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Advance in Pig Cloning May Help Transplants

Scientists knock out a gene that triggers immune problems

THURSDAY, Jan. 3, 2002 (HealthDayNews) -- This little piggy might one day get a kinder greeting from your immune system.

Independent teams of scientists in the United States and Europe say they've cloned pigs whose cells are at least halfway toward being less threatening to the human immune system when transplanted.

The work, reported separately, involves "knock-out" technology in which researchers deleted one copy of a gene from the animals' portfolio of proteins -- in this case, one that produces a cell surface sugar that shouts "I'm a pig!" to human immune agents. Eliminating the second copy of the gene could send up a white flag to a graft recipient's immune cells and make them more likely to accept the tissue.

"I think that this is the first step in solving one of the major hurdles in xenotransplantation," says Dr. Laurence Turka, a University of Pennsylvania kidney specialist and president of the American Society of Transplantation. Xenotransplantation is the science of grafting animal organs and tissues into human patients.

Nearly 80,000 Americans are currently on waiting lists for organ transplants, according to the United Network for Organ Sharing. In 2000, doctors in this country performed roughly 23,000 transplants.

Pigs are considered a prime and potentially inexhaustible source of organ and tissue transplants, and their cells have already been used to produce insulin in diabetics and repair brain damage in patients with Parkinson's disease. However, patients must take a lifetime of immune-suppressing drugs to prevent rejection of human organ transplants, and this problem looms even larger when the tissue comes from a different species.

In one study, reported today in the online issue of the journal Science, researchers at the University of Missouri-Columbia and their colleagues at Immerge BioTherapeutics Inc. say they've created a litter of four piglets missing a copy of the gene for alpha-1,3-galactosyltransferase (GGTA1). This enzyme tacks a sugar molecule onto every pig cell surface that becomes a scarlet letter to human immune cells.

Randall Prather, a University of Missouri cloning specialist who collaborated on the work, says his group used nuclear transfer technology to place genetic material from fetal pig cells into embryos stripped of their own instructions. Before the switch, one copy of GGTA1 was taken out of the original cell genome.

Prather's team created about 3,000 embryos, and implanted 28 into sows, who ultimately gave birth to seven piglets. Two died immediately, and a third died of a heart anomaly after less than a month. Prather says the success rate of the cloning procedure was somewhat lower than usual because the gene deletion forced him to use relatively old cells. "We have a number of things we're thinking about" to make the process more efficient, he says.

Julia Greenstein, president and chief executive officer of Immerge, says the miniature swine -- which at 300 pounds fully grown are hardly petite -- offer at least two advantages over the common hogs that can weigh three times as much or more.

For starters, unlike larger swine, this sub-species of miniature pigs she and her colleagues work on doesn't seem to carry a virus believed to pose an infection threat to tissue recipients. What's more, their organs are smaller, and thus more likely to be a good fit for a human patient.

"When you start thinking about heart transplants, it's very important to match the size of the donor and recipient," Greenstein says.

Greenstein's company now plans to engineer miniature swine that are missing both copies of GGTA1, either through more cloning or simple breeding. Once they have created GGTA1-free animals, they'll then try to transplant their tissue and organs into primates, and eventually people.

In an identical but unrelated finding, scientists at PPL Therapeutics, of England and Blacksburg, Va., this week announced the results of their own version of the cloning experiment. The work hasn't undergone peer review, nor has it been published in a research journal.

David Ayares, chief operating officer and vice president for research at the company, which announced its results in a press release, says five female piglets were born on Christmas. Each of the animals carries identical genes, but are lacking one copy of GGTA1.

"This is the key sugar that's recognized by the human immune system," Ayares says.

PPL hopes to test grafts of the cloned animals' tissue in primates within about two years, Ayares says, most likely starting with insulin-producing cells from the pancreas. Similar work in humans could begin two years after that, he says.

Although eliminating GGTA1 should help stop rejection of pig grafts, it won't eliminate the need for prolonged immune suppression, Ayares says.

"We are trying to get to the point where these organs will be like a human organ," which still makes the immune system bristle, he explains.

Dr. Massimo Trucco, a transplant expert at the University of Pittsburgh whose group has been studying this approach, says the technique is "not a solution" to the problem of immune reactivity.

"Just removing this gene takes care of the fulminant reaction, but theoretically you have to knock out three or four genes" to make the graft completely transparent, Trucco says.

What To Do

To find out more about cloning, try the Roslin Institute, home of Dolly the ewe, the first clone.

For more on xenotransplantation, check out the U.S. Food and Drug Administration or the Cleveland Clinic.

SOURCES: Interviews with Laurence Turka, M.D., professor of medicine, chief of the renal division, University of Pennsylvania, Philadelphia, and president, American Society of Transplantation; Julia Greenstein, Ph.D., president and chief executive officer, Immerge BioTherapeutics Inc., Charlestown, Mass.; Randall Prather, Ph.D., professor, reproductive biotechnology, University of Missouri-Columbia; Massimo Trucco, M.D., professor of pediatrics, University of Pittsburgh, Pittsburgh; David Ayares, Ph.D., chief operating officer, vice president, research, PPL Therapeutics, Blacksburg, Va.; Jan. 3, 2002, Sciencexpress
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