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Enzyme replacement therapy with recombinant human GAA (rhGAA) is the standard\u2010of\u2010care treatment for PD, however, its efficacy is limited due to poor uptake in muscle and the development of an immune response. Multiple clinical trials are ongoing in PD with adeno\u2010associated virus (AAV) vectors based on liver\u2010 and muscle\u2010targeting. Current gene therapy approaches are limited by liver proliferation, poor muscle targeting, and the potential immune response to the hGAA transgene. To generate a treatment tailored to infantile\u2010onset PD, we took advantage of a novel AAV capsid able to increase skeletal muscle targeting compared to AAV9 while reducing liver overload. When combined with a liver\u2010muscle tandem promoter (LiMP), and despite the extensive liver\u2010detargeting, this vector had a limited immune response to the hGAA transgene. This combination of capsid and promoter with improved muscle expression and specificity allowed for glycogen clearance in cardiac and skeletal muscles of <jats:italic>Gaa<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> adult mice. In neonate <jats:italic>Gaa<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>, complete rescue of glycogen content and muscle strength was observed 6\u2009months after AAV vector injection. Our work highlights the importance of residual liver expression to control the immune response toward a potentially immunogenic transgene expressed in muscle. In conclusion, the demonstration of the efficacy of a muscle\u2010specific AAV capsid\u2010promoter combination for the full rescue of PD manifestation in both neonate and adult <jats:italic>Gaa<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> provides a potential therapeutic avenue for the infantile\u2010onset form of this devastating disease.<\/jats:p>","DOI":"10.1002\/jimd.12625","type":"journal-article","created":{"date-parts":[[2023,5,19]],"date-time":"2023-05-19T13:04:21Z","timestamp":1684501461000},"page":"119-134","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Muscle\u2010specific, liver\u2010detargeted <scp>adeno\u2010associated virus<\/scp> gene therapy rescues Pompe phenotype in adult and neonate <scp><i>Gaa<\/i><sup>\u2212\/\u2212<\/sup><\/scp> mice"],"prefix":"10.1002","volume":"47","author":[{"given":"P.","family":"Sellier","sequence":"first","affiliation":[{"name":"Universit\u00e9 Paris\u2010Saclay Univ Evry, Inserm, Genethon, Integrare Research Unit UMR_S951  Evry France"},{"name":"Genethon  Evry France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P.","family":"Vidal","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris\u2010Saclay Univ Evry, Inserm, Genethon, Integrare Research Unit UMR_S951  Evry France"},{"name":"Genethon  Evry France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B.","family":"Bertin","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris\u2010Saclay Univ Evry, Inserm, Genethon, Integrare Research Unit UMR_S951  Evry France"},{"name":"Genethon  Evry France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.","family":"Gicquel","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris\u2010Saclay Univ Evry, Inserm, Genethon, Integrare Research Unit UMR_S951  Evry France"},{"name":"Genethon  Evry France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.","family":"Bertil\u2010Froidevaux","sequence":"additional","affiliation":[{"name":"Genethon  Evry France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Georger","sequence":"additional","affiliation":[{"name":"Genethon  Evry France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L.","family":"van Wittenberghe","sequence":"additional","affiliation":[{"name":"Genethon  Evry France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Miranda","sequence":"additional","affiliation":[{"name":"Genethon  Evry France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N.","family":"Daniele","sequence":"additional","affiliation":[{"name":"Genethon  Evry France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I.","family":"Richard","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris\u2010Saclay Univ Evry, Inserm, Genethon, Integrare Research Unit UMR_S951  Evry France"},{"name":"Genethon  Evry France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. 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