Therapeutic Role of Pharmacological Chaperones in Lysosomal Storage Disorders: A Review of the Evidence and Informed Approach to Reclassification

Abstract

The treatment landscape for lysosomal storage disorders (LSDs) is rapidly evolving. An increase in the number of preclinical and clinical studies in the last decade has demonstrated that pharmacological chaperones are a feasible alternative to enzyme replacement therapy (ERT) for individuals with LSDs. A systematic search was performed to retrieve and critically assess the evidence from preclinical and clinical applications of pharmacological chaperones in the treatment of LSDs and to elucidate the mechanisms by which they could be effective in clinical practice. Publications were screened according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) reporting guidelines. Fifty-two articles evaluating 12 small molecules for the treatment of seven LSDs are included in this review. Overall, a substantial amount of preclinical and clinical data support the potential of pharmacological chaperones as treatments for Fabry disease, Gaucher disease, and Pompe disease. Most of the available clinical evidence evaluated migalastat for the treatment of Fabry disease. There was a lack of consistency in the terminology used to describe pharmacological chaperones in the literature. Therefore, the new small molecule chaperone (SMC) classification system is proposed to inform a standardized approach for new, emerging small molecule therapies in LSDs.

Keywords: Fabry disease; Gaucher disease; Niemann–Pick disease type C; Pompe disease; lysosomal storage disorders; molecular chaperone.

Figure 1

Literature evidence map for chaperones in lysosomal storage disorders. Orange circles = preclinical studies. Blue squares = clinical studies. Closed squares = one study; open square = 2 articles reporting data from the same study. ^a One citation reported an analysis including both chaperones N-butyl-deoxynojirimycin (NB-DNJ) and 1-deoxynojirimycin (DNJ), counted twice. Abbreviations: DGJ, 1-deoxygalactonojirimycin/migalastat; DNJ, 1-deoxynojirimycin; NB-DNJ, N-butyl-deoxynojirimycin/miglustat; NN-DNJ, N-Nonyldeoxynojirimycin; NOEV, N-octyl-4-epi-beta-valienamine; NPC, Niemann–Pick Disease Type C; MPSI, Muco-polysaccharidosis 1.

Figure 2

Reclassification of small molecule chaperones (SMC) into two distinct pathways: monotherapy chaperone (left panel) or combined/co-administered stabilizer (right panel). Chaperone/endogenous lysosomal enzyme (left): (1) Chaperone leaves circulation by paracellular diffusion, enters the cell, and distributes to the ER within target tissues; (2) synthesis of unstable endogenous mutant enzyme protein on the rough ER; (3) chaperone binds and stabilizes endogenous enzyme by facilitating the correct folding required to progress from the ER to the Golgi; (4) enzyme–chaperone complex transported through Golgi; (5) enzyme–chaperone complex phosphorylated and binds to CI-MPR; (6) enzyme–chaperone complex transported through endosomes to lysosome; (7) chaperone dissociates from endogenous enzyme due to low pH and high substrate concentration in the lysosome, resulting in endogenous enzyme being available within lysosome. Stabilizer/exogenously administered lysosomal enzyme (right): (1) Stabilizer binds to exogenously administered enzyme in the blood; (2a) enzyme–stabilizer complex binds to CI-MPR; (2b) without the stabilizer, less active enzyme is available to bind to the CI-MPR; (3) enzyme–stabilizer complex undergoes endocytosis into the muscle cell after binding CI-MPR; (4) enzyme–stabilizer complex transported through endosomes; (5) enzyme–stabilizer complex transported to lysosome; (6) stabilizer dissociates from exogenous enzyme in the lysosome. Abbreviations: CI-MPR, cation-independent mannose 6-phosphate receptor; ER, endoplasmic reticulum; ERT, enzyme replacement therapy.