Understanding the factors that drive neurological dysfunction in Duchenne muscular dystrophy

Dr Angus Lindsay is aiming to improve the quality of life and increase life expectancy of patients with a devastating muscle wasting disease.

Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disease affecting 1 in 3,500-5000 males.

DMD is caused by the loss of dystrophin protein, resulting in severe muscle wasting and weakness. Patients with DMD also suffer from neurocognitive dysfunction, including anxiety, impaired working memory and lower IQ.

Dr Angus Lindsay is working to better understand the mechanisms regulating neurological dysfunction in DMD with the intention of identifying new therapies to improve the quality of life for patients.

Through a Phillip Wrightson Fellowship from the Neurological Foundation (New Zealand), Dr Lindsay is utilising gene therapy, hormonal manipulations and quantitative multi-omics platforms to achieve his research aims.

“There is currently no cure for DMD. Clinical trials to restore dystrophin in patients with DMD are progressing well, but there is still a need for “right-now” therapies to improve the quality of life for patients,” Dr Lindsay said.

“My research could determine the underlying factors that drive or contribute to neurological disorders in patients with DMD, which will help identify therapies to improve quality of life and support inclusion of patients into everyday society.”

Dr Lindsay explained that most available therapies target restoration of skeletal and cardiac muscle function, but patients with DMD could also greatly benefit from understanding the mechanisms that drive neurological dysfunction.

Patients with DMD are routinely prescribed glucocorticoids, a type of steroid, to extend the time they are able to walk, and their life expectancy. However, one of the severe side-effects of chronic glucocorticoid therapy is adrenal insufficiency. This means the body does not produce an adequate supply of certain hormones, which then limits a patient’s ability to adequately respond to a physiological or psychological stress. Without this ability to respond adequately, patients with DMD are at risk of severe complications.

“Outcomes from my fellowship offer a real prospect of fine tuning the complex balance of benefits and side-effects from the current use of glucocorticoids for DMD, such that the negative aspects of using these drugs could be eliminated,” Dr Lindsay said.

Previously, Dr Lindsay was part of a group of scientists at the University of Minnesota that determined loss of dystrophin in a mouse model of DMD predisposes it to behavioural/psychological stress hyper-sensitivity. Exposure to behavioural/psychological stress can worsen disease pathology and even cause sudden death.

More recently, his IPAN research identified that the stress response of mdx mice (a specific type of mouse used for the scientific study of DMD) is regulated by several muscle and hormonal factors.

Ultimately, Dr Lindsay hopes to clarify the molecular mechanisms that drive neurological dysfunction in patients with DMD; and identify a mechanism(s) which could lead to a clinical trial to improve the quality of life for patients with DMD and extend their life expectancy.