Novel transferrin receptor-mediated enzyme replacement therapy efficiently treats myogenic and neurogenic aspects of Pompe disease in mice.

Pompe disease (PD) is a multisystemic progressive disease caused by acid-alpha glucosidase (GAA) deficiency. Patients display a spectrum of phenotypes ranging from the severe, rapidly progressive infantile-onset PD (IOPD) form to the slower progressing late-onset PD (LOPD). Enzyme replacement therapies (ERTs) are the only approved treatments; they decrease mortality in IOPD while maintaining or improving motor and respiratory function in LOPD. These therapies do not cross the blood-brain barrier (BBB) and the long-term survival of ERT-treated IOPD patients revealed underlying neurological disease. We used PD as a model to evaluate delivery of GAA across the BBB using anti-transferrin receptor (TfR) antibodies and show robust glycogen clearance and reduced neuroinflammation in the CNS of mice with PD. Importantly, anti-TfR-GAA treatment resulted in superior glycogen clearance in skeletal muscle compared with two approved ERTs. Glyco-chemical exchange saturation transfer/nuclear overhauser effect magnetic resonance imaging successfully estimated glycogen content in Pompe mouse brains, providing a non-invasive and translational method to evaluate brain-penetrant therapies for PD. Moreover, hexose tetrasaccharide was elevated in the cerebrospinal fluid of diseased mice and mirrored CNS glycogen levels, suggesting it may be a promising CNS biomarker. These data support the theory that the neurogenic and myogenic manifestations of PD can be effectively treated by anti-TfR-GAA.