BioWorld International Correspondent
LONDON - PPL Therapeutics plc laid claim to the world’s first cloned knockout pigs with the birth of five cloned piglets, genetically engineered to make the organs of their offspring suitable for xenotransplantation.
The piglets, all females, all are missing one of their two copies of the alpha 1,3 galactosyl transferase (GT) gene that is responsible for expressing an enzyme that generates the sugar 1,3-galactase, on the surface of pig cells. It is this sugar that is recognized by the human immune system as foreign, and would trigger hyperacute rejection of transplanted pig organs.
Research Director Alan Colman told BioWorld International, “This is a huge advance. With one of the major technical hurdles and scientific risks overcome, the promise of xenotransplantation is now a reality, with the potential to revolutionize the transplant industry.”
Because they have one copy of the GT gene, the female pigs still generate 1,3-galactase. A litter of male piglets with the same gene knockout is expected to be born soon, and when mature the pigs will be crossbred with the aim of producing offspring with no GT gene. It is not known yet if pigs with no GT gene are viable.
In addition to overcoming early hyperacute rejection, PPL, based in Edinburgh, Scotland, has shown proof of concept and has patents on methods of avoiding other aspects of rejection, including delayed rejection, coagulopathy and chronic T-cell-mediated rejection. The company said the GT knockout pigs will provide a platform for adding up to three more genes.
However, PPL is short of money and is looking to spin out the xenotransplantation program.
“It is an expensive program that will need £20 million (US$28.8 million) for the next three to four years,” Colman said. “We tried to spin it out two years ago and were unsuccessful, and we feel if we can’t do it with this latest news we can’t do it at all.” PPL wants to set up an independent company in which it will retain a stake. It expects the first application of the xenotransplantation technology to be in the production of insulin-producing islet cells for the treatment of diabetes.
PPL’s cloned knockout piglets were born at the company’s U.S. subsidiary in Blacksburg, Va., on Dec. 25. PPL announced their arrival by press release last Wednesday, thus scooping Immerge BioTherapeutics Inc., of Charlestown, Mass., which announced the birth of cloned piglets with the same gene knockout in the journal Science a day later. However, Immerge’s piglets were born in September.
Colman defended the decision to announce the birth of the piglets by press release, rather than in a journal. This has been company policy ever since PPL was reprimanded by investors for not informing them of the commercially significant news of the arrival of Dolly, the cloned sheep, before publishing the paper in Nature. Nature’s embargo on publicizing Dolly’s birth was broken by the UK newspaper, The Observer. Colman expects a paper on its GT pigs to be published shortly.
It was also announced last week that Dolly has developed arthritis. This has raised the fears that as a clone produced from adult cells, Dolly is prematurely aging. Colman said it was not clear if the condition is linked to this fact. “Dolly is middle-aged, I m middle-aged. Dolly has an arthritic hip, I have an arthritic hip. It is relevant to avoid hypocrisy here: Most sheep don t live long enough to get arthritis because they are on the platter.”
Even if a link is established there are no commercial implications for PPL’s major program of producing therapeutic proteins in the milk of transgenic animals. “Obviously,” Colman said, “we don t want to breed animals with health problems, but we are not interested in the founder animals; the founders are the means to producing offspring with the genetic profile we want. Dolly has had six lambs without problems, and we have seen no problems in offspring produced by normal breeding.”