Led by chief investigators Professor Roger Chung and Dr Jennilee Davidson of the Macquarie MND Research Centre, the project will centre on using innovative gene therapy-based technologies to precisely control the expression of their gene therapy in affected nerve cells (neurones).
Their gene therapy uses the protein shell of a virus to deliver a beneficial segment of DNA (a therapeutic gene) into a person's cells without causing infection, and is increasingly seen as a promising approach to the treatment of neurodegenerative disease like MND.
In almost all patients with MND – also known as amyotrophic lateral sclerosis (ALS) – the protein TDP-43 is known to accumulate and aggregate inside nerve cells that carry signals controlling the movement of muscles (motor neurones), causing them to malfunction and die.
Professor Chung, Dr Davidson and their colleagues Mr Tyler Chapman (a PhD student) and Dr Cecilia Mei have been working on this new gene therapy approach that combines two therapeutic components. Firstly, the therapy expresses a therapeutic protein that specifically reduces the levels of TDP-43 in motor neurones. And secondly, they have developed an on/off switch that is directly responsive to the levels of TDP-43, so that the therapy is turned on when TDP-43 levels are too high, and turns back off when the TDP-43 levels are restored to normal.
"The switches are an innovative technology that will turn on expression of the beneficial therapeutic gene when TDP-43 accumulates at pathological levels and turn off the gene when TDP-43 levels return to baseline healthy levels," says Dr Davidson.
The NHMRC-funded project aims to validate these TDP-43 responsive on/off switches and evaluate whether they can provide a precision gene-expression control mechanism for potential gene therapy for MND.
If found to be successful, a control mechanism like this could establish a new technology that can personalise the gene therapy for individual patients and would be of significant clinical and commercial interest, Dr Davidson says.
