic[J]. EBioMedicine, 2021, 71: 103562. DOI: 10.1016/j.ebiom.2021.103562.