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

1
Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, 08193 Barcelona, Spain
2
Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas (CSIC), 28049 Madrid, Spain
3
Departamento de Química Biológica Ranwel Caputto, Centro de Investigaciones en Química Biológica de Córdoba, CONICET, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba 5016, Argentina
4
Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), c/Monforte de Lemos 3–5, 28029 Madrid, Spain
5
Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, Bellaterra, 08193 Barcelona, Spain
*
Author to whom correspondence should be addressed.
Academic Editor: Ivano Condò
Int. J. Mol. Sci. 2021, 22(12), 6518; https://doi.org/10.3390/ijms22126518
Received: 17 May 2021 / Revised: 9 June 2021 / Accepted: 14 June 2021 / Published: 17 June 2021
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. View Full-Text
Keywords: alpha-galactosidase A; Fabry disease; pharmacological chaperones; rare diseases; enzyme replacement therapy alpha-galactosidase A; Fabry disease; pharmacological chaperones; rare diseases; enzyme replacement therapy
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MDPI and ACS Style

Modrego, A.; Amaranto, M.; Godino, A.; Mendoza, R.; Barra, J.L.; Corchero, J.L. Human α-Galactosidase A Mutants: Priceless Tools to Develop Novel Therapies for Fabry Disease. Int. J. Mol. Sci. 2021, 22, 6518. https://doi.org/10.3390/ijms22126518

AMA Style

Modrego A, Amaranto M, Godino A, Mendoza R, Barra JL, Corchero JL. Human α-Galactosidase A Mutants: Priceless Tools to Develop Novel Therapies for Fabry Disease. International Journal of Molecular Sciences. 2021; 22(12):6518. https://doi.org/10.3390/ijms22126518

Chicago/Turabian Style

Modrego, Andrea, Marilla Amaranto, Agustina Godino, Rosa Mendoza, José L. Barra, and José L. Corchero. 2021. "Human α-Galactosidase A Mutants: Priceless Tools to Develop Novel Therapies for Fabry Disease" International Journal of Molecular Sciences 22, no. 12: 6518. https://doi.org/10.3390/ijms22126518

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