Abstract
Fabry disease is an X-linked multisystemic disorder caused by the impairment of lysosomal α-Galactosidase A, which leads to the progressive accumulation of glycosphingolipids and to defective lysosomal metabolism. Currently, Fabry disease is treated by enzyme replacement therapy or the orally administrated pharmacological chaperone Migalastat. Both therapeutic strategies present limitations, since enzyme replacement therapy has shown low half-life and bioavailability, while Migalastat is only approved for patients with specific mutations. The aim of this work was to assess the efficacy of PBX galactose analogues to stabilize α-Galactosidase A and therefore evaluate their potential use in Fabry patients with mutations that are not amenable to the treatment with Migalastat. We demonstrated that PBX compounds are safe and effective concerning stabilization of α-Galactosidase A in relevant cellular models of the disease, as assessed by enzymatic activity measurements, molecular modelling, and cell viability assays. This experimental evidence suggests that PBX compounds are promising candidates for the treatment of Fabry disease caused by mutations which affect the folding of α-Galactosidase A, even for GLA variants that are not amenable to the treatment with Migalastat.
Highlights
IntroductionFabry Disease (FD, OMIM #301500) is a genetic disorder caused by mutations in GLA (NC_000023.1, Xq22) [1], with an incidence estimated from 1:40,000 to 1:117,000
The enzymatic deficit leads to the progressive accumulation of glycosphingolipids, such as globotriaosylceramide (Gb3) and its deacylated form Lyso-Gb3, within the lysosome of a variety of cell types [4]
The experimental evidence presented in this work suggests that PBX compounds are very promising candidates for the treatment of FD determined by mutations which affect the folding of the protein, even for α-GalA variants that are not amenable to the treatment with Migalastat
Summary
Fabry Disease (FD, OMIM #301500) is a genetic disorder caused by mutations in GLA (NC_000023.1, Xq22) [1], with an incidence estimated from 1:40,000 to 1:117,000. This value can reach up to 1:3000, according to newborn screening studies or including late-onset variants [2,3]. GLA encodes for α-Galactosidase A (α-GalA, EC3.2.1.22), a rate limiting enzyme in lysosomal metabolism. The enzymatic deficit leads to the progressive accumulation of glycosphingolipids, such as globotriaosylceramide (Gb3) and its deacylated form Lyso-Gb3, within the lysosome of a variety of cell types (endothelial cells, smooth muscle cells, renal podocytes, tubular cells, glomerular endothelial, mesangial and interstitial cells, cardiac cardiomyocytes fibroblasts, and nerve cells) [4]. FD courses as Biomolecules 2021, 11, 1856.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
