Pompe disease is a lysosomal glycogen storage disorder primarily affecting the skeletal and cardiac muscle. It is caused by mutations in the gene encoding for acid alpha-glucosidase(GAA). The absence of GAA results in an inability to metabolize intra-lysosomal glycogen which causes an entrapment of glycogen leading to extra-lysosomal events including defective autophagy, structural defects, metabolic defects and signaling defects throughout the body. Enzyme replacement therapy(ERT) using recombinant GAA is currently the standard of care and has drastically changed the natural history of the disease. However, as survival improved, new myopathic and neurological symptoms came to the forefront in these patients and highlight the need for further therapies for Pompe disease.
Here we present a Substrate reduction therapy(SRT) targeting the amount of glycogen available for entrapment into the lysosomal. The glycogen biosynthetic pathways are channeled through Glycogen Synthase (Gys1) which is the rate limited step in the synthesis of glycogen. Humans with Gys1 haplosufficiency develop normally and have no obvious phenotype. Targeting Gys1 can reduce the glycogen substrate available for the pathogenic glycogen accumulation in Pompe disease. AAV9 encoding siRNA against Gys1 was intravenously delivered into neonatal Pompe disease model mice. We showed improvements in several histological, biochemical, and functional outcomes from this treatment. We propose that AAV9 mediated RNAi targeting of Gys1 can be used as substrate reduction therapy in Pompe disease that can complement the existing ERT.