Coformulation of a Novel Human α -Galactosidase A With the Pharmacological Chaperone AT1001 Leads to Improved Substrate Reduction in Fabry Mice

Abstract

Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the gene that encodes α-galactosidase A and is characterized by pathological accumulation of globotriaosylceramide and globotriaosylsphingosine. Earlier, the authors demonstrated that oral coadministration of the pharmacological chaperone AT1001 (migalastat HCl; 1-deoxygalactonojirimycin HCl) prior to intravenous administration of enzyme replacement therapy improved the pharmacological properties of the enzyme. In this study, the authors investigated the effects of coformulating AT1001 with a proprietary recombinant human α-galactosidase A (ATB100) into a single intravenous formulation. AT1001 increased the physical stability and reduced aggregation of ATB100 at neutral pH in vitro, and increased the potency for ATB100-mediated globotriaosylceramide reduction in cultured Fabry fibroblasts. In Fabry mice, AT1001 coformulation increased the total exposure of active enzyme, and increased ATB100 levels in cardiomyocytes, cardiac vascular endothelial cells, renal distal tubular epithelial cells, and glomerular cells, cell types that do not show substantial uptake with enzyme replacement therapy alone. Notably, AT1001 coformulation also leads to greater tissue globotriaosylceramide reduction when compared with ATB100 alone, which was positively correlated with reductions in plasma globotriaosylsphingosine. Collectively, these data indicate that intravenous administration of ATB100 coformulated with AT1001 may provide an improved therapy for Fabry disease and thus warrants further investigation.

Using CRISPR/Cas9-Mediated GLA Gene Knockout as an In Vitro Drug Screening Model for Fabry Disease

“…The 1-deoxygalactonojirimycin (DGJ), a pharmacological chaperone, served as a positive control to evaluate the sensitivity of our established GLA-null cells as the platform for screening of the potential drug candidates in maintenance of the intracellular rhα-GLA stability. Previous studies have indicated that 10–100 µM DGJ is sufficient for sustaining the rhα-GLA activity [18,20] As shown in Figure 3C,E, cells co-treated with DGJ significantly increased the rhα-GLA protein levels and the GLA enzyme activity, respectively, in a dose-dependent manner. Collectively, these results suggested that the GLA-null cells are feasible and capable of screening potential drug candidates for maintaining intracellular rhα-GLA stability.…”

“…Administration of the selective PCs to the mutated α-Gal A, particularly the missense mutants [11,12], facilitates the mutated α-Gal A to pass the protein quality control system in endoplasmic reticulum (ER) and potentiates their folding, maturation and/or cellular trafficking, hence resulting in effective lysosomal delivery of α-Gal A [13,14,15,16]. In addition, the selective PC was reported to enhance the ERT efficacy in vivo by prolonging rhα-GLA stability and reducing rhα-GLA degradation [17,18]. These results suggested that the proteostasis network, which consists of pathways that influence protein synthesis, folding, trafficking, disaggregation and degradation in cells, plays an important role in ERT efficacy.…”

The Large Phenotypic Spectrum of Fabry Disease Requires Graduated Diagnosis and Personalized Therapy: A Meta-Analysis Can Help to Differentiate Missense Mutations

“…DGJ can be used in synergy with ERT either co-administrating both drugs intravenously or one orally (DGJ) and the other intravenously (recombinant enzyme). DGJ prolongs the half-life of AGAL in vivo, both in mouse models and in humans and leads to an improved clearance of Gb3 [44,45,46]. …”

Relative Distribution of Gb 3 Isoforms/Analogs in Nod/Scid/Fabry Mice Tissues Determined by Tandem Mass Spectrometry

“…Development of antibodies against the infused enzyme has been observed in some patients [13][14][15]. Other treatments such as chaperone therapy [16,17] and substrate reduction therapy [18] are also under investigation.…”