Background and Aims:

Fabry disease is an X-linked lysosomal storage disease resulting from deficient activity of the enzyme α-galacotsidase (α-Gal) A. Accumulation of glycosphingolipids, especially globotriaosylceramide, leads to various organ damage in Fabry disease. Recently, replacement with recombinant α-Gal A has become available for the treatment of this disease. However, the pathogenic mechanism of this disease, which is the accumulation of glycosphingolipids, is still unknown. Understanding the pathogenesis of Fabry disease may allow more efficient treatments. We examined whether the selective inhibition of α-Gal A with phosphorothioate antisense oligonucleotides could be used as a renal cellular model for Fabry disease.

 

Methods: Phosphorothioate antisense oligonucleotides designed to hyrbridize to sites on the human α-Gal A mRNA were tested for inhibition of α-Gal A expression in human mesangial cells. α-Gal A activity was measured using an artificial substrate, 4-methylumbelliferyl-α-D-galactoside.

Results: Two antisense oligonucleotides selectively inhibited α-Gal A activity to below 20% of the mean control activity. These oligonucleotides did not affect other lysosomal enzyme activities.

Conclusions: These data indicate that phosphorothioate oligonucleotides are capable of selectively inhibiting α-Gal A expression. It may be a useful model for renal mesangial cells in Fabry disease.

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Background and Aims:

Fabry disease is an X-linked lysosomal storage disease resulting from deficient activity of the enzyme α-galacotsidase (α-Gal) A. Accumulation of glycosphingolipids, especially globotriaosylceramide, leads to various organ damage in Fabry disease. Recently, replacement with recombinant α-Gal A has become available for the treatment of this disease. However, the pathogenic mechanism of this disease, which is the accumulation of glycosphingolipids, is still unknown. Understanding the pathogenesis of Fabry disease may allow more efficient treatments. We examined whether the selective inhibition of α-Gal A with phosphorothioate antisense oligonucleotides could be used as a renal cellular model for Fabry disease.

 

Methods: Phosphorothioate antisense oligonucleotides designed to hyrbridize to sites on the human α-Gal A mRNA were tested for inhibition of α-Gal A expression in human mesangial cells. α-Gal A activity was measured using an artificial substrate, 4-methylumbelliferyl-α-D-galactoside.

Results: Two antisense oligonucleotides selectively inhibited α-Gal A activity to below 20% of the mean control activity. These oligonucleotides did not affect other lysosomal enzyme activities.

Conclusions: These data indicate that phosphorothioate oligonucleotides are capable of selectively inhibiting α-Gal A expression. It may be a useful model for renal mesangial cells in Fabry disease.

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Selective Inhibition of ?-Galactosidase A with Antisense Oligodeoxynucleotide in Mesangial Cells: A Renal Cellular Model for Fabry Disease

AUTHORS

Kouichi Utsumi 1 , * , Kohji Itoh 2 , Akio Hirama 3 , Kae Ueda 3 , Masanori Sakamaki 3 , Tomohiro Kaneko 3 , Mineo Yamazaki 3 , Yuichi Komaba 3 , Ken Ichiro Katsura 3 , Yasuhiko Iino 3 , Yasuo Katayama 3

1 Department of Internal Medicine, Divisions of Neurology, Nephrology, and Rheumatology, Nippon Medical School, [email protected], Japan

2 Department of Medical Biotechnology, Institute for Medical Resources, Graduate School of Pharmaceutical Sciences, the University of Tokushima, Japan

3 Department of Internal Medicine, Divisions of Neurology, Nephrology, and Rheumatology, Nippon Medical School, Japan

How to Cite: Utsumi K, Itoh K, Hirama A, Ueda K, Sakamaki M, et al. Selective Inhibition of ?-Galactosidase A with Antisense Oligodeoxynucleotide in Mesangial Cells: A Renal Cellular Model for Fabry Disease, Nephro-Urol Mon. Online ahead of Print ; 2(3):397-400.

ARTICLE INFORMATION

Nephro-Urology Monthly: 2 (3); 397-400
Article Type: Research Article
Received: July 22, 2009
Accepted: September 8, 2009
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Abstract

Background and Aims:

Fabry disease is an X-linked lysosomal storage disease resulting from deficient activity of the enzyme α-galacotsidase (α-Gal) A. Accumulation of glycosphingolipids, especially globotriaosylceramide, leads to various organ damage in Fabry disease. Recently, replacement with recombinant α-Gal A has become available for the treatment of this disease. However, the pathogenic mechanism of this disease, which is the accumulation of glycosphingolipids, is still unknown. Understanding the pathogenesis of Fabry disease may allow more efficient treatments. We examined whether the selective inhibition of α-Gal A with phosphorothioate antisense oligonucleotides could be used as a renal cellular model for Fabry disease.

 

Methods: Phosphorothioate antisense oligonucleotides designed to hyrbridize to sites on the human α-Gal A mRNA were tested for inhibition of α-Gal A expression in human mesangial cells. α-Gal A activity was measured using an artificial substrate, 4-methylumbelliferyl-α-D-galactoside.

Results: Two antisense oligonucleotides selectively inhibited α-Gal A activity to below 20% of the mean control activity. These oligonucleotides did not affect other lysosomal enzyme activities.

Conclusions: These data indicate that phosphorothioate oligonucleotides are capable of selectively inhibiting α-Gal A expression. It may be a useful model for renal mesangial cells in Fabry disease.

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