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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Huynh, Ha T. Sly, William S. Grubb, Jeffrey H. Vogler, Carole |
| Description | Author Affiliation: Huynh HT ( Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.); |
| Abstract | Enzyme replacement therapy has been used successfully in many lysosomal storage diseases. However, correction of brain storage has been limited by the inability of infused enzyme to cross the blood-brain barrier (BBB). We recently reported that PerT-GUS, a form of ß-glucuronidase (GUS) chemically modified to eliminate its uptake and clearance by carbohydrate-dependent receptors, crossed the BBB and cleared neuronal storage in an immunotolerant model of murine mucopolysaccharidosis (MPS) type VII. In this respect, the chemically modified enzyme was superior to native ß-glucuronidase. Chemically modified enzyme was also delivered more effectively to heart, kidney, and muscle. However, liver and spleen, which express high levels of carbohydrate receptors, received nearly fourfold lower levels of PerT-GUS compared with native GUS. A recent report on PerT-treated sulfamidase in murine MPS IIIA confirmed enhanced delivery to other tissues but failed to observe clearance of storage in neurons. To confirm and extend our original observations, we compared the efficacy of 12 weekly i.v. infusions of PerT-GUS versus native GUS on (i) delivery of enzyme to brain; (ii) improvement in histopathology; and (iii) correction of secondary elevations of other lysosomal enzymes. Such correction is a recognized biomarker for correction of neuronal storage. PerT-GUS was superior to native GUS in all three categories. These results provide additional evidence that long-circulating enzyme, chemically modified to escape carbohydrate-mediated clearance, may offer advantages in treating MPS VII. The relevance of this approach to treat other lysosomal storage diseases that affect brain awaits confirmation. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 42 |
| Volume Number | 109 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2012-10-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Blood-Brain Barrier Metabolism Enzyme Replacement Therapy Glucuronidase Therapeutic Use Glycosaminoglycans Mucopolysaccharidosis VII Drug Therapy Neurons Drug Effects Beta-Glucosidase Animals Dose-Response Relationship, Drug Genetics Mice Enzymology Research Support, N.I.H., Extramural Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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