the pharmacological chaperone at2220 increases recombinant human acid α-glucosidase uptake and glycogen reduction in a mouse model of pompe disease药理伴侣at2220增加重组人类α-glucosidase吸收酸和糖原减少筛疾病的小鼠模型.pdfVIP

The Pharmacological Chaperone AT2220 Increases Recombinant Human Acid a-Glucosidase Uptake and Glycogen Reduction in a Mouse Model of Pompe Disease Richie Khanna*, John J. Flanagan, Jessie Feng, Rebecca Soska, Michelle Frascella, Lee J. Pellegrino, Yi Lun, Darlene Guillen, David J. Lockhart, Kenneth J. Valenzano Amicus Therapeutics Inc, Cranbury, New Jersey, United States of America Abstract Pompe disease is an inherited lysosomal storage disease that results from a deficiency in the enzyme acid a-glucosidase (GAA), and is characterized by progressive accumulation of lysosomal glycogen primarily in heart and skeletal muscles. Recombinant human GAA (rhGAA) is the only approved enzyme replacement therapy (ERT) available for the treatment of Pompe disease. Although rhGAA has been shown to slow disease progression and improve some of the pathophysiogical manifestations, the infused enzyme tends to be unstable at neutral pH and body temperature, shows low uptake into some key target tissues, and may elicit immune responses that adversely affect tolerability and efficacy. We hypothesized that co- administration of the orally-available, small molecule pharmacological chaperone AT2220 (1-deoxynojirimycin hydrochlo- ride, duvoglustat hydrochloride) may improve the pharmacological properties of rhGAA via binding and stabilization. AT2220 co-incubation prevented rhGAA denaturation and loss of activity in vitro at neutral pH and 37uC in both buffer and blood. In addition, oral pre-administration of AT2220 to rats led to a greater than two-fold increase in the circulating half-life of intravenous rhGAA. Importantly, co-administration of AT2220 and rhGAA to GAA knock-out (KO) mice resulted in significantly greater rhGAA levels in plasma, and greater uptake and glycogen reduction in heart and skeletal muscles, compar