Gene-edited pigs may reduce Brazil’s transplant waiting list. Still in its initial stages and presented at FAPESP Week London, a project will assess how patients awaiting kidney transplants react to porcine blood (photo: Brazil's Ministry of Health)
Published on 05/13/2021
By André Julião, in London | Agência FAPESP – The potential to reduce or even eliminate Brazil’s organ transplant waiting list may become a reality through xenotransplantation.
That is what we call the process of cross-species transplantation, in this case, the Sus scrofa domesticus and the Homo sapiens: pig-to-human.
The science behind the initiative is being coordinated by the University of São Paulo's Biosciences Institute (IB-USP), under the auspices of the Human Genome and Stem-Cell Research Center (HUG-CELL), one of the Research, Innovation and Dissemination Centers (RIDCs) funded by FAPESP.
Other institutions associated with the project are the Institute of Advanced Studies of USP and the Immunology Laboratory of the Heart Institute (InCor).
The project is a partnership between pharmaceutical company EMS and FAPESP within the framework of the Research Partnership for Technical Innovation Program (PITE). It is being led by Professor Silvano Raia of the University of São Paulo's School of Medicine (FMUSP). Raia was the first physician to perform a liver transplant using a cadaver donor in Latin America and the first in the world to perform a living donor liver transplant.
The initiative was presented on Day One of FAPESP Week London, which takes place February 11-12, 2019.
“Pig organs are very similar to human organs, but if they were to be transplanted today, they would be rejected. The idea is to modify them so they can be made compatible with the human body,” said Mayana Zatz, a professor at IB-USP and principal investigator of the study, during her session.
Pigs modified for this purpose are being bred now in countries like Germany and the United States, and there have been promising results in organ transplants into primates.
The geneticist explained that three genes that cause rejection are well known. By deactivating these using the gene editing technique known as CRISPR-Cas9, it is possible to cause the human immune system to stop rejecting the organs.
The serum from the blood of these pigs will be tested with the blood of waitlisted kidney transplant patients to determine the presence of antibodies in a Brazilian population that could reject the pig organs.
The specimens are part of the sample collection at the InCor Immunology Laboratory managed by physician Jorge Kalil, a professor at FMUSP and one of the project’s principal investigators. The collection currently holds over 1,000 samples of serum from kidney transplant candidates who have had rejection to human kidneys.
At the same time, Kalil and Professor Maria Rita Passos-Bueno of IB-USP, another researcher on the project, are planning to develop new follow-up protocols for future transplant recipients in order to monitor the emergence of antibodies in the blood that could cause rejection.
Brazil ranks second in terms of absolute number of transplants, behind only the United States. However, the waiting list for organs exceeds the 41,000 registered in 2016. Kidney transplants are what present the biggest discrepancy between the number of patients on the waiting list and the procedures performed: there were 5,592 transplants and 24,914 registered on the waiting list. In 2017, 1,716 patients died while waiting for a kidney.
“It’s about developing a product based on domestic biotechnology, whose ultimate goal will be to provide those people on the transplant waiting list with a viable and lasting therapeutic alternative that can shorten the suffering of patients and their families,” Zatz told Agência FAPESP.
Today, even transplants between humans require transplant recipients to take immunosuppressing medications to fight rejection, some for the rest of their lives. In cases where patients need a kidney transplant, there is also the added cost of dialysis for those who are waiting for a new organ.
The initial phase of the project is expected to last three years and seeks to reconcile the ethical, religious and legal aspects of xenotransplantation by establishing a center for the subject at the Institute of Advanced Studies.
During her session, Zatz presented the most recent findings on the development of organs from stem cells. As part of the PhD work of Ernesto Goulart and the post doc work of Luiz Caires and Luciano Abreu Brito, all of them FAPESP grant recipients, the liver and hepatic artery of rats were created using stem cells from the same animal.
The rat aorta and liver were decellularized, which means all the cells are removed using special acids, leaving only a scaffold of collagen. Human stem cells were then placed in these scaffolds and reprogrammed into hepatic and aorta cells, creating new organs.
In the future, this may be a solution for those who need organ transplants. Since they are performed using the patient’s own cells, the body will not reject them.
Zatz presented other possibilities for the use of genetics for healthy aging, such as P4 Medicine (predictive, preventative, personalized and participatory). By analyzing a patient’s genetic profile, it is possible to determine which diseases a person may come to develop. That will enable disease prevention and even participation in medical treatments.
“From studies on thousands of people throughout the world with diseases, compared with healthy people, we are able to derive what we call polygenic risks scores, which signify the increased risks for diseases such as diabetes, heart problems, hypertension, and cancer. While these diseases depend largely on genes, they also depend on the environment,” Zatz explained.
The researcher also presented the 80+ project, which sequenced the genome of 1,324 people over the age of 60 in an effort to understand what those who remained healthy after age 80, or even after age 100, have that is different and perhaps could be applied to the population as a whole. There are nearly 500,000 people in the world over the age of 100 alive today.
Read more about FAPESP Week London at: www.fapesp.br/week2019/london/.