Pig-to-Monkey Islet Xenotransplantation Using Multi-Transgenic Pigs

Abstract

The generation of pigs with genetic modifications has significantly advanced the field of xenotransplantation. New genetically-engineered pigs were produced on an α1,3-galactosyltransferase gene-knockout background with ubiquitous expression of human CD46 (GTKO/CD46 pigs), with islet beta cell-specific expression of human tissue factor pathway inhibitor (hTFPI) and/or human CD39 and/or porcine CTLA4-lg. Isolated islets from pigs with 3, 4, or 5 genetic modifications were transplanted intraportally into streptozotocin-diabetic, immunosuppressed cynomolgus monkeys (n=5). Immunosuppression was based on anti-CD154mAb costimulation blockade. Monitoring included features of early islet destruction, glycemia, exogenous insulin requirement, and histopathology of the islets at necropsy. Using these modified pig islets, there was evidence of reduced islet destruction in the first hours after transplantation, compared with two series of historical controls that received identical therapy but were transplanted with islets from pigs with either no or only one genetic modification. Despite encouraging effects on early islet loss, these multi-transgenic islet grafts did not demonstrate consistency in regard to long-term success, with only 2 of 5 demonstrating function beyond 5 months.

Use of genetically-engineered pig donors in islet transplantation

“…It is anticipated that the new therapy based on anti-CD40mAb would have similar effects on islet transplantation as well. It should also be noted that in our successful anti-CD154mAb based studies, no incidence of thrombosis were detected in any of the recipients [12,16] . Additional costimulationblocking based therapies are already in clinical use that might prove effective in the xenotransplantation setting, especially in conjunction with transgenic donors designed to optimize tissue compatibility.…”

“…Interestingly, some of the transgenes were selectively driven under the insulin promotor, thus, expressed on islet beta cells only (Figure 1). While, in the pig-to-nonhuman primate model, transgenic expression of hCD39 did not appear to provide the anticipated protection against IBMIR (more specifically against platelet activation), one of the diabetic monkeys that received islets from a pig transgenic for GTKO/ hCD46/hTFPI/CTLA4-Ig remained insulin independent for > 1 year and, significantly, showed evidence of reduced early islet lysis [16] . Factors associated to the Bottino R et al .…”

“…In many other ways, the pig is a suitable source of islets for xenotransplantation into human recipients. In the last decade, several groups from around the world have shown success in restoring insulin independence for a period > 6 mo in diabetic nonhuman primate recipients of pig islets, a breakthrough achievement in xenotransplantation [9][10][11][12][13][14][15][16][17] . While the results of pigto-nonhuman primate models cannot fully predict the pig-to-human results due to dissimilarities among the different donors and recipient species, they are necessary steps to reach clinical application [18,19] .…”

Gene Editing, Gene Therapy, and Cell Xenotransplantation: Cell Transplantation Across Species

“…Whereas transgenic pCTLA4 expression in pigs seemed to compromise their immune system [48], beta cell-specific or ubiquitous LEA29Y expression had no deleterious effect on pig health or reproduction [49,50]. Pig-tomouse transplantation of anti-CD2-or LEA29-expressing islets benefited from CD3 + T-cell depletion and protection against human peripheral blood mononuclear cells respectively [47,49] but pig-to-primate transplantation of pCTLA4-expressing islets did not provide significant amelioration of long-term survival (less than 5 months) [51]. Indeed, comparable survival time was reported in non-human primates implanted with wild-type encapsulated islets without immunosuppression [29].…”

Phenylketonuria felnőttkorban

“…A májsejtátültetés az előbbivel ellentétben nem igé-nyel sok mellékhatással járó immunterápiát. Sikeres állatkísérleteket követően az első humán vizsgálatot 2016-ban zárták le [47]. A beavatkozás minimális invazivitással járt, és potenciálisan ismételhető, így alkalmas lehet azon betegek kezelésére, akiknél a mentális érin-tettség miatt a diéta tartósan nem betartható [48].…”