NDLI: A Genetic Model of Substrate Reduction Therapy for Mucopolysaccharidosis

Content Provider	Journal of Biological Chemistry (JBC)
Author	Lamanna, William C. Lawrence, Roger Sarrazin, Stéphane Lameda-Diaz, Carlos Gordts, Philip L. S. M. Moremen, Kelley W. Esko, Jeffrey D.
Abstract	Inherited defects in the ability to catabolize glycosaminoglycans result in lysosomal storage disorders known as mucopolysaccharidoses (MPS), causing severe pathology, particularly in the brain. Enzyme replacement therapy has been used to treat mucopolysaccharidoses; however, neuropathology has remained refractory to this approach. To test directly whether substrate reduction might be feasible for treating MPS disease, we developed a genetic model for substrate reduction therapy by crossing MPS IIIa mice with animals partially deficient in heparan sulfate biosynthesis due to heterozygosity in Ext1 and Ext2, genes that encode the copolymerase required for heparan sulfate chain assembly. Reduction of heparan sulfate by 30–50% using this genetic strategy ameliorated the amount of disease-specific biomarker and pathology in multiple tissues, including the brain. In addition, we were able to demonstrate that substrate reduction therapy can improve the efficacy of enzyme replacement therapy in cell culture and in mice. These results provide proof of principle that targeted inhibition of heparan sulfate biosynthetic enzymes together with enzyme replacement might prove beneficial for treating mucopolysaccharidoses.
Related Links	http://www.jbc.org/content/287/43/36283.abstract
Ending Page	36290
Starting Page	36283
Page Count	8
File Format	HTM / HTML PDF
ISSN	00219258
Journal	Journal of Biological Chemistry (JBC)
Issue Number	43
Volume Number	287
DOI	10.1074/jbc.M112.403360
e-ISSN	1083351X
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2012-10-19
Access Restriction	Open
Subject Keyword	Glycosaminoglycan Heparan Sulfate Lysosomal Storage Disease Metabolism Mouse Enzyme Replacement Therapy Ext Sanfilippo
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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