A novel technology-driven enzyme replacement therapy for Pompe disease

Pompe disease, a prototypical lysosomal storage disorder (LSD), is caused by a deficiency of glycogen-degrading lysosomal enzyme acid alpha-glucosidase (GAA). Enzyme replacement therapy (ERT) options for Pompe disease have recently expanded to include avalglucosidase alfa and cipaglucosidase alfa/miglustat. These new recombinant enzymes (rhGAAs) were designed to overcome the limitations of alglucosidase alfa, the first-generation ERT. Both rhGAAs have a higher content of bis-phosphorylated mannose-6-phosphate (bis-M6P) N-glycans for more efficient muscle targeting via the cation-independent mannose 6-phosphate receptor. Despite the initial positive response, new ERTs offer only incremental advances, and some patients continue to decline. Here, we used a novel technology to co-express rhGAA with engineered GlcNAc-1-phosphotransferase to produce a new compound, M021, with exceptionally high levels of natural bis-M6P glycans. In this large preclinical study, we demonstrate that M021 outperforms avalglucosidase and cipaglucosidase-evaluated here as a standalone rhGAA component-in removing accumulated glycogen and ameliorating autophagy-lysosomal pathway dysfunction. Importantly, monthly dosing rather than standard biweekly treatment following debulking sustained low levels of glycogen and autophagic markers. Furthermore, initiating a monthly regimen from the start of therapy resulted in similarly low glycogen levels. The bis-M6P enrichment platform offers a strategy with therapeutic potential across the spectrum of LSDs.