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

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.

Effects of exercise training during infusion on late-onset Pompe disease patients receiving enzyme replacement therapy

“…These data taken together suggest that the blood flow towards the skeletal muscles may not be the limiting factor for the effective delivery/action of the recombinant enzyme to the skeletal muscles and the enhancement of their functional capacity. Indeed, other factors such as the stability of the recombinant enzyme at body pH and temperature, seem to affect its effectiveness in target tissues [13]. Nevertheless, the present study does not provide insights to the mechanisms of the recombinant enzyme delivery/action to the skeletal muscles.…”

New strategies for the treatment of lysosomal storage diseases (Review)

“…Although pharmacological chaperone therapy (PCT) has been developed as a strategy to rescue mutant enzymes from degradation, recent studies showed that chaperones are also able to enhance physical stability and potentiate the therapeutic action of the enzymes used for ERT (40)(41)(42)(43). These studies, performed in cell systems and in the animal models of Pompe and Fabry disease, suggested a major change in the use of PCT.…”

Antisense oligonucleotide-mediated suppression of muscle glycogen synthase 1 synthesis as an approach for substrate reduction therapy of Pompe disease

“…In addition, a small molecule chaperone that improves the stability of the enzyme and enhances glycogen clearance in Pompe mice is being tested clinically. 14 Gene therapy with recombinant AAV vectors encoding GAA is also being evaluated. 15,16 Substrate reduction that abates the production of glycogen represents another therapeutic strategy for lysosomal storage disorders.…”