New York, Oct 12 In a medical breakthrough, a monkey has survived for more than two years with a kidney transplanted from a genetically engineered pig.
The experiment, carried out by researchers at the US biotech company eGenesis and Harvard Medical School, may one day develop to be a potential solution to the global shortage of donors for patients with organ failure.
“This is a major step forward for the field of transplantation,” said Tatsuo Kawai, Professor of Surgery at Harvard Medical School.
Writing in the journal Nature, the scientists explained how they carried out 69 genomic edits into the pig kidneys which enhanced compatibility and reduced rejection by the recipient’s immune system.
The donor kidneys carried three types of edits: (1) knock out of three genes involved in the synthesis of glycan antigens implicated in hyperacute rejection, (2) insertion of seven human transgenes involved in the regulation of several pathways that modulate rejection: inflammation, innate immunity, coagulation, and complement, and (3) inactivation of the endogenous retroviruses in the porcine genome.
Donor kidneys carrying human transgenes resulted in longer survival time when transplanted into NHPs. Donor kidneys containing only knock out of the three-glycan antigens experienced poor graft survival, whereas those harbouring the knockouts and human transgenes resulted in more than seven times longer duration -- a median of 24 days versus 176 days, respectively. In the case of one recipient, survival of over two years (758 days) was achieved.
The results indicate the benefit of human transgene expression in porcine kidney grafts on long-term survival.
“One of the biggest hurdles has been long-term survival of the genetically engineered organ in the NHP (non-human-primate) recipient, and this dataset demonstrates remarkable progress in editing the porcine genome to minimise hyperacute rejection, improve recipient compatibility and address the risk of viral transmission from donor to host,” Kawai said.
“We anticipate that transplant outcomes in humans will be even more favourable, as these gene edited organs are a better match for humans, as compared with NHPs,” he added.
In vitro functional analysis showed that edited porcine kidney endothelial cells modulated inflammation in a manner that mirrored human endothelial cells, suggesting the edited cells acquired a high level of human immune compatibility.
Furthermore, the evaluation of renal function biomarkers in recipients with stable grafts revealed that a single transplanted porcine kidney provided sufficient filtration of metabolites to compensate for the lack of two native kidneys.
Organ failure is a life-threatening condition for which transplantation is considered the gold standard treatment. However, the demand for organs far outstrips supply. 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.
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