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.
Highlights
IntroductionPompe disease (acid maltase deficiency, glycogen storage disease type II; OMIM 232300) is a lysosomal storage disorder caused by mutations in the gene (GAA) that encodes the lysosomal hydrolase acid a-glucosidase (GAA) [1,2]
Pompe disease is a lysosomal storage disorder caused by mutations in the gene (GAA) that encodes the lysosomal hydrolase acid a-glucosidase (GAA) [1,2]
Previous studies indicated that the iminosugar 1-deoxynojirimycin (AT2220; duvoglustat hydrochloride) acts as a pharmacological chaperone for various mutant forms of acid a-glucosidase (GAA) [26]
Summary
Pompe disease (acid maltase deficiency, glycogen storage disease type II; OMIM 232300) is a lysosomal storage disorder caused by mutations in the gene (GAA) that encodes the lysosomal hydrolase acid a-glucosidase (GAA) [1,2]. Infantile-onset Pompe disease patients have little or no GAA activity, present with hypotonia, cardiomegaly, and cardiorespiratory distress, and typically die by age 2 if untreated [4]. Late-onset forms of Pompe disease typically show some detectable GAA activity, present in childhood or adulthood, and progress more slowly, with musculoskeletal and pulmonary involvement leading to progressive weakness and respiratory insufficiency [5]. Treatment with rhGAA improves cardiac function, motor skills, and life span in infantile-onset patients [6,7,8,9,10,11], and leads to mild improvements in motor and respiratory function in late-onset patients [12,13]. A clear unmet medical need still exists for many Pompe patients
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