Abstract
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 preclinical data highlight the potentially beneficial effects of AT2220 on rhGAA in vitro and in vivo. As such, a Phase 2 clinical study has been initiated to investigate the effects of co-administered AT2220 on rhGAA in Pompe patients.
Highlights
Pompe disease (OMIM 23200), referred to as glycogen storage disease type II or acid maltase deficiency, is a lysosomal storage disease (LSD) caused by mutations in the gene (GAA) that encodes the lysosomal hydrolase acid a-glucosidase (GAA) [1,2]
Or infantile-onset Pompe disease occurs before 12 months of age, has a rapid rate of progression, and is typically characterized by severe muscle weakness, frequent respiratory infections, hepatomegaly, massive cardiomegaly, cardiomyopathy, and cardiorespiratory failure that usually results in death between 1 and 2 years of age [1,3]
The effect of AT2220 binding on the stability of recombinant human GAA (rhGAA) was assessed using a fluorescence-based denaturation assay described previously [28]
Summary
Pompe disease (OMIM 23200), referred to as glycogen storage disease type II or acid maltase deficiency, is a lysosomal storage disease (LSD) caused by mutations in the gene (GAA) that encodes the lysosomal hydrolase acid a-glucosidase (GAA) [1,2]. Despite the clinical benefits of ERT, a number of reports suggest that correction of the skeletal muscle phenotype is challenging, and that not all patients respond well to treatment [2,7,12,13]. These limitations are at least partially due to insufficient targeting/uptake into disease-relevant tissues, as well as poor tolerability due to severe ERT-mediated anaphylactic and immunologic reactions [5,11,14,15,16,17,18]
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