Pig- Kidney- Xenotransplantation-performing-optimally-after-32-d

文章为转载，原始来源：https://nyulangone.org/news/pig-kidney-xenotransplantation-performing-optimally-after-32-days-human-body

做了机翻，在文末。

NEW YORK, NY, AUGUST 16, 2023 — Surgeons at NYU Langone Health have transplanted a genetically engineered pig kidney that continues to function well after 32 days in a man declared dead by neurologic criteria and maintained with a beating heart on ventilator support. This represents the longest period that a gene-edited pig kidney has functioned in a human, and the latest step toward the advent of an alternate, sustainable supply of organs for transplant.

Multimedia Materials Available Multimedia materials, including photos and a B-roll package, are available for download.

About the Procedure The procedure, performed on July 14, 2023, and led by Robert Montgomery, MD, DPhil, the H. Leon Pachter, MD Professor of Surgery, chair of the Department of Surgery, and director of the NYU Langone Transplant Institute, was the fifth xenotransplant performed at NYU Langone. Observation is ongoing and the study will continue through mid-September 2023.

“This work demonstrates a pig kidney—with only one genetic modification and without experimental medications or devices—can replace the function of a human kidney for at least 32 days without being rejected,” said Dr. Montgomery, who had previously performed the world’s first genetically modified pig kidney transplant into a human decedent on September 25, 2021, followed by a second similar procedure on November 22, 2021. Surgeons with the Transplant Institute performed two genetically engineered pig heart transplants in summer 2022.

Removing Troublesome Gene Again Shows Promise

The first hurdle to overcome in xenotransplants is preventing so-called hyperacute rejection, which typically occurs just minutes after an animal organ is connected to the human circulatory system. By “knocking out” the gene that encodes the biomolecule known as alpha-gal—which has been identified as responsible for a rapid antibody-mediated rejection of pig organs by humans—immediate rejection has been avoided in all five xenotransplants at NYU Langone. Additionally, the pig’s thymus gland, which is responsible for educating the immune system, was embedded underneath the outer layer of the kidney to stave off novel, delayed immune responses. The combination of modifications has been shown to prevent rejection of the organ while preserving kidney function.

To ensure the body’s kidney function was sustained solely by the pig kidney, both of the transplant recipient’s native kidneys were surgically removed. One pig kidney was then transplanted and started producing urine immediately without any signs of hyperacute rejection. During the observation phase, intensive care clinical staff maintained the decedent on support while the pig kidney’s performance was monitored and sampled with weekly biopsies. Levels of creatinine, a bodily waste product found in the blood and an indicator of kidney function, were in the optimal range during the length of the study, and there was no evidence on biopsy of rejection.

The surgery was the latest in a larger study approved by a specific research ethics oversight board at NYU Langone and was performed after consultation with the New York State Department of Health. This important research, which study leaders say could save many lives in the future, was made possible by the family of a 57-year-old male who elected to donate his body after a brain death declaration and a circumstance in which his organs or tissues were not suitable for transplant.

LiveOnNY, the nonprofit organization that facilitates organ and tissue donation in the greater New York City area, was a critical partner in the effort to inform, support, and collaborate throughout the authorization process with the donor family.

A Big Leap Toward a New Organ Source

In the United States, there are more than 103,000 people on the waiting list for transplant, with nearly 88,000 of those waiting for a kidney, according to recent federal Organ Procurement and Transplantation Network (OPTN) data. In 2022, about 26,000 people received a kidney transplant. Meanwhile, nearly 808,000 people in the U.S. have end-stage renal disease.

“There are simply not enough organs available for everyone who needs one,” said Dr. Montgomery, who received a hepatitis C–positive heart transplant himself in 2018. “Too many people are dying because of the lack of available organs, and I strongly believe xenotransplantation is a viable way to change that.”

The kidney and thymus gland used in this procedure were procured from a GalSafeTM pig, an animal engineered by Revivicor, Inc., a subsidiary of United Therapeutics Corporation. In December 2020, the U.S. Food and Drug Administration (FDA) approved the GalSafe pig as a potential source for human therapeutics as well as a food source for people with alpha-gal syndrome, a meat allergy caused by a tick bite.

Less May Be More in Kidney Xenotransplants

While previous genetically engineered pig organ transplants have incorporated up to 10 genetic modifications, this latest study shows that a single-gene knockout pig kidney can still perform optimally for at least 32 days without rejection.

“We’ve now gathered more evidence to show that, at least in kidneys, just eliminating the gene that triggers a hyperacute rejection may be enough along with clinically approved immunosuppressive drugs to successfully manage the transplant in a human for optimal performance—potentially in the long-term,” said Dr. Montgomery.

The NYU Langone team used standard transplant immunosuppression medications combined with enhanced screening of porcine cytomegalovirus (pCMV) in the donor pig to ensure safety. Recent studies have shown pCMV may affect organ performance and potentially trigger organ failure. No pCMV was detected after 32 days, and close surveillance of porcine endogenous retrovirus (PERV), along with six other viruses of interest, was performed.

Next Steps

Monitoring of the pig kidney recipient will continue for another month with permission from the family, ethics committee approval, and continued support from United Therapeutics. The additional data from the next several weeks will be analyzed further to develop a deeper understanding of this unique medical advance.

“We think using a pig already deemed safe by the FDA in combination with what we have found in our xenotransplantation research so far, gets us closer to the clinical trial phase,” said Dr. Montgomery. “We know this has the potential to save thousands of lives, but we want to ensure the utmost safety and care as we move forward.”

GalSafe is a trademark of Revivicor, Inc.

Media Inquiries

Colin DeVries Phone: 212-404-3588 colin.devries@nyulangone.org

紐約州紐約，2023 年 8 月 16 日 — 紐約大學朗格尼健康中心的外科醫生移植了一種基因工程豬腎，該腎在 32 天后繼續運作良好，該腎在一名根據神經系統標準宣佈死亡並在呼吸機支援下維持心臟跳動的男性身上。這代表了基因編輯豬腎臟在人類中發揮作用的最長時間，也是朝著替代的、可持續的移植器官供應的出現邁出的最新一步。

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關於該程式 該程式於 2023 年 7 月 14 日進行，由羅伯特·蒙哥馬利醫學博士、DPhil、H. Leon Pachter、醫學博士外科教授、外科系主任和紐約大學朗格尼移植研究所所長領導，是紐約大學朗格尼分校進行的第五次異種移植。觀察正在進行中，研究將持續到 2023 年 9 月中旬。

蒙哥馬利博士說：“這項工作表明，豬腎——只有一種基因改造，沒有實驗性藥物或設備——可以替代人類腎臟的功能至少 32 天而不會被拒絕，” 蒙哥馬利博士說，他之前曾在 2021 年 9 月 25 日對人類死者進行了世界上第一例轉基因豬腎移植， 隨後於 2021 年 11 月 22 日進行了第二次類似的程式。移植研究所的外科醫生在 2022 年夏天進行了兩次基因工程豬心臟移植手術。

去除麻煩基因再次顯示出希望

異種移植中要克服的第一個障礙是防止所謂的超急性排斥反應，這通常發生在動物器官連接到人體循環系統幾分鐘後。通過「敲除」編碼稱為α-gal的生物分子的基因 - 已被確定為人類對豬器官的快速抗體介導排斥的原因 - 在所有五種異種中都避免了立即排斥反應紐約大學朗格尼分校的植物。此外，豬的胸腺，負責教育免疫系統，嵌入在腎臟的外層下，以避免新的，延遲的免疫反應。修改的組合已被證明可以防止器官排斥，同時保留腎功能。

為了確保身體的腎功能僅由豬腎臟維持，移植受者的兩個自體腎臟都被手術切除。然後移植一頭豬腎並立即開始產生尿液，沒有任何超急性排斥反應的跡象。在觀察階段，重症監護臨床工作人員維持死者的支援，同時監測豬腎的性能並通過每周活檢進行採樣。肌酐（一種在血液中發現的身體廢物和腎功能指標）的水準在研究期間處於最佳範圍內，並且沒有關於排斥反應活檢的證據。

該手術是紐約大學朗格尼分校特定研究倫理監督委員會批准的一項大型研究中的最新一項，是在與紐約州衛生部協商後進行的。研究負責人表示，這項重要的研究可以在未來挽救許多生命，這是由一名57歲男性的家人實現的，他在宣佈腦死亡以及他的器官或組織不適合移植的情況下選擇捐贈他的身體。

LiveOnNY 是一家促進大紐約市地區器官和組織捐贈的非營利組織，是在整個授權過程中與捐贈者家庭進行通知、支援和合作的重要合作夥伴。

向新器官來源邁出一大步

在美國，有超過103，000人在等待移植的名單上，其中近88，000人等待腎臟，根據最近的聯邦器官採購和移植網路（OPTN）da啪啪2022年，約有26，000人接受了腎移植手術。與此同時，美國有近808，000人患有終末期腎病。

“根本沒有足夠的器官供每個需要的人使用，”蒙哥馬利博士說，他在2018年接受了丙型肝炎陽性心臟移植手術。“由於缺乏可用的器官，太多人正在死亡，我堅信異種移植是改變這種情況的可行方法。

該程式中使用的腎臟和胸腺是從GalSafeTM豬採購的，GalSafeTM豬是由United Therapeutics Corporation的子公司Revivicor，Inc.設計的動物。2020 年 12 月，美國食品和藥物管理局 （FDA） 批准 GalSafe 豬作為人類治療藥物的潛在來源，以及 α-半乳糖綜合征（一種由蜱蟲叮咬引起的肉類過敏）患者的食物來源。

腎異種移植中少即是多

雖然以前的基因工程豬器官移植已經包含了多達10種基因改造，但這項最新研究表明，單基因敲除豬腎仍然可以在至少32天內保持最佳狀態而不會產生排斥反應。

“我們現在收集了更多的證據表明，至少在腎臟中，僅僅消除引發超急性排斥反應的基因可能就足以與臨床批准的免疫抑製藥物一起成功地管理人類移植以獲得最佳性能 - 可能是長期的，”蒙哥馬利博士說。

NYU Langone團隊使用標準移植免疫抑製藥物，並在供體豬中加強豬巨細胞病毒（pCMV）篩查，以確保安全性。最近的研究表明，pCMV可能會影響器官功能，並可能引發器官衰竭。32天后未檢出pCMV，並對豬內源性逆轉錄病毒（PERV）以及其他六種感興趣的病毒進行了密切監測。

後續步驟

在家人的許可、倫理委員會的批准以及聯合治療公司的持續支援下，對豬腎接受者的監測將再持續一個月。未來幾周的其他數據將進一步分析，以更深入地瞭解這一獨特的醫學進步。

“我們認為使用FDA已經認為安全的豬，結合我們迄今為止在異種移植研究中發現的豬，使我們更接近臨床試驗階段，”蒙哥馬利博士說。“我們知道這有可能挽救數千人的生命，但我們希望在前進的過程中確保最大的安全和關懷。

GalSafe 是 Revicor， Inc. 的商標。

媒體查詢

科林·德弗里斯 電話： 212-404-3588 colin.devries@nyulangone.org