Grant: Operating Grant

The PBD are inherited childhood conditions that are only moderately rare, but have been neglected in terms of clinical investigations and therapeutic interventions. They are caused by defects in any one of 14 peroxisome biogenesis genes and result in faulty assembly of peroxisomes. Peroxisomes are cellular organelles that contain enzymes involved in lipid metabolism. In the PBD, peroxisome numbers are reduced and peroxisome enzymes are deficient. For most patients, peroxisome malfunction affects development after birth, and causes destruction of brain white matter, vision and hearing losses, liver disease and bone problems. Treatment options are urgently needed; at present there is only supportive care, which does not address the underlying genetic and enzyme defects. Since the disease course is one of progressive deterioration, it should be correctable by therapies that improve peroxisome function. Our goal is to substantially accelerate the discovery and clinical application of novel drug treatments for the PBD. To streamline therapies we will partner expert peroxisome researchers in basic biology, translational research and clinical trials. We will tackle this task by (1) studying mouse and insect models to better understand the disease (2) screening drug libraries in patient cells to find drugs that can improve peroxisome functions, and screening gene pathways in insect cells to find pathways that affect peroxisome function and can be modified by drugs and, (3) improve patient diagnosis by developing a novel gene sequencing platform and longitudinal patient natural history studies, in which we can gather the data required for initiating future therapeutic trials. Finally, the impact of this research goes beyond the PBD, as peroxisome malfunction is reported in Alzheimer's disease, premature newborn lung disease and type II diabetes. Thus, improved understanding of peroxisome functions is predicted to impact on treatment of more common conditions