A novel CD71 Centyrin:Gys1 siRNA targeting and delivery platform reduces glycogen synthesis and glycogen levels in a mouse model of Pompe disease

Pompe disease is caused by acid alpha-glucosidase (GAA) deficiency, resulting in lysosomal glycogen accumulation. This disease is characterized by progressive skeletal muscle weakness, respiratory distress, and in the infantile-onset form, cardiomyopathy. The only approved treatment is enzyme replacement therapy (ERT) with human recombinant GAA. While ERT therapy extends life span, residual symptoms remain, with poor muscle uptake and immunogenicity limiting efficacy. We examined a novel Centyrin protein - short interfering ribonucleic acid (siRNA) conjugate targeting CD71 (transferrin receptor type 1, TfR1) and GYS1, a key enzyme involved in glycogen synthesis. Unlike existing ERTs designed to degrade aberrant glycogen deposits observed in Pompe patients, the CD71 Centyrin:Gys1 siRNA is designed to restore glycogen balance by inhibiting glycogen synthesis. To this end, we administered the CD71 Centyrin:Gys1 siRNA conjugate to the 6