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New gene therapy prevents muscle wasting associated with cancer

July 22, 2016

Australian researchers have demonstrated a new gene therapy-based strategy that could be used to prevent the loss of muscle mass and physical strength associated with advanced cancer. The findings are published today in the journal Science Translational Medicine.

Up to 80 per cent of patients with advanced cancer suffer from "cachexia", a condition of pronounced weight loss, frailty and fatigue, associated with severe wasting of muscle and fat. For these individuals, muscle wasting is a predictor of poor outcomes and reduced survival, as debilitating frailty leads to loss of independent movement, impaired respiratory function, and reduced tolerance for aggressive chemotherapy regimens.

To-date, Cachexia has been difficult to treat. Most efforts have focused on trying to "block" proteins released from the tumour or immune system which are responsible for causing cachexia by targeting proteins in the blood stream. However, some of the most promising experimental therapies have been abandoned after clinical trials raised concerns over risks of side effects.

By targeting the processes that take place inside the muscle cells themselves, researchers from Baker IDI Heart and Diabetes Institute, Monash University, and The University of Melbourne have identified a way to treat the frailty of cachexia in a pre-clinical model without side-effect risks.

Taking advantage of the processes by which viruses introduce genetic material into cells, the team developed purpose-built "viral vectors"; tiny particles that deliver a therapeutic gene to muscles and the heart. Once inside the muscle and heart cells, the therapeutic gene produces a protein that prevents cachexia-causing factors in the blood stream from switching on the signalling responsible for muscle wasting.

Explaining the cellular mechanism, Dr Paul Gregorevic, one of the senior members of the team, likened the muscle and heart cells to a house being battered in a storm; "By targeting how wasting signals are switched on in muscles, what we've done is try to find a way to board up the windows of the house to protect what's inside. Outside, the storm is still raging, but inside, the contents are protected."

The team demonstrated that the gene therapy approach prevented muscle wasting in pre-clinical mouse models of cachexia. As the signalling mechanisms that cause wasting in cancer have also been linked to wasting associated with other forms of chronic illness, the team suggests that this approach could also have benefits for treating frailty in other common conditions, including heart and lung disease. The team is now exploring opportunities to advance this research towards trials of the therapy in humans, and applicability of their novel gene therapy strategy for illnesses beyond cancer.
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Baker IDI Heart and Diabetes Institute

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