Xenotransplantation: back to the future?

Abstract

The field of xenotransplantation has fluctuated between great optimism and doubts over the last 50 years. The initial clinical attempts were extremely ambitious but faced technical and ethical issues that prompted the research community to go back to preclinical studies. Important players left the field due to perceived xenozoonotic risks and the lack of progress in pig-to-nonhuman-primate transplant models. Initial apparently unsurmountable issues appear now to be possible to overcome due to progress of genetic engineering, allowing the generation of multiple-xenoantigen knockout pigs that express human transgenes and the genomewide inactivation of porcine endogenous retroviruses. These important steps forward were made possible by new genome editing technologies, such as CRISPR/Cas9, allowing researchers to precisely remove or insert genes anywhere in the genome. An additional emerging perspective is the possibility of growing humanized organs in pigs using blastocyst complementation. This article summarizes the current advances in xenotransplantation research in nonhuman primates, and it describes the newly developed genome editing technology tools and interspecific organ generation.

The role of human CD46 in early xenoislet engraftment in a dual transplant model

“…For example, donor animals deficient in non‐gal xenoantigens will minimize epitopes for immunoglobulin binding . Expression of human CD39 and CD73 and deletion of porcine von Willebrand factor (vWF) may further reduce platelet aggregation and deposition on NPIs, while various human coagulation regulatory proteins, including EPCR, TM, and TFPI, may inhibit downstream clotting . Lastly, expression of human HLA‐E and CD47 on NPIs reduces NK and macrophage infiltration .…”

“…This may be achieved either via its known mechanism at promoting cleavage of C3b and C4b, or via other unknown mechanisms related to platelet activation and leukocyte adhesion. [32][33][34][35][36] Lastly, expression of human HLA-E and CD47 on NPIs reduces NK and macrophage infiltration. 37,38 Although germline genetic modifications are generally required in solid organ xenotransplantation, genetic modifications may also be achieved temporarily in NPIs via viral vectors.…”

Expression profile of human porcine endogenous retrovirus A receptors (HuPAR‐1, HuPAR‐2) and transcription factor activator protein‐2γ (TFAP‐2C) genes in infected human fibroblasts—Model in vitro

“…Animal cells, tissues, and organs appear as an attractive source of biomaterials in various areas of regenerative medicine and transplantology. Genetically modified domestic pigs ( Sus scrofa domestica ) seem to be the most promising source of xenogenic tissues mainly because of the ease of breed and physiology similar to human . However, the use of porcine tissues for xenotransplantation raises concerns, especially in the context of the potential interspecies transmission of porcine endogenous retroviruses (PERVs) …”

“…Genetically modified domestic pigs (Sus scrofa domestica) seem to be the most promising source of xenogenic tissues mainly because of the ease of breed and physiology similar to human. 1,2 However, the use of porcine tissues for xenotransplantation raises concerns, especially in the context of the potential interspecies transmission of porcine endogenous retroviruses (PERVs). 3 Recently implemented CRISPR-Cas9 technology of gene edition may be able to eliminate the risk posed by PERVs; however, the risk of xenozoonosis with other viruses remains.…”

Rabbit Biomodels of Human Diseases Developed Using New Genomic Technologies. Crispr/Cas9 (Review)

“…Для редактирования геномов более востребованной оказалась технология РНК-направляемых эндонуклеаз -CRISPR/Cas9. Начиная с 2013 года, CRISPR-технология активно применяется для получения ГМ животных с целью их использования в качестве биомоделей для изучения физиологии и болезней человека или животных, биореакторов для получения биологически активных белков, доноров органов для трансплантации [44,57,78].…”