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Pharmacological Chaperones: A Therapeutic Approach for Diseases Caused by Destabilizing Missense Mutations
Article

Assessment of Gene Variant Amenability for Pharmacological Chaperone Therapy with 1-Deoxygalactonojirimycin in Fabry Disease

1
Translational Neurodegeneration Section “Albrecht-Kossel“, Department of Neurology, University Medical Center Rostock, 18147 Rostock, Germany
2
Center for Transdisciplinary Neurosciences Rostock (CTNR), University Medical Center Rostock, University of Rostock, 18147 Rostock, Germany
3
Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Università degli Studi della Campania “Luigi Vanvitelli”, 81100 Caserta, Italy
4
Institute of Biomolecular Chemistry, CNR, 80078 Pozzuoli, Italy
5
Centogene AG, 18055 Rostock, Germany
6
German Center for Neurodegenerative Diseases (DZNE) Rostock/Greifswald, 18147 Rostock, Germany
7
Department of Biology, University Federico II, 80126 Naples, Italy
8
University Medical Center Rostock, University of Rostock, 18057 Rostock, Germany
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(3), 956; https://doi.org/10.3390/ijms21030956
Received: 21 December 2019 / Revised: 20 January 2020 / Accepted: 29 January 2020 / Published: 31 January 2020
(This article belongs to the Special Issue Rare Diseases: Molecular Mechanisms and Therapeutic Strategies (II))
Fabry disease is one of the most common lysosomal storage disorders caused by mutations in the gene encoding lysosomal α-galactosidase A (α-Gal A) and resultant accumulation of glycosphingolipids. The sugar mimetic 1-deoxygalactonojirimycin (DGJ), an orally available pharmacological chaperone, was clinically approved as an alternative to intravenous enzyme replacement therapy. The decision as to whether a patient should be treated with DGJ depends on the genetic variant within the α-galactosidase A encoding gene (GLA). A good laboratory practice (GLP)-validated cell culture-based assay to investigate the biochemical responsiveness of the variants is currently the only source available to obtain pivotal information about susceptibility to treatment. Herein, variants were defined amenable when an absolute increase in enzyme activity of ≥3% of wild type enzyme activity and a relative increase in enzyme activity of ≥1.2-fold was achieved following DGJ treatment. Efficacy testing was carried out for over 1000 identified GLA variants in cell culture. Recent data suggest that about one-third of the variants comply with the amenability criteria. A recent study highlighted the impact of inter-assay variability on DGJ amenability, thereby reducing the power of the assay to predict eligible patients. This prompted us to compare our own α-galactosidase A enzyme activity data in a very similar in-house developed assay with those from the GLP assay. In an essentially retrospective approach, we reviewed 148 GLA gene variants from our former studies for which enzyme data from the GLP study were available and added novel data for 30 variants. We also present data for 18 GLA gene variants for which no data from the GLP assay are currently available. We found that both differences in experimental biochemical data and the criteria for the classification of amenability cause inter-assay discrepancy. We conclude that low baseline activity, borderline biochemical responsiveness, and inter-assay discrepancy are alarm signals for misclassifying a variant that must not be ignored. Furthermore, there is no solid basis for setting a minimum response threshold on which a clinical indication with DGJ can be justified. View Full-Text
Keywords: Lysosomal storage disorders; pharmacological chaperones; method comparison study; personalized medicine Lysosomal storage disorders; pharmacological chaperones; method comparison study; personalized medicine
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MDPI and ACS Style

Lukas, J.; Cimmaruta, C.; Liguori, L.; Pantoom, S.; Iwanov, K.; Petters, J.; Hund, C.; Bunschkowski, M.; Hermann, A.; Cubellis, M.V.; Rolfs, A. Assessment of Gene Variant Amenability for Pharmacological Chaperone Therapy with 1-Deoxygalactonojirimycin in Fabry Disease. Int. J. Mol. Sci. 2020, 21, 956. https://doi.org/10.3390/ijms21030956

AMA Style

Lukas J, Cimmaruta C, Liguori L, Pantoom S, Iwanov K, Petters J, Hund C, Bunschkowski M, Hermann A, Cubellis MV, Rolfs A. Assessment of Gene Variant Amenability for Pharmacological Chaperone Therapy with 1-Deoxygalactonojirimycin in Fabry Disease. International Journal of Molecular Sciences. 2020; 21(3):956. https://doi.org/10.3390/ijms21030956

Chicago/Turabian Style

Lukas, Jan, Chiara Cimmaruta, Ludovica Liguori, Supansa Pantoom, Katharina Iwanov, Janine Petters, Christina Hund, Maik Bunschkowski, Andreas Hermann, Maria V. Cubellis, and Arndt Rolfs. 2020. "Assessment of Gene Variant Amenability for Pharmacological Chaperone Therapy with 1-Deoxygalactonojirimycin in Fabry Disease" International Journal of Molecular Sciences 21, no. 3: 956. https://doi.org/10.3390/ijms21030956

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