Arimoclomol as a potential therapy for neuronopathic Gaucher Disease

Gaucher Disease is caused by mutations of the GBA gene which affects the function of the encoded lysosomal enzyme acid beta-glucosidase by primarily perturbing its protein homeostasis. Heat shock proteins are well known cytoprotective molecules with functions in protein homeostasis and lysosomal function. The investigational drug arimoclomol is a well-characterized HSP amplifier and has been extensively clinically tested. Importantly, arimoclomol efficiently crosses the blood-brain-barrier presenting an opportunity to target the neurological manifestations of GD, which remains without a disease-modifying therapy. In the present study, we found that arimoclomol induced relevant HSPs such as ER-resident HSP70 (BiP) and enhanced the folding, maturation, activity and correct cellular localization of mutated GCase across several genotypes including the common L444P and N370S mutations in primary cells from GD patients. These effects where recapitulated in a human neuronal model of GD obtained by differentiation of multipotent adult stem cells. These data demonstrate the potential of HSP-targeting therapies in GCase-deficiencies and strongly support the clinical development of arimoclomol as a potential first therapeutic option for the neuronopathic forms of GD.