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J. Biol. Chem., Vol. 279, Issue 48, 50336-50341, November 26, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/48/50336    most recent M409676200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhu, Y. Articles by Cheng, S. H. Search for Related Content PubMed PubMed Citation Articles by Zhu, Y. Articles by Cheng, S. H. Social Bookmarking                      What's this?

Conjugation of Mannose 6-Phosphate-containing Oligosaccharides to Acid -Glucosidase Improves the Clearance of Glycogen in Pompe Mice^*

Yunxiang Zhu, Xuemei Li, Josephine Kyazike, Qun Zhou, Beth L. Thurberg, Nina Raben, Robert J. Mattaliano, and Seng H. Cheng¶

From the Genzyme Corporation, Framingham, Massachusetts 01701-9322 and the National Institutes of Health, Bethesda, Maryland 20892

Clinical studies of enzyme replacement therapy for Pompe disease have indicated that relatively high doses of recombinant human acid -glucosidase (rhGAA) may be required to reduce the abnormal glycogen storage in cardiac and skeletal muscles. This may be because of inefficient cation-independent mannose 6-phosphate receptor (CI-MPR)-mediated endocytosis of the enzyme by the affected target cells. To address this possibility, we examined whether the addition of a high affinity ligand to rhGAA would improve its delivery to these cells. Chemical conjugation of high mannose oligosaccharides harboring mono- and bisphosphorylated mannose 6-phosphates onto rhGAA (neo-rhGAA) significantly improved its uptake characteristics by muscle cells in vitro. Infusion of neo-rhGAA into Pompe mice also resulted in greater delivery of the enzyme to muscle tissues when compared with the unmodified enzyme. Importantly, this increase in enzyme levels was associated with significantly improved clearance of glycogen (5-fold) from the affected tissues. These results suggest that CI-MPR-mediated endocytosis of rhGAA is an important pathway by which the enzyme is delivered to the affected lysosomes of Pompe muscle cells. Hence, the generation of rhGAA containing high affinity ligands for the CI-MPR represents a strategy by which the potency of rhGAA and therefore the clinical efficacy of enzyme replacement therapy for Pompe disease may be improved.

Received for publication, August 23, 2004 , and in revised form, September 21, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Genzyme Corporation, 31 New York Ave., Framingham, MA 01701-9322. Tel.: 508-270-2458; Fax: 508-872-4091; E-mail: seng.cheng{at}genzyme.com.

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				D. E. Sleat, H. Zheng, M. Qian, and P. Lobel Identification of Sites of Mannose 6-Phosphorylation on Lysosomal Proteins Mol. Cell. Proteomics, April 1, 2006; 5(4): 686 - 701. [Abstract] [Full Text] [PDF]