Human α-Galactosidase A Mutants: Priceless Tools to Develop Novel Therapies for Fabry Disease

• Published in: International journal of molecular sciences Vol. 22; no. 12; p. 6518
• Main Authors: Modrego, Andrea, Amaranto, Marilla, Godino, Agustina, Mendoza, Rosa, Barra, José Luis, Corchero, José Luis
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 17-06-2021; MDPI
• Subjects: Alleles; alpha-Galactosidase - chemistry; alpha-Galactosidase - genetics; alpha-Galactosidase - metabolism; alpha-galactosidase A; Animals; Biomarkers; Chemical bonds; Combined Modality Therapy - adverse effects; Combined Modality Therapy - methods; Disease Management; Drug development; Endoplasmic reticulum; Enzymatic activity; Enzyme Activation; enzyme replacement therapy; Enzymes; Fabry disease; Fabry Disease - diagnosis; Fabry Disease - genetics; Fabry Disease - metabolism; Fabry Disease - therapy; Fabry's disease; Females; Galactosidase; Gene therapy; Genetic Predisposition to Disease; Genotype & phenotype; Globotriaosylceramide; Glycosphingolipids; Humans; Lysosomal storage diseases; Mutants; Mutation; pharmacological chaperones; Pharmacology; Protein folding; Proteins; rare diseases; Review; Structure-Activity Relationship; Treatment Outcome; X chromosomes; rare diseases; Fabry disease; alpha-galactosidase A; pharmacological chaperones; enzyme replacement therapy
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22126518

Fabry disease (FD) is a lysosomal storage disease caused by mutations in the gene for the α-galactosidase A (GLA) enzyme. The absence of the enzyme or its activity results in the accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3), in different tissues, leading to a wide range of clinical manifestations. More than 1000 natural variants have been described in the GLA gene, most of them affecting proper protein folding and enzymatic activity. Currently, FD is treated by enzyme replacement therapy (ERT) or pharmacological chaperone therapy (PCT). However, as both approaches show specific drawbacks, new strategies (such as new forms of ERT, organ/cell transplant, substrate reduction therapy, or gene therapy) are under extensive study. In this review, we summarize GLA mutants described so far and discuss their putative application for the development of novel drugs for the treatment of FD. Unfavorable mutants with lower activities and stabilities than wild-type enzymes could serve as tools for the development of new pharmacological chaperones. On the other hand, GLA mutants showing improved enzymatic activity have been identified and produced in vitro. Such mutants could overcome several complications associated with current ERT, as lower-dose infusions of these mutants could achieve a therapeutic effect equivalent to that of the wild-type enzyme.