2023-10-11 17:00:00
Updated Wednesday, October 11, 2023 – 17:00
The researchers made 69 genetic modifications to avoid hyperacute rejection, the common reaction to a transplant between different species.
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Obtaining ‘spare’ organs, developed in animals and available for transplantation in humans, is an objective pursued by different research groups around the world.
Although in 2022 several xenotrasplantes experimental, such as implanting a genetically modified pig heart into a Baltimore patient suffering from serious heart disease; This type of approach is still far from reaching the clinic. First, important biotechnological challenges posed by the ‘jump’ between species must be resolved, such as hyperacute rejection after grafting or the risk of zoonoses.
Research led by scientists from Harvard University and the eGenesis company paves this path by having managed to implant genetically edited pig kidneys in macaques and achieve remarkable survival figures. One of the transplanted specimens lived more than two years with the kidney graft. The details of the research are published in the journal Nature.
To minimize the risk of rejection and the possibility of transmission of porcine viruses with the transplant, the researchers made 69 genetic modifications in the donor animal, a Yucatan pig.
These modifications can be grouped into three blocks: first, they eliminated three glycan antigens, ‘markers’ present on the surface of cells that induce immediate rejection. In addition, they introduced changes so that the animal cells expressed seven human genes with the aim of improving tolerance and neutralizing other phenomena associated with hyperacute rejection. And finally, they inactivated all copies of the genetics related to porcine retroviruses.
In combination with immunosuppressive medicationthis genetic engineering cocktail provided survival of up to 758 days to one of the transplanted macaques.
Keys to xenotransplantation
One of the main keys to achieving this prolonged survival was the manipulation to add humanized genes, involved in several pathways related to rejection, such as inflammation, innate immunity or coagulation, as the researchers explained in a press conference. .
In vitro studies, the scientists point out, showed that renal endothelial cells from animals with these genetic edits were capable of modulating inflammation in a manner “indistinguishable” from human endothelial cells. “Our results put us one step ahead in achieving human compatibility,” he stressed. Michael Curtishead of eGenesis at the meeting with the press.
This design and development is a “proof of concept” that “supports progress towards clinical development” of the main candidate that the eGenesis company is designing for kidney transplantation, called OWN-2784the company said in a statement.
For Beatriz Domnguez-Gildirector of the National Transplant Organization (ONT), this design “is a model that provides very promising results.”
Domnguez-Gil highlights the design of genetic modifications that has allowed achieving “prolonged survival in non-human primates.”
But it also emphasizes the fact that development provides “an experimental model that will allow us to advance in the field of xenotransplantation in a much safer way.”
This design allows us to take an important step “in demonstrating that an approach is safe and effective before making the leap to clinical trials.”
From these two perspectives, “it is a very novel and very relevant study,” emphasizes Domnguez-Gil, who also points out that the use of this type of non-human primates as recipients in the experiments can facilitate the subsequent translation of the results to the clinic. “It is a model that is probably more transferable to human reality than those that have been used previously,” she highlights.
A long way to go
In any case, the director of the ONT recalls that “there are still many steps left on this path of bringing xenotransplantation to the clinic.”
There is still a lot of work to be done in the preclinical field, Domnguez-Gil emphasizes. In this sense, the researchers themselves recognize in the scientific journal that the proposed genetic modifications must be refined to achieve clinical results.
But, in addition, we must also address the ethical issues that poses this type of procedures. “Among other things, we have to decide which patient is going to be offered this option versus the alternative; that is, what criteria a patient has to meet to enter a clinical trial of these characteristics when we already have a very consolidated type of transplant between humans, which is an already common clinical reality and which offers extraordinary results,” he points out.
Issues related to the protection of animals must also be addressed, as well as planning how these treatments are going to be achieved. “extraordinarily expensive” can reach patients in an equitable way, says the director of the ONT.
“There are many issues to advance and to take into account, but I believe that In the next 10 years we are going to see an important leap to clinical of this therapeutic option”, concludes Domnguez-Gil.
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