Xenotransplantation: past, present, and future

Abstract

Purpose of review: To review the progress in the field of xenotransplantation with special attention to most recent encouraging findings which will eventually bring xenotransplantation to the clinic in the near future.

Recent findings: Starting from early 2000, with the introduction of galactose-α1,3-galactose (Gal)-knockout pigs, prolonged survival especially in heart and kidney xenotransplantation was recorded. However, remaining antibody barriers to non-Gal antigens continue to be the hurdle to overcome. The production of genetically engineered pigs was difficult requiring prolonged time. However, advances in gene editing, such as zinc finger nucleases, transcription activator-like effector nucleases, and most recently clustered regularly interspaced short palindromic repeats (CRISPR) technology made the production of genetically engineered pigs easier and available to more researchers. Today, the survival of pig-to-nonhuman primate heterotopic heart, kidney, and islet xenotransplantation reached more than 900, more than 400, and more than 600 days, respectively. The availability of multiple-gene pigs (five or six genetic modifications) and/or newer costimulation blockade agents significantly contributed to this success. Now, the field is getting ready for clinical trials with an international consensus.

Summary: Clinical trials in cellular or solid organ xenotransplantation are getting closer with convincing preclinical data from many centers. The next decade will show us new achievements and additional barriers in clinical xenotransplantation.

Figure 1. Disorders for which xenotransplantation is a potential therapy*

* Reproduced with permission from Ekser et al [2].

Figure 2. Longest survival times of organ and cell xenotransplantation from pigs to nonhuman primates

Microencapsulated pancreatic xeno-islets survived for 804 days with retransplantation, but 250 days without retransplantation. Neuronal xeno-cells survived for 521 days. Pancreatic xeno-islets survived for >603 days. Corneal (deep-lamellar) xenografts survived for >389 days. Xeno-hepatocytes survived for 243 days with retransplantation, but 80 days without retransplantation. Heterotopic xeno-heart survived for >900 days. Kidney xenograft (life-supporting) survived for 405 days. Orthotopic xeno-heart survived for 57 days. Liver xenograft survived for 29 days. Lung xenograft survived for 5 days.