Justification of specific genetic modifications in pigs for clinical organ xenotransplantation.
Justification of specific genetic modifications in pigs for clinical organ xenotransplantation.
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DOI：
10.1111/xen.12516
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发表时间：
2019-07
影响因子：
3.9
通讯作者：
Ayares, David
中科院分区：
文献类型：
--
作者：
Cooper, David K. C.;Hara, Hidetaka;Iwase, Hayato;Yamamoto, Takayuki;Li, Qi;Ezzelarab, Mohamed;Federzoni, Elena;Dandro, Amy;Ayares, David
近年来，异种移植研究取得了长足的进步，这主要是由于具有多种基因修饰的猪的可用性增加。我们建议，一头拥有9种基因修饰(即目前可用的)的猪将提供器官(最初是肾脏和心脏)，这些器官将在移植到终末期器官衰竭患者身上后，在一段有临床价值的时间内发挥作用，例如12个月。然而，国家监管当局可能需要基于体外和/或体内实验数据的证据，以证明在猪身上包括每一种单独的基因改造是合理的。我们从自己和其他人的经验中提供了关于猪的优势的数据，其中：(A)所有三种已知的碳水化合物异种抗原都已被删除(三基因敲除猪)，(B)表达了两种人类补体调节蛋白(CD46，CD55)和两种人类凝血调节蛋白(血栓调节蛋白，内皮细胞蛋白C受体)，(C)表达了抗细胞凋亡和抗炎的分子人血红素加氧酶-1，以及(D)表达了人CD47，以抑制巨噬细胞和T细胞反应的成分。虽然可以对器官来源的猪进行许多替代的基因修改，但我们认为，我们上面确定的基因操作都将有助于首次临床猪肾或心脏移植的成功，并且每个单独操作的有益贡献都得到了大量实验证据的支持。
Xenotransplantation research has made considerable progress in recent years, largely through the increasing availability of pigs with multiple genetic modifications. We suggest that a pig with nine genetic modifications (ie, currently available) will provide organs (initially kidneys and hearts) that would function for a clinically valuable period of time, for example, >12 months, after transplantation into patients with end-stage organ failure. The national regulatory authorities, however, will likely require evidence, based on in vitro and/or in vivo experimental data, to justify the inclusion of each individual genetic modification in the pig. We provide data both from our own experience and that of others on the advantages of pigs in which (a) all three known carbohydrate xenoantigens have been deleted (triple-knockout pigs), (b) two human complement-regulatory proteins (CD46, CD55) and two human coagulation-regulatory proteins (thrombomodulin, endothelial cell protein C receptor) are expressed, (c) the anti-apoptotic and “anti-inflammatory” molecule, human hemeoxygenase-1 is expressed, and (d) human CD47 is expressed to suppress elements of the macrophage and T-cell responses. Although many alternative genetic modifications could be made to an organ-source pig, we suggest that the genetic manipulations we identify above will all contribute to the success of the initial clinical pig kidney or heart transplants, and that the beneficial contribution of each individual manipulation is supported by considerable experimental evidence.
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影响因子：
3.9
作者：
Cooper DK;Ekser B;Burlak C;Ezzelarab M;Hara H;Paris L;Tector AJ;Phelps C;Azimzadeh AM;Ayares D;Robson SC;Pierson RN 3rd
通讯作者：
Pierson RN 3rd
影响因子：
3.9
作者：
Buermann, Anna;Petkov, Stoyan;Schwinzer, Reinhard
通讯作者：
Schwinzer, Reinhard
影响因子：
5.2
作者：
Agrawal P;Nawadkar R;Ojha H;Kumar J;Sahu A
通讯作者：
Sahu A
影响因子：
3.9
作者：
Dieckhoff, Britta;Petersen, Bjoern;Denner, Joachim
通讯作者：
Denner, Joachim
DOI：
10.1002/path.4635
发表时间：
2016-01
期刊：
The Journal of pathology
影响因子：
--
作者：
Cooper DK;Ekser B;Ramsoondar J;Phelps C;Ayares D
通讯作者：
Ayares D