Enzyme Replacement Therapy for FABRY Disease: Possible Strategies to Improve Its Efficacy

Enzyme replacement therapy is the only therapeutic option for Fabry patients with completelyabsent AGAL activity. However, the treatment has side effects, is costly, and requires conspicuousamounts of recombinant human protein (rh-AGAL). Thus, its optimization would benefit patientsand welfare/health services (i.e., society at large). In this brief report, we describe preliminary resultspaving the way for two possible approaches: i. the combination of enzyme replacement therapy withpharmacological chaperones; and ii. the identification of AGAL interactors as possible therapeutictargets on which to act. We first showed that galactose, a low-affinity pharmacological chaperone,can prolong AGAL half-life in patient-derived cells treated with rh-AGAL. Then, we analyzed theinteractomes of intracellular AGAL on patient-derived AGAL-defective fibroblasts treated with thetwo rh-AGALs approved for therapeutic purposes and compared the obtained interactomes to theone associated with endogenously produced AGAL (data available as PXD039168 on ProteomeXchange).Common interactors were aggregated and screened for sensitivity to known drugs. Such aninteractor-drug list represents a starting point to deeply screen approved drugs and identify thosethat can affect (positively or negatively) enzyme replacement therapy.