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Enzyme replacement therapy is the only available treatment. AT845 is an adeno\u2010associated viral vector designed to express human GAA specifically in skeletal muscle and heart. Systemic administration of AT845 in\n                    <jats:italic>Gaa<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice led to a dose\u2010dependent increase in GAA activity, glycogen clearance in muscles and heart, and functional improvement. AT845 was tolerated in cynomolgus macaques at low doses, while high doses caused anti\u2010GAA immune response, inflammation, and cardiac abnormalities resulting in unscheduled euthanasia of two animals. Conversely, a vector expressing the macaque GAA caused no detectable pathology, indicating that the toxicity observed with AT845 was an anti\u2010GAA xenogeneic immune response. Western blot analysis showed abnormal processing of human GAA in cynomolgus muscle, adding to the species\u2010specific effects of enzyme expression. Overall, these studies show that AAV\u2010mediated GAA delivery to muscle is efficacious in\n                    <jats:italic>Gaa<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice and highlight limitations in predicting the toxicity of AAV vectors encoding human proteins in non\u2010human species.\n                  <\/jats:p>","DOI":"10.15252\/emmm.202113968","type":"journal-article","created":{"date-parts":[[2021,12,1]],"date-time":"2021-12-01T03:25:45Z","timestamp":1638329145000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Muscle\u2010directed gene therapy corrects Pompe disease and uncovers species\u2010specific GAA immunogenicity"],"prefix":"10.1038","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5387-2118","authenticated-orcid":false,"given":"Michelle","family":"Eggers","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3617-8081","authenticated-orcid":false,"given":"Charles H","family":"Vannoy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianyong","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pravinkumar","family":"Purushothaman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3305-3163","authenticated-orcid":false,"given":"Jacqueline","family":"Brassard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Fonck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Meng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariah J","family":"Prom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael W","family":"Lawlor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justine","family":"Cunningham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chanchal","family":"Sadhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0459-4320","authenticated-orcid":false,"given":"Fulvio","family":"Mavilio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,12,1]]},"reference":[{"key":"BFEMMM202113968_CR1","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1089\/humc.2014.2514","volume":"25","author":"PI Byrne","year":"2014","unstructured":"Byrne PI, Collins S, Mah CC, Smith B, Conlon T, Martin SD, Corti M, Cleaver B, Islam S, Lawson LA (2014) Phase I\/II trial of diaphragm delivery of recombinant adeno\u2010associated virus acid alpha\u2010glucosidase (rAAV1\u2010CMV\u2010GAA) gene vector in patients with Pompe disease. 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M.W.L. is or was recently a member of advisory boards for Audentes Therapeutics, Ichorion Therapeutics, and Solid Biosciences and receives or has recently received research support from these companies. M.W.L. is also a consultant for Audentes Therapeutics, Encoded Therapeutics, AGADA Biosciences, Prothelia, BioMarin, Kate Therapeutics, Lacerta Therapeutics, Affinia Therapeutics, Modis Therapeutics, Rocket Therapeutics, and Dynacure.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of Interest"}}],"article-number":"EMMM202113968"}}