Inhibition of glycogen biosynthesis via mTORC1 suppression as an adjunct therapy for Pompe disease.
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.
Ashe
Karen M
KM
Genzyme Corporation, 49 New York Avenue, Framingham, MA 01701-9322, USA.
Taylor
Kristin M
KM
Chu
Qiuming
Q
Meyers
Elizabeth
E
Ellis
Allen
A
Jingozyan
Varvara
V
Klinger
Katherine
K
Finn
Patrick F
PF
Cooper
Christopher G F
CG
Chuang
Wei-Lien
WL
Marshall
John
J
McPherson
John M
JM
Mattaliano
Robert J
RJ
Cheng
Seng H
SH
Scheule
Ronald K
RK
Moreland
Rodney J
RJ
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
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