Gene therapy breakthrough

Approximately 8% of Australians live with a rare disease, that is around 2 million people. These diseases are varied and life-threatening, yet most remain undiagnosed and have no effective treatments. 

Gene therapy is one way to tackle this – by delivering good copies of genes or even directly modifying genes within the target organ. It’s a rapidly advancing field that has the power to transform medicine by tackling diseases at their genetic origins, targeting underlying causes at the molecular level rather than simply treating them with drugs or surgery.

Perfectly positioned to take on the challenge is Dr Charles (Chuck) Bailey, Head of the Centenary Institute’s Centre for Rare Diseases and Gene Therapy.

He joined Centenary in 2001, quickly delivering a breakthrough in the understanding of inherited metabolic diseases. 

He successfully described the genetic basis of three of the five principal inherited amino acid transport disorders in humans – a huge step forward, showing exactly which gene changes cause the disease. It’s a discovery that has helped to better diagnose these conditions, provide improved patient care, and uncover potential routes towards new treatments.

Most recently, Chuck and his team have discovered a previously unknown gateway for delivering therapeutic genes into human cells that could dramatically improve the safety, effectiveness, and accessibility of gene therapies.

The breakthrough is born from work to develop a new molecular technology that can safely deliver healthy genes to cells in the body via a harmless virus called adeno-associated virus (AAV). 

Although it is a virus, AAV doesn’t cause illness in humans and is an effective way to transport healthy genes to parts of the body where a faulty gene needs to be replaced. 

The new gateway into human cells – a receptor called AAVR2 – is a landmark discovery by Chuck and Dr Bijay Dhungel, that could be used to help treat a range of serious genetic disorders, including Duchenne muscular dystrophy, Pompe disease and haemophilia.

A safer solution

Currently, some AAV-based therapies require very high doses, which can be toxic and even deadly to the patient. The higher doses can trigger unwanted immune responses and also make them a very costly treatment option. 

This newly uncovered pathway could allow lower doses of virus to be used in treatment, helping to reduce side effects and improving patient outcomes.

“We found that many AAV types that are used clinically can use this newly identified receptor, AAVR2, to enter cells, providing an alternative to the previously known entry route,” said Dr Bijay Dhungel, lead author of the study. 

“This discovery uncovers a completely new pathway for delivering genes into cells. Modulating this pathway can potentially make gene therapies safer, cheaper and more precise,” he said.

Using advanced genetic, biochemical and biophysical techniques, the researchers defined the components of AAVR2 that play a crucial role in helping AAV enter cells more efficiently.

“We not only identified this new receptor AAVR2 but also discovered how it binds to the viruses that deliver the genes,” said co-senior author Dr Chuck Bailey.

“We then went a step further and engineered a miniature version of the receptor and demonstrated that this significantly enhances how efficiently the gene therapy is taken up in human cells and tissues. We believe this knowledge will ultimately improve the accessibility of gene therapies to patients.”

The findings have important implications for the future of gene therapy, offering new strategies to tailor treatments, lower required doses and potentially avoid immune-related complications that have limited some current approaches.

The discovery also advances scientific understanding of how therapeutic viruses interact with human cells. This is essential knowledge for developing the next generation of safe, effective and
precision-guided gene therapies.

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