title: The pharmacological chaperone AT2220 increases the specific activity and lysosomal delivery of mutant acid alpha-glucosidase, and promotes glycogen reduction in a transgenic mouse model of Pompe disease.
abstract: Pompe disease is an inherited lysosomal storage disorder that results from a deficiency in acid α-glucosidase (GAA) activity due to mutations in the GAA gene. Pompe disease is characterized by accumulation of lysosomal glycogen primarily in heart and skeletal muscles, which leads to progressive muscle weakness. We have shown previously that the small molecule pharmacological chaperone AT2220 (1-deoxynojirimycin hydrochloride, duvoglustat hydrochloride) binds and stabilizes wild-type as well as multiple mutant forms of GAA, and can lead to higher cellular levels of GAA. In this study, we examined the effect of AT2220 on mutant GAA, in vitro and in vivo, with a primary focus on the endoplasmic reticulum (ER)-retained P545L mutant form of human GAA (P545L GAA). AT2220 increased the specific activity of P545L GAA toward both natural (glycogen) and artificial substrates in vitro. Incubation with AT2220 also increased the ER export, lysosomal delivery, proteolytic processing, and stability of P545L GAA. In a new transgenic mouse model of Pompe disease that expresses human P545L on a Gaa knockout background (Tg/KO) and is characterized by reduced GAA activity and elevated glycogen levels in disease-relevant tissues, daily oral administration of AT2220 for 4 weeks resulted in significant and dose-dependent increases in mature lysosomal GAA isoforms and GAA activity in heart and skeletal muscles. Importantly, oral administration of AT2220 also resulted in significant glycogen reduction in disease-relevant tissues. Compared to daily administration, less-frequent AT2220 administration, including repeated cycles of 4 or 5 days with AT2220 followed by 3 or 2 days without drug, respectively, resulted in even greater glycogen reductions. Collectively, these data indicate that AT2220 increases the specific activity, trafficking, and lysosomal stability of P545L GAA, leads to increased levels of mature GAA in lysosomes, and promotes glycogen reduction in situ. As such, AT2220 may warrant further evaluation as a treatment for Pompe disease.
authors.affiliation: Amicus Therapeutics Inc., Cranbury, New Jersey, United States of America.
authors.forename: Richie
authors.initials: R
authors.lastname: Khanna
authors.affiliation: Amicus Therapeutics Inc., Cranbury, New Jersey, United States of America.
authors.forename: Allan C
authors.initials: AC
authors.lastname: Powe
authors.affiliation: Amicus Therapeutics Inc., Cranbury, New Jersey, United States of America.
authors.forename: Yi
authors.initials: Y
authors.lastname: Lun
authors.affiliation: Amicus Therapeutics Inc., Cranbury, New Jersey, United States of America.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Soska
authors.affiliation: Amicus Therapeutics Inc., Cranbury, New Jersey, United States of America.
authors.forename: Jessie
authors.initials: J
authors.lastname: Feng
authors.affiliation: Amicus Therapeutics Inc., Cranbury, New Jersey, United States of America.
authors.forename: Rohini
authors.initials: R
authors.lastname: Dhulipala
authors.affiliation: Amicus Therapeutics Inc., Cranbury, New Jersey, United States of America.
authors.forename: Michelle
authors.initials: M
authors.lastname: Frascella
authors.affiliation: Amicus Therapeutics Inc., Cranbury, New Jersey, United States of America.
authors.forename: Anadina
authors.initials: A
authors.lastname: Garcia
authors.affiliation: Amicus Therapeutics Inc., Cranbury, New Jersey, United States of America.
authors.forename: Lee J
authors.initials: LJ
authors.lastname: Pellegrino
authors.affiliation: Amicus Therapeutics Inc., Cranbury, New Jersey, United States of America.
authors.forename: Su
authors.initials: S
authors.lastname: Xu
authors.affiliation: Amicus Therapeutics Inc., Cranbury, New Jersey, United States of America.
authors.forename: Nastry
authors.initials: N
authors.lastname: Brignol
authors.affiliation: Amicus Therapeutics Inc., Cranbury, New Jersey, United States of America.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Toth
authors.affiliation: Amicus Therapeutics Inc., Cranbury, New Jersey, United States of America.
authors.forename: Hung V
authors.initials: HV
authors.lastname: Do
authors.affiliation: Amicus Therapeutics Inc., Cranbury, New Jersey, United States of America.
authors.forename: David J
authors.initials: DJ
authors.lastname: Lockhart
authors.affiliation: Amicus Therapeutics Inc., Cranbury, New Jersey, United States of America.
authors.forename: Brandon A
authors.initials: BA
authors.lastname: Wustman
authors.affiliation: Amicus Therapeutics Inc., Cranbury, New Jersey, United States of America.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Valenzano
mesh_terms: D017485:1-Deoxynojirimycin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000284:Administration, Oral; D000818:Animals; D055162:Biocatalysis / Q000187:drug effects; D001682:Biological Availability; D019556:COS Cells; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D004795:Enzyme Stability / Q000187:drug effects; D055786:Gene Knockout Techniques; D005087:Glucan 1,4-alpha-Glucosidase / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D006003:Glycogen / Q000378:metabolism*; D006009:Glycogen Storage Disease Type II / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D021381:Protein Transport / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects
chemical_list: D007527:Isoenzymes; D050505:Mutant Proteins; D017485:1-Deoxynojirimycin; D006003:Glycogen; D005087:Glucan 1,4-alpha-Glucosidase