Human α-galactosidase a mutants: Priceless tools to develop novel therapies for fabry disease

Autores
Modrego, Andrea; Amaranto, Marilla; Godino, Agustina; Mendoza, Rosa; Barra, Jose Luis; Corchero, José Luis
Año de publicación
2021
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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). How-ever, as both approaches show specific drawbacks, new strategies (such as new forms of ERT, or-gan/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 equiv-alent to that of the wild-type enzyme.
Fil: Modrego, Andrea. Universitat Autònoma de Barcelona; España. Consejo Superior de Investigaciones Científicas. Centro Nacional de Biotecnología; España
Fil: Amaranto, Marilla. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina
Fil: Godino, Agustina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina
Fil: Mendoza, Rosa. Universitat Autònoma de Barcelona; España. Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina; España
Fil: Barra, Jose Luis. Universidad Nacional de Córdoba; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina
Fil: Corchero, José Luis. Universitat Autònoma de Barcelona; España. Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina; España
Materia
ALPHA-GALACTOSIDASE A
ENZYME REPLACEMENT THERAPY
FABRY DISEASE
PHARMACOLOGICAL CHAPERONES
RARE DISEASES
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/165898
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/165898
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Human α-galactosidase a mutants: Priceless tools to develop novel therapies for fabry diseaseModrego, AndreaAmaranto, MarillaGodino, AgustinaMendoza, RosaBarra, Jose LuisCorchero, José LuisALPHA-GALACTOSIDASE AENZYME REPLACEMENT THERAPYFABRY DISEASEPHARMACOLOGICAL CHAPERONESRARE DISEASEShttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Fabry 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). How-ever, as both approaches show specific drawbacks, new strategies (such as new forms of ERT, or-gan/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 equiv-alent to that of the wild-type enzyme.Fil: Modrego, Andrea. Universitat Autònoma de Barcelona; España. Consejo Superior de Investigaciones Científicas. Centro Nacional de Biotecnología; EspañaFil: Amaranto, Marilla. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Godino, Agustina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Mendoza, Rosa. Universitat Autònoma de Barcelona; España. Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina; EspañaFil: Barra, Jose Luis. Universidad Nacional de Córdoba; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Corchero, José Luis. Universitat Autònoma de Barcelona; España. Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina; EspañaMDPI AG2021-06info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/165898Modrego, Andrea; Amaranto, Marilla; Godino, Agustina; Mendoza, Rosa; Barra, Jose Luis; et al.; Human α-galactosidase a mutants: Priceless tools to develop novel therapies for fabry disease; MDPI AG; International Journal of Molecular Sciences; 22; 12; 6-2021; 1-181661-65961422-0067CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.3390/ijms22126518info:eu-repo/semantics/altIdentifier/url/https://www.mdpi.com/1422-0067/22/12/6518info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:23:58Zoai:ri.conicet.gov.ar:11336/165898instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 10:23:58.856CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Human α-galactosidase a mutants: Priceless tools to develop novel therapies for fabry disease
title Human α-galactosidase a mutants: Priceless tools to develop novel therapies for fabry disease
spellingShingle Human α-galactosidase a mutants: Priceless tools to develop novel therapies for fabry disease
Modrego, Andrea
ALPHA-GALACTOSIDASE A
ENZYME REPLACEMENT THERAPY
FABRY DISEASE
PHARMACOLOGICAL CHAPERONES
RARE DISEASES
title_short Human α-galactosidase a mutants: Priceless tools to develop novel therapies for fabry disease
title_full Human α-galactosidase a mutants: Priceless tools to develop novel therapies for fabry disease
title_fullStr Human α-galactosidase a mutants: Priceless tools to develop novel therapies for fabry disease
title_full_unstemmed Human α-galactosidase a mutants: Priceless tools to develop novel therapies for fabry disease
title_sort Human α-galactosidase a mutants: Priceless tools to develop novel therapies for fabry disease
dc.creator.none.fl_str_mv Modrego, Andrea
Amaranto, Marilla
Godino, Agustina
Mendoza, Rosa
Barra, Jose Luis
Corchero, José Luis
author Modrego, Andrea
author_facet Modrego, Andrea
Amaranto, Marilla
Godino, Agustina
Mendoza, Rosa
Barra, Jose Luis
Corchero, José Luis
author_role author
author2 Amaranto, Marilla
Godino, Agustina
Mendoza, Rosa
Barra, Jose Luis
Corchero, José Luis
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv ALPHA-GALACTOSIDASE A
ENZYME REPLACEMENT THERAPY
FABRY DISEASE
PHARMACOLOGICAL CHAPERONES
RARE DISEASES
topic ALPHA-GALACTOSIDASE A
ENZYME REPLACEMENT THERAPY
FABRY DISEASE
PHARMACOLOGICAL CHAPERONES
RARE DISEASES
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv 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). How-ever, as both approaches show specific drawbacks, new strategies (such as new forms of ERT, or-gan/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 equiv-alent to that of the wild-type enzyme.
Fil: Modrego, Andrea. Universitat Autònoma de Barcelona; España. Consejo Superior de Investigaciones Científicas. Centro Nacional de Biotecnología; España
Fil: Amaranto, Marilla. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina
Fil: Godino, Agustina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina
Fil: Mendoza, Rosa. Universitat Autònoma de Barcelona; España. Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina; España
Fil: Barra, Jose Luis. Universidad Nacional de Córdoba; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina
Fil: Corchero, José Luis. Universitat Autònoma de Barcelona; España. Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina; España
description 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). How-ever, as both approaches show specific drawbacks, new strategies (such as new forms of ERT, or-gan/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 equiv-alent to that of the wild-type enzyme.
publishDate 2021
dc.date.none.fl_str_mv 2021-06
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/165898
Modrego, Andrea; Amaranto, Marilla; Godino, Agustina; Mendoza, Rosa; Barra, Jose Luis; et al.; Human α-galactosidase a mutants: Priceless tools to develop novel therapies for fabry disease; MDPI AG; International Journal of Molecular Sciences; 22; 12; 6-2021; 1-18
1661-6596
1422-0067
CONICET Digital
CONICET
url http://hdl.handle.net/11336/165898
identifier_str_mv Modrego, Andrea; Amaranto, Marilla; Godino, Agustina; Mendoza, Rosa; Barra, Jose Luis; et al.; Human α-galactosidase a mutants: Priceless tools to develop novel therapies for fabry disease; MDPI AG; International Journal of Molecular Sciences; 22; 12; 6-2021; 1-18
1661-6596
1422-0067
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.3390/ijms22126518
info:eu-repo/semantics/altIdentifier/url/https://www.mdpi.com/1422-0067/22/12/6518
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv MDPI AG
publisher.none.fl_str_mv MDPI AG
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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