The drug Pioglitazone helps restore bacterial killing activity in CGD

Encouraging research published in the Journal of Allergy and Clinical Immunology has shown that the drug pioglitazone can help restore the bactericidal activity of CGD cells towards Staphylococcus aureus and Burkholderia cepacia, significant causes of infection in people with CGD.

Pioglitazone is a drug that acts upon the peroxisome proliferator activated receptor and is currently approved for the treatment of type 2 diabetes.

Dr Bratton, Professor of Pediatrics, from the National Jewish Health in Denver and the lead author on the paper explains the findings. 'The fundamental problem in CGD is the inability to produce any or enough oxidant products known as reactive oxygen species (ROS) to kill bacteria. We were aware that pioglitazone could increase ROS production in cells so we tested it in mouse models replicating the defect in human X-CGD.  We found that short-term treatment with pioglitazone caused a stimulation of ROS production in X-CGD mouse cells and significantly helped kill off infection caused by Staph. aureus and B. cepacia.

The work showed that mitochondria were the source of the stimulated ROS production in CGD cells. Mitochondria are specialised parts of cells that generate the energy that cells need to their job and often referred to as powerhouses of cells. Importantly, mitochondrial oxidant production was restored by pioglitazone treatment of human CGD cells as well as those from X-CGD mice. ‘Our work shows that pioglitazone bypasses the usual pathways for ROS production, which are defective in CGD, and offers real hope for restoring defence systems against infection in CGD.’ comments Dr Bratton.

‘Simply stated, without initial funding from the CGD Society, this work would not have been possible. We deeply appreciate the generosity of this foundation and its donors,’ said Dr. Bratton. Dr. Bratton noted further, that the data generated in this initial study has resulted in funding from the National Institutes of Health for the continued investigation of pioglitazone treatment, and the next steps towards clinical trials of pioglitazone in CGD. 

Reference: Pioglitazone restores phagocyte mitochondrial oxidants and bactericidal capacity in chronic granulomatous disease
Fernandez-Boyanapalli RF, Frasch SC, Thomas SM, Malcolm KC, Nicks M, Harbeck RJ, Jakubzick CV, Nemenoff R, Henson PM, Holland SM, Bratton DL.
Journal of Allergy and Clinical Immunology. 2015 Feb;135(2):517-527.e12.