Beneficial effects of substrate reduction therapy in a mouse model of GM1 gangliosidosis
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. Subs...
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| Veröffentlicht in: | Molecular genetics and metabolism 2008-06, Vol.94 (2), p.204-211 |
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| creator | Elliot-Smith, Elena Speak, Anneliese O. Lloyd-Evans, Emyr Smith, David A. Spoel, Aarnoud C. van der Jeyakumar, Mylvaganam Butters, Terry D. Dwek, Raymond A. d’Azzo, Alessandra Platt, Frances M. |
| description | 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. |
| doi_str_mv | 10.1016/j.ymgme.2008.02.005 |
| format | Article |
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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.</description><identifier>ISSN: 1096-7192</identifier><identifier>EISSN: 1096-7206</identifier><identifier>DOI: 10.1016/j.ymgme.2008.02.005</identifier><identifier>PMID: 18387328</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject><![CDATA[1-Deoxynojirimycin - administration & dosage ; 1-Deoxynojirimycin - analogs & derivatives ; 1-Deoxynojirimycin - therapeutic use ; Animals ; beta-Galactosidase - antagonists & inhibitors ; beta-Galactosidase - genetics ; beta-Galactosidase - metabolism ; Brain - drug effects ; Brain - immunology ; Brain - metabolism ; Disease Models, Animal ; Enzyme Inhibitors - administration & dosage ; Enzyme Inhibitors - therapeutic use ; Feces - chemistry ; GA1 ; Gangliosidosis, GM1 - drug therapy ; Gangliosidosis, GM1 - immunology ; Gangliosidosis, GM1 - metabolism ; Gangliosidosis, GM1 - physiopathology ; Glucosyltransferases - antagonists & inhibitors ; Glucosyltransferases - metabolism ; Glycosphingolipid ; Glycosphingolipids - antagonists & inhibitors ; Glycosphingolipids - metabolism ; GM1 ; GM1 gangliosidosis ; Humans ; Imino sugar ; Lysosomal storage disease ; Macrophage Activation - drug effects ; Mice ; Mice, Knockout ; Miglustat ; Motor Activity - drug effects ; N-Butyldeoxygalactonojirimycin ; N-Butyldeoxynojirimycin ; Protein Transport - drug effects ; Substrate reduction therapy]]></subject><ispartof>Molecular genetics and metabolism, 2008-06, Vol.94 (2), p.204-211</ispartof><rights>2008 Elsevier Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c423t-96f2b18d307a76c06b4e28f62f3a8148ebdd53cb3d6a6c4c53586e62440acbfb3</citedby><cites>FETCH-LOGICAL-c423t-96f2b18d307a76c06b4e28f62f3a8148ebdd53cb3d6a6c4c53586e62440acbfb3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S1096719208000504$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18387328$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Elliot-Smith, Elena</creatorcontrib><creatorcontrib>Speak, Anneliese O.</creatorcontrib><creatorcontrib>Lloyd-Evans, Emyr</creatorcontrib><creatorcontrib>Smith, David A.</creatorcontrib><creatorcontrib>Spoel, Aarnoud C. van der</creatorcontrib><creatorcontrib>Jeyakumar, Mylvaganam</creatorcontrib><creatorcontrib>Butters, Terry D.</creatorcontrib><creatorcontrib>Dwek, Raymond A.</creatorcontrib><creatorcontrib>d’Azzo, Alessandra</creatorcontrib><creatorcontrib>Platt, Frances M.</creatorcontrib><title>Beneficial effects of substrate reduction therapy in a mouse model of GM1 gangliosidosis</title><title>Molecular genetics and metabolism</title><addtitle>Mol Genet Metab</addtitle><description>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.</description><subject>1-Deoxynojirimycin - administration & dosage</subject><subject>1-Deoxynojirimycin - analogs & derivatives</subject><subject>1-Deoxynojirimycin - therapeutic use</subject><subject>Animals</subject><subject>beta-Galactosidase - antagonists & inhibitors</subject><subject>beta-Galactosidase - genetics</subject><subject>beta-Galactosidase - metabolism</subject><subject>Brain - drug effects</subject><subject>Brain - immunology</subject><subject>Brain - metabolism</subject><subject>Disease Models, Animal</subject><subject>Enzyme Inhibitors - administration & dosage</subject><subject>Enzyme Inhibitors - therapeutic use</subject><subject>Feces - chemistry</subject><subject>GA1</subject><subject>Gangliosidosis, GM1 - drug therapy</subject><subject>Gangliosidosis, GM1 - immunology</subject><subject>Gangliosidosis, GM1 - metabolism</subject><subject>Gangliosidosis, GM1 - physiopathology</subject><subject>Glucosyltransferases - antagonists & inhibitors</subject><subject>Glucosyltransferases - metabolism</subject><subject>Glycosphingolipid</subject><subject>Glycosphingolipids - antagonists & inhibitors</subject><subject>Glycosphingolipids - metabolism</subject><subject>GM1</subject><subject>GM1 gangliosidosis</subject><subject>Humans</subject><subject>Imino sugar</subject><subject>Lysosomal storage disease</subject><subject>Macrophage Activation - drug effects</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Miglustat</subject><subject>Motor Activity - drug effects</subject><subject>N-Butyldeoxygalactonojirimycin</subject><subject>N-Butyldeoxynojirimycin</subject><subject>Protein Transport - drug effects</subject><subject>Substrate reduction therapy</subject><issn>1096-7192</issn><issn>1096-7206</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE1vGyEQhlGVqE7c_oJKFafcvBlgl2UPPTRR6kRK1Esr9YZYGFys_XBhN5L_fXDtKLccgDk878zwEPKFQcGAyettse83PRYcQBXAC4DqA7lg0MhVzUGevdas4QtymdIWgLGqKT-SBVNC1YKrC_LnBgf0wQbTUfQe7ZTo6Gma2zRFMyGN6GY7hXGg01-MZrenYaCG9uOcMN8OuwO_fmJ0Y4ZNF8YUXD7pEzn3pkv4-fQuye8fd79u71ePP9cPt98fV7bkYlo10vOWKSegNrW0INsSufKSe2EUKxW2zlXCtsJJI21pK1EpiZKXJRjb-lYsydWx7y6O_2ZMk-5Dsth1ZsC8o66hlmWlmgyKI2jjmFJEr3cx9CbuNQN9EKq3-r9QfRCqgessNKe-ntrPbY_uLXMymIFvRwDzJ58DRp1swMGiCzHb1G4M7w54AXZTiMo</recordid><startdate>200806</startdate><enddate>200806</enddate><creator>Elliot-Smith, Elena</creator><creator>Speak, Anneliese O.</creator><creator>Lloyd-Evans, Emyr</creator><creator>Smith, David A.</creator><creator>Spoel, Aarnoud C. van der</creator><creator>Jeyakumar, Mylvaganam</creator><creator>Butters, Terry D.</creator><creator>Dwek, Raymond A.</creator><creator>d’Azzo, Alessandra</creator><creator>Platt, Frances M.</creator><general>Elsevier Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>200806</creationdate><title>Beneficial effects of substrate reduction therapy in a mouse model of GM1 gangliosidosis</title><author>Elliot-Smith, Elena ; Speak, Anneliese O. ; Lloyd-Evans, Emyr ; Smith, David A. ; Spoel, Aarnoud C. van der ; Jeyakumar, Mylvaganam ; Butters, Terry D. ; Dwek, Raymond A. ; d’Azzo, Alessandra ; Platt, Frances M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c423t-96f2b18d307a76c06b4e28f62f3a8148ebdd53cb3d6a6c4c53586e62440acbfb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>1-Deoxynojirimycin - administration & dosage</topic><topic>1-Deoxynojirimycin - analogs & derivatives</topic><topic>1-Deoxynojirimycin - therapeutic use</topic><topic>Animals</topic><topic>beta-Galactosidase - antagonists & inhibitors</topic><topic>beta-Galactosidase - genetics</topic><topic>beta-Galactosidase - metabolism</topic><topic>Brain - drug effects</topic><topic>Brain - immunology</topic><topic>Brain - metabolism</topic><topic>Disease Models, Animal</topic><topic>Enzyme Inhibitors - administration & dosage</topic><topic>Enzyme Inhibitors - therapeutic use</topic><topic>Feces - chemistry</topic><topic>GA1</topic><topic>Gangliosidosis, GM1 - drug therapy</topic><topic>Gangliosidosis, GM1 - immunology</topic><topic>Gangliosidosis, GM1 - metabolism</topic><topic>Gangliosidosis, GM1 - physiopathology</topic><topic>Glucosyltransferases - antagonists & inhibitors</topic><topic>Glucosyltransferases - metabolism</topic><topic>Glycosphingolipid</topic><topic>Glycosphingolipids - antagonists & inhibitors</topic><topic>Glycosphingolipids - metabolism</topic><topic>GM1</topic><topic>GM1 gangliosidosis</topic><topic>Humans</topic><topic>Imino sugar</topic><topic>Lysosomal storage disease</topic><topic>Macrophage Activation - drug effects</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Miglustat</topic><topic>Motor Activity - drug effects</topic><topic>N-Butyldeoxygalactonojirimycin</topic><topic>N-Butyldeoxynojirimycin</topic><topic>Protein Transport - drug effects</topic><topic>Substrate reduction therapy</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Elliot-Smith, Elena</creatorcontrib><creatorcontrib>Speak, Anneliese O.</creatorcontrib><creatorcontrib>Lloyd-Evans, Emyr</creatorcontrib><creatorcontrib>Smith, David A.</creatorcontrib><creatorcontrib>Spoel, Aarnoud C. van der</creatorcontrib><creatorcontrib>Jeyakumar, Mylvaganam</creatorcontrib><creatorcontrib>Butters, Terry D.</creatorcontrib><creatorcontrib>Dwek, Raymond A.</creatorcontrib><creatorcontrib>d’Azzo, Alessandra</creatorcontrib><creatorcontrib>Platt, Frances M.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular genetics and metabolism</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Elliot-Smith, Elena</au><au>Speak, Anneliese O.</au><au>Lloyd-Evans, Emyr</au><au>Smith, David A.</au><au>Spoel, Aarnoud C. van der</au><au>Jeyakumar, Mylvaganam</au><au>Butters, Terry D.</au><au>Dwek, Raymond A.</au><au>d’Azzo, Alessandra</au><au>Platt, Frances M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Beneficial effects of substrate reduction therapy in a mouse model of GM1 gangliosidosis</atitle><jtitle>Molecular genetics and metabolism</jtitle><addtitle>Mol Genet Metab</addtitle><date>2008-06</date><risdate>2008</risdate><volume>94</volume><issue>2</issue><spage>204</spage><epage>211</epage><pages>204-211</pages><issn>1096-7192</issn><eissn>1096-7206</eissn><abstract>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.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>18387328</pmid><doi>10.1016/j.ymgme.2008.02.005</doi><tpages>8</tpages></addata></record> |
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| ispartof | Molecular genetics and metabolism, 2008-06, Vol.94 (2), p.204-211 |
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| subjects | 1-Deoxynojirimycin - administration & dosage 1-Deoxynojirimycin - analogs & derivatives 1-Deoxynojirimycin - therapeutic use Animals beta-Galactosidase - antagonists & inhibitors beta-Galactosidase - genetics beta-Galactosidase - metabolism Brain - drug effects Brain - immunology Brain - metabolism Disease Models, Animal Enzyme Inhibitors - administration & dosage Enzyme Inhibitors - therapeutic use Feces - chemistry GA1 Gangliosidosis, GM1 - drug therapy Gangliosidosis, GM1 - immunology Gangliosidosis, GM1 - metabolism Gangliosidosis, GM1 - physiopathology Glucosyltransferases - antagonists & inhibitors Glucosyltransferases - metabolism Glycosphingolipid Glycosphingolipids - antagonists & inhibitors Glycosphingolipids - metabolism GM1 GM1 gangliosidosis Humans Imino sugar Lysosomal storage disease Macrophage Activation - drug effects Mice Mice, Knockout Miglustat Motor Activity - drug effects N-Butyldeoxygalactonojirimycin N-Butyldeoxynojirimycin Protein Transport - drug effects Substrate reduction therapy |
| title | Beneficial effects of substrate reduction therapy in a mouse model of GM1 gangliosidosis |
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