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Cloned Knockout Mini-pigs Hold Potential for Organ Xenotransplantation

By deleting the immunogenic alpha-1,3-galactosyltransferase (GGTA1) gene in cloned miniature swine, researchers in the US and Korea appear to have moved closer to making animal-to-human organ transplantation a reality.

“This [homozygous] alteration in the gene structure will likely be enough to inhibit the initial immune response, what is called hyperacute rejection, when pig organs are transplanted into humans,” Dr. Randall S. Prather, of the University of Missouri at Columbia, told Reuters Health. “It’s likely there are other molecules that will have to be altered after that [to maintain long-term survival.]”

Dr. Prather and associates obtained donor cells from fetal pigs. A gene trap targeting vector was used to replace one allele of the GGTA1 locus. The investigators performed nuclear transfer from cloned donor cells into matured oocytes, which were then grown in surrogate mothers.

Seven nuclear transfer-derived piglets were delivered by cesarean section, the investigators report online in the journal Science at the Science Express web site. Two died immediately from respiratory distress syndrome, and a third at day 17 from a cardiac defect.

Among the four surviving piglets, mild deformities appeared–flexure tendon deformities, an ocular defect, small ear flaps, and cleft palate. “We think that most of the abnormalities are the result of the nuclear transfer and that they won’t be passed on to future generations,” Dr. Prather told Reuters Health.

The next challenge the researchers hope to address, according to Dr. Julia L. Greenstein, “is to get the full knockout, because right now we just have one of the two alleles inactivated. We’ll do this either by breeding or by further genetic modification.”

Dr. Greenstein is President and CEO of Immerge BioTherapeutics Inc., in Charlestown, Massachusetts, which is working in collaboration with the University of Missouri at Columbia. In an interview with Reuters Health, she said that once homozygous knockouts have been generated, “then we will use those animals as donors for preclinical models, which mostly involve transplantation into primates.”

“At that point we’ll address what change we’ve made to the biology of rejection,” she added. She noted that the miniature pig is a good candidate for xenotransplantation into humans because their organ size is appropriate for human recipients, and this particular line of pigs does not transmit porcine endogenous retrovirus to human cells in culture.

“We’re hopeful that by putting this together with our tolerance-inducing technology, we’ll get long-term survival of pig organs in nonhuman primates, which will then lead to early clinical trials,” Dr. Greenstein continued. She hopes that this will take no more than a few years.

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