Regulation of Clinical Xenotransplantation—Time for a Reappraisal

Abstract

The continual critical shortage of organs and cells from deceased human donors has stimulated research in the field of cross-species transplantation (xenotransplantation), with the pig selected as the most suitable potential source of organs. Since the US Food and Drug Administration concluded a comprehensive review of xenotransplantation in 2003, considerable progress has been made in the experimental laboratory to improve cell and organ xenograft survival in several pig-to-nonhuman primate systems that offer the best available models to predict clinical outcomes. Survival of heart, kidney, and islet grafts in nonhuman primates is now being measured in months or even years. The potential risks associated with xenotransplantation, for example, the transfer of an infectious microorganism, that were highlighted in the 2003 Food and Drug Administration guidance and subsequent World Health Organization consensus documents have been carefully studied and shown to be either less likely than previously thought or readily manageable by donor selection or recipient management strategies. In this context, we suggest that the national regulatory authorities worldwide should re-examine their guidelines and regulations regarding xenotransplantation, so as to better enable design and conduct of safe and informative clinical trials of cell and organ xenotransplantation when and as supported by the preclinical data. We identify specific topics that we suggest require reconsideration.

Long-term survival of pig-to-rhesus macaque renal xenografts is dependent on CD4 T cell depletion

“…We report the first translational model of life-sustaining renal xenotransplant achieving survival beyond 1 year -a milestone in progress in the pig-to-NHP kidney transplant model. [63][64][65] As our capabilities to rapidly genetically engineer porcine donors improve through the use of CRISPR/CAS9 technology, we and others are increasingly able to silence epitopes that put the xenograft at risk as well as selectively insert genes that confer protection against innate mechanisms such as the complement and coagulation cascades. Our report offers an exciting advance for the field of transplantation with the suggestion that life-sustaining kidney xenotransplant is much closer to clinical reality than previously thought.…”

“…However, as demonstrated by previous data from our group, 17 macaques are fully capable of a robust antibody-mediated response in a pig-to-primate xenotransplant model. [63][64][65] As our capabilities to rapidly genetically engineer porcine donors improve through the use of CRISPR/CAS9 technology, we and others are increasingly able to silence epitopes that put the xenograft at risk as well as selectively insert genes that confer protection against innate mechanisms such as the complement and coagulation cascades. 17 These long-term survival times offer an exciting advancement for a field that continues to see landmark scientific progress in genetic engineering, antibody depletion, T cell suppression, and tolerance strategies.…”

Advances in the immunology of heart transplantation

“…73 Not only was this a gene editing “tour de force,” but the availability of pigs with a PERV-free genome makes moot any argument to limit clinical xenotransplantation based on the unlikely risk of pig-to-human viral transmission. 74 The goal now is using CRISPR/Cas9 to generate pigs with increased biologic compatibility with humans, perhaps using PERV-free pigs as a foundation strain.…”

Bringing Home The Bacon: Update on The State of Kidney Xenotransplantation

“…The potential risk of a pig microorganism being transferred to the patient is considered small. The timing of such a clinical trial will to some extent depend on the requirements of the regulatory authorities [29]. …”