Abstract
Fabry disease (FD) results from mutations in the gene (GLA) that encodes the lysosomal enzyme α-galactosidase A (α-Gal A), and involves pathological accumulation of globotriaosylceramide (GL-3) and globotriaosylsphingosine (lyso-Gb3). Migalastat hydrochloride (GR181413A) is a pharmacological chaperone that selectively binds, stabilizes, and increases cellular levels of α-Gal A. Oral administration of migalastat HCl reduces tissue GL-3 in Fabry transgenic mice, and in urine and kidneys of some FD patients. A liquid chromatography-tandem mass spectrometry method was developed to measure lyso-Gb3 in mouse tissues and human plasma. Oral administration of migalastat HCl to transgenic mice reduced elevated lyso-Gb3 levels up to 64%, 59%, and 81% in kidney, heart, and skin, respectively, generally equal to or greater than observed for GL-3. Furthermore, baseline plasma lyso-Gb3 levels were markedly elevated in six male FD patients enrolled in Phase 2 studies. Oral administration of migalastat HCl (150 mg QOD) reduced urine GL-3 and plasma lyso-Gb3 in three subjects (range: 15% to 46% within 48 weeks of treatment). In contrast, three showed no reductions in either substrate. These results suggest that measurement of tissue and/or plasma lyso-Gb3 is feasible and may be warranted in future studies of migalastat HCl or other new potential therapies for FD.
Highlights
Fabry disease (FD, OMIM # 301500) is an X-linked lysosomal storage disorder caused by mutations in the gene (GLA; Gene/ Locus MIM # 300644, Ref Seq NM_000169.2) that encodes the lysosomal hydrolase a-galactosidase A (a-Gal A, EC 3.2.1.22) [1]
The selected reaction monitoring (SRM) transition m/ z = 460 R m/z = 280 was used to quantify glucopsychosine in plasma and tissue homogenates
Lyso-Gb3, a deacylated analogue of GL-3, the primary substrate which accumulates in FD, has recently been shown to be elevated in the plasma of Fabry patients and is an important new indicator of FD [8]
Summary
Fabry disease (FD, OMIM # 301500) is an X-linked lysosomal storage disorder caused by mutations in the gene (GLA; Gene/ Locus MIM # 300644, Ref Seq NM_000169.2) that encodes the lysosomal hydrolase a-galactosidase A (a-Gal A, EC 3.2.1.22) [1]. The clinical presentation of FD spans a broad spectrum of severity, and roughly correlates with residual a-Gal A activity [1]. Males with FD who have little or no detectable a-Gal A activity are commonly referred to as ‘‘classic’’ Fabry patients and are most severely affected. Female Fabry patients may be mildly symptomatic or as severely affected as classic males [6]. Many individuals with FD present with a ‘‘later-onset’’ form, and generally have higher residual a-Gal A activity than ‘‘classic’’ patients [7]
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