Fabry disease (FD) is an X-linked lysosomal storage disorder that is caused by deficiency of α-galactosidase A (GLA) with consecutive cellular accumulation of Gb3. Many FD patients suffer from episodic acral pain triggered by peripheral stimuli such as heat, cold or inflammation, the underlying pathophysiology is only partially known. FD-specific treatment via enzyme replacement or chaperone hardly has analgesic effects. In a forward and reverse translational approach, we have determined small fibre pathology as a main contributor to FD pain at nociceptor level. We have found lysosomal Gb3 overload, hints for disturbance of mitochondrial mobility in sensory neuron neurites, and heat-induced hypersensitivity of sensory neurons derived from FD patients. In patient biomaterial and in a mouse model of FD, we have further obtained evidence for an imbalance of pro- and anti-inflammatory mediators and for disturbed endothelial cell function associated with hypoxia. Using MRI, we observed enlargement of the dorsal root ganglia (DRG) with a T2 signal increase that distinguished the painful phenotype from the painless FD phenotype using novel methods of 3T human DRG MR imaging. We then made similar observations in the GLA KO model completing our imaging methods with 7T mouse DRG MRI.

In our large cohort of FD patients and in the GLA KO mouse model, we are now following up the FD pain-associated DRG MRI signature under treatment: enzyme replacement, chaperone, anti-inflammatory, and peripheral de-sensitization. Using functional BOLD MRI, we test the perfusion adaption of the DRG directly under simultaneous peripheral electrostimulation. DRG structural and functional MRI methods will be further developed and validated for pain. To assess the effects of potentially druggable targets, we will use a fully patient-derived and innervated 3D skin model based on induced pluripotent stem cell-derived skin cells for molecular and electrophysiological characterization upon in vitro treatment. Finally, we will assess the effects of compounds targeting hypoxia and inflammation on FD pain in patients.