Safety and Efficacy of Recombinant Human α-Galactosidase A Replacement Therapy in Fabry's Disease

Eng, Christine M.; Guffon, Nathalie; Wilcox, William R.; Germain, Dominique P.; Lee, Philip; Waldek, S.; Caplan, Louis R.; Linthorst, Gabor E.; Desnick, Robert J.

doi:10.1056/nejm200107053450102

Cited by 1,425 publications

(1,138 citation statements)

References 16 publications

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“…Patients lacking expression of LAMAN1, 3, 6 may develop antibodies against the recombinant enzyme affecting ERT efficacy. However, in this first clinical study for alpha‐mannosidosis the frequency of infusion‐related reactions as well as the production of antibodies against the recombinant enzyme was low19 in comparison with other ERT studies 50, 51, 52, 53, 54. Furthermore, these rhLAMAN‐specific antibodies were shown not to be neutralizing, suggesting only mild immunological complications with regard to future ERT.…”

Section: Discussioncontrasting

confidence: 55%

Chronic enzyme replacement therapy ameliorates neuropathology in alpha‐mannosidosis mice

Damme

Lüdemann

Rothaug

et al. 2015

Ann Clin Transl Neurol

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ObjectiveThe lysosomal storage disease alpha‐mannosidosis is caused by the deficiency of the lysosomal acid hydrolase alpha‐mannosidase (LAMAN) leading to lysosomal accumulation of neutral mannose‐linked oligosaccharides throughout the body, including the brain. Clinical findings in alpha‐mannosidosis include skeletal malformations, intellectual disabilities and hearing impairment. To date, no curative treatment is available. We previously developed a beneficial enzyme replacement therapy (ERT) regimen for alpha‐mannosidase knockout mice, a valid mouse model for the human disease. However, humoral immune responses against the injected recombinant human alpha‐mannosidase (rhLAMAN) precluded long‐term studies and chronic treatment.MethodsHere, we describe the generation of an immune‐tolerant alpha‐mannosidosis mouse model that allowed chronic injection of rhLAMAN by transgenic expression of a catalytically inactive variant of human LAMAN in the knockout background.ResultsChronic ERT of rhLAMAN revealed pronounced effects on primary substrate storage throughout the brain, normalization of lysosomal enzyme activities and morphology as well as a decrease in microglia activation. The positive effect of long‐term ERT on neuronal lysosomal function was reflected by an improvement of cognitive deficits and exploratory activity. in vivo and in vitro uptake measurements indicate rapid clearance of rhLAMAN from circulation and a broad uptake into different cell types of the nervous system.InterpretationOur data contribute to the understanding of neurological disorders treatment by demonstrating that lysosomal enzymes such as rhLAMAN can penetrate into the brain and is able to ameliorate neuropathology.

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Section: Discussioncontrasting

confidence: 55%

Chronic enzyme replacement therapy ameliorates neuropathology in alpha‐mannosidosis mice

Damme

Lüdemann

Rothaug

et al. 2015

Ann Clin Transl Neurol

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“…Recently, clinical trials have shown that enzyme replacement with recombinant human a-galactosidase A can increase a-galactosidase A levels, decrease endothelial inclusions, and improve pain symptoms. 16,17 However, enzyme replacement therapy costs approximately $160 000 annually. 4 Thus, with this now readily available but expensive therapy, it is imperative for clinicians to be aware of the rare patient whose Fabry-like syndrome is iatrogenically induced and who does not require a-galactosidase A replacement.…”

Section: Discussionmentioning

confidence: 99%

Chloroquine-induced lipidosis mimicking Fabry disease

et al. 2005

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“…The classic form of the disease affects male homozygotes and presents in adolescence with burning extremity pain (acroparesthesia) and progressive multi-organ failure [65]. AFD can cause left ventricular hypertrophy (LVH) due to storage of glycosphingolipid in myocytes, valves and vascular endothelium [66]. The cardiac decompensation in AFD is secondary to progressive myocardial fibrosis and is usually more extensive in men than in affected women [64].…”

Section: Anderson Fabry Disease (Afd)mentioning

confidence: 99%

T1, T2 Mapping and Extracellular Volume Fraction (ECV): Application, Value and Further Perspectives in Myocardial Inflammation and Cardiomyopathies

Roller¹,

Harth²,

Schneider³

et al. 2015

Fortschr Röntgenstr

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!Cardiac magnetic resonance imaging (CMRI) is a versatile diagnostic tool. One of its main advantages is the possibility of tissue characterization. T1-weighted images for scar and T2-weighted images for edema visualization are key methods for tissue characterization. Otherwise these sequences are strongly limited for the detection of diffuse myocardial pathologies. Recently, rapid technical innovations have generated new techniques. T1, T2 mapping and evaluation of the extracellular volume fraction (ECV) allow quantification of diffuse myocardial pathologies and showed great potential in the visualization of fibrosis, edema, amyloid, iron overload and lipid. In the future these techniques might enable the detection of early cardiac involvement, even act as a prognosticator. Moreover, therapy monitoring and follow-up might be possible due to versatile parameter quantification with these new techniques. Key points:▶ CMR allows for tissue characterization via T1-and T2-weighted sequences.▶ In cases of diffuse, global myocardial pathologies, correct image interpretation with traditional CMR sequences might be difficult.▶ T1, T2 mapping and ECV can quantify diffuse, global myocardial pathologies.

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Safety and Efficacy of Recombinant Human α-Galactosidase A Replacement Therapy in Fabry's Disease

Abstract: Recombinant alpha-galactosidase A replacement therapy cleared microvascular endothelial deposits of globotriaosylceramide from the kidneys, heart, and skin in patients with Fabry's disease, reversing the pathogenesis of the chief clinical manifestations of this disease.

Cited by 1,425 publications

References 16 publications

Chronic enzyme replacement therapy ameliorates neuropathology in alpha‐mannosidosis mice

Chronic enzyme replacement therapy ameliorates neuropathology in alpha‐mannosidosis mice

Chloroquine-induced lipidosis mimicking Fabry disease

T1, T2 Mapping and Extracellular Volume Fraction (ECV): Application, Value and Further Perspectives in Myocardial Inflammation and Cardiomyopathies

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