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

Abstract

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.

Human kidney organoids reveal the role of glutathione in Fabry disease

“…Recently, identification of new molecules through high-throughput screening has emerged as an attractive approach to search for new pharmacological chaperone therapies for Fabry disease 35 . Kidney organoids derived from hPSCs have shown great potential in high-throughput screening 36 .…”

“…In this context, GLA-mutant kidney organoids can also be applied for high-throughput screening systems for Fabry disease. This strategy will help shorten the time required for treatment development and will reduce costs 35 .…”

Identification and Characterization of a Thermostable GH36 α-Galactosidase from Anoxybacillus vitaminiphilus WMF1 and Its Application in Synthesizing Isofloridoside by Reverse Hydrolysis

“…α-Galactosidases are known to be potentially useful in diverse applications. In the pharmaceutical industry, they have been shown to be effective against Fabry disease [ 4 ]. Additionally, α-galactosidases, which act as hydrolases in nature, can be used in the food industry, such as the hydrolysis of galactosyl residues from raffinose to improve the crystallization of sucrose [ 5 ].…”

Rare Monogenic Diseases: Molecular Pathophysiology and Novel Therapies

“…However, depending on the random X chromosome inactivation, female patients may exhibit milder signs and symptoms. Modrego et al provide a systematic overview of the knowledge stemming from the countless mutations affecting the GLA gene in FD patients [ 4 ]. By analyzing the structure-function relationships of GLA enzyme, these authors illustrate the potential use of recombinant GLA mutants characterized by increased enzyme activity, improved protein stability or lower immunogenicity.…”

“…By analyzing the structure-function relationships of GLA enzyme, these authors illustrate the potential use of recombinant GLA mutants characterized by increased enzyme activity, improved protein stability or lower immunogenicity. Altogether, the proposed approach may generate novel therapeutics to promptly improve ERT and PCT for the treatment of FD [ 4 ]. Mucopolysaccharidosis type II (MPS II) is another X-linked LSD caused by a mutation in the gene encoding iduronate 2-sulphatase ( IDS ).…”