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

  • Immunology, Transplantation, and Regenerative Medicine (L Piemonti and V Sordi, Section Editors)
  • Published:
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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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Funding

This work was supported by the Horizon2020 Program, Grant Number 760986 ‘iNanoBIT’, and by the German Research Foundation (DFG), Grant Number 213602983, TRR 127: Biology of xenogeneic cell and organ transplantation—from bench to bedside.

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Authors and Affiliations

  1. Gene Center, and Center for Innovative Medical Models (CiMM), LMU Munich, Feodor-Lynen-Str. 25, 81377, Munich, Germany

    Elisabeth Kemter & Eckhard Wolf

  2. Robert Koch Institute, Nordufer 20, 13353, Berlin, Germany

    Joachim Denner

  3. German Center for Diabetes Research (DZD), Neuherberg, Germany

    Eckhard Wolf

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  1. Elisabeth Kemter
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Elisabeth Kemter, Joachim Denner, and Eckhard Wolf declare that they have no conflict of interest.

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This article is part of the Topical Collection on Immunology, Transplantation, and Regenerative Medicine

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Kemter, E., Denner, J. & Wolf, E. Will Genetic Engineering Carry Xenotransplantation of Pig Islets to the Clinic?. Curr Diab Rep 18, 103 (2018). https://doi.org/10.1007/s11892-018-1074-5

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