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.

Figure 1.
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