2023-10-11 17:00:11
The most famous case of xenotransplantation (transplantation of an animal organ to a human) was that of David Bennett, an American patient who suffered from terminal heart disease. A team of University of Maryland School of Medicine Medical Center (USA) transplanted a pig heart modified with human genes. But despite all efforts, the 57-year-old man died two months later. Even so, it was considered a milestone, as it was the first time that this intervention was carried out.
Now, a team from the American biotechnology company eGenesis has published a work in Nature in which it announces an improvement in the compatibility of porcine kidneys for future transplantation in humans, although for the moment it has been validated with monkeys. The donor pigs were modified to carry 69 genomic edits, using the editing technique CRISPR Cas9.
The company eGenesis has published a paper in Nature in which it announces an improvement in the compatibility of porcine kidneys for transplantation into humans.
This company, which develops what it calls “human compatible organs” o HuCo™ (human compatibility), has released long-term survival data from a proof-of-concept study evaluating porcine donor kidneys transplanted into a cynomolgus macaque model.
The authors have reported that one of the primates transplanted with genetically modified porcine kidneys has survived more than two years (758 days). “The results will allow us to advance the clinical development of the company’s main candidate for kidney transplantation, the EGEN-2784 model,” the researchers comment in a company statement.
“Our results represent the largest and most comprehensive preclinical data set published in this field to date,” they add. “Historically, the survival of xenotransplant recipients in this preclinical setting has been measured in weeks or, at most, months.”
Michael CurtisCEO of eGenesis, notes that the company is focused on “improving the long-term survival of transplant recipients from months to years.”
“Our HuCo™ organs offer hope of a new source of donors for the hundreds of thousands of people who need life-saving organ transplants. Data published in Nature “They illustrate our rapid progress in engineering porcine donor organs to improve compatibility and long-term survival, a critical step toward successful translation into human clinical trials,” he emphasizes.
Historically, survival of xenotransplant recipients in the preclinical setting has been measured in weeks or, at most, months.
As happens internationally, the most common type of transplant in Spain is the kidney, with a total of 3,402 interventions in 2022according to data from the National Transplant Organization (ONT).
The kidneys of the donor pigs evaluated in this study carried three types of edits. First of all, the so-called knock out [eliminación] of three genes involved in the synthesis of glycan antigens involved in hyperacute rejection. Then, the insertion of seven human transgenes involved in the regulation of several pathways that modulate rejection: inflammation, innate immunity, coagulation and complement. And finally, the inactivation of endogenous retroviruses embedded in the porcine genome.
The authors explain that organs from donor pigs carrying modified human transgenes resulted in longer survival times when transplanted into primates.
The pig kidneys that only contained knock out of the three glycan antigens experienced poor transplant survival, while those that also incorporated the human transgenes resulted in a duration more than seven times longer: a median of 24 days versus 176 days, respectively. The results indicate the benefit of the expression of human transgenes in porcine kidney grafts on long-term survival.
High human immune compatibility
Functional analyzes in vitro showed that edited porcine kidney endothelial cells modulated inflammation similarly to human endothelial cells, suggesting that the edited ones acquired a high level of human immune compatibility.
Furthermore, evaluation of biomarkers of kidney function in recipients with stable grafts revealed that a single transplanted porcine kidney provided sufficient metabolite filtration to compensate for the lack of two original kidneys.
“It is a great step forward in the field of transplants,” he noted. Tatsuo Kawaiholder of the A. Benedict Cosimi Chair of Transplant Surgery at Massachusetts General Hospital and co-author of the work.
Our data demonstrate remarkable progress in porcine genome editing to minimize hyperacute rejection, improve recipient compatibility, and address the risk of viral transmission from donor to host.
Tatsuo Kawai, co-author of the work
According to Kawai, “one of the biggest obstacles has been the long-term survival of the genetically modified organ in the recipient primate, and this data set demonstrates remarkable progress in editing the porcine genome to minimize hyperacute rejection, improve the compatibility of the recipient and address the risk of viral transmission from the donor to the host. “We anticipate that the outcomes of human transplants will be even more favorable, as these gene-edited organs are more compatible, compared to non-human primates.”
The data generated in this study supports the advancement of the company’s lead kidney transplant candidate, EGEN-2784, into clinical development, the company emphasizes.
In addition, eGenesis is also advancing extracorporeal liver perfusion programs as well as heart transplantation.
The organ failure It is a life-threatening disease for which transplantation is considered the standard of care. However, the demand for organs far exceeds the supply.
In Spain, a country that registers the record number of organ transplants in the world, there is a waiting list for kidney transplants of about 4,800 people, according to the ONT.
The authors of this study state that “the current treatment paradigm for organ failure is not optimal for either patients or the healthcare system, due to organ incompatibility and the variable quality of donor organs.”
Reference:
Wenning Qin et al. “Design and testing of a humanized porcine donor for xenotransplantation”. Nature (octubre, 2023)
Rights: Creative Commons.
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