Discovering the secrets of a debilitating immune deficiency

An international group of scientists headed by University of Victoria biochemist John Burke and students Gillian Dornan and Braden Siempelkamp have taken a critical first step toward an effective treatment for a rare and crippling genetic disease.

The team has uncovered how mutation of an enzyme called phosphoinositide 3 kinase delta (PI3Kd) causes Activated Pl3K Delta Syndrome (APDS), a disorder that impairs the immune system and leads to recurrent serious infections such as pneumonia and severe viral infections, and may cause early death in some patients. Identified in 2013, APDS is so new to clinicians it can only be diagnosed through genetic testing and the number of cases is currently unknown.

Burke’s lab studies the mechanistic basis of how enzymes mediate cellular functions and their role in a wide range of diseases, including cancer and viral infection. Using powerful structural, biochemical and biophysical methods his team can map out the molecular mechanisms by which these enzymes function. 

“We were able to determine the molecular basis for how the Pl3K enzyme is being disrupted by APDS promoting mutations,” says Burke. “This allowed us to screen clinically approved PI3K inhibitors against these mutated versions, and we found all potently inhibited enzyme activity. The result reveals a promising therapeutic strategy for treating APDS patients.”

The findings were published in the Proceeds of the National Academy of Sciences earlier this month.