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Possible Unlimited Supply of Islet Cells

Dec 9, 2008

Pig organs: Ready for humans at last? IN THE not too distant future, a person in need of a heart transplant could be offered a pig’s organ. That’s the hope of a group that met in China last week to agree global guidelines for the first clinical trials of “xenotransplants”.

The meeting of clinicians, researchers and regulators in Changsha, Hunan province, which was organized by the World Health Organization, resulted in the so-called Changsha Communiqué – a document that should eventually guide global regulation of xenotransplants.

It sets out principles for research, recommends how the WHO and individual countries should monitor such research, and includes guidelines for trials (see “Trials and transplants”). Perhaps most importantly, with human organs in desperately short supply, it reflects how far research has come since a decade ago, when some of the problems associated with xenotransplants seemed insurmountable.

For example, one big concern related to porcine endogenous retroviruses (PERVs). These are dormant viral DNA present in the pig genome that researchers feared would reawaken in an organ transplanted into humans, who, unlike pigs, might not be able to keep the viruses dormant. Pigs have now been genetically engineered either to lack PERVs entirely or to carry RNA interference molecules primed to sabotage any that become active. “Most of us now agree the risk is quite manageable,” says Megan Sykes of Massachusetts General Hospital in Boston, who attended the meeting.

The first pig tissue to find its way into humans probably won’t be an organ, but insulin-producing islet cells from the pancreas, to treat people with diabetes. Two years ago, Bernard Hering’s team at the University of Minnesota in Minneapolis reported injecting unaltered pig islet cells into the livers of diabetic monkeys, along with immunosuppressive drugs. The monkeys were able to go without insulin injections for the duration of the 100-day experiment (Nature Medicine, vol 12, p 301). Hering is now in discussions with the US Food and Drug Administration (FDA) about how to proceed with a human trial.

David White and his colleagues at the Robarts Institute in London, Ontario, Canada, are also talking to the FDA about a possible trial next year. To make islet cells less likely to be rejected, White mixes them with Sertoli cells from pig testes, which contain a molecule that seems to damp down attacks by human T-cells. White explains that Sertoli cells are equipped with the cellular machinery to protect sperm, which would otherwise be vulnerable to attack by the immune system because they have half the chromosomes of other cells.

Rafael Valdés-González of the Children’s Hospital of Mexico in Mexico City, who first pioneered the Sertoli cell technique, has already tested it in a small number of people and claims that one patient is still insulin-independent as a result (Clinical Transplantation, DOI: 10.1111/j.1399-0012.2007.00648.x).

Also some grounds for optimism come from a handful of trials of pig islet cells in countries where regulation is less tight. In Russia, the New Zealand company LCT claims to have had some success treating five patients with pig islet cells, which they disguised from the immune system by encapsulating them in alginate, a substance from seaweed that allows nutrients and hormones to diffuse in and out but prevents contact with immune cells. Last month, LCT won authorization to begin a trial in New Zealand.

Sykes hopes that success with initial islet trials will bring greater public acceptance of xenotransplantation, leading to the really exciting prospect of transplanting full organs. These naturally pose greater problems, though, mainly because they must be hooked up to a blood supply and so face the full force of the immune system.

Because of the potential success of such experiments, guidelines are essential now. Peter Doyle, a delegate at the meeting and former secretary of the now-defunct UK Xenotransplantion Interim Regulatory Authority says: “Xenotransplantation has the potential to treat millions of people, but the threatened dangers are worrying unless it’s properly regulated globally.”

World Health Organization