“Eyeing Organs for Human Transplants, Companies Unveil the Most Extensively Gene-Edited Pigs Yet”, 2019-12-19 (; backlinks; similar):
If any swine is fit to be an organ donor for people, then the dozens of pigs snuffling around Qihan Bio’s facility in Hangzhou, China, may be the best candidates so far. The Chinese company and its US collaborators reported today that they have used the genome editor CRISPR to create the most extensively genetically engineered pigs to date—animals whose tissues, the researchers say, finally combine all the features necessary for a safe and successful transplant into humans. “This is the first prototype”, says Luhan Yang, a geneticist at Qihan Bio. In a preprint published today on bioRxiv, Qihan researchers and collaborators, including Cambridge, Massachusetts-based eGenesis—which Yang co-founded with Harvard University geneticist George Church—described the new generation of animals and various tests on their cells; the researchers have already begun to transplant the pigs’ organs into nonhuman primates, a key step toward human trials.
…In the new study, the team for the first time combined these PERV “knockouts” with a suite of other changes to prevent immune rejection, for a record-setting 13 modified genes. In pig ear cells, they removed three genes coding for enzymes that help produce molecules on pig cells that provoke an immune response. They also inserted six genes that inhibit various aspects of the human immune response and three more that help regulate blood coagulation. The researchers then put the DNA-containing nuclei of these edited cells into eggs from pig ovaries collected at a slaughterhouse. These eggs developed into embryos that were implanted into surrogate mothers. Cells from the resulting piglets got another round of edits to remove the PERV sequences, after which their DNA went into another set of egg cells to create a new generation of pigs with all the desired edits. (In future, Yang says, the team will try to make all the modifications in a single generation.)
The resulting pigs appeared healthy and fertile with functioning organs, the team reports today. And initial tests of their cells in lab dishes suggest their organs will be much less prone to immune rejection than those of unmodified pigs: The tendency of the pig cells to bind to certain human antibodies was reduced by 90%, and the modified cells better survived interactions with human immune cells. But a key test is still to come: Yang says her team has begun to transplant organs from the highly edited pigs into monkeys to gauge their safety and longevity.
The combination of edits described in the new paper is “a technical feat”, says Marilia Cascalho, a transplant immunologist at the University of Michigan in Ann Arbor. “Whether it offers an advantage [over other engineered pig organs]… the jury is out on that”, she says…Yang says that Qihan plans to remain “laser-focused” on preclinical studies in 2020, but expects to be testing pig organs in humans within 5 years. Many in the field now feel an inevitable momentum around xenotransplantation: “There is so much need for organs”, Cascalho says. “I think it’s going to be a reality.”