Virus-based enzymatic nanoreactors with acid alpha-glucosidase for the potential treatment of Pompe disease

Abstract

Pompe disease is an inherited disorder originating from the enzyme acid alpha-glucosidase (GAA) deficiency that induces glycogen accumulation inside lysosomes. Enzyme replacement therapy (ERT) is the main treatment for Pompe disease. However, its effectivity is reduced by the immune response, enzyme proteolysis, and the enzyme difficulty in crossing the blood–brain barrier (BBB). This work aimed to design and synthesize enzymatic nanoreactors based on the enzyme confinement inside virus-like particles to improve the ERT for Pompe disease. The GAA confinement was performed by self-assembling the coat proteins of the brome mosaic virus in the presence of GAA. Then, nanoreactors were surface functionalized with a 6-phosphate mannose derivative using modified polyethylene glycol (PEG) to improve their capacity to cross the brain–blood barrier (BBB). The functionalized enzymatic nanoreactors showed a 1.6 times faster crossing rate than the unfunctionalized nanoreactors in an in vitro model of the BBB. In conclusion, enzymatic nanoreactors with GAA activity were successfully synthesized and functionalized with a 6-phosphate mannose derivative to improve the enzyme replacement therapy (ERT) and reduce the immunogenic response for Pompe disease treatment. The advantages of using virus-like particles as enzyme nanocarriers for treating Pompe disease are discussed.