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

• Published in: International journal of molecular sciences Vol. 21; no. 3; p. 956
• Main Authors: Lukas, Jan, Cimmaruta, Chiara, Liguori, Ludovica, Pantoom, Supansa, Iwanov, Katharina, Petters, Janine, Hund, Christina, Bunschkowski, Maik, Hermann, Andreas, Cubellis, Maria Vittoria, Rolfs, Arndt
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 31-01-2020; MDPI
• Subjects: 1-Deoxynojirimycin - analogs & derivatives; 1-Deoxynojirimycin - therapeutic use; Agreements; alpha-Galactosidase - genetics; alpha-Galactosidase - metabolism; Amino Acid Substitution; Assaying; Biochemistry; Biological Assay; Cell culture; Classification; Criteria; Enzymatic activity; Enzyme activity; Enzymes; Fabry Disease - drug therapy; Fabry Disease - genetics; Fabry Disease - metabolism; Fabry's disease; Galactosidase; Genetic diversity; Glycosphingolipids; Health services; HEK293 Cells; Humans; Intravenous administration; Lysosomal storage diseases; lysosomal storage disorders; method comparison study; Mutation; Patients; personalized medicine; pharmacological chaperones; Pharmacology; Precision Medicine; Reproducibility; Reproducibility of Results; Retrospective Studies; pharmacological chaperones; Lysosomal storage disorders; method comparison study; personalized medicine
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21030956

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 (
). 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
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
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
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.