title: Pharmacological Chaperone Therapy: Preclinical Development, Clinical Translation, and Prospects for the Treatment of Lysosomal Storage Disorders.
abstract: Lysosomal storage disorders (LSDs) are a group of inborn metabolic diseases caused by mutations in genes that encode proteins involved in different lysosomal functions, in most instances acidic hydrolases. Different therapeutic approaches have been developed to treat these disorders. Pharmacological chaperone therapy (PCT) is an emerging approach based on small-molecule ligands that selectively bind and stabilize mutant enzymes, increase their cellular levels, and improve lysosomal trafficking and activity. Compared to other approaches, PCT shows advantages, particularly in terms of oral administration, broad biodistribution, and positive impact on patients' quality of life. After preclinical in vitro and in vivo studies, PCT is now being translated in the first clinical trials, either as monotherapy or in combination with enzyme replacement therapy, for some of the most prevalent LSDs. For some LSDs, the results of the first clinical trials are encouraging and warrant further development. Future research in the field of PCT will be directed toward the identification of novel chaperones, including new allosteric drugs, and the exploitation of synergies between chaperone treatment and other therapeutic approaches.
authors.affiliation: Department of Translational Medical Sciences, Section of Pediatrics, Federico II University, Naples, Italy; Telethon Institute of Genetics and Medicine, Pozzuoli, Italy. Electronic address: parenti@unina.it.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Parenti
authors.affiliation: Department of Translational Medical Sciences, Section of Pediatrics, Federico II University, Naples, Italy.
authors.forename: Generoso
authors.initials: G
authors.lastname: Andria
authors.affiliation: Amicus Therapeutics, Cranbury, New Jersey, USA.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Valenzano
mesh_terms: D004795:Enzyme Stability / Q000187:drug effects*; D006801:Humans; D008024:Ligands; D016464:Lysosomal Storage Diseases / Q000235:genetics / Q000628:therapy*; D008247:Lysosomes / Q000187:drug effects / Q000235:genetics / Q000473:pathology; D018832:Molecular Chaperones / Q000627:therapeutic use*; D014176:Protein Biosynthesis / Q000187:drug effects; D017510:Protein Folding / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects
chemical_list: D008024:Ligands; D018832:Molecular Chaperones