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ABSTRACT FABRY DISEASE IS A DISORDER OF GLYCOSPHINGOLIPID METABOLISM CAUSED BY DEFICIENCY OF LYSOSOMAL Α–GALACTOSIDASE A (Α–GAL A), RESULTING IN RENAL FAILURE ALONG WITH PREMATURE MYOCARDIAL

INFARCTION AND STROKES1,2. NO EFFECTIVE TREATMENT OF THIS DISORDER IS AVAILABLE AT PRESENT. STUDIES OF RESIDUAL ACTIVITIES OF MUTANT ENZYMES IN MANY FABRY PATIENTS SHOWED THAT SOME OF THEM

HAD KINETIC PROPERTIES SIMILAR TO THOSE FOR NORMAL Α–GAL A, BUT WERE SIGNIFICANTLY LESS STABLE, ESPECIALLY IN CONDITIONS OF NEUTRAL PH (REFS. 3,4,5 ). THE BIOSYNTHETIC PROCESSING WAS DELAYED

IN CULTURED FIBROBLASTS OF A FABRY PATIENT6, AND THE MUTANT PROTEIN FORMED AN AGGREGATE IN ENDOPLASMIC RETICULUM7, INDICATING THAT THE ENZYME DEFICIENCY IN SOME MUTANTS WAS MAINLY CAUSED BY

ABORTIVE EXIT FROM THE ENDOPLASMIC RETICULUM, LEADING TO EXCESSIVE DEGRADATION OF THE ENZYME. WE REPORT HERE THAT 1–DEOXY–GALACTONOJIRIMYCIN (DGJ), A POTENT COMPETITIVE INHIBITOR OF Α–GAL

A, EFFECTIVELY ENHANCED Α–GAL A ACTIVITY IN FABRY LYMPHOBLASTS, WHEN ADMINISTRATED AT CONCENTRATIONS LOWER THAN THAT USUALLY REQUIRED FOR INTRACELLULAR INHIBITION OF THE ENZYME. DGJ SEEMED

TO ACCELERATE TRANSPORT AND MATURATION OF THE MUTANT ENZYME. ORAL ADMINISTRATION OF DGJ TO TRANSGENIC MICE OVEREXPRESSING A MUTANT Α–GAL A SUBSTANTIALLY ELEVATED THE ENZYME ACTIVITY IN SOME

ORGANS. WE PROPOSE A NEW MOLECULAR THERAPEUTIC STRATEGY FOR GENETIC METABOLIC DISEASES OF ADMINISTERING COMPETITIVE INHIBITORS AS 'CHEMICAL CHAPERONS' AT SUB–INHIBITORY

INTRACELLULAR CONCENTRATIONS. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your

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our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS OPTIMIZING HUMAN Α-GALACTOSIDASE FOR TREATMENT OF FABRY DISEASE Article Open access 23 March 2023 THERAPEUTIC

EFFECTS OF LOMERIZINE ON VASCULOPATHY IN FABRY DISEASE Article Open access 02 April 2025 PRECLINICAL EVALUATION OF FLT190, A LIVER-DIRECTED AAV GENE THERAPY FOR FABRY DISEASE Article Open

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Handa (Tokyo Medical and Dental University) for providing CTH; M. Ito (Kyushu University) for providing sphingolipid ceramide N–deacylase; K. Mannen (Oita Medical University) for animal

care; A. Oshima (National Institute of Infectious Diseases, Japan), N. Ishida, H. Kubo, and Y. Hashimoto (The Tokyo Metropolitan Institute of Medical Science) for technical advice; R.O.

Brady (NIH) for discussions; Y.C. Lee (The Johns Hopkins University) for critical reading and advice on preparing the manuscript as well as suggestions; and A. Suzuki (The Tokyo Metropolitan

Institute of Medical Science) for discussions. This work was supported in part by grants from the Ministry of Education, Science, Sports and Culture and the Ministry of Health and Welfare

of Japan._ AUTHOR INFORMATION Author notes * Jian-Qiang Fan Present address: Department of Human Genetics, Mt Sinai School of Medicine, Fifth Avenue at 100th Street, New York, New York,

10029, USA AUTHORS AND AFFILIATIONS * Department of Membrane Biochemistry, The Tokyo Metropolitan Institute of Medical Science, Tokyo, 113–8613, Japan Jian-Qiang Fan * The Tokyo Metropolitan

Institute of Medical Science, , Tokyo, 113–8613, Japan Yoshiyuki Suzuki * Usuki Bio Research Center, Oita, 875–0061, Japan Satoshi Ishii * Faculty of Pharmaceutical Sciences, Hokuriku

University , Kanazawa, 920–1181, Japan Naoki Asano Authors * Jian-Qiang Fan View author publications You can also search for this author inPubMed Google Scholar * Satoshi Ishii View author

publications You can also search for this author inPubMed Google Scholar * Naoki Asano View author publications You can also search for this author inPubMed Google Scholar * Yoshiyuki Suzuki

View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Jian-Qiang Fan. RIGHTS AND PERMISSIONS Reprints and permissions

ABOUT THIS ARTICLE CITE THIS ARTICLE Fan, JQ., Ishii, S., Asano, N. _et al._ Accelerated transport and maturation of lysosomal α–galactosidase A in Fabry lymphoblasts by an enzyme inhibitor.

_Nat Med_ 5, 112–115 (1999). https://doi.org/10.1038/4801 Download citation * Received: 28 September 1998 * Accepted: 03 November 1998 * Issue Date: January 1999 * DOI:

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