What is chaperone therapy for Fabry disease?
Pharmacological chaperones are small-molecule ligands that selectively bind to and act upon unstable enzymes to increase cellular enzyme levels and improve lysosomal activity and trafficking.1 Variants of genes encoding lysosomal enzymes in patients with lysosomal storage disorders can cause protein misfolding, enzyme retention within the endoplasmic reticulum or Golgi apparatus, degradation, improper protein processing, and/or defective transport to lysosomes.1,2 In patients with Fabry disease, the lysosomal enzyme alpha-galactosidase A (α-Gal A) may be improperly folded due to missense variants of the GLA gene.3,4 Misfolded α-Gal A variants have residual enzymatic activity but are considered unstable.5 Deficient activity of α-Gal A leads to an accumulation of the glycosphingolipids globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) within almost all cell types and various organs.6-8 In patients with Fabry disease, pharmacological chaperones can bind to α-Gal A to stabilise its structure in the endoplasmic reticulum, thereby allowing proper trafficking of α-Gal A to the lysosomes (Figure 1).9-11 One oral chaperone therapy, migalastat, is available for patients diagnosed with Fabry disease and who have an amenable variant.12 The availability of migalastat differs between countries. For further information, please consult your local prescribing information.
Chaperone therapy corrects the folding error of some missense variants of the GLA gene to facilitate normal trafficking of α-Gal A to the lysosome in patients with Fabry disease.3,9-11
C-ANPROM/INT/FAB/0017; Date of preparation: March 2021
- Parenti G, Andria G, Ballabio A. Lysosomal storage diseases: from pathophysiology to therapy. Annu Rev Med 2015; 66: 471-486.
- Parenti G, Moracci M, Fecarotta S, et al. Pharmacological chaperone therapy for lysosomal storage diseases. Future Med Chem 2014; 6: 1031-1045.
- Garman SC, Garboczi DN. Structural basis of Fabry disease. Mol Genet Metab 2002; 77: 3-11.
- Garman SC, Garboczi DN. The molecular defect leading to Fabry disease: structure of human alpha-galactosidase. J Mol Biol 2004; 337: 319-335.
- Yam GH-F, Bosshard N, Zuber C, et al. Pharmacological chaperone corrects lysosomal storage in Fabry disease caused by trafficking-incompetent variants. Am J Physiol Cell Physiol 2006; 290: C1076-C1082.
- Felis A, Whitlow M, Kraus A, et al. Current and investigational therapeutics for Fabry disease. Kidney Int Rep 2019; 5: 407-413.
- Schiffmann R, Hughes DA, Linthorst GE, et al. Screening, diagnosis, and management of patients with Fabry disease: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) Controversies Conference. Kidney Int 2017; 91: 284-293.
- Brady RO, Gal AE, Bradley RM, et al. Enzymatic defect in Fabry's disease. Ceramidetrihexosidase deficiency. N Engl J Med 1967; 276: 1163-1167.
- McCafferty EH, Scott LJ. Migalastat: a review in Fabry disease. Drugs 2019; 79: 543-554.
- Fan JQ, Ishii S, Asano N, et al. Accelerated transport and maturation of lysosomal alpha-galactosidase A in Fabry lymphoblasts by an enzyme inhibitor. Nat Med 1999; 5: 112-115.
- Yam GH-F, Zuber C, Roth J. A synthetic chaperone corrects the trafficking defect and disease phenotype in a protein misfolding disorder. FASEB J 2005; 19: 12-18.
- Amicus Therapeutics Europe Ltd. Galafold® EU Summary of Product Characteristics. Last updated August 2020.