Research ArticleGene Therapy

Rescue of Pompe disease in mice by AAV-mediated liver delivery of secretable acid α-glucosidase

See allHide authors and affiliations

Science Translational Medicine  29 Nov 2017:
Vol. 9, Issue 418, eaam6375
DOI: 10.1126/scitranslmed.aam6375

Revealing a secretable GAA for Pompe disease

Pompe disease is a genetic disorder caused by mutations in the acid α-glucosidase (GAA) gene, leading to glycogen accumulation in all cells of the body. This accumulation leads to severe neuromuscular disabilities that can be life-threatening. Puzzo et al. used bioinformatic analysis, protein engineering, and gene therapy to develop and deliver a GAA transgene encoding a secretable GAA. Liver-specific, adeno-associated virus (AAV) vector–mediated GAA delivery rescued the Pompe disease phenotype in a mouse model and increased GAA expression in healthy monkeys, opening possibilities for future translation of this approach for treating Pompe disease.


Glycogen storage disease type II or Pompe disease is a severe neuromuscular disorder caused by mutations in the lysosomal enzyme, acid α-glucosidase (GAA), which result in pathological accumulation of glycogen throughout the body. Enzyme replacement therapy is available for Pompe disease; however, it has limited efficacy, has high immunogenicity, and fails to correct pathological glycogen accumulation in nervous tissue and skeletal muscle. Using bioinformatics analysis and protein engineering, we developed transgenes encoding GAA that could be expressed and secreted by hepatocytes. Then, we used adeno-associated virus (AAV) vectors optimized for hepatic expression to deliver the GAA transgenes to Gaa knockout (Gaa−/−) mice, a model of Pompe disease. Therapeutic gene transfer to the liver rescued glycogen accumulation in muscle and the central nervous system, and ameliorated cardiac hypertrophy as well as muscle and respiratory dysfunction in the Gaa−/− mice; mouse survival was also increased. Secretable GAA showed improved therapeutic efficacy and lower immunogenicity compared to nonengineered GAA. Scale-up to nonhuman primates, and modeling of GAA expression in primary human hepatocytes using hepatotropic AAV vectors, demonstrated the therapeutic potential of AAV vector–mediated liver expression of secretable GAA for treating pathological glycogen accumulation in multiple tissues in Pompe disease.

View Full Text

Stay Connected to Science Translational Medicine