Infusion of α-galactosidase A reduces tissue globotriaosylceramide storage in patients with Fabry disease

Abstract

Fabry disease is a lysosomal storage disorder caused by a deficiency of the lysosomal enzyme ␣-galactosidase A (␣-gal A). This enzymatic defect results in the accumulation of the glycosphingolipid globotriaosylceramide (Gb 3; also referred to as ceramidetrihexoside) throughout the body. To investigate the effects of purified ␣-gal A, 10 patients with Fabry disease received a single i.v. infusion of one of five escalating dose levels of the enzyme. The objectives of this study were: (i) to evaluate the safety of administered ␣-gal A, (ii) to assess the pharmacokinetics of i.v.-administered ␣-gal A in plasma and liver, and (iii) to determine the effect of this replacement enzyme on hepatic, urine sediment and plasma concentrations of Gb3. ␣-Gal A infusions were well tolerated in all patients. Immunohistochemical staining of liver tissue approximately 2 days after enzyme infusion identified ␣-gal A in several cell types, including sinusoidal endothelial cells, Kupffer cells, and hepatocytes, suggesting diffuse uptake via the mannose 6-phosphate receptor. The tissue half-life in the liver was greater than 24 hr. After the single dose of ␣-gal A, nine of the 10 patients had significantly reduced Gb3 levels both in the liver and shed renal tubular epithelial cells in the urine sediment. These data demonstrate that single infusions of ␣-gal A prepared from transfected human fibroblasts are both safe and biochemically active in patients with Fabry disease. The degree of substrate reduction seen in the study is potentially clinically significant in view of the fact that Gb 3 burden in Fabry patients increases gradually over decades. Taken together, these results suggest that enzyme replacement is likely to be an effective therapy for patients with this metabolic disorder.

Immune‐Mediated Myocarditis in Fabry Disease Cardiomyopathy

“…The heart is a major target of FD, and its involvement strongly influences life expectancy that was reduced, before ERT introduction, to 58.2 years for men and to 75.4 years for women 21. The impact of ERT on FDCM is still controversial because some studies show benefits from ERT administration in terms of relief,8, 9, 10 and others deny benefits, reporting an unaffected progressive trend 11, 12. Most experts agree on evidence showing that early ERT administration, particularly in prehypertrophic FDCM (MWT <11 mm), prevents disease progression, whereas the advanced form (MWT >15 mm) appears to be irreversible 12.…”

“…Indeed, the impact of enzyme replacement therapy (ERT) on FDCM is still controversial,8, 9, 10, 11, 12 and although there is agreement that early ERT administration, particularly in prehypertrophic FDCM, prevents progression of the disease, the advanced form is believed to be irreversible.…”

Changes in plasma and urine globotriaosylceramide levels do not predict Fabry disease progression over 1 year of agalsidase alfa

“…Both plasma and urine samples were analyzed with high-performance liquid chromatography using a validated assay, as described previously. 16 …”

Reduction of Plasma Globotriaosylsphingosine Levels After Switching from Agalsidase Alfa to Agalsidase Beta as Enzyme Replacement Therapy for Fabry Disease

“…The level of GL-3 is used as a surrogate marker to assess treatment efficacy, and clearance of GL-3 from the tissues, mainly the liver and kidneys, has been used in several studies as an outcome measure (reported as relative to normal and/or percentage decrease from baseline) (Eng et al 2001;Schiffmann et al 2000). Short-term therapy has been shown to rapidly decrease plasma GL-3 levels in adult and pediatric male patients with FD (Clarke et al 2007;Schiffmann et al 2010).…”