The heat shock protein amplifier arimoclomol improves refolding, maturation and lysosomal activity of glucocerebrosidase

Abstract

BackgroundGaucher 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.MethodsWe 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.FindingsWe 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.InterpretationThese 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.FundingThe research was funded by Orphazyme A/S, Copenhagen, Denmark.

Functional characterization of the first missense variant in CEP78 , a founder allele associated with cone‐rod dystrophy, hearing loss, and reduced male fertility

“…No clear ultrastructural defects could be demonstrated in nasal brushes and semen sample however. Remarkably, heterozygous carriers of the missense variant displayed an intermediate cellular phenotype, a feature that has already been described both in ciliary and nonciliary contexts (Fog et al, 2018; Noone et al, 2004). Downstream analysis of the Sonic Hedgehog (SHH) signaling pathway was not informative under the given experimental setup (data not shown).…”

GBA RNAi but not catalytic inhibition of glucocerebrosidase with Conduritol-β-epoxide increases levels of total α-synuclein in SH-SY5Y cells

“…Recently, a group demonstrated a slow release system for ambroxol (Enshaei et al, 2019). Another, interesting recent finding is that Arimoclomol, a heat shock protein amplifier has been shown to increase levels of GCase and GCase activity in GD models (Fog et al, 2018). Therefore, our first study supports the claim that GCase modulation can be a useful treatment for PD and indicates that chaperone therapy enabling correct folding and trafficking of GCase is a promising approach.…”

Pharmacological Chaperones: A Therapeutic Approach for Diseases Caused by Destabilizing Missense Mutations

“…Arimoclomol is an aromatic heteromonocyclic compound that underwent clinical trial phase 3 for Amyotrophic Lateral Sclerosis [92]. It rescues glucocerebrosidase in fibroblasts of Gaucher patients both in terms of quantity and in terms of maturation [93] and prevents aggregation of a missense mutant of rhodopsin, P23H, which is frequently encountered in retinitis pigmentosa [94]. Kelly et al [95] suggested that co-administration of a proteostasis regulator and of pharmacological chaperone could have a synergistic effect on rescuing missense pathogenic mutants.…”