Australian researchers are taking the final steps towards being the first in the world to take pancreatic islet cells from genetically modified pigs and transplant them into human patients. Their goal: to cure type 1 diabetes (T1D).
The culmination of decades of work was supported by multiple National Health and Medical Research Council (NHMRC) grants and Breakthrough T1D grants. Most recently receiving an NHMRC “Ideas Grant” of almost $4 million, awarded to Dr Wayne Hawthorne, Professor of Transplantation at the University of Sydney, last year.
“We’re now trying to get to the point where we can transplant these islet cells into patients” Hawthorne told Cosmos.
“We’ve got animals surviving out past 2 years post-transplant, with no hyperacute rejection, no rejection, and with cured diabetes in that pre-clinical model.
“We’re hopeful, certainly by the end of our NHMRC grant, I would hope even sooner, that we would love to go to the clinic for very, very, very select patients.”
Pancreatic islets are clusters of cells within the pancreas. They secrete insulin, the hormone which plays a crucial role in regulating blood sugar levels by allowing cells to take in glucose after a meal. But in people with T1D, the immune system attacks and destroys these cells.
There are more than 140,000 people living with T1D in Australia.
These people must supplement their body’s lack of insulin through injections several times each day, to ensure their blood sugar levels (BSL’s) don’t get too high (hyperglycaemia). They also measure their BSL’s multiple times a day to ensure it stays in a normal range and doesn’t get too low, which is life threatening.
If left untreated, diabetes can lead to short term, life-threatening complications like diabetic ketoacidosis and even death. In the long term, persistent high blood sugar can damage blood vessels, leading to nerve, eye, kidney, and heart problems.
On the other end of the scale, when a patient’s blood sugar levels get too low (hypoglycaemia), they must take in glucose. A “hypo” is usually accompanied by symptoms such as trembling, light-headedness, sweating, or irritability, which can alert someone with T1D that they need to eat.
But, according to Hawthorne, there are some patients who cannot tell when their blood sugar is low.
“If you can’t detect low blood sugar, you can’t give yourself food or even understand that you’re going to collapse into a coma and die. So, a number of these patients will sadly die.”
As Director of the National Pancreas and Islet Transplant Laboratories at Westmead Institute for Medical Research and Westmead Hospital in Sydney, Hawthorne’s team has been performing “allotransplants” – human-to-human transplants – to treat the most unwell diabetics for decades.
The Westmead team originally developed combined pancreas and kidney transplants in the early 2000s to treat a subset of patients who, due to poor luck in the genetic lottery, develop many secondary complications of type 1 diabetes, including kidney failure.
“If we can put a pancreas in, we can prevent them subsequently going blind, getting nerve damage, kidney failure or losing limbs,” says Hawthorne.
The pancreas is a large organ with lots of blood vessels, and transplants involve major surgery that takes many hours and comes with lots of potential complications. Doing so in combination with a kidney only adds to the procedure’s complexity.
Additionally, not every pancreas donated by a brain-dead person will be ideal. Age, excess fat, underlying comorbidity including vascular disease can make it impossible to use the pancreas for a whole organ transplant.
Once, these sub-optimal organs were destined for the bin. Until, Hawthorne recalls, about 30 years ago, “…we thought, well, why can’t we take that pancreas and try and extract the islet cells?”
“We’ve developed a technology where we can basically put the pancreas in a blender and pull out the islet cells … It’s a very complex procedure that takes me 8-10 hours, but at the end of it, we have these beautiful separated islet cells.”
Pancreatic islet transplants are a less invasive alternative to whole organ transplants, so are suited to a subset of patients with T1D and severe hypoglycaemia unawareness. The cells are infused into the patient’s liver where, within a couple of weeks, they start to release insulin.
This restores the biofeedback mechanism that allows patients to prevent low blood sugar and can even eliminate the need for daily insulin injections entirely.
But, in practice, the pancreases donated by brain-dead patients aren’t always large enough for this procedure.
“It’s only about 40% of the time that we get enough islet cells to transplant into a T1D patient,” says Hawthorne.
The organ must provide a minimum number of islets to justify giving the patient immunosuppressive drugs, which is required to stop their immune system from rejecting the foreign cells but can also potentially make them more likely to develop infections and cancer.
This has led to a yawning gap between donor pancreas supply and demand, which leaves patients waiting for years for a transplant or dying before receiving one.
“My specialty has always been treating patients with type one diabetes by whatever means we can … that has meant allotransplants, and now we’re looking at xenotransplants,” says Hawthorne.
Xenotransplantation – taking the cells, tissues, or organs from one species and putting them into another – has been pursued by clinicians and scientists since the 1960s as a solution to the global organ shortage crisis. This year, the first clinical trials to transplant gene-edited pig kidneys into humans with end-stage renal failure will begin in the US.
The pigs are genetically modified to prevent the human immune system from recognising their cells as extremely foreign.
But, while overseas researchers can now order the GM pig lines as required, it’s impossible to import them into Australia due to the country’s strict biosecurity laws.
Hawthorne and his co-collaborators – Professor Peter Cowan, Head of immunology at St Vincent’s Hospital Melbourne, and Associate ProfessorMark Nottle, Head of reproductive biotechnology group at the University of Adelaide – have had to develop their own special transgenic pig lines.
“We have our own transgenic pigs, completely separate to the US and Europe and China and so on, and we’ve done the hard yards for decades to get us to the point now where we can use these for transplants,” he says.
The cells of these transgenic pigs have been optimised to prevent hyperacute rejection, immune rejection, coagulation, and to provide additional immunosuppressive protection.
“I can potentially transplant these into a patient and give the minimum amount of immunosuppression, which means it’s more applicable to a wider range of patients,” says Hawthorne.
But he cautions, this won’t be carried out in children.
“Immunosuppression for a child is not necessarily a good thing in the long-term,” he says.
“It will be a very select cohort of patients with, like our other islet transplant patients, who suffer severe hypoglycaemia unawareness. We’ll treat very, very select patients first.
“The beauty of this, though, is we can potentially expand it to more patients than can currently receive islets from human donors.”
But this won’t be possible without first developing necessary infrastructure associated with the procedure, such as the specialised piggery to source the transgenic pig islet cells, which Hawthorne says will require millions of dollars in funding.
“We will need to increase our … capacity to screen the product to transplant,” says Hawthorne.
“We need to increase the number of associated teams of people to do the transplants, to do the observations of the patients, to continue following those patients, and then putting them in the [Australian and New Zealand Islet and Pancreas Transplant Registry] to ensure that we’re following those patients for development of potential problems.
“The question remains are we going to get all the money from the health budget to do this, over someone dying of cancer or other diseases? There is only so much money in the bucket in the health system.”
