Long-term efficacy after [E1(-), polymerase(-)] adenovirus-mediated transfer of human acid-alpha-glucosidase gene into glycogen storage disease type II knockout mice

Glycogen storage disease type II (GSD-II) is a lethal, autosomal recessive metabolic myopathy caused by a lack of acid-a-glucosidase (GAA) activity in the cardiac and skeletal muscles. Absence of adequate intralysosomal GAA a ctivity results in massive amounts of glycogen accumulation in multiple mus cle groups, resulting in morbidity and mortality secondary to respiratory e mbarrassment and/or cardiomyopathy. In a mouse model of GSD-II, we demonstr ate that infection of the murine liver with a modified adenovirus (Ad) vect or encoding human GAA (hGAA) resulted in long-term persistence of the vecto r in liver tissues for at least 6 months. Despite both a rapid shutdown of hGAA mRNA expression from the vector, as well as the elicitation of anti-hG AA antibody responses (hGAA is a foreign antigen in this model), the hGAA s ecreted by the liver was taken up by all muscle groups analyzed and, remark ably, persisted in them for at least 6 months. The persistence of the prote in also correlated with long-term correction of pathologic intramuscular gl ycogen accumulations in all muscle groups tested, hut most notably the card iac tissues, which demonstrated a significantly decreased glycogen content for at least 190 days after a single vector injection. The results suggest that gene therapy strategies may have the potential to significantly improv e the clinical course for GSD-II patients.