title: Glycosylation-independent lysosomal targeting of acid α-glucosidase enhances muscle glycogen clearance in pompe mice.
abstract: We have used a peptide-based targeting system to improve lysosomal delivery of acid α-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.
authors.affiliation: ZyStor Therapeutics, Milwaukee, Wisconsin 53226-4838, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Maga
authors.forename: Jianghong
authors.initials: J
authors.lastname: Zhou
authors.forename: Ravi
authors.initials: R
authors.lastname: Kambampati
authors.forename: Susan
authors.initials: S
authors.lastname: Peng
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.forename: Richard N
authors.initials: RN
authors.lastname: Bohnsack
authors.forename: Angela
authors.initials: A
authors.lastname: Thomm
authors.forename: Sarah
authors.initials: S
authors.lastname: Golata
authors.forename: Peggy
authors.initials: P
authors.lastname: Tom
authors.forename: Nancy M
authors.initials: NM
authors.lastname: Dahms
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Byrne
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: LeBowitz
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods; D056947:Enzyme Replacement Therapy / Q000379:methods*; D005087:Glucan 1,4-alpha-Glucosidase / Q000235:genetics / Q000378:metabolism*; D006003:Glycogen / Q000378:metabolism*; D006009:Glycogen Storage Disease Type II / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D006031:Glycosylation; D057809:HEK293 Cells; D006207:Half-Life; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D008247:Lysosomes / Q000187:drug effects* / Q000201:enzymology; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D050506:Mutant Chimeric Proteins / Q000235:genetics / Q000378:metabolism; D032446:Myoblasts / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D010957:Plasmids; D017527:Receptor, IGF Type 2 / Q000819:agonists / Q000378:metabolism; D014162:Transfection
chemical_list: D050506:Mutant Chimeric Proteins; D017527:Receptor, IGF Type 2; D007335:Insulin-Like Growth Factor II; D006003:Glycogen; D005087:Glucan 1,4-alpha-Glucosidase