Feature: Xenotransplantation offers hope to diabetes sufferers

Back when Living Cell Technologies’s (LCT) current Medical Director and Founder, Professor Bob Elliott, was working in his Auckland clinic, he decided that the treatments available for patients with Type I diabetes simply weren’t good enough.

“Giving multiple insulin injections and measuring the dose according to the change in blood glucose level, this had not progressed from what Banting and Best were doing back in 1921, and it was clearly not working adequately for the patient.” Frederick Banting, working with Charles Best, discovered insulin in 1921, providing the first ray of hope for diabetes sufferers – if not a cure. “Too many people are still getting the long-term complications of diabetes because it is simply too hard to regulate the body’s blood glucose levels accurately and reliably.”

Type I diabetes, also known as insulin-dependent or juvenile diabetes, is a chronic autoimmune disease caused by the insulin-producing beta cells of the pancreas dying off and eventually destroying the body’s capability to regulate blood glucose levels. Insulin is the hormone responsible for ensuring that glucose entering the bloodstream following a meal gets to where it is needed inside cells for energy conversion. A lack of insulin thus means unstable energy metabolism and high levels of glucose in the blood and urine. People with Type I diabetes, therefore, require daily insulin injections to normalise their blood glucose levels and minimise the harmful effects. Without such injections, coma and death may occur startlingly rapidly. Even on insulin treatment, severe complications involving the cardiovascular and nervous system can shorten the lifespan of sufferers by a third on average.

According to Elliott, a major problem with Type I diabetes is ‘hypoglycaemic unawareness’. “Attempts to normalise blood glucose in Type I diabetics often overshoot and it goes too low. Early on, patients recognise the signs of this and can do something about it. But when it has been going for years, they start to not realise, which becomes very dangerous and quite debilitating. They get no warning symptoms or, in other words, they lose awareness.

“Consequently, they can lose consciousness quite suddenly – in a few seconds – which is bad news if they’re driving a car or swimming. In fact, eight per cent of diabetics die from these low blood-glucose episodes, and around 20 per cent of all Type I patients progress to that sort of severity.”

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Making xenotransplantation personal

Elliott had long explored the concept of simply replacing the insulin-producing cells in the body with new ones that would not be rejected by the immune system. Realising this idea, however, was not all that simple, and he had actually put the research aside. “Then, about 20 years ago, a man called David Collinson turned up in my clinic and wanted to know what the future might hold for his two-year-old child with diabetes. I told him about my research and he decided almost there and then to bankroll the entire project. David was really the entrepreneur that got it all going.”

In 1987, Elliott and Collinson founded a company that grew into LCT. The major technology to come out of that partnership is now the subject of multiple patents in several worldwide jurisdictions and, all going well, could be on the shelf in clinics within a few years. LCT now employs around 50 people and has a unique combination of capabilities with its virus-free pig herd, good manufacturing practice-approved (GMP) facilities, accredited diagnostic laboratory and patented proprietary technology. It was also the first company worldwide to receive an International Accreditation New Zealand (IANZ) tick for a xenotransplantation laboratory. This accreditation means that LCT’s laboratory testing is accepted in 49 countries, including the US, Canada, the UK, Australia and New Zealand.

“Setting out on this journey, we realised from previous attempts elsewhere that using human donors might end up just being a waste of time, as well as being expensive and fraught with the constant problems of tissue availability and the need to use immunosuppression, which can be almost as bad for the patients as having the disease,” Elliott recalls.

He and his colleagues therefore decided on a new approach: using pancreatic islets isolated from pigs as the source of insulin-producing cells, and an immune barrier instead of immune suppression, made from a seaweed-derived alginate, a carbohydrate akin to starch.

This nifty idea developed into what is now LCT’s flagship product for treating insulin-dependent diabetes, called DiabeCell. This semi-permeable gel capsule full of piggy pancreas cells allows the insulin out and the nutrients in, but prevents most of the contact, and therefore activation, of the host immune system. Treatment with DiabeCell involves implanting these little insulin factories into the patient’s peritoneal cavity via a simple laparoscopic procedure. According to Elliott, the implanted capsules attach to the outside of various organs such as the intestine and almost immediately start to produce insulin.

In vivo experiments subsequently indicated that these biocapsules could survive in the harsh peritoneal environment for at least 215 days. In addition, pancreatic beta cells in vivo are quite long-lived and do not reproduce, so they are quite happy hanging out in the alginate drops and doing the thing they do, which is to produce much-needed insulin.

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Trying times

The clinical trials of the DiabeCell technology actually started back in 1996 in New Zealand. “We injected a couple of patients with a very primitive prototype of the alginate/cell capsules and got enough of a response to make me think that this just could work. This was very exciting because there has always been general scepticism. There still is, actually. I got a lot of people telling me I was dreaming, so to speak.”

Unfortunately, the clinical trials of the pig-cell implants came to an abrupt end not long after they started due to an emerging scare of possible transfer to humans of a retrovirus recently discovered in the DNA of pigs. “A whole lot of other work that followed found the risk of transfer to be nothing more than a theoretical possibility,” says Elliott. “No labs ever showed it to be possible despite sterling efforts to do so.”

In the wake of the retrovirus scare, New Zealand effectively banned xenotransplantation trials in 2002, then two years later Australia – another possible trial site – imposed a blanket moratorium on xenotransplantation. When a New Zealand Ethics Council report in 2005 recommended that xenotransplantation trials could go ahead, LCT was again knocking on the regulators’ door.

“The authorities dealt with the issue by making clinical research groups get special permission from the minister of the day to do the sorts of trials we wanted to, and so we went down that road, and the approval finally came through in December of last year!”

Meanwhile, Elliott was still following the original 1996 trial patients. All showed transient benefits from the implanted cells and some evidence of circulating pig insulin for about a year, but eventually these signs of success diminished. “The exception was one patient who continued to report some benefit years later. So, about 10 years after we treated these patients, he finally persuaded me to look back in his belly and lo’ and behold, we found live cells still there in his peritoneum that were still making a small amount of insulin. That told us that this approach was definitely going to work and that it was just a matter of honing the technology and proving to everybody else that it worked from there on in, and that is what we have been engaged in since.”

In 2007, LCT also began a clinical trial of DiabeCell with a group in Russia, organised through a major shareholder. As Elliott explains: “This guy is a Russian-born American who has a couple of kids with diabetes and a school friend still living in Russia who was doing research in this area. Following some discussions and mutual visits, we decided to pursue a trial with our cells and approach, but in Russia where the regulatory environment made it a little easier to get approval.”

Eight patients received small doses of LCT’s insulin-producing biocapsules on up to three occasions. The major aims were to assess the safety of multiple doses and monitor how long the insulin secretion would last at the right doses in the circulation. So far there have been no adverse reactions at all – and all but one patient has shown long-term production of pig insulin. These results were formally reported last month at a meeting of the American Diabetes Association.

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Bringing it home

The Russian trial results were a great boost to LCT’s plans. Not only did they meet the required end points for safety and tolerability, but based on the preliminary findings, LCT got the go-ahead with another trial on New Zealand patients. “This eight-patient trial started in October 2009 and is already progressing well,” says Elliott.

“The first four patients have received the starting dose and we are about to do the same in the next four, again using a single dose, but at a higher dosage and with a dose escalation built into the trial. I should stress that all these patients are very severe diabetics with unaware hypoglycaemia who have a lot of trouble getting their insulin doses right. It is the main condition of our trials.”

Not far into the NZ trial, Elliott is already justifiably delighted. “Although the first patient was treated only eight months ago, as early as four to five weeks after the injection, he was reporting fewer episodes of unaware hypoglycaemia, and, from two months in, he has been completely free of episodes. Considering that he was having three to six episodes of uncontrolled low blood sugar per week, he is very happy with the result, as are we.

“The patients still require regular self-injection of insulin, but at much lower doses, and the real standout result is the abolition of the unaware hypoglycaemia. We are waiting for further outcomes later this year and we hope to start another trial with a different dosing schedule very soon.”

A number of other countries including Australia and the USA have shown interest in conducting trials of DiabeCell in conjunction with LCT, although the groups concerned have yet to gain approval from their respective regulators. As Elliott says, “this is no easy task. It took us 14 years in New Zealand.”

After another couple of years of dose-seeking exercises and the pivotal studies required by the regulators for product registration, LCT is hoping that 2013 will see the first clinical administration of DiabeCell in a patients with Type I diabetes outside of the trial setting.

“The regulatory hurdle has certainly been the major problem,” Elliott says. “But in the meantime we have refined the technology quite considerably. We are into Phase II trials now and things are gathering momentum for scale-up.”

“We have other promising disease targets for the LCT technology, including NTCell for neurological repair,” says Elliott. “But most of this is on the backburner at the moment. We are not a big company and cannot do everything at once. The diabetes focus at the moment is full steam ahead and once that is under way we can spread our wings a bit.”

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That’ll do, pig

LCT has its very own pig containment facilities, giving it full control over that aspect of the technology. A major requirement of such animal cell sources is that they are free of disease and infection. According to Elliott, LCT hunted high and low for the best herd nearby. “In the end, we found this herd of pigs on an uninhabited island down near the Antarctic that had been left there around 200 years ago by sailors. These pigs were completely infection-free.”

These porcine saviours are housed in two specialised containment facilities in New Zealand that have no contact with the outside world. The air is filtered and is pumped in under positive pressure. All food and water and bedding is sterilised and there are strict procedures for anyone entering the facility. These facilities will need to grow for full commercial production, but currently produce enough material for the clinical trials.

Professor Elliott trained as a paediatrician at Adelaide University before moving to New Zealand in 1970 to become the Foundation Professor of Paediatrics at the University of Auckland. He is currently an Emeritus Professor of Child Health Research, Professor of Paediatrics and a world leader in diabetes and autoimmune-related research. Elliott is on the board of the New Zealand Child Health Foundation, Wings Trust (a NZ trust for the treatment of alcohol and substance abuse) and is patron of the NZ Cystic Fibrosis Foundation. In 1999 he was awarded a Companion of the New Zealand Order of Merit (CNZM) for services to the community.