Alpha-galactosidase A replacement therapy for Fabry disease.
Item
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Title
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Alpha-galactosidase A replacement therapy for Fabry disease.
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Identifier
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AAI9908386
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identifier
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9908386
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Creator
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Zeidner, Ken M.
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Contributor
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Adviser: Yiannis A. Ioannou
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Date
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1998
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Language
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English
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Publisher
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City University of New York.
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Subject
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Biology, Genetics | Health Sciences, Medicine and Surgery
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Abstract
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Fabry disease is an X-linked glycosphingolipid storage disease resulting from a deficiency of lysosomal {dollar}\alpha{dollar}-galactosidase A {dollar}(\alpha{dollar}-Gal A; EC 3.2.1.21) and accumulation of its glycosphingolipid substrate, globotriaosylceramide (Gal{dollar}\alpha{dollar}1-4Gal{dollar}\beta{dollar}1-4{dollar}\beta{dollar}Glc1-4Cer; GL-3). Presently, no treatment exists for this disease. These studies were undertaken to characterize a murine model of Fabry disease and to assess the effectiveness of enzyme replacement therapy (ERT).;Mice hemizygous for a null {dollar}\alpha{dollar}-Gal A allele appeared normal at birth and possessed normal lifespans and fertility. These mice were completely deficient of {dollar}\alpha{dollar}-Gal A activity, with markedly elevated levels of GL-3 detected in all tissues. These {dollar}\alpha{dollar}-Gal A-deficient mice were administered recombinant human {dollar}\alpha{dollar}-Gal A to determine its biodistributions pharmacokinetics. At a single dose of 1 mg enzyme/kg body weight (mg/kg), the majority of enzyme was recovered from the liver, with a small amount present in the spleen and kidneys, and none detected in lungs, heart, or brain. Increasing the dose led to a redistribution of enzyme, with activity detectable in heart and kidney. Multiple administrations of {dollar}\alpha{dollar}-Gal A completely restored enzyme levels to those of wild-type mice in all tissues examined, except brain. The enzyme exhibited a half-life of {dollar}\sim{dollar}40 hr in liver, {dollar}\sim{dollar}20 hr in spleen and kidney, and {dollar}<{dollar}5 min in circulation.;The effect of {dollar}\alpha{dollar}-Gal A on GL-3 accumulation in {dollar}\alpha{dollar}-Gal A-deficient mice was examined. Single administrations of {dollar}\alpha{dollar}-Gal A at doses of 0.3-10 mg/kg hydrolyzed the accumulated GL-3 in liver, spleen, heart, kidney, and skin in a dose-dependent manner. Multiple administrations of 3 or 10 mg/kg cleared all the accumulated GL-3 from liver, spleen, heart, and kidney and greatly reduced the GL-3 accumulation in skin. All doses of {dollar}\alpha{dollar}-Gal A led to a decrease in circulating levels of GL-3 in a dose-dependent manner. Thirty days following a single 3 mg/kg dose, GL-3 levels in the liver were still below detection, whereas GL-3 levels in plasma, spleen, and heart were still below the predose values. GL-3 reaccumulation in plasma preceded reaccumulation in tissues, suggesting that plasma GL-3 levels may be an indicator of ERT effectiveness. It is therefore concluded that ERT is warranted for Fabry disease.
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
