Gene therapy trial for type 1 diabetes to proceed

A clinical trial to test a gene therapy for type 1 diabetes, developed at the Garvan Institute of Medical Research, 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. The trial is set to be the first time that genetically engineered pancreatic islet cells will be transplanted into humans to treat type 1 diabetes.

Type 1 diabetes occurs when the body’s immune system attacks its own islet cells in the pancreas, which are responsible for sensing the concentration of sugar in the blood and producing the hormone insulin. Insulin controls blood sugar levels by signalling the body to convert sugar (glucose) into energy for cells. With insufficient insulin, sugar levels rise unchecked (hyperglycaemia), which can lead to complications such as nerve and blood vessel damage if untreated. Treatment with external insulin administration can result in very low blood sugar levels (hypoglycaemia), which can lead to seizures and loss of consciousness.

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 so it won’t destroy the donor cells, but that leaves a patient vulnerable to side effects including infections and kidney damage.

“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,” said Professor Shane Grey, Head of the Transplantation Immunology lab at Garvan.

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. He explained, “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. 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, Grey and his team developed a viral delivery system called GARV-AAV2-A20, which transports the gene that makes A20 into donor islet cells, which then start making higher levels of A20. Preclinical trials of the cells in animal models have been highly successful.

“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,” Grey said. A further study in pig and human cells showed A20-engineering of islet cells was safe.

The team also discovered that not only does A20 turn down the immune system, it helps the immune system recognise the donor islet cells as its own. According to Grey, “The genetically engineered cells seem to re-educate the immune system to accept the transplant as self. It’s a really amazing discovery — that the transplant can tweak the whole immune system.”

Production of GARV-AAV2-A20 will begin over the coming months and patients will be recruited through the Royal Adelaide Hospital in mid-2024. If successful, the new therapy will reduce or eliminate dependency on external insulin administration and reduce serious health impacts, which would be a game changer for type 1 diabetes management.

“We’ve worked on this research for 20 years and to see it now reach a stage of translating to people is amazing,” Grey said. “It’s the beginning of a long journey, but it’s an exciting step.”

Image credit: iStock.com/PixelsEffect

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