In the past 30 years, with the rise of gene editing and other technologies, great progress has been made in the preclinical research of xenotransplantation. Through gene transformation technology, the problems of hyperacute rejection and coagulation disorder faced by xenotransplantation have been basically overcome.
——Pan Dengke, deputy head of xenotransplantation group of organ transplantation credit association of Chinese Medical Association and deputy director of organ transplantation research institute of Sichuan Provincial People's Hospital
On January 20 local time, the American Journal of transplantation published a paper by researchers from Alabama State University, revealing that they successfully completed the trial of transplanting a pair of genetically edited pig kidneys to a brain dead patient in September last year. This is also the second known case of pig kidney allogeneic transplantation.
On January 7 local time, the surgical team of the University of Maryland School of medicine successfully transplanted the heart of a genetically modified pig into a 57 year old male patient with heart failure. This is the first operation in the world to transplant transgenic pig heart into human body.
On January 15, Professor Wu Zhongjun, director of the artificial organ Laboratory of the University of Maryland, revealed that the patient had left the support of extracorporeal membrane lung oxygenation (artificial lung) and began to walk on the ground.
Xenotransplantation has been tried many times
Pan Dengke, deputy head of the xenotransplantation group of the organ transplantation credit association of the Chinese Medical Association and deputy director of the organ transplantation Institute of the Sichuan Academy of Medical Sciences and the Sichuan Provincial People's Hospital, said that humans had begun to try xenotransplantation a long time ago. In the 1980s, American doctors transplanted a baboon's heart for an infant unfortunately suffering from congenital heart disease, However, due to acute immune rejection, the child's life lasted less than a month.
However, the pig heart accepted by patients with heart failure this time has been genetically modified. The researchers edited 10 genes of pigs providing heart, knocked out three genes related to immune rejection and one gene related to excessive growth of pig heart tissue, and inserted six genes related to immune, coagulation and inflammation regulation. In addition, a newly developed immunosuppressant anti-CD40 antibody was used to prevent rejection of xenotransplantation. There was no hyperacute immune rejection after transplantation, and the patient was in good condition after operation.
Prior to gene editing pig heart transplantation, scientists have completed key tests on the safety and effectiveness of gene editing organ transplantation into monkeys.
From October to December last year, the langney health center of New York University successfully transplanted the genetically edited pig kidney to brain death cases twice, without hyperacute rejection, and the renal function was normal within 54 hours.
In October 2019, the Massachusetts General Hospital team of Harvard Medical School successfully used genetically engineered pig skin to cover human burn wounds. This is the first clinical trial of non-human organ transplantation approved by the U.S. Food and Drug Administration (FDA). It is also the first successful attempt to transplant gene edited animal tissue directly into human wounds.
At present, the longest survival time of pig organ transplant recipients is 557 days for orthotopic kidney, 195 days for orthotopic heart and 945 days for ectopic heart.
At present, only the "first step of the long march" has been taken
Pandenko believes that whether the donor comes from pigs, baboons or others, xenotransplantation must overcome three major problems, namely immune rejection, coagulation dysfunction and biosafety.
Among them, immune rejection includes hyperacute, acute and cellular immune rejection, which is the main problem faced by xenotransplantation. Pandenko said that in the past 30 years, with the rise of gene editing and other technologies, great progress has been made in the preclinical research of xenotransplantation, and the problems of hyperacute rejection and coagulation disorder faced by xenotransplantation have been basically overcome through genetic transformation technology. In addition, the development of immunosuppressants has greatly promoted the development of xenotransplantation.
"Biosafety mainly refers to the risk of cross infection between species, such as disease transmission and endogenous retrovirus infection, which is also a difficult problem that must be solved in xenotransplantation." Pan Dengke said that pigs carrying pathogens that may cause human infection include Campylobacter, Salmonella typhimurium, and Yersinia pestis, including viruses such as circovirus, porcine cytomegalovirus, swine retrovirus and so on.
In view of the biosafety of transplanted organs, the donor pigs can be purified by using the barrier environment and caesarean section. In addition, gene editing technology can also be used to remove porcine endogenous virus.
In 2017, Professor Yang Luhan of Harvard University and her team completed the knockout of porcine endogenous retrovirus related enzyme genes by using gene scissors technology through endogenous gene editing method, and successfully cloned "pig 2.0" without endogenous virus.
"Although great progress has been made in the research of xenotransplantation, the functional compatibility of transplanted organs has become a problem to be solved. Whether the transplanted pig organs can give full play to the functions of the original human organs to maintain hormone secretion and metabolic balance remains to be tested." Yang Luhan said that solving the risk of xenovirus transmission and immune compatibility of donor pigs is only the "first step of the long march". At present, we still need to constantly explore and improve the functional compatibility of xenograft organs.
Xenotransplantation in China is ready
In the field of xenotransplantation, although the leading enterprises are mainly American enterprises, Chinese enterprises are also gaining momentum. At present, domestic enterprises engaged in xenotransplantation research mainly include sinobio and zhongkeoge.
On August 9, 2005, International Online reported that China's first cloned pig was born, and pandenko participated in the cultivation of this cloned pig. In November 2010, the scientific research team of Beijing Institute of animal husbandry and veterinary medicine, Chinese Academy of Agricultural Sciences successfully bred four genetically modified pigs suitable for human organ transplantation. Pandenko said that these four pigs are the first organ transplant pigs in China to eliminate hyperacute immune rejection genes. In 2018, the Chinese Academy of Agricultural Sciences transferred more than 10 years of scientific research achievements - the core technology of genetically modified pig research and development and gene editing pig population to zhongkeoge, transforming laboratory technology into industrial technology.
Pandenko introduced that in the research of gene editing pig organ transplantation to non-human primates, China has adopted the human clinical immunosuppression scheme and carried out in-depth immune basic research of xenotransplantation.
At present, xenotransplantation is mainly experimental treatment when no other methods are available. With the rapid development of this field in China, the approval, supervision and ethical system of xenotransplantation need to be established urgently. (reporter Wu Chun, correspondent Wang Xiaoxiao of Xinluo Chaoshu)