Unravelling the mechanism of action of enzyme replacement therapy in Fabry disease.

Fabry disease (FD) is a rare X-linked recessive glycosphingolipid-storage disorder caused by deficient activity of the lysosomal enzyme alpha-galactosidase A. Intravenous enzyme replacement therapy (ERT) has been used to supplement deficient enzyme activity in patients with FD. Despite its clinical effect and manifestations, clear criteria for the clinical effectiveness and cost-effectiveness of ERT have not been well established. In this study, we investigated the pharmacodynamic actions and short-term effects of ERT in patients with FD through direct molecular profiling from blood samples of patients before and after ERT. Based on this comparison, we observed that immune/inflammation-related pathways and growth factor-related pathways such as innate/adaptive immune pathway, lymphocyte proliferation and leukocyte proliferation were actively regulated under ERT. We also found that TINAGL1, DAAM2, CDK5R1 and MYO5B known to be related with clinical symptoms of FD showed increased levels after ERT, leading to the amelioration of clinical manifestations. Especially the catabolic process-related genes, including USP15 and ERUN1, showed direct increasing after ERT in vivo in male patients. These results suggest that male patients with FD respond more actively to ERT than do female patients with FD. Pathway analysis revealed that oxidative phosphorylation pathway-related genes are downregulated under ERT. ERT has a role to protect the proteins from oxidative damage and such deactivation of oxidative phosphorylation is one of direct pharmacodynamic actions of ERT. These results extended our understanding of the pathophysiology of ERT. To our knowledge, this is the first study to observe the molecular basis for the mechanism of ERT in vivo through the comprehensive comparison of transcriptome study with next-generation sequencing data.