BACKGROUND: Gaucher Disease 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 are well known cytoprotective molecules 
with 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 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 presenting 
an opportunity to target the neurological manifestations of GD, which remains 
without a disease-modifying therapy.
METHODS: We used a range of biological and biochemical in vitro assays to assess 
the effect of arimoclomol on GCase activity in ex vivo systems of primary 
fibroblasts and neuronal-like cells from GD patients.
FINDINGS: 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.
INTERPRETATION: These data demonstrate the potential of HSP-targeting therapies 
in GCase-deficiencies and strongly support the clinical development of 
arimoclomol as a potential therapeutic option for the neuronopathic forms of GD.
FUNDING: The research was funded by Orphazyme A/S, Copenhagen, Denmark.