title: Glycoengineered acid alpha-glucosidase with improved efficacy at correcting the metabolic aberrations and motor function deficits in a mouse model of Pompe disease.
abstract: Improving the delivery of therapeutics to disease-affected tissues can increase their efficacy and safety. Here, we show that chemical conjugation of a synthetic oligosaccharide harboring mannose 6-phosphate (M6P) residues onto recombinant human acid alpha-glucosidase (rhGAA) via oxime chemistry significantly improved its affinity for the cation-independent mannose 6-phosphate receptor (CI-MPR) and subsequent uptake by muscle cells. Administration of the carbohydrate-remodeled enzyme (oxime-neo-rhGAA) into Pompe mice resulted in an approximately fivefold higher clearance of lysosomal glycogen in muscles when compared to the unmodified counterpart. Importantly, treatment of immunotolerized Pompe mice with oxime-neo-rhGAA translated to greater improvements in muscle function and strength. Treating older, symptomatic Pompe mice also reduced tissue glycogen levels but provided only modest improvements in motor function. Examination of the muscle pathology suggested that the poor response in the older animals might have been due to a reduced regenerative capacity of the skeletal muscles. These findings lend support to early therapeutic intervention with a targeted enzyme as important considerations in the management of Pompe disease.
authors.affiliation: Genzyme Corporation, Framingham, Massachusetts 01701-9322, USA. yunxiang.zhu@genzyme.com
authors.forename: Yunxiang
authors.initials: Y
authors.lastname: Zhu
authors.forename: Ji-Lei
authors.initials: JL
authors.lastname: Jiang
authors.forename: Nathan K
authors.initials: NK
authors.lastname: Gumlaw
authors.forename: Jinhua
authors.initials: J
authors.lastname: Zhang
authors.forename: Scott D
authors.initials: SD
authors.lastname: Bercury
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Ziegler
authors.forename: Karen
authors.initials: K
authors.lastname: Lee
authors.forename: Mariko
authors.initials: M
authors.lastname: Kudo
authors.forename: William M
authors.initials: WM
authors.lastname: Canfield
authors.forename: Timothy
authors.initials: T
authors.lastname: Edmunds
authors.forename: Canwen
authors.initials: C
authors.lastname: Jiang
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mattaliano
authors.forename: Seng H
authors.initials: SH
authors.lastname: Cheng
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006003:Glycogen / Q000378:metabolism; D006009:Glycogen Storage Disease Type II / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D008360:Mannosephosphates / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009844:Oligosaccharides / Q000737:chemistry*; D011485:Protein Binding; D015202:Protein Engineering / Q000379:methods*; D017527:Receptor, IGF Type 2 / Q000378:metabolism; D000520:alpha-Glucosidases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D008360:Mannosephosphates; D009844:Oligosaccharides; D017527:Receptor, IGF Type 2; D006003:Glycogen; C509951:GAA protein, human; D000520:alpha-Glucosidases