Xeno hopes raised by LCT study

A study of 18 type 1 diabetes patients transplanted with insulin-secreting pancreatic islet cells from pigs more than a decade ago appears to have cleared away a major obstacle to transplanting pig cells, tissues and organs into seriously ill human patients.

A report in the November issue of the Journal of Clinical Microbiology (JCM) has detected no trace of endogenous pig retroviruses, which posed a hypothetical risk to patients' health.

That hypothetic risk led Western health authorities to impose a moratorium on the procedure in 1996, out of concern that patients infected by porcine endogenous retroviruses (PERVs) could ignite a global pandemic of an AIDS-like retroviral disease.

The JCM</> paper reports that sensitive virus-detection tests have detected no trace of PERVs in the tissues of the original patients, nor any trace of non-integrating viruses commonly found in pig tissues.

The findings have boosted the commercial prospects of New Zealand medical biotechnology company Life Sciences Technologies (ASX:LCT), which developed the revolutionary xenotransplantation technology used in the patients.

Eminent NZ diabetes expert Prof Robert Elliott, who founded the company -- originally known as Diatranz -- in 1987, developed a technique for encapsulating insulin-secreting islet cells in an extremely pure alginate polymer, as an experimental treatment for type 1 diabetes.

Type 1 diabetics lose their ability to secrete insulin, to modulate their blood-glucose levels, when an auto-immune attack destroys their own islet cells. Elliott devised the therapy as a potentially permanent remedy, and an alternative to daily insulin injections of human insulin. Before researchers produced human insulin from genetically modified cells in the early 1980s, type 1 diabetics relied on porcine insulin extracted from pigs.

The alginate membrane developed by Elliott protects the transplanted pig islet cells against attack by antibody-secreting B-cells and cytotoxic T-cells from the patient's immune system, which would rapidly destroy the cells. The alginate remains permeable to insulin secreted by the cells into the patient's bloodstream, and to nutrients from the patient's bloodstream.

Elliott said there was no trace of the porcine cells transplanted into the six original patients between 1992 and 1994 -- the alginate capsule is slightly 'leaky' to antibodies, but a second group of 12 patients transplanted in 1999-2000 still have detectable insulin-secreting activity.

Some of these patients are now receiving a second transplant of porcine islet cells, on the basis of research evidence that the long-lived original transplant induces a degree of immune tolerance that should help protect subsequent transplants.

At their most active, the transplanted cells secrete about half of the insulin required for normal metabolism, and must be supplemented by injections of human insulin -- but less often than in a control group of untreated patients.

"We've done what we said we hoped to do, and nothing has happened, Elliott said. "Provided we select pigs that do not release retroviruses, and haven't make any mistakes measuring virus activity, there is no evidence that any animal model, or any primate, has picked up a pig retrovirus."

Dormant retroviruses litter the genomes of all mammals, but appear to be species-specific, according to Elliott. Early concerns about porcine retroviral infections were raised when researchers using a mouse model mistook a mouse retrovirus for a pig retrovirus, but the result was later disproved.

Elliott said, "We've gone for a long time in humans, and the vast weight of evidence is that the retrovirus thing is a bit of a red herring -- medical researchers were wise to stop when the retrovirus concerns were first raised in 1996, but as far as we can ever know, it looks like it doesn't occur.

"We're not the only ones reporting this, but we've had the longest follow-up study. Researchers at the Karolinska Institute in Sweden transplanted porcine islet cells into 10 patients before we did our first experiment, and a group in Boston transplanted some pig brain cells into Parkinson's patients who likewise showed no evidence of infection.

"Altogether, there are about 250 well documented cases of humans who have been transplanted with pig cells, who have shown no signs of PERV infections. That's very reassuring."

Elliott said LCT was now awaiting the report of Australia's xenotransplantation advisory committee, which was due to publish new guidelines for research before Christmas.

Getting on the fast track

In the US, the National Institutes of Health had already produced new guidelines, and LCT would apply to the US Food and Drug Administration to conduct a Phase I clinical trial of its diabetes xenotransplantation therapy around the middle of 2005.

"We'd also like to run a Phase I trial in Australia, if the committee comes out in favour of the new draft guidelines," he said. "We also have a potential collaborator in Italy, and another in Switzerland, if the European Union does not approve clinical trials," Elliott said.

"How we proceed from there depends a great deal on the outcome of the trials -- they're aimed primarily at establishing the procedure is safe, but if we have a great deal of success in terms of clinical benefit to the patients, we could be fast-tracked by the FDA. Remember that the NIH approved human-islet transplantation with immunosuppressants in a very short time, without Phase I or II clinical trials.

"Unlike a drug that might have only minor advantages in treating diabetes, this would go so rapidly that it would exceed our capacity to meet demand.

"There are 170 million diabetics around the world, most of them in developed nations, and about 10 per cent of them are severe type 1 diabetics. Type 1 diabetes is also increasing rapidly in nations like China as they westernise -- it was virtually unknown in China 20 only years ago."