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Beneficial effects of substrate reduction therapy in a mouse model of GM1 gangliosidosis

Elliot-Smith, Elena, Speak, Anneliese, Lloyd-Evans, Emyr ORCID:, Smith, David A., Spoel, Aarnoud C. van der, Jeyakumar, Mylvaganam, Butters, Terry, Dwek, Raymond, d'Azzo, Alessandra and Platt, Frances 2008. Beneficial effects of substrate reduction therapy in a mouse model of GM1 gangliosidosis. Molecular Genetics and Metabolism 94 (2) , pp. 204-211. 10.1016/j.ymgme.2008.02.005

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GM1 gangliosidosis is an inherited neurodegenerative disorder caused by lysosomal β-galactosidase deficiency, resulting in the storage of GM1 and GA1, primarily in the central nervous system. This disease typically afflicts infants and young children and there is currently no effective therapy. Substrate reduction therapy (SRT) could be of potential benefit.The imino sugars N-butyldeoxynojirimycin (NB-DNJ, miglustat, Zavesca™) and N-butyldeoxygalactonojirimycin (NB-DGJ) used for SRT inhibit glucosylceramide synthase (GlcCerS) that catalyses the first committed step in glycosphingolipid biosynthesis. We have compared the efficacy and tolerability of NB-DNJ and NB-DGJ in the β-galactosidase knockout mouse. NB-DGJ was better tolerated than NB-DNJ, due to intrinsic gastrointestinal tract dysfunction that was exacerbated by NB-DNJ. However, functional improvement was greatest with NB-DNJ treatment which may potentially be caused by novel anti-inflammatory properties of NB-DNJ.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Subjects: Q Science > QH Natural history > QH426 Genetics
Uncontrolled Keywords: GM1 gangliosidosis; lysosomal storage disease; glycosphingolipid; GM1; GA1; substrate reduction therapy; miglustat; imino sugar; N-Butyldeoxynojirimycin; N-Butyldeoxygalactonojirimycin
Publisher: Elsevier
ISSN: 1096-7192
Last Modified: 19 Oct 2022 09:11

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