The Pharmacological Chaperone AT2220 Increases Recombinant Human Acid α-Glucosidase Uptake and Glycogen Reduction in a Mouse Model of Pompe Disease

作者：Richie Khanna, John J. Flanagan, Jessie Feng, Rebecca Soska, Michelle Frascella, Lee Pellegrino, Yi Lun, Darlene Guillen, David J. Lockhart, Kenneth J. Valenzano · 发表于：PLoS ONE · 年份：2012 · DOI：10.1371/journal.pone.0040776 · 被引用次数：83 · 研究领域：Lysosomal Storage Disorders Research、Glycogen Storage Diseases and Myoclonus、Trypanosoma species research and implications

Pompe disease is an inherited lysosomal storage disease that results from a deficiency in the enzyme acid α-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 hydrochloride, 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 37°C 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, compared to administration of rhGAA alone. Collectively, these preclini...