{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T23:26:49Z","timestamp":1770334009323,"version":"3.49.0"},"reference-count":32,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2010,10,22]],"date-time":"2010-10-22T00:00:00Z","timestamp":1287705600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Gene Medicine"],"published-print":{"date-parts":[[2010,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Lysosomal storage disorders such as Pompe disease can be more effectively treated, if immune tolerance to enzyme or gene replacement therapy can be achieved. Alternatively, immune responses against acid \u03b1\u2010glucosidase (GAA) might be evaded in Pompe disease through muscle\u2010specific expression of GAA with adeno\u2010associated virus (AAV) vectors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>An AAV vector containing the MHCK7 regulatory cassette to drive muscle\u2010specific GAA expression was administered to GAA knockout (KO) mice, immune tolerant GAA\u2010KO mice and mannose\u20106\u2010phosphate deficient GAA\u2010KO mice. GAA activity and glycogen content were analyzed in striated muscle to determine biochemical efficacy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The biochemical efficacy from GAA expression was slightly reduced in GAA\u2010KO mice, as demonstrated by higher residual glycogen content in skeletal muscles. Next, immune tolerance to GAA was induced in GAA\u2010KO mice by co\u2010administration of a second AAV vector encoding liver\u2010specific GAA along with the AAV vector encoding muscle\u2010specific GAA. Antibody formation was prevented by liver\u2010specific GAA, and the biochemical efficacy of GAA expression was improved in the absence of antibodies, as demonstrated by significantly reduced glycogen content in the diaphragm. Efficacy was reduced in old GAA\u2010KO mice despite the absence of antibodies. The greatest impact upon gene therapy was observed in GAA\u2010KO mice lacking the mannose\u20106\u2010phosphate receptor in muscle. The clearance of stored glycogen was markedly impaired despite high GAA expression in receptor\u2010deficient Pompe disease mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Overall, antibody formation had a subtle effect upon efficacy, whereas the absence of mannose\u20106\u2010phosphate receptors markedly impaired muscle\u2010targeted gene therapy in murine Pompe disease. 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