Treating lysosomal storage diseases with pharmacological chaperones: from concept to clinics
Open Access
- 5 August 2009
- journal article
- review article
- Published by Springer Science and Business Media LLC in EMBO Molecular Medicine
- Vol. 1 (5), 268-279
- https://doi.org/10.1002/emmm.200900036
Abstract
Lysosomal storage diseases (LSDs) are a group of genetic disorders due to defects in any aspect of lysosomal biology. During the past two decades, different approaches have been introduced for the treatment of these conditions. Among them, enzyme replacement therapy (ERT) represented a major advance and is used successfully in the treatment of some of these disorders. However, ERT has limitations such as insufficient biodistribution of recombinant enzymes and high costs. An emerging strategy for the treatment of LSDs is pharmacological chaperone therapy (PCT), based on the use of chaperone molecules that assist the folding of mutated enzymes and improve their stability and lysosomal trafficking. After proof‐of‐concept studies, PCT is now being translated into clinical applications for Fabry, Gaucher and Pompe disease. This approach, however, can only be applied to patients carrying chaperone‐responsive mutations. The recent demonstration of a synergistic effect of chaperones and ERT expands the applications of PCT and prompts a re‐evaluation of their therapeutic use and potential. This review discusses the strengths and drawbacks of the potential therapies available for LSDs and proposes that future research should be directed towards the development of treatment protocols based on the combination of different therapies to improve the clinical outcome of LSD patients.Keywords
This publication has 71 references indexed in Scilit:
- The Pharmacological Chaperone N-butyldeoxynojirimycin Enhances Enzyme Replacement Therapy in Pompe Disease FibroblastsMolecular Therapy, 2009
- Glycoengineered Acid α-Glucosidase With Improved Efficacy at Correcting the Metabolic Aberrations and Motor Function Deficits in a Mouse Model of Pompe DiseaseMolecular Therapy, 2009
- Effects of pH and Iminosugar Pharmacological Chaperones on Lysosomal Glycosidase Structure and StabilityBiochemistry, 2009
- Identification of Pharmacological Chaperones for Gaucher Disease and Characterization of Their Effects on β‐Glucocerebrosidase by Hydrogen/Deuterium Exchange Mass SpectrometryChemBioChem, 2008
- Isofagomine Induced Stabilization of GlucocerebrosidaseChemBioChem, 2008
- Chemical and Biological Approaches Synergize to Ameliorate Protein-Folding DiseasesCell, 2008
- Isofagomine increases lysosomal delivery of exogenous glucocerebrosidaseBiochemical and Biophysical Research Communications, 2008
- Chemically modified β-glucuronidase crosses blood–brain barrier and clears neuronal storage in murine mucopolysaccharidosis VIIProceedings of the National Academy of Sciences, 2008
- Three classes of glucocerebrosidase inhibitors identified by quantitative high-throughput screening are chaperone leads for Gaucher diseaseProceedings of the National Academy of Sciences, 2007
- Autophagy and Mistargeting of Therapeutic Enzyme in Skeletal Muscle in Pompe DiseaseMolecular Therapy, 2006