A study conducted by researchers at the Johns Hopkins School of Medicine and Revivicor, a subsidiary of United Therapeutics, demonstrates the consistent survival rates observed in consecutive cases of kidney xenotransplantation from pigs to non-human primates (NHPs). This study is the first report of pig-to-NHP kidney xenotransplantation using source pigs with 10 genetic modifications (called 10GE pigs).

Additionally, the research showcases the viability of a regulatory-compliant approach for acquiring and preserving porcine kidneys. It reveals that kidneys obtained from 10GE pigs at a designated pathogen-free (DPF) facility can be effectively preserved and successfully transplanted after 3–5 hours of cold preservation.

The study is significant because it closes the long-standing divide between NHP and clinical transplantation immunosuppressive strategies. It is the first to show that genetically modified pig-to-baboon kidney transplantation can survive long using conventional immunosuppression already available in clinical settings. The presented data offer crucial corroborating evidence regarding the safety and viability of human kidney xenotransplantation in clinical settings. 

The research article, “Consistent survival in consecutive cases of life-supporting porcine kidney xenotransplantation using 10GE source pigs,” was published in Nature Communications.

The regulatory road to kidney xenotransplantation

Xenotransplantation presents a potentially viable resolution to the scarcity of donor organs. Significant advancements have been made in the domain of xenotransplantation during the past two decades. Notably, recent studies have documented the successful transplantation of pig-to-NHP heart and kidney xenografts, resulting in survival rates exceeding six months.

Nevertheless, there are still apprehensions regarding the secure application of these findings in clinical settings due to the lack of consistency in reported survival rates and the significant disparities between preclinical procurement and immunosuppression and the established clinical standards of care. It is worth mentioning that there is a lack of research on solid organ pig-to-NHP transplantation that has demonstrated xenograft survival exceeding one month in the absence of CD40/CD154 costimulatory blockade. It is important to highlight that this immunosuppression strategy is not currently approved by the FDA.

The FDA has recently provided guidance on a regulatory pathway for solid organ xenotransplantation, outlining the subsequent measures required for more comprehensive clinical translation. The FDA’s regulatory framework has heightened scrutiny in the field regarding the uniformity of outcomes, the technique of organ acquisition and preservation, and the utilization of non-FDA-approved drugs in immunosuppression protocols.

While the FDA has not yet approved clinical trials in kidney xenotransplantation, it may be necessary to show consistent survival rates of over six months in consecutive preclinical NHP experiments. Although NHP studies have provided several instances of long-term survival, no published case series have demonstrated consistent (>50%) survival beyond six months in consecutive (>3 recipients) experiments. The majority of studies exclude recipients who encounter hyperacute xenograft rejection or early adverse outcomes as a result of technical complications. To assess the safety and effectiveness of xenografts in human subjects, providing a clear and comprehensive demonstration of consecutive long-term survival is crucial while acknowledging the possibility of adverse outcomes.

10GE pig kidneys support life with stable renal function in baboons

This study is a component of a broader Investigational New Drug (IND)-enabling nonclinical investigation, which is backed by United Therapeutics. The results indicate an exceptional and prolonged survival period of 220 days (mean) and 261 days (median) for a set of six consecutive NHP xenotransplants. These transplants were obtained from a specialized transplantation facility and transported using preservation technologies approved by the FDA. Notably, this study represents the first instance of long-term survival of solid organ xenografts without CD40/CD154 blocking agents.

Furthermore, they demonstrated extended survival following a cold preservation period of more than three hours for xenografts, as well as long-term survival when employing immunosuppression approved by the FDA. In addition, the study of long-term survival in the absence of CD40/CD154 costimulatory blockade could offer valuable insights for the evaluation of immunosuppression regimens in the context of initial human clinical trials. This situation poses a challenging decision for regulators, clinicians, and patients: should they opt for a conventional immunosuppression regimen with a xenograft in pig-to-NHP solid organ transplantation, despite the absence of preclinical evidence, or should they choose a clinically unproven immunosuppression regimen based on preclinical pig-to-NHP data, which is considered safer?

Currently, the potential consequences of these implications may be restricted to individuals who receive 10GE xenografts. This is because the consistent transgenic expression of various human complement regulatory, anti-coagulant, and anti-inflammatory transgenes in 10GE source pigs could eliminate the necessity for CD40/CD154 blockade. The replication of these data is necessary in order to address a significant disparity between preclinical pig-to-NHP xenotransplantation data and the clinical allotransplantation outcome. Consequently, these findings hold immediate significance for the design of upcoming xenotransplantation clinical trials.

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