c5e25eb151a41aa2b25a04e5356e9ea3 pmc_34204583.pdf 6e239966e41198473b60764538da9be58d6f97fa pmc_34204583.pdf 79f6e066dae41efc6572b9b02ab63c2b6a8c7d9219996e8a748778f51323a78c pmc_34204583.pdf Title: Human -Galactosidase A Mutants: Priceless Tools to Develop Novel Therapies for Fabry Disease Subject: Fabry disease (FD) is a lysosomal storage disease caused by mutations in the gene for the -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. Keywords: alpha-galactosidase A; Fabry disease; pharmacological chaperones; rare diseases; enzyme replacement therapy Author: Andrea Modrego, Marilla Amaranto, Agustina Godino, Rosa Mendoza, José Luis Barra and José Luis Corchero Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Mon Jun 21 03:43:16 2021 CEST ModDate: Mon Jun 21 03:45:36 2021 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 17 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1664455 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- BTFGED+VnURWPalladioL-Bold Type 1 Custom yes yes no 10 0 IHGURL+EURM7 Type 1 Builtin yes yes no 15 0 MWHIBA+VnURWPalladioL Type 1 Custom yes yes no 19 0 QDCWHF+EURM10 Type 1 Builtin yes yes no 23 0 PYRJTD+URWPalladioL-Ital Type 1 Custom yes yes no 27 0 OJVOYB+URWPalladioL-Bold Type 1 Custom yes yes 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MIMEtype: application/pdf PDFMetadata: Objects: 486 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Fabry Disease Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: The Human Gla Enzyme Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Children: Item: Title: Structure of GLA Enzyme Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: GLA Synthesis and Trafficking Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: Catalytic Mechanism of GLA Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: Current Treatments For FD Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Children: Item: Title: Enzyme Replacement Therapy Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: Pharmacological Chaperones Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: GLA Mutations Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Children: Item: Title: Most Frequent GLA Mutant Variants Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Item: Title: Most Frequently Mutated Residues Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77f99a05 Item: Title: Nonsense Mutations Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@63440df3 Item: Title: Location-Dependent Biological Effect of Mutations Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@3aeaafa6 Item: Title: GLA Mutants with Low Activity and/or Stability Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@76a3e297 Item: Title: GLA Mutants with Improved Activity and/or Stability Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4d3167f4 Item: Title: Other Modifications in Recombinant GLAs in Innovative FD Therapies Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@ed9d034 Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@6121c9d6 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@87f383f Info: Title: Human -Galactosidase A Mutants: Priceless Tools to Develop Novel Therapies for Fabry Disease Author: Andrea Modrego, Marilla Amaranto, Agustina Godino, Rosa Mendoza, José Luis Barra and José Luis Corchero Subject: Fabry disease (FD) is a lysosomal storage disease caused by mutations in the gene for the -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. 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