G.P.8.05 The pharmacological chaperone AT2220 increases mutant acid alpha-glucosidase levels and reduces tissue glycogen in a mouse model of Pompe disease

Pompe disease, also known as glycogen storage disease type II (GSD II), is an autosomal recessive neuromuscular disorder caused by mutations in the gene encoding the lysosomal hydrolase, acid alpha-glucosidase (GAA). GAA deficiency results in lysosomal glycogen accumulation in multiple tissues including skeletal and cardiac muscle and leads to muscle weakness, reduced cardiac function, and respiratory insufficiency. As a potential treatment for Pompe disease, we are developing the pharmacological chaperone AT2220 (1-deoxynojirimycin-HCl) that directly binds to and stabilizes GAA. In Pompe patient-derived fibroblasts and transiently transfected COS-7 cells, AT2220 significantly increased the levels of several mutant forms of GAA, including the P545L variant. To investigate the effect of AT2220 in vivo, we developed a new Pompe transgenic mouse model in which the human form of P545L GAA is expressed on a GAA knock-out background (hP545L GAA Tg/KO). Two Pompe transgenic mouse lines that express ‘Moderate’ (10%) and ‘Low’ (3%) levels of the transgene (relative to wild-type) and that also accumulate glycogen in disease-relevant tissues were generated. Daily oral administration (ad libitum) of AT2220 for four weeks to ‘Moderate’ hP545L GAA Tg/KO mice resulted in significant and dose-dependent increases in tissue GAA levels. Importantly, increased GAA activity resulted in a decrease in glycogen levels in multiple tissues including heart, skeletal muscles, and brain. Additional studies to investigate the effects of AT2220 in ‘Low’ hP545L GAA Tg/KO mice and to optimize dosing regimens for maximal glycogen clearance are ongoing. Collectively, these results indicate that AT2220 can increase mutant GAA levels both in vitro and in vivo and reduce muscle glycogen levels in mice. As such, AT2220 warrants further evaluation as a treatment for Pompe disease.