October 26, 2023
Cambridge, Mass. (October 26, 2023) – eGenesis, a biotechnology company developing human-compatible (HuCoTM) organs for the treatment of organ failure, will present new data and host a symposium during the IPITA (International Pancreas and Islet Transplant Association), IXA (International Xenotransplantation Association), and CTRMS (Cell Transplant and Regenerative Medicine Society) joint congress, held in San Diego, October 26-29, 2023.
The company will give three presentations during the conference. Two presentations will highlight data from the company’s landmark preclinical proof of concept study for kidney transplant recently published in Nature. A third presentation will share the results of a study evaluating pancreatic islets from genetically engineered porcine donors transplanted into a mouse model.
“Cross-species organ transplantation is advancing and eGenesis is playing an important role in the progress being made in this field,” said Mike Curtis, CEO of eGenesis. “We’re thrilled to share data highlighting our lead candidate for kidney transplant, EGEN-2784, as well as additional data supporting our genome engineering platform. Our goal is to develop donor organs that provide durable long-term recipient survival for the hundreds of thousands of individuals in need of lifesaving organ transplants.”
Findings from the presentation titled, “Design and creation of a clinically compatible porcine donor for xenotransplantation,” will feature data from the company’s recent Nature publication, highlighting the largest preclinical study of its kind to evaluate organ transplantation in non-human primates. The data indicate that molecular incompatibilities between porcine donors and primate recipients can be addressed via genome engineering to achieve more durable survival than has been seen historically in the field. Human transgenes were inserted into a genomic safe harbor site. Long-read whole-genome sequencing confirmed that a single copy of the sequence was inserted and direct RNA sequencing confirmed that transcription occurred as expected.
Humanized porcine donors were genetically engineered using the Yucatan miniature pig breed to carry 69 genomic edits through CRISPR/Cas 9 technology. The modifications span three classes of edits: (1) knockout of three genes involved in the synthesis of glycan antigens implicated in hyperacute rejection, (2) insertion of human transgenes involved in the regulation of several immune system-related pathways that modulate rejection, and (3) inactivation of the porcine endogenous retrovirus. Additional key takeaways from the presentation are as follows:
- Engineered porcine kidney endothelial cells were found to acquire molecular compatibilities similar to human endothelial cells – those containing human transgene expression were resistant to the molecular processes driving rejection, including complement dependent cytotoxicity
- Long term graft survival and life supporting function were achieved in NHPs, with one recipient surviving for more than two years
- The median survival was 176 days for the group receiving organs carrying antigen knockouts plus human transgenes versus 24 days for the group with organs harboring antigen knockouts alone
In a second presentation titled, “Amplification-free activation of primate complement by porcine triple-knockout cells is driven by the classical pathway,” eGenesis researchers found that porcine kidney cells with the three glycan antigen knockouts demonstrated reduced complement system activation – a critical driver of the innate immune response and hyperacute rejection – when exposed to NHP recipient sera. The results suggest that the antigen knockouts influence complement regulation and could decrease the risk of hyperacute rejection in cross-species organ transplantation. Additional key takeaways from the presentation are as follows:
- While deletion of the antigens in porcine donor cells greatly reduces preformed antibody binding and subsequent complement activation, prevents hyperacute rejection, and prolongs graft survival, a low but substantial amount of residual antibody and complement deposition remained detectable on the cells
- Complement activation was largely driven by the classical pathway on porcine donor cells devoid of the 3 glycan antigens, rather than the alternative pathway
- The data point to the antigen knockout modification as an optimal background for preventing antibody-driven rejection of xenografts and could help inform strategies of complement regulation in the future
Oral presentations by eGenesis collaborators will highlight progress made across the company’s heart, kidney, and liver programs:
- Pilot evaluation of a clinical xeno heart transplant regimen in a preclinical model (Richard Pierson and Ikechukwu Ileka, Massachusetts General Hospital)
- Ischemia minimization is associated with improved cardiac function in an ex vivo xeno working heart model (Richard Pierson and Graham McGrath, Massachusetts General Hospital)
- Long-term (2 years) survival of porcine to nonhuman primate life-sustaining kidney xenotransplantation (Tatsuo Kawai and Ahmad Karadagi, Massachusetts General Hospital)
- 48-hour normothermic xenoperfusion of genetically engineered porcine livers with whole human blood (Alexander Sagar, OrganOx and eGenesis)
Organ failure is a life-threatening condition for which transplantation is considered the gold standard treatment. However, the demand for organs far outstrips supply – of the more than 100,000 individuals on the organ transplantation waitlist in the U.S., 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. Cross-species transplantation is viewed as a viable solution to address the organ shortage crisis.
About eGenesis
eGenesis is pioneering a genome engineering-based approach in the development of safe and effective transplantable organs. The eGenesis Genome Engineering and Production (EGEN™) Platform is the only technology of its kind to comprehensively address cross-species molecular incompatibilities and viral risk via genetic engineering. eGenesis has demonstrated durable preclinical success to date and is advancing development programs for acute liver failure, kidney transplant, and pediatric as well as adult heart transplant. Learn more at www.egenesisbio.com.
eGenesis Media Contact
Kimberly Ha
kimberly.ha@egenesisbio.com