The Disease Mechanisms and Therapies group uses cell and animal models to unlock the mechanisms causing nerve and muscle disorders to inform evidence-based therapies. The team's research is closely linked with patients receiving treatment for their neuromuscular condition at The Children's Hospital at Westmead clinical service. Real-life patient mutations provide scientists with a vital clue; that this specific mistake in a gene disrupts a protein function that is vital for human life.

The Disease Mechanisms and Therapies group is led by Dr Frances Evesson and includes three teams studying different mechanistic pathways: Membrane Repair, Redox Biology and Muscle Contractility. Using animal models and cell and tissue samples collected from muscular dystrophy patients, we differentiate normal from abnormal behaviour of muscle and nerve cells, to understand the disease-causing effects of mutations. We find core pathways that cause muscle weakness, and use this specific mechanistic insight to illuminate novel avenues for therapeutic intervention.

Membrane Repair Team

Our studies of a rare muscular dystrophy (LGMD2B - dysferlinopathy) have provided key insight into the precise mechanism by which cells recognise and repair a membrane injury. Using dysferlin as the key, the team aims to unlock the molecular steps required to survive a membrane injury, a process that is particularly important in skeletal muscle membrane injuries that occur on muscle stretching. The team has developed new ways to test therapies to improve recovery from membrane injuring events, and aims ultimately to control the membrane-resealing pathway as treatment for neuromuscular disease, and recovery from cardiac injury and stroke.

Redox Biology Team

We have identified PYROXD1 as a new gene causing an infantile myopathy. PYROXD1 belongs to a family of powerful reductive enzymes that protect our cells from oxidative stress. Our group is the first to discover PYROXD1, and have shown that cells and animals are not viable without PYROXD1 activity. Our team is studying how PYROXD1 responds to oxidative stress, and which are its substrates that must be reduced for cellular life to exist. PYROXD1 myopathy highlights redox biology as a core mechanism in the myopathies, and emphasizes the potential clinical merit of existing redox targeting therapies (used in neurodegenerative ageing disorders) for families affected by devastating NMDs, for whom there are currently few or no treatment options.

Muscle Contractility Team

The Muscle Contractility team has the long-term goal to develop technical platforms to precisely and efficiently characterise the underlying mechanistic basis of muscle weakness in patients with congenital myopathies due to various genetic causes. This team employs sophisticated mechanistic studies of muscle contractility and physiology, to identify exactly how the contractile machinery is defective, with a view to evaluating the clinical merit of two existing therapies targeting cardiac contractile dysfunction, for patients with rare congenital myopathies.