Human α-galactosidase a mutants : Priceless tools to develop novel therapies for fabry disease
Modrego, Andrea (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Amaranto, Marilla (Universidad Nacional de Córdoba (Argentina))
Godino, Agustina (Universidad Nacional de Córdoba (Argentina))
Mendoza, Rosa (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Barra, José Luis (Universidad Nacional de Córdoba (Argentina))
Corchero Nieto, José Luis (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia)

Fecha:	2021
Resumen:	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.
Ayudas:	European Commission 720942 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-229229
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Alpha-galactosidase A ; Fabry disease ; Pharmacological chaperones ; Rare diseases ; Enzyme replacement therapy
Publicado en:	International journal of molecular sciences, Vol. 22, Issue 12 (June 2021) , art. 6518, ISSN 1422-0067

DOI: 10.3390/ijms22126518
PMID: 34204583

17 p, 1.2 MB

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