Utsumi K
Department of Internal Medicine, Divisions of Neurology, Nephrology, and Rheumatology, Nippon Medical School, Tokyo, Japan

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

Hirama A
Department of Internal Medicine, Divisions of Neurology, Nephrology, and Rheumatology, Nippon Medical School, Tokyo, Japan

Ueda K
1 Department of Internal Medicine, Divisions of Neurology, Nephrology, and Rheumatology, Nippon Medical School, Tokyo, Japan

Sakamaki M
Department of Internal Medicine, Divisions of Neurology, Nephrology, and Rheumatology, Nippon Medical School, Tokyo, Japan

Kaneko T
1 Department of Internal Medicine, Divisions of Neurology, Nephrology, and Rheumatology, Nippon Medical School, Tokyo, Japan

Yamazaki M
Department of Internal Medicine, Divisions of Neurology, Nephrology, and Rheumatology, Nippon Medical School, Tokyo, Japan

Komaba Y
Department of Internal Medicine, Divisions of Neurology, Nephrology, and Rheumatology, Nippon Medical School, Tokyo, Japan

Katsura KI
Department of Internal Medicine, Divisions of Neurology, Nephrology, and Rheumatology, Nippon Medical School, Tokyo, Japan

Iino Y
Department of Internal Medicine, Divisions of Neurology, Nephrology, and Rheumatology, Nippon Medical School, Tokyo, Japan

Katayama Y
Department of Internal Medicine, Divisions of Neurology, Nephrology, and Rheumatology, Nippon Medical School , Tokyo, Japan

Correspondence:

Kouichi Utsumi, M.D.
Department: Department of Internal Medicine, Divisions of Neurology, Nephrology, and Rheumatology, Nippon Medical School
Address: 1-1-5, Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan
City: Tokyo
Country: Japan
E-mail: utsumi@nms.ac.jp
Tel: 81-3-3822-2131
Fax: 81-3-3822-4865

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, α-galactosidase A, Antisense Oligodeoxynucleotide, Globotriaosylceramide,