Another big medical outlet in the future: “complete pig matching”?

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93cc1a62ad42135 - Another big medical outlet in the future: "complete pig matching"?

after 30 years of searching, scientists finally bred a perfect kidney donor pig

in the past, in most situations, a patient who needed organ transplantation could only wait, and only a very small number of lucky people could wait and transplant successfully

in the 1990s, xenotransplantation research with pig organs as the main target donors has appeared in the industry. From the beginning, it was sought after by people, and later faced technical difficulties, and was banned by who because of ethical problems. In recent years, with the progress of genetic technology, the “genetically modified pig” has become more suitable for organ culture. The experiment of New York University also proves that xenotransplantation may usher in a period of rapid development after 20 years

“complete piglets” may be another major medical outlet in the future

“no rejection reaction yet”

the recipient was a brain dead patient with signs of renal insufficiency. After negotiation, the family agreed to participate in the trial before removing the life support instrument

the transplanted kidney comes from a pig developed by revivicor, a subsidiary of United therapeutics, which scientists intend to change the genome – galsafe pig. After gene editing, knockout can catalyze cell surface expression in pigs α- Galactose( α- Gal), a gene of sugar molecule that may induce human rejection

Robert Montgomery, a surgeon at the Langer medical center of New York University School of medicine, connected the pig kidney to the blood vessels of the patient’s legs outside the abdomen. The new kidney is attached to the blood vessels of the patient’s legs and kept outside the body. It is covered with a protective cover for observation and renal tissue sampling

54 hours later, there was no rejection of the receptor immune system. The researchers removed the subjects’ ventilator, marking the end of the experiment

this operation uses a model collectively referred to as in vivo perfusion. Montgomery said that the function of pig kidney seems quite normal. It produces the same amount of urine as expected by human kidney transplantation. The patient’s original abnormal creatinine level (an index for evaluating renal function) returned to normal after pig kidney transplantation. “The kidneys from the dead often take days to weeks to take effect, and the pig kidney takes effect immediately.”

experts are very excited about this. “The waiting list for organ donation may become quite short immediately.”

usually, immune rejection caused by xenotransplantation occurs at the junction of human blood supply and organs, But it did not appear in this operation

however, after the initial success of this experiment, some complex key problems still need to be solved. Although the kidney of gene editing pigs did not cause hyperacute rejection (rejection within 48 hours of organ transplantation), it is not known whether it will produce accelerated rejection (48 hours to 5 days), acute rejection (more than 1 week) and chronic rejection

in addition, the current gene editing pigs only knock out the genes that can catalyze galactose molecules, but there are many substances that may potentially trigger human immune rejection and microorganisms that may cause human diseases, such as viruses unique to pigs

of course, the initial success of this experiment still brings a lot of hope. In the current situation of insufficient human kidney supply, such pig kidney may be used to treat patients with acute renal failure and maintain their life in a short time until available human kidney appears, or the pig kidney can be retained in the body as a permanent graft. Dr. Montgomery said that genetically engineered pigs “may become a sustainable and renewable source of organs”

at present, the shortage of human organs is a worldwide problem. About 2 million people worldwide need organ transplantation to treat diseases every year, but the ratio of organ donors to recipients is less than 1:20

the average waiting time for kidney transplantation is three to five years, and 40% of patients waiting for transplantation may die within five years. According to the United organ sharing network, nearly 107000 people in the United States are waiting for organ transplantation, of which more than 90000 are waiting for kidney transplantation. According to China organ transplantation development report (2019), by the end of 2019, there were still 47382 people waiting for kidney transplantation in China

Huang Jiefu, President of China organ transplantation development foundation, pointed out in 2020 that at present, there are about 300000 patients waiting for organ transplantation due to end-stage organ failure in China every year, but the number of organ transplantation is only about 20000 every year

“12 years of stagnation”

xenotransplantation refers to the transplantation of tissue from one species into another. Unlike allografts, xenografts are unlikely to succeed. There are great differences between different species. The immune system responsible for tissue rejection can easily identify foreign tissue and strongly reject it

compared with primates with higher similarity to humans, pigs have more litter and grow faster, so the maintenance cost is low and it is not easy to cause ethical problems. Moreover, pig organs and human organs are very similar in size and function. Considering all aspects, pigs have a huge application space in human organ transplantation

however, the clinical application of pig organ transplantation to human body is difficult due to the safety problems such as innate immunity, inflammatory reaction, coagulation system disorder and the harm of virus carried by pig organs

scientists have found that the main reason for rejection caused by pig organ transplantation is that natural antibodies in human body can recognize the surface of pig cells α- Galactosidase( α- gal)、 β- Galactosidase( β- Gal) and N-acetylneuraminate hydroxylase (Neu5Gc protein), which are catalyzed by GGTA1, b4galnt2 and CMAH genes, respectively. Only when all the above three genes are knocked out can there be almost no major rejection after pig organ transplantation to human body, which has the basis for entering clinical trials

the kidney used in this operation was obtained by knocking out the pig gene encoding sugar molecules

Another big medical outlet in the future: “complete pig matching”?

experimental logic of transgenic pigs, source: revivicor

in the 1990s, pig organ transplantation project was once sought after all over the world. Major pharmaceutical manufacturers and enterprises were committed to developing drugs free of rejection, but, Transplantation of pig organs into the human body will not only produce immune rejection, but also the retroviral sequence contained in the pig gene has potential risks to humans. Therefore, the World Health Organization has ordered to stop all clinical trials of xenogeneic organs before finding a solution

in 2000, the international heart and lung transplantation Association proposed that once 60% of primates transplanted with pig heart can survive for 3 months and there are at least some signs that they can survive longer, they should consider experimenting with pig heart in humans

in 2018, a report in nature pointed out that the genetically edited pig heart survived 195 days after being transplanted into baboons. German scientists selected the hearts of young pigs, genetically modified pigs, and transplanted them into five baboons whose blood pressure fell to the same level as that of pigs. The successful operation means that humans may be able to carry out such organ transplantation experiments

Yang Luhan is the co-founder and chief scientist of egenesis. During her postdoctoral study at Harvard University, she and her mentor George church pioneered the method of modifying the pig cell genome using cripsr-cas9 technology, and began the work of eliminating possible pathogenic genes in the pig genome in 2014

she said, “the xenotransplantation industry has suffered a heavy blow and experienced 12 years of stagnation due to the inability to predict when and how to solve these problems.” in September 2020, the paper published by Yang Luhan’s team in natural biomedical engineering showed that the third generation gene editing pig (“pig 3.0”) developed by his team had been successful, Pig 3.0 not only made a breakthrough in immune rejection, but also knocked out endogenous retrovirus (PERV). Pig 3.0 cells have stronger compatibility with human coagulation system, reduce the risk of coagulation and prolong the life of transplanted organs.

in December 2020, xenotransplantation ushered in a new chapter. The U.S. Food and Drug Administration (FDA) The first transgenic pig that can be used for human food consumption and as a potential source of therapy has been approved for marketing, that is, galsafe pig developed by revivicor.

that is, the donor pig of kidney used in this operation.

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xenotransplantation companies with publicly available information all over the world The total number is not large.

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egenesis, as a sister company of qihan biology, is one of the most well-known companies. In March this year, the company announced that it had completed a round C financing of US $125 million to promote major projects in kidney and islet cell transplantation and optimize Existing gene editing platform and GMP plant. The company is creating three kinds of pig models and testing the effectiveness and safety of genetically engineered organs. It is expected that clinical trials will begin in 2022.

the pigs with pig kidneys used in surgery are genetically engineered by revivicor. Revivicor is one of the few companies in the United States committed to developing pig organs for transplantation One of the biotechnology companies implanted in humans. Last December, the FDA approved the genetic modification of revivicor pigs, which can be used in human food and drug manufacturing. At present, the company has more than 100 genetically modified pigs for transplantation experiments and other drug research.

miromatrix medical, which focuses on human xenotransplantation using pig organs, was established in June this year Listed on Nasdaq, it has become the first listed xenotransplantation company. It is expected that by the end of 2022, the company will start human clinical trials on its bioengineering liver with the support of external liver assist system. The company has developed perfusion acellular and re cellular methods, which can transform waste pig organs into transplantable human organs.

domestic aspects , zhongkeoge Biotechnology Co., Ltd., positioned as the “future organ factory”, is cultivating more than 10 kinds of genetically modified humanized pigs through gene editing and cloning technology for xenotransplantation research and development to solve the shortage of clinical transplanted organs. In September this year, the company has completed a round of financing of 45 million yuan and is currently preparing to build an ultra clean pig facility (DPF) Medical grade xenograft medical donor base is being prepared for clinical trials.

bio is committed to the breakthrough of medical technology for xenotransplantation for diabetes. It extracts pancreas from the donor pig and prepares pig islet cell biological agent, and transplants into the specific part of the body (mainly liver). To reconstruct a more complete islet system for diabetics, for type 1 diabetes, insulin dependent type 2 diabetes, and pancreatic resection for various reasons.