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

Kouichi Utsumi; Kohji Itoh; Akio Hirama; Kae Ueda; Masanori Sakamaki; Tomohiro Kaneko; Mineo Yamazaki; Yuichi Komaba; Ken Katsura; Yasuhiko Iino; Yasuo Katayama

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

Author(s):

Kouichi Utsumi^1,*,

Kohji Itoh²,

Akio Hirama³,

Kae Ueda³,

Masanori Sakamaki³,

Tomohiro Kaneko³,

Mineo Yamazaki³,

Yuichi Komaba³,

Ken Ichiro Katsura³,

Yasuhiko Iino³,

Yasuo Katayama³

1Department of Internal Medicine, Divisions of Neurology, Nephrology, and Rheumatology, Nippon Medical School, utsumi@nms.ac.jp, Japan

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

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

Nephro-Urology Monthly:Vol. 2, issue 3; 397-400

Article type:Research Article

Received:Jul 22, 2009

Accepted:Sep 08, 2009

How to Cite:Kouichi UtsumiKohji ItohAkio HiramaKae UedaMasanori SakamakiTomohiro KanekoMineo YamazakiYuichi KomabaKen Ichiro KatsuraYasuhiko IinoYasuo Katayamaet al.Selective Inhibition of ?-Galactosidase A with Antisense Oligodeoxynucleotide in Mesangial Cells: A Renal Cellular Model for Fabry Disease.Nephro-Urol Mon.2(3):397-400.

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.

Keywords

Fabry Disease

?-galactosidase A

Antisense Oligodeoxynucleotide

Globotriaosylceramide

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