争取达到最佳目标：猪心脏异种移植的基因组编辑

SCI

19 MAy 2022

SHOOTING FOR THE MOON: GENOME EDITING FOR PIG HEART XENOTRANSPLANTATION

(The Journal of Thoracic and Cardiovascular Surgery, IF: 5.209)

• David K.C. Cooper, S. Sikandar Raza, Ryan Chaban, Richard N. Pierson, III

• CORRESPONDENCE TO: rchaban@mgh.harvard.edu

Abstract 摘要

Clinical heart transplantation from gene-edited pigs has the potential to overcome the limitation in the number of heart transplants that can be performed annually. Xenotransplantation using genetically-modified pig donors provides an immense opportunity to minimize recipient treatment and optimize outcomes. To date, genetic engineering of the organ-source pig has had most impact on resisting the human innate immune response (i) by deleting expression of pig xenoantigens against which humans have natural antibodies (by gene-knockout), and (ii) by the introduction of human transgenes to express ‘protective’ proteins that augment graft resistance to injury. These transgenes include human complement-and coagulation-regulatory proteins and self-recognition molecules to dampen the human immune response. The current gene-editing technique of CRISPR-Cas9 allows multiple genetic modifications to be made simultaneously. Increasing attention is now being directed towards reducing the impact of the human adaptive immune response, with the aim of minimizing the exogenous immunosuppressive therapy that is required. We envision further truly revolutionary ‘engineered’ modifications that could eventually yield organs that are safely and effectively protected from the human immune response without exogenous immunosuppression.

“That’s one small step for man, one giant leap for mankind.”

Neil Armstrong, as he stepped on to the surface of the moon in 1969.

基因编辑猪的临床心脏移植有可能克服每年心脏移植数量少的限制。使用转基因猪供体的异种移植为最小化受体治疗和优化结果提供了巨大的机会。迄今为止，器官源猪的基因工程在抵抗人类先天性免疫反应方面影响最大（i）通过删除人类具有天然抗体的猪异种抗原的表达（通过基因敲除），以及（ii）通过引入人类转基因来表达增强移植物抗损伤能力的“保护性”蛋白质。这些转基因包括人类补体和凝血调节蛋白以及抑制人类免疫反应的自我识别分子。目前的基因编辑技术CRISPR-Cas9允许同时进行多种基因修饰。现在人们越来越关注减少人类获得性免疫反应的影响，目的是尽量减少所需的外源性免疫抑制治疗。我们设想进一步进行真正革命性的“工程化”改造，最终可以安全有效地保护器官免受人类免疫反应的影响，而无需外源性免疫抑制。

“这是个人的一小步，却是人类的一大步。”

1969年，尼奥·阿姆斯特朗踏上月球表面。

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