Lysosomal leukocyte β-d-glucuronidase during enzyme replacement therapy in Fabry disease

Goi, G.; Massaccesi, Luca; Herrera, C.J. Baquero; Lombardo, A.; Tettamanti, Guido; Burlina, Alberto

doi:10.1016/j.bbadis.2005.05.002

Cited by 2 publications

(1 citation statement)

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“…Recently, enzyme replacement therapy (ERT) was approved for patients with Fabry disease: two recombinant glycoprotein products, Replagal® (Transkaryotic Therapies, Cambridge, MA, U.S.A.) and Fabrazyme® (Genzyme, Cambridge, MA, U.S.A.), are now available (Goi et al, 2005;Hoffmann et al, 2006). Because kidney and heart involvements are important causes of the morbidity and mortality in patients with Fabry disease, they should be the main targeted organs in therapies designed to treat it.…”

Section: Resultsmentioning

confidence: 99%

Novel mutations of the GLA gene in Japanese patients with Fabry disease and their functional characterization by active site specific chaperone

et al. 2008

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Fabry disease is an X-linked recessive inborn metabolic disorder caused by a deficiency of the lysosomal enzyme α-galactosidase A (EC 3.2. throughout the 7 exons of the α-galactosidase A gene (GLA). Mutation hotspots for Fabry disease do not exist. We examined 62 Fabry patients in Japan and found 24 GLA mutations, including 11 novel ones. A potential treatment reported for Fabry disease is active site specific chaperone (ASSC) therapy using 1-deoxygalactonojirimycin (DGJ), an inhibitor of α-galactosidase A, at subinhibitory concentrations. We transfected COS-7 cells with the 24 mutant GLAs and analyzed the α-galactosidase A activities. We then treated the transfected COS-7 cells with DGJ and analyzed its effect on the mutant enzyme activities. The activity of 11 missense mutants increased significantly with DGJ. Although ASSC therapy is useful only for misfolding mutants and therefore not applicable to all cases, it may be useful for treating many Japanese patients with Fabry disease. © 2007 Wiley-Liss, Inc.KEY WORDS: α-galactosidase A; GLA; lysosomal storage disease; 1-deoxygalactonojirimycin; chaperone therapy INTRODUCTIONFabry disease (FD; MIM# 301500) is a pan-ethnic, X-linked, lysosomal storage disorder caused by a deficiency in the lysosomal enzyme α-galactosidase A (EC 3.2.1.22) (Brady et al., 1967). Human α-galactosidase A is a homodimeric glycoprotein with three N-linked oligosaccharide chains on each subunit. Enzyme deficiency results in a systemic lysosomal accumulation of glycolipids, primarily globotriosylceramide (Gb3), in the vascular endothelium and other tissues. In the classical form of the disease, the patient develops angiokeratoma, hypohidrosis, and episodic pain crises in the extremities during childhood or adolescence. With advancing age, the morbidity of renal failure, cardiac disease, and early onset of stroke increases. The severity of the clinical manifestations depends on the amount of residual α-galactosidase A activity. Hemizygous male patients with no or very low α-galactosidase A activity usually have severe clinical symptoms and die as young adults. Heterozygous female Fabry patients exhibit a wide range of severity, from a virtually symptom-free course (Marguery et al., 1993) to one comparable to that of their male counterparts (Whybra et al., 2001), although they usually have no symptoms or very mild manifestations.We examined Fabry patients in Japan and sequenced the patients' α-galactosidase A gene (GLA) (MIM# 300644). To analyze the mutant α-galactosidase A activities, we transfected COS-7 cells with the mutant GLAs. In addition, since 1-deoxygalactonojirimycin (DGJ) stabilizes the α-galactosidase A conformation and improves its stability (Asano et al., 2000;Ishii et al., 2000;Yam et al., 2006), we added DGJ to the incubation medium and examined its effect on the mutant α-galactosidase A activities. MATERIALS AND METHODS PatientsWe examined 62 Fabry patients from 31 unrelated families. Diagnosis was based on reduced or absent α-galactosidase A activity and typical signs an...

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Section: Resultsmentioning

confidence: 99%

Novel mutations of the GLA gene in Japanese patients with Fabry disease and their functional characterization by active site specific chaperone

et al. 2008

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Agalsidase Beta

Keating

Simpson

2007

Drugs

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Agalsidase beta (Fabrazyme) is a recombinant human alpha-galactosidase A enzyme approved for intravenous use in the treatment of Fabry disease. Fabry disease is a progressive, multisystemic, potentially life threatening disorder caused by a deficiency of alpha-galactosidase A. This deficiency results in accumulation of glycosphingolipids, particularly globotriaosylceramide (GL-3), in the lysosomes of various tissues. This accumulation is the underlying driver of disease progression. Agalsidase beta provides an exogenous source of alpha-galactosidase A.Intravenous agalsidase beta is effective and well tolerated in patients with Fabry disease. In a phase III trial, agalsidase beta was shown to clear GL-3 from various target cells and, in a subsequent extension of this trial, prevent GL-3 reaccumulation. In a post-approval trial, agalsidase beta was shown to provide significant clinical benefit by reducing the risk of a major clinical event. Thus, agalsidase beta represents an important advance in the treatment of Fabry disease, and agalsidase beta therapy should be strongly considered in patients with Fabry disease who are suitable candidates.

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Lysosomal leukocyte β-d-glucuronidase during enzyme replacement therapy in Fabry disease

Cited by 2 publications

References 37 publications

Novel mutations of the GLA gene in Japanese patients with Fabry disease and their functional characterization by active site specific chaperone

Novel mutations of the GLA gene in Japanese patients with Fabry disease and their functional characterization by active site specific chaperone

Agalsidase Beta

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