Cambridge, Mass, June 05, 2023
Cambridge, Mass. (June 5, 2023) – eGenesis, a biotechnology company developing human-compatible organs for the treatment of organ failure, will present new data during the American Transplant Congress (ATC) 2023, held June 3 – June 7, 2023 in San Diego, CA. The findings advance understanding of several molecular and cellular aspects of xenotransplantation – the transplantation of living organs, tissues, or cells from one species to another – laying critical groundwork for further evaluation in prospective clinical trials.
“The data we are presenting at ATC 2023 demonstrate eGenesis’ continued leadership in the field of xenotransplantation,” said Mike Curtis, Ph.D., CEO of eGenesis. “Great progress has been made to now achieve successful longer-term nonclinical transplants with engineered porcine donors. Based on our understanding of the mechanisms that contribute to xenograft health, we recently nominated a donor for clinical development that includes genome modifications addressing hyperacute rejection, recipient compatibility and the risk of zoonosis. We are eager to advance towards clinical studies and ultimately, addressing the tremendous patient need for new donor organs.”
Presentation and poster details are outlined below.
Oral Presentation: Genetically Modified Porcine Kidneys Expressing Human Transgenes Support >2-year Survival in Porcine Donor to Cynomolgus Macaque Recipient Xenotransplantation. Takayuki Hirose, MD, PhD, Research Fellow/Assistant Professor Transplant Surgery, Mass General Hospital / Department of Urology, Hokkaido University
- Xenotransplantation offers a promising solution to the transplantable organ shortage crisis, and recent advances in gene editing have enabled the introduction of genetic modifications – xenoantigen elimination, human transgene (TG) expression, and retroviral inactivation – to improve the compatibility and safety of xenogeneic organs.
- eGenesis scientists genetically engineered porcine donors to remove three known xenoantigens implicated in hyperacute rejection. A second set of donors were engineered to carry the three xenoantigen knockouts (triple knockout, 3KO) as well as additional edits: (1) expression of seven human proteins involved in innate and adaptive immunity as well as complement regulation and coagulation, and in some donors, (2) inactivation of porcine endogenous retrovirus.
- Cynomolgus macaque recipients experienced markedly improved survival when transplanted with porcine donor xenografts containing TGs compared to recipients receiving xenografts containing the 3KO (a median survival time of 24 days versus 176 days). Long-term survival times ranged from one recipient surviving for more than two years, two surviving for 18 months and several surviving for more than a year.
- The porcine kidneys demonstrated effective filtration and chemistry parameters were generally within or near normal primate ranges
Oral Presentation: Contribution of Anti-SLA Antibodies to Rejection in Nonhuman Primate Model of Kidney Xenotransplantation. William T. Serkin, Senior Research Associate, eGenesis, Inc.
- Antibody mediated rejection (AMR) is a leading cause of transplant failure in xenotransplantation studies, and the degree to which recipient antibodies target donor swine leukocyte antigens (SLA) remains largely unknown.
- To identify the role of SLA in AMR, blood sera samples gathered post-transplant from cynomolgus macaques that received porcine kidney xenografts were screened for antibodies against SLA.
- While six out of the 14 recipients were found to produce antibodies against SLA, most porcine-reactive antibodies bound non-SLA antigens, suggesting that SLA alone does not account for the majority of anti-porcine antibodies in non-human primate recipients.
- In some animals, high levels of anti-porcine antibodies were elicited without detectable targeting of SLA.
Poster: Pre- and Post-Transplant Donor Specific Anti-Porcine Antibodies In Transplantation of Kidney Xenografts with Triple Knock-Out With or Without Multiple Human Transgenes in Nonhuman Primates. Ahmad Karadagi, Postdoctoral Research Fellow, Harvard Medical School / Massachusetts General Hospital
- Preformed anti-porcine antibodies can be detrimental to xenograft survival, and porcine cells engineered to remove three xenoantigen knockouts (3KO) have been shown to markedly decrease binding of naturally occurring, donor-specific anti-porcine antibodies (DSA) in vitro. The introduction of TGs offers an additional avenue to improve and extend xenograft survival.
- In non-human primate recipients, survival was significantly longer with xenokidneys containing the 3KO and TG insertion compared to xenokidneys expressing the 3KO alone.
- Among all recipients, there was no clear correlation observed between pre-transplant DSA and xenograft survival.
- In recipients of both 3KO and 3KO/TG xenokidneys, elevation of post-transplant DSA titers was associated with antibody-mediated rejection (AMR) and thrombotic microangiopathy (TMA). In recipients of 3KO only xenokidneys, graft losses were associated with acute tubular injury (ATI) and AMR but without high DSA titers.
Poster: Longitudinal Monitoring of Donor Cell-Free DNA in Porcine Kidney Xenotransplantations. Kristen Getchell, Scientist, eGenesis, Inc.
- Donor cell-free DNA (dcfDNA) has been proposed as a predictive biomarker for solid organ rejection in transplantation, leading scientists to develop an optimized protocol to collect, process and analyze dcfDNA, then assess its value as a potential diagnostic indicator for monitoring graft health over time (an integral component of successful post-transplant management).
- Plasma was the more sensitive sample type compared to serum, with samples as low as 0.25 mL capable of adequately capturing dcfDNA status.
- Long term survivors exhibit lower dcfDNA levels over time.
- dcfDNA fluctuations may also be influenced by other clinical events in addition to graft injury, further complicating how the predictive utility of dcfDNA is interpreted.
About Transplantation and Xenotransplantation
Organ failure is a life-threatening condition for which transplantation is considered to be the gold standard treatment. However, the growing demand for organs far outstrips supply – of the more than 100,000 individuals on the organ transplantation waitlist in the United States, less than 40% will receive a potentially life-saving organ. In addition, the existing organ failure treatment paradigm is suboptimal for patients and the healthcare system due to organ incompatibility and variable donor organ quality.
Xenotransplantation – the transplantation of cells, tissues, and organs from one species to another – is widely viewed by the transplant community to be a viable solution to address the organ shortage crisis. The advent of gene editing technologies, such as CRISPR, has enabled scientists to address the virologic and immunologic hurdles that have historically prevented the advancement of xenotransplantation.
eGenesis is leveraging a genome engineering-based approach in the development of safe, effective, and transplantable organs. The company’s platform is the only technology of its kind to address both viral risk and cross-species molecular incompatibilities. eGenesis has demonstrated durable preclinical success to date and is advancing development programs for acute liver failure, kidney transplant, and heart transplant. Learn more at www.egenesisbio.com.
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