The FORCE(TM) platform is a versatile therapeutic approach that enables delivery of biologics and oligonucleotides to muscle and CNS via a fragment antigen binding antibody (Fab) highly specific for human transferrin receptor type 1 (TfR1). Traditional enzyme replacement therapy (ERT) with recombinant human acid alpha-glucosidase (GAA) delivered via the mannose-6-phospate receptor is the current standard of care (SOC) for Pompe disease. Unfortunately, the SOC has insufficient efficacy in skeletal muscle and does not address the central nervous system (CNS) manifestations of Pompe. Traditional ERT also requires frequent bi-weekly dosing and high dose levels. To overcome the limitations of SOC, we engineered the FORCE platform to create DYNE-401, which enables TfR1-mediated uptake of GAA in muscle and CNS. The Fab of the FORCE platform does not bind to murine TfR1, and to test DYNE-401 in vivo, we generated hTfR1/6Neo mice that express human TfR1 and lack GAA expression. The potential for lower dose levels and reduced dosing frequency was tested in this model of Pompe disease. Monthly intravenous administration of DYNE-401 led to dose dependent glycogen clearance in muscle. DYNE-401 normalized glycogen levels in the CNS at the lowest dose tested. Glycogen reduction was also associated with functional improvement. DYNE-401 achieved similar effects in muscle and CNS when administered once every other month to hTfR1/6Neo mice. Even with this infrequent dosing regimen, DYNE-401 retained the ability to normalize serum neurofilament light chain levels, indicating correction of neuronal damage. Collectively, these data demonstrate the potential of low and infrequent dosing with DYNE-401 to deliver functional improvement in Pompe disease.