Grant: Team Grant: E-Rare Joint Transnational Call

Peroxisome biogenesis disorders (PBD) are rare autosomal recessive disorders caused by defects in any one of 14 PEX genes, whose protein products are required for peroxisome assembly. Defective peroxisome assembly results in multiple peroxisomal enzyme deficiencies and multi-organ failure over the whole life span. The majority of patients have PEX gene defects that show partial protein function, and thus should respond to drug therapies that can improve residual protein function or override the defects in downstream biochemical pathways. Importantly, there is a window to intervene in PBD and prevent or diminish disease progression. Currently, there is no treatment for PBD. In pilot studies, we identified chaperone drugs that can recover peroxisome functions in patient cell lines. We have also identified drugs that increase peroxisome numbers and correct affected downstream signaling pathways. We have shown that plasmalogens, a critical missing compound, can be replaced in various body tissues by supplementation. Thus, we hypothesize that pharmacological therapies, based on manipulating the affected molecular and metabolic pathways, have valid potential to benefit PBD patients. In this project, we will utilize our complementary resources and expertise to focus on identifying drug therapies that can recover peroxisome functions in our cell and mouse model systems. With our clinical expertise, we will mine our patient databases to determine accurate clinical endpoints for human trials. The completion of this project will lay solid groundwork for industry to optimize these therapeutic approaches for future clinical trials.