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NS 28 Aug 99

Heartening TRANSPLANTS of pig organs into human patients have edged closer following reassuring results from a longawaited safety study. Patients treated with live pig tissue showed no signs of infection with porcine endogenous retroviruses (PERVS) Some doctors worried that the viruses might spread to people causing new infec tious diseases. "Overall, we think the study is very good news," says Corinne Savill of lmutran, the Cambridge-based company developing pig hearts and kidneys for "xenotransplantation". Patients have routinely received pig heart valves since 1964, but these contain no live cells. Transplanted organs would still contain live pig cells potentially capable of transmitting viruses. To discover whether live pig tissue poses a threat, researchers from lmutran trawled the world for patients who had been treated with live pig tissue. Of the 160 patients they identified, 131 had undergone operations in which their blood had temporarily circulated through live pig tissue. A total of 14 patients were exposed to pig tissue for a year or more when they were given pig pancreatic islet cells, which manufacture insulin. Another 15 received grafts of pig skin that were in place for more than a week. Kaz Parades of lmutran and his colleagues report no traces of PERV infection in any of the 160 patients (Science, vol 285, p 1236). One unexpected finding, however, was the survival of pig cells in 23 patients, one of whom was treated more than eight years ago. Savill says that the first xenotransplants are probably between two and five years away. Opponents of xenotransplantation are less reassured by the results, however. "They provide only limited confidence," says Gill Langley, scientific adviser to the Dr Hadwen Trust for Humane Research, which is opposed to animal experiments. "it only takes one instance to create a disaster," she says. Andy Coghlan

NS 4 Sept 99

WITHIN a few years, the first human will have his or her dying heart or kidney replaced with a healthy one from a pigtransplant scientists are sure of it. But even if the pioneering surgery buys the patient a longer life, it could be at a price. Quite apart from having to take drugs to stop their bodies rejecting the foreign organ, patients may face social exile as a precondition for treatment. No more sex, at least for a year or two. No babies once the sex curfew has been lifted. No visits to anyone other than close family and friends. And an indefinite ban on social outings. Too far-fetched to be true? Senior figures in key agencies such as the US Food and Drug Administration (FDA) don't think so. Such a scenario could form part of their plans to ensure that recipients of pig organs don't unleash dangerous new viruses on an unsuspecting world. The high levels of immune suppression required to prevent rejection may actually ease transmission of pig viruses. And these fears persist in spite of new findings which suggest that transplant patients will be safe from such viruses. Kaz Paradis and his team at Imutran, the Cambridge-based company developing pig hearts and kidneys for transplant, screened tissue samples from 160 patients around the world treated with live pig tissue. Blood from 131 had been filtered through live pig tissue during operations. The remaining 29 had received grafts of pig tissue. Despite earlier experiments when such viruses infected human cells in the lab, Paradis's team found no evidence that porcine endogenous retroviruses (PERVS) had infected any of the patients (New Scientist, 21 August, p 20). Corinne Savill, chief executive officer of Imutran, a subsidiary of the Basel-based pharmaceuticals giant Novartis, says the first organs could be transplanted within two years.

Protecting the public

The company is now experimenting with primates to fine-tune the lifelong drug regimes transplant patients would need to prevent rejection of their pig organs. Providing Imutran gains regulatory approval, human trials could begin on a group of around 10 patients, probably in Canada. But despite Imutran's optimism, independent experts such as Jonathan Stoye, who studies pig viruses at Britain's National Institute of Medical Research in Mill Hill, London, say public safety is far from assured. Stoye concedes that studies so far suggest that the risks PERVs pose are unlikely to outweigh the benefits for a transplant patient. "But the question about broader risks to the general population remains unanswered," he says. Even Imutran acknowledges this possibility. "The concern people have raised is not the safety of the recipient," says Savill. "It's whether there's a possibility of transmission." Regulatory agencies around the world are already developing guidelines on how to quarantine pioneers who receive the first transplants. A working group set up by the LJK Xenotransplantation Interim Regulatory Authority (XIRA)-which vets applications for xenotransplant trials-has prepared a confidential draft report on monitoring and surveillance for patients. In the US, federal agencies that oversee transplants are revising their guidelines to accommodate the first recipients of xenotransplants, Philip Noguchi, director of the FDA's division of cellular and gene therapies told New Scientist. "We understand those concerns [about viral infections] and intend to address them," he says. "We must know the status of patients after they've undergone transplants." Two years ago, 10 patients waiting for transplants at Northwestern University Medical School in Chicago were about to be hooked up to pig livers for short periods (New Scientist, 18 October 1997, p 4) . But the FDA pulled the plug at the last moment as fears about PERVs mounted.

Even if "quarantine" regulations are agreed, enforcing them could prove very tough. Stoye's greatest fear is that if the treatments fail, patients will see no reason to stick to the rules and go AWOL. "It's a very difficult issue, and there's no law that would allow [compulsory isolation] of recipients or anyone else they infect," says Stoye. 'Any participation in a clinical trial is purely voluntary, so if you say you must follow these people indefinitely, and this is an absolute requirement of the treatment, you have a real problem," he says. People who currently receive human organ transplants are not supposed to give blood, and Stoye expects the same rule to apply to recipients of xenografts. "But you can't force people not to have sex, or sterilise people-these are not on," he says. Savill says the XIRA has invited Imutran to discuss the issue. "You would do testing at fairly regular intervals, and for the first recipients, you would not advise having any children until more is known about the therapy. But that's a condition of many new treatments," she says. Even before patients get near the operating table, Imutran has problems of a more practical nature to overcome. The most pressing task facing Savill and her colleagues is finding the right mix of powerful drugs to prevent patients' immune systems destroying their new organs. Xenografts present a special problem. Not only do they have to contend with T cells, like a new human organ, but they are also a target for antibodies made by B cells. This means dampening down not just one but two arms of the immune system to prevent vascular rejection. The company hopes that a new class of drugs currently under development called macrolides will do the trick, since they dampen both responses. But critics of xenotransplants say that this high level of immunosuppression could make it easier for pig viruses to infect human cells. Proponents of xenotransplantation point to encouraging data emerging from other trials that involve small implants of animal tissue or other limited exposure (New Scientist, 8 August 1998, p4). Diacrin of Charlestown, Massachusetts, for example, has had some success implanting brain cells from pig fetuses into the brains of patients with Parkinson's disease and Huntington's disease. Circe Biomedical of Lexington, Massachusetts, continues to successfully cleanse the blood of patients with liver failure by passing it through a device containing pig liver cells. The absence of PERV transmission in these experiments will reassure advocates of xenotransplantation.

Desperate need

But Gill Langley of the Hadwen Trust for Humane Research in Hitchin, Hertfordshire, believes replacing an entire organ will be far more risky than anyfl-ting tried so far. "The organ is expected to reside in intimate contact with the patient's tissues and blood for months or years at a time," she says. However, because organs are so desperately needed, Stoye does support trials of complete pig organ transplants at some stagealbeit extremely cautious ones. While individuals in desperate need of a transplant stand to gain, the theoretical risk of a public health disaster cannot be discounted. So why risk xenotransplants when emerging stem cell technology could create substitute organs from a patient's own cells? Some researchers hope these cells, which have the potential to become "customised organs", will one day provide an inexhaustible supply of human organs that will do away with the need for immunosuppressive drugs. "Under perfect circumstances, I would want to use human organs, but that's science fiction," says Jon Allen, a virologist at the Southwest Foundation for Biomedical Research in San Antonio, Texas. "There's a much greater chance that xenotransplantation may fill that niche for the next 10 years." For now at least, we may have to tolerate a degree of human quarantine if we want to save the lives of people with failing organs, as well as safeguarding the health of everyone else. Andy Coghlan