Arimoclomol as a potential therapy for neuronopathic Gaucher Disease

Abstract

These studies provide proof-of-concept for the development of the Heat shock protein amplifier, arimoclomol, as a potential therapy for neuronopathic Gaucher disease as arimoclomol enhances folding, maturation, activity and correct localization of GCase in neuronopathic and non-neuronopathic Gaucher disease models. AbstractGaucher Disease (GD) is caused by mutations of the GBA gene which encodes the lysosomal enzyme acid beta-glucosidase (GCase). GBA mutations commonly affect GCase function by perturbing its protein homeostasis rather than its catalytic activity. Heat shock proteins (HSPs) are well known cytoprotective molecules with numerous functions in protein homeostasis and lysosomal function and their manipulation has been suggested as a potential therapeutic strategy for GD. The investigational drug arimoclomol, which is currently in phase II/III clinical trials, is a well-characterized HSP amplifier and has been extensively clinically tested. Importantly, arimoclomol efficiently crosses the blood-brain-barrier hereby 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 a number of 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. Taken together, 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.