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Written by Gianliuca Quaglio.

Since the first successful organ transplant in 1954, the procedure has become increasingly prevalent, revolutionising the treatment of end-stage organ failure. Nevertheless, organ shortage remains a critical problem that could potentially be overcome by xenotransplantation, a promising alternative approach.

While the field of organ and cell allotransplantation (from a donor of the same species) remains limited, xenotransplantation (from the Greek xenos, meaning ‘foreign’) could alleviate the increasing demand for donor organs. Xenotransplantation, defined as the transplantation of animal-derived organs and cells into humans, is currently a very active focus of research, as it over-rides some of the obstacles encountered with tissue engineering, such as revascularisation and innervation. The resurgence of interest in xenotransplantation is mainly attributed to the improvement of gene-editing techniques (such as CRISPR/Cas9), since genetically engineered animals have been bred to overcome organ rejection. However, xenotransplantation also raises multiple biological and ethical questions that should be taken into consideration.

Potential impacts and developments

Pigs, the most suitable xenograft source.The greatest difficulty encountered in transplantation is rejection caused by the mounting of immune responses against the donor organ, perceived as a foreign threat by the human body. Graft rejection can be classified as hyperacute, acute or chronic, depending on the time it takes for antibodies to react against donor antigens, known as substances that trigger the immune system. While non-human primates (NHPs) are phylogenetically closer to humans than pigs, the latter are regarded as a more appropriate xenograft source for multiple reasons.

Pigs not only reproduce easily and have organs of comparable size to humans, they also present physiological similarities. For instance, porcine valve replacement has been successful for over 30 years and is considered a better alternative to mechanical valves, which are more prone to blood clot formation. Attempts have also been made to transplant pig kidneys, corneas and livers, but the main challenge remains that of overcoming the immune barriers to xenotransplantation. Finally, there are fewer ethical and other implications when working with pigs than with NHPs.

Genome editing. The implementation of potent immunosuppressive regimens has helped to prolong xenograft survival significantly by reducing the risk of rejection. However, a number of issues, such as coagulation dysfunction between the pig-derived graft and the human, remain problematic, as certain molecular incompatibilities cannot simply be overcome by immunosuppression. As a result, scientists have focused primarily on the generation of genetically modified pigs.

These not only have engineered organs that are less prone to rejection, but are also protected from a number of viruses that could cause the transmission of zoonoses following xenotransplantation. The dynamic developments in this field of research have occurred mainly as a result of CRISPR/Cas9, a novel gene-editing technology that has revolutionised biomedical research. It basically consists of an enzyme (Cas9) acting as a pair of ‘molecular scissors’ that follow the guide RNA (gRNA) to a target sequence in the DNA in order to introduce changes or make deletions.

Examples of transgenic pigs for xenotransplantation purposes. Pig-antigens are not synthesised by the human species and can cause mounting immune responses that lead to organ rejection. It is therefore of vital importance to eliminate the pig genes responsible for encoding these antigens for the organ recipient. A recent study involving the inactivation of three such pig genes and the insertion of nine human genes using CRISPR/Cas9 technology generated very encouraging results. Importantly, one of the genes inserted plays a crucial role in regulating the coagulation system. The cells resulting from these genetically modified pigs were resistant to rejection, demonstrating greater compatibility with humans in terms of the immune system as well as the blood-coagulation system.

Another promising achievement beyond overcoming rejection is the use of CRISPR/Cas9 technology to limit the risk of cross-species transmission of infectious viruses, therefore removing a major hurdle to using pigs for xenotransplantation. In an attempt to mitigate incompatibility, various studies have so far attempted more than 40 genetic modifications on the pig genome thanks to the development of new gene-editing tools. This global effort has very recently culminated in the first successful pig to human xenotransplantation of a genetically modified heart, raising hopes that we are ‘one step closer to solving the organ shortage crisis’.

Anticipatory policy-making

The rate of organ donations increased by 14 % in the EU between 2010 and 2019, with kidney transplants accounting for 85 % of all transplants. This is partly the result of some EU countries (such as Belgium, Austria and France) adopting the opt-out system and endorsing the principle of presumed consent, according to which all brain-dead individuals are considered donors unless otherwise stated. However, the supply of organ donations does not meet demand, despite overall progress.

This is illustrated by the death in 2020 of 668 individuals who were on the Eurotransplant waiting list. Eurotransplant is an institution that manages an international collaborative framework responsible for allocating donor organs in eight EU Member States. Another key organisation is the European Society for Organ Transplantation (ESOT), which structures and streamlines transplant activities in Europe and worldwide.

The European Medicines Agency (EMA) classifies xenogeneic cell therapy and products as advanced therapy medicinal products (ATMPs). The ATMP regulatory framework centres on Regulation (EC) No 1394, adopted in 2007. This is associated with an EMA guideline issued in 2009 that sets out general principles for the development, authorisation and pharmacovigilance of xenogeneic cell-based medicinal products. Overall, these documents stress the importance of quality and manufacturing aspects of ATMPs, taking into account the source, procurement and processing of xenogeneic materials (e.g. animal tissues and organs).

There have been no major legislative developments specific to xenotransplantation in the EU in recent years however. While the above-mentioned regulation marked an important step towards a unified ethical and legal EU framework on xenotransplantation, a more competent regulatory authority is needed in order for this promising practice to reach its full potential.

As mentioned by the Committee for Medicinal Products for Human Use (CHMP), a quality assurance system specific to xenotransplantation is crucial to guarantee the correct pathogen-free health status of donor animals. It is also vital to ensure that the animals are kept under the best possible conditions, so as to prevent their suffering during the procedure before organ explant. These issues are also being addressed by the World Health Organization and the International Xenotransplantation Association (IXA), both of which play a critical role in the drafting of xenotransplantation directives, notably regarding preclinical efficacy requirements.

In conclusion, multiple issues have still to be resolved before xenotransplantation becomes commonplace in clinical practice. However, the EU regulatory aspects of xenotransplantation were drafted in part at a time when the risks involved with the procedure were higher, not reflecting the latest ground-breaking developments in this fast-evolving field. Their revised interpretation by regulatory authorities and research institutes could therefore facilitate the safer design and conduct of clinical trials, in order to arrive at an appropriate compromise between existing and adapted guidelines.

Read this ‘at a glance’ on ‘What if xenotransplantation was the answer to the donor organ shortage?‘ in the Think Tank pages of the European Parliament.

Listen to policy podcast ‘What if xenotransplantation was the answer to the donor organ shortage?’ on YouTube.

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