Diabetes gene therapy trial

A new world-first clinical trial could bring fresh hope for Australian sufferers of type 1 diabetes.

The trial, announced on 31 October 2022, will examine how genetically engineered cells could restore insulin function and reduce the need for immunosuppression in patients with type 1 diabetes.

This will be the first time that genetically engineered pancreatic islet cells will be transplanted into humans to treat the disease, and if successful, the new therapy will reduce or eliminate dependency on external insulin administration and reduce serious health impacts for the 125,000 Australians who live with the disease.

The authors, led by Professor Shane Grey, Head of the Transplantation Immunology lab at the Garvan Institute of Medical Research believe that this could be a game changer for the management of type 1 diabetes.

“We’ve worked on this research for 20 years and to see it now reach a stage of translating to people is amazing,” Professor Grey, said.

“It’s the beginning of a long journey, but it’s an exciting step: the holy grail is to make islet cells that the body adopts as its own, which function normally to sense glucose and produce the appropriate amount of insulin.”

Transplant treatments of donor pancreatic islet cells into the liver have been successful in patients experiencing severe episodes of hypoglycaemia, reducing their reliance on insulin injections; however, two to three transplants are needed, and the effectiveness of the transplanted islet cells usually subsides within five years.

In addition, immunosuppression medication is required to turn down the immune system, preventing it from destroying the donor cells, but that leaves a patient vulnerable to serious side effects, including infections and kidney damage.

Professor Grey and his team identified that a key protein known as A20, involved in inflammation and autoimmune disorders, could be used in the genetic engineering of insulin-producing islet cells to slow, or stop the immune system from damaging them.

“A20 is like a thermostat for the immune system; it can turn it down to a simmer, or ramp it up to be more aggressive,” Professor Grey explained.

“For type 1 diabetes, we can use it as a handbrake on the immune system to stop the damage to pancreatic islet cells.”

To engineer islet cells with high expression of A20, the researchers developed a viral delivery system called GARV-AAV2-A20, which transports the gene that makes A20 into donor islet cells, causing them to start making higher levels of A20.

“We showed that genetically engineered islet cells with high A20 expression in mouse models had 80-100% survival of the islet grafts, without the need for heavy immunosuppression – it was a fantastic outcome,” Professor Grey said.

A further study in pig and human cells not only showed that A20-engineering of islet cells was safe in turning down the immune system, but also helped the immune system to recognise the donor islet cells as its own.

“The genetically engineered cells seem to re-educate the immune system to accept the transplant as self,” Professor Grey said.

“It’s a really amazing discovery – that the transplant can tweak the whole immune system.”

For patients, the new treatment could significantly improve their quality of life and the trial will proceed thanks to a Medical Research Future Fund boost from the Australian Government’s Targeted Translation Research Accelerator program for diabetes and cardiovascular disease.

Production of GARV-AAV2-A20 will begin over the next months at the Viral Vector Initiative, and patients will be recruited through the Royal Adelaide Hospital in mid-2024.