title: Inhibition of glycogen biosynthesis via mTORC1 suppression as an adjunct therapy for Pompe disease.
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.
authors.affiliation: Genzyme Corporation, 49 New York Avenue, Framingham, MA 01701-9322, USA.
authors.forename: Karen M
authors.initials: KM
authors.lastname: Ashe
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Taylor
authors.forename: Qiuming
authors.initials: Q
authors.lastname: Chu
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Meyers
authors.forename: Allen
authors.initials: A
authors.lastname: Ellis
authors.forename: Varvara
authors.initials: V
authors.lastname: Jingozyan
authors.forename: Katherine
authors.initials: K
authors.lastname: Klinger
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Finn
authors.forename: Christopher G F
authors.initials: CG
authors.lastname: Cooper
authors.forename: Wei-Lien
authors.initials: WL
authors.lastname: Chuang
authors.forename: John
authors.initials: J
authors.lastname: Marshall
authors.forename: John M
authors.initials: JM
authors.lastname: McPherson
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mattaliano
authors.forename: Seng H
authors.initials: SH
authors.lastname: Cheng
authors.forename: Ronald K
authors.initials: RK
authors.lastname: Scheule
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Moreland
mesh_terms: D000375:Aging / Q000187:drug effects / Q000473:pathology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D056947:Enzyme Replacement Therapy; D006003:Glycogen / Q000096:biosynthesis*; D006009:Glycogen Storage Disease Type II / Q000188:drug therapy / Q000201:enzymology / Q000628:therapy*; D006006:Glycogen Synthase / Q000378:metabolism; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011506:Proteins; D011994:Recombinant Proteins / Q000627:therapeutic use; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000520:alpha-Glucosidases / Q000378:metabolism / Q000627:therapeutic use
chemical_list: D046912:Multiprotein Complexes; D011506:Proteins; D011994:Recombinant Proteins; D014157:Transcription Factors; D006003:Glycogen; D006006:Glycogen Synthase; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D000520:alpha-Glucosidases; D020123:Sirolimus