1. Inhibition of glycogen biosynthesis via mTORC1 suppression as an adjunct therapy for Pompe disease.
- Author
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Ashe KM, Taylor KM, Chu Q, Meyers E, Ellis A, Jingozyan V, Klinger K, Finn PF, Cooper CG, Chuang WL, Marshall J, McPherson JM, Mattaliano RJ, Cheng SH, Scheule RK, and Moreland RJ
- Subjects
- Aging drug effects, Aging pathology, Animals, Dose-Response Relationship, Drug, Enzyme Replacement Therapy, Glycogen Storage Disease Type II drug therapy, Glycogen Storage Disease Type II enzymology, Glycogen Synthase metabolism, Humans, Mechanistic Target of Rapamycin Complex 1, Mice, Multiprotein Complexes, Muscle, Skeletal drug effects, Muscle, Skeletal enzymology, Muscle, Skeletal pathology, Myocardium metabolism, Myocardium pathology, Phosphorylation drug effects, Proteins, Recombinant Proteins therapeutic use, Sirolimus analogs & derivatives, Sirolimus pharmacology, TOR Serine-Threonine Kinases, Transcription Factors metabolism, alpha-Glucosidases metabolism, alpha-Glucosidases therapeutic use, Glycogen biosynthesis, Glycogen Storage Disease Type II therapy, Transcription Factors antagonists & inhibitors
- Abstract
Pompe disease, also known as glycogen storage disease (GSD) type II, is caused by deficiency of lysosomal acid alpha-glucosidase (GAA). The resulting glycogen accumulation causes a spectrum of disease severity ranging from a rapidly progressive course that is typically fatal by 1-2years of age to a more slowly progressive course that causes significant morbidity and early mortality in children and adults. Recombinant human GAA (rhGAA) improves clinical outcomes with variable results. Adjunct therapy that increases the effectiveness of rhGAA may benefit some Pompe patients. Co-administration of the mTORC1 inhibitor rapamycin with rhGAA in a GAA knockout mouse reduced muscle glycogen content more than rhGAA or rapamycin alone. These results suggest mTORC1 inhibition may benefit GSDs that involve glycogen accumulation in muscle., (Copyright 2010 Elsevier Inc. All rights reserved.)
- Published
- 2010
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