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.
Highlights
Treatment of neuropathology in mucopolysaccharidoses may be possible by substrate reduction therapy
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
Genetic Substrate Reduction Therapy Improves Turnover and Reduces Lysosomal Storage in MPS IIIa MEFs—To generate a mouse model for genetic substrate reduction therapy (gSRT), mice heterozygous for sulfamidase deficiency were crossed with mice heterozygous for the genes encoding the heparan sulfate copolymerase, Ext1 and Ext2
Summary
Lamanna‡, Roger Lawrence‡, Stéphane Sarrazin‡1, Carlos Lameda-Diaz‡, Philip L. Esko‡2 From the ‡Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California at San Diego, La Jolla, California 92093-0687 and the §Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia 30602-4712
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