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Erschienen in: Current Diabetes Reports 11/2018

01.11.2018 | Immunology, Transplantation, and Regenerative Medicine (L Piemonti and V Sordi, Section Editors)

Will Genetic Engineering Carry Xenotransplantation of Pig Islets to the Clinic?

verfasst von: Elisabeth Kemter, Joachim Denner, Eckhard Wolf

Erschienen in: Current Diabetes Reports | Ausgabe 11/2018

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Abstract

Purpose of Review

Porcine islets represent a potentially attractive beta-cell source for xenotransplantation into patients with type 1 diabetes, who are not eligible to islet allo-transplantation due to a lack of suitable human donor organs. Recent progress in genetic engineering/gene editing of donor pigs provides new opportunities to overcome rejection of xeno-islets, to improve their engraftment and insulin secretion capacity, and to reduce the risk for transmission of porcine endogenous retroviruses. This review summarizes the current issues and progress in islet xenotransplantation with special emphasis on genetically modified/gene edited donor pigs.

Recent Findings

Attempts to overcome acute rejection of xeno-islets, especially after intraportal transplantation into the liver, include the genetic elimination of specific carbohydrate antigens such as αGal, Neu5Gc, and Sd(a) for which humans and—in part—non-human primates have natural antibodies that bind to these targets leading to activation of complement and coagulation. A complementary approach is the expression of one or more human complement regulatory proteins (hCD46, hCD55, hCD59). Transgenic attempts to overcome cellular rejection of islet xenotransplants include the expression of proteins that inhibit co-stimulation of T cells. Expression of glucagon-like peptide-1 and M3 muscarinic receptors has been shown to increase the insulin secretion of virally transduced porcine islets in vitro and it will be interesting to see the effects of these modifications in transgenic pigs and islet products derived from them. Genome-wide inactivation of porcine endogenous retrovirus (PERV) integrants by mutating their pol genes using CRISPR/Cas9 is a recent approach to reduce the risk for PERV transmission by xeno-islets.

Summary

Genetic engineering/gene editing of xeno-islet donor pigs facilitated major progress towards clinical islet xenotransplantation. The required set of genetic modifications will depend on the source of islets (fetal/neonatal vs. adult), the mode of delivery (encapsulated vs. free), and the transplantation site.
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Metadaten
Titel
Will Genetic Engineering Carry Xenotransplantation of Pig Islets to the Clinic?
verfasst von
Elisabeth Kemter
Joachim Denner
Eckhard Wolf
Publikationsdatum
01.11.2018
Verlag
Springer US
Erschienen in
Current Diabetes Reports / Ausgabe 11/2018
Print ISSN: 1534-4827
Elektronische ISSN: 1539-0829
DOI
https://doi.org/10.1007/s11892-018-1074-5

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