Faculty Bibliography

Enzyme activity can be deficient in the lysosome because certain newly synthesised mutation-bearing proteins are unstable and prone to misfolding. These structurally defective proteins are detected by the quality control system in the endoplasmic reticulum and subsequently diverted to cellular pathways of degradation. Recent studies have shown that low molecular weight ligands that are competitive inhibitors for some of these lysosomal enzymes can, in subinhibitory concentrations, act as 'chaperones' and rescue the mutant proteins, leading to the reconstitution of their hydrolytic activity within the lysosome. The potential of these agents as a therapeutic option will be dependent on their safety and tolerability profile, and the absence of toxic metabolic byproducts resulting from their use; there should be no or minimal nonspecific interference with other physiological or adaptive cellular activities. Compared with enzyme replacement therapy, the plausible advantages of using small molecule chaperones derive from the ease of oral administration, lack of immunogenicity and the possibility of delivery across the blood-brain barrier; and thus the potential to treat neurodegenerative clinical variants. The major challenges in developing therapies for rare diseases, such as the lysosomal storage disorders (LSDs), include recruitment of a sufficient number of suitable study patients and establishment of the optimal (dose/frequency) regimen to achieve a meaningful outcome. Multiple therapeutic approaches for the LSDs will provide patients with a range of options, which may be adequate as singular strategies or when given in combination. This review examines the characteristics of select agents that represent current candidates for a chaperone-mediated approach to the treatment of a subgroup of the LSDs, specifically the glycosphingolipidoses. Clinical trial experience with the use of these drugs will clarify their position in the management algorithm, which currently has enzyme replacement therapy as its linchpin. A major therapeutic goal would be improved physical and functional wellbeing, leading to increased meaningful survival