Pompe disease is a lysosomal storage disease characterized by loss of function mutations in alpha acid glucosidase (GAA), an enzyme responsible for the degradation of lysosomal glycogen in muscle tissues. Reducing the production of glycogen via decreasing glycogen synthase 1 (Gys1) mRNA and protein may provide a more effective, alternative strategy versus enzyme replacement for the treatment of Pompe disease. We have designed a Centyrin targeting CD71 (Type 1 Transferrin receptor) conjugated to a Gys1 specific siRNA to achieve muscle selective Gys1 mRNA and protein inhibition, and subsequent normalization of muscle glycogen levels. We have found that a Centyrin-siRNA conjugate targeting murine CD71 and the murine Gys1 mRNA was highly effective, after a single 3mpk dose, in reducing Gys1 mRNA and protein in skeletal muscle by >80% in the mouse Pompe disease model. Decreases in Gys1 were also seen, to a lesser extent, in cardiac muscle. Minimal to no decrease of Gys1 was detected in liver or kidney. The Centyrin-siRNA conjugate had durable pharmacodynamic activity for greater than 6 weeks after a single dose in the mouse model. In a multi-dose study decreases in Gys1 mRNA and protein led to significant decreases in skeletal muscle glycogen. In summary, our studies demonstrate efficient targeting of a Gys1 specific siRNA to skeletal muscle, leading to Gys1 mRNA, protein and glycogen decreases in a murine model of Pompe disease. These data provide the basis for studying Centyrin-siRNA conjugates in patients with Pompe disease and pre-clinical studies are ongoing to support an IND in 2023.