Effects of Triple Knockout and Human Transgenes on Survival of Kidney Xenografts in Nonhuman Primates Presented at NKF Spring Clinical Meetings

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Apr 13, 2023, 08:10 ET

AUSTIN, Texas, April 13, 2023 /PRNewswire/ -- During the National Kidney Foundation's (NKF) Spring Clinical Meetings in Austin, TX from April 11-15, 2023, Massachusetts General Hospital (MGH), researchers will present new data highlighting long-term outcomes for cynomolgus macaques transplanted with kidney xenografts from porcine donors harboring genetic modifications.

In the study, kidney xenografts from porcine donors modified to remove three major carbohydrate xenoantigens (TKO) and express up to seven human transgenes, were evaluated in a non-human primate transplant model. The genetic modifications were intended to address cross-species molecular incompatibilities that lead to organ rejection, a major hurdle in the field of xenotransplantation (the transplantation of organs or tissues from one species to another). Xenografts from donors with TKO and human transgenes demonstrated prolonged survival compared to those with TKO alone, with one graft surviving over two years post-transplant.

"The two-year transplant survival outcome is a highly encouraging finding and represents a significant milestone for the xenotransplantation field," said Dr. Toshihide Tomosugi, Research Fellow in Surgery at MGH. "This groundbreaking study brings us one step closer to clinical testing of a gene-edited porcine renal graft in humans, potentially offering a much-needed approach to supply human compatible organs to alleviate the organ shortage and also providing an alternative therapeutic option for end-stage kidney disease."

It is estimated that 37 million Americans have kidney disease (also known as chronic kidney disease) and about 90,000 of these individuals are waitlisted for a kidney transplant. About 25,000 of those waiting for a kidney received one this year, one-third of which came from living donors. The average wait time for a kidney transplant is three to seven years. The use of genome engineering in xenotransplantation has the potential to meaningfully transform the treatment of chronic kidney disease by providing a transplant earlier in the disease process and possibly ending waitlist mortality altogether.

Porcine cells devoid of the three major carbohydrate xenoantigens of α-Gal, Neu5Gc, and Sda (otherwise known as TKO) have been shown to exhibit markedly decreased binding of naturally occurring anti-porcine antibodies in vitro. However, this study demonstrated that a TKO strategy alone is still insufficient to enable longer-term xenotransplantation survival.

Study Highlights:

The porcine donors used in this study were produced by eGenesis, Inc. Donors with three different sets of genetic modifications were evaluated – TKO, TKO with six human transgenes, and TKO with seven human transgenes. Certain donors were also edited to inactivate porcine endogenous retroviruses.
The combination of human transgenes with TKO was found to be beneficial in prolonging graft survival relative to TKO alone.
Recipients were pre-selected for low levels of naturally occurring anti-porcine antibodies. No correlation between anti-porcine antibody levels and xenograft survival was observed, suggesting recipients were within an acceptable threshold for pre-transplant antibody levels.
The immunosuppression regimen included T and B cell depletion, followed by weekly administration of anti-CD154 antibody and daily mycophenolate mofetil. A short course of corticosteroid and tacrolimus was also administered.
Mechanisms of graft rejection varied with duration of survival.

NKF Spring Clinical Meetings

For the past 31 years, nephrology healthcare professionals from across the country have come to NKF's Spring Clinical Meetings to learn about the newest developments related to all aspects of nephrology practice; network with colleagues; and present their research findings. The NKF Spring Clinical Meetings are designed for meaningful change in the multidisciplinary healthcare teams' skills, performance, and patient health outcomes. It is the only conference of its kind that focuses on translating science into practice for the entire healthcare team.

Each year NKF considers the work of hundreds of specialists in the field of nephrology and selects among them those who most exemplify the relentless efforts of NKF to enhance the lives of patients through action, education, and accelerating change. The prestigious awards are presented to the recipients during the annual gathering of clinicians and kidney health professionals during the conference.

About Kidney Disease

In the United States, more than 37 million adults are estimated to have kidney disease, also known as chronic kidney disease —and approximately 90 percent don't know they have it. About 1 in 3 adults in the U.S. are at risk for kidney disease. Risk factors for kidney disease include: diabetes, high blood pressure, heart disease, obesity, and family history. People of Black or African American, Hispanic or Latino, American Indian or Alaska Native, Asian American, or Native Hawaiian or Other Pacific Islander descent are at increased risk for developing the disease. Black or African American people are about four times as likely as White people to have kidney failure. Hispanics experience kidney failure at about double the rate of White people.

NKF Professional Membership

Healthcare professionals can join NKF to receive access to tools and resources for both patients and professionals, discounts on professional education, and access to a network of thousands of individuals who treat patients with kidney disease.

About the National Kidney Foundation

The National Kidney Foundation is the largest, most comprehensive, and longstanding patient-centric organization dedicated to the awareness, prevention, and treatment of kidney disease in the U.S. For more information about NKF, visit www.kidney.org.

About the Massachusetts General Hospital

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The Mass General Research Institute conducts the largest hospital-based research program in the nation, with annual research operations of more than $1 billion and comprises more than 9,500 researchers working across more than 30 institutes, centers and departments. In July 2022, Mass General was named #8 in the U.S. News & World Report list of "America's Best Hospitals." MGH is a founding member of the Mass General Brigham healthcare system.

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SOURCE The National Kidney Foundation