Glycosylation-independent Lysosomal Targeting of Acid α-Glucosidase Enhances Muscle Glycogen Clearance in Pompe Mice

被引：86

作者：

Maga, John A. ^{[1
]}

Zhou, Jianghong ^{[1
]}

Kambampati, Ravi ^{[1
]}

Peng, Susan ^{[1
]}

Wang, Xu ^{[2
]}

Bohnsack, Richard N. ^{[3
]}

Thomm, Angela ^{[1
]}

Golata, Sarah ^{[1
]}

Tom, Peggy ^{[1
]}

Dahms, Nancy M. ^{[3
]}

Byrne, Barry J. ^{[2
]}

LeBowitz, Jonathan H. ^{[1
]}

机构：

[1] ZyStor Therapeut, Milwaukee, WI 53226 USA

[2] Univ Florida, Coll Med, Powell Gene Therapy Ctr, Gainesville, FL 32610 USA

[3] Med Coll Wisconsin, Dept Biochem, Milwaukee, WI 53226 USA

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2013年 / 288卷 / 03期

关键词：

MANNOSE 6-PHOSPHATE RECEPTOR; II BINDING-SITE; ALGLUCOSIDASE ALPHA; MOUSE MODEL; INSULIN; STORAGE; RECOMBINANT; DISEASE; INFANTILE; ENZYME;

D O I：

10.1074/jbc.M112.438663

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

We have used a peptide-based targeting system to improve lysosomal delivery of acid alpha-glucosidase (GAA), the enzyme deficient in patients with Pompe disease. Human GAA was fused to the glycosylation-independent lysosomal targeting (GILT) tag, which contains a portion of insulin-like growth factor II, to create an active, chimeric enzyme with high affinity for the cation-independent mannose 6-phosphate receptor. GILT-tagged GAA was taken up by L6 myoblasts about 25-fold more efficiently than was recombinant human GAA (rhGAA). Once delivered to the lysosome, the mature form of GILT-tagged-GAA was indistinguishable from rhGAA and persisted with a half-life indistinguishable from rhGAA. GILT-tagged GAA was significantly more effective than rhGAA in clearing glycogen from numerous skeletal muscle tissues in the Pompe mouse model. The GILT-tagged GAA enzyme may provide an improved enzyme replacement therapy for Pompe disease patients.

引用

页码：1428 / 1438

页数：11

共 41 条

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