{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T09:52:43Z","timestamp":1790675563662,"version":"4.1.0"},"reference-count":92,"publisher":"SAGE Publications","issue":"1","license":[{"start":{"date-parts":[[2015,11,4]],"date-time":"2015-11-04T00:00:00Z","timestamp":1446595200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Human Gene Therapy"],"published-print":{"date-parts":[[2016,1]]},"abstract":"<jats:p>\n                    Pompe disease is a progressive neuromuscular disorder caused by lysosomal accumulation of glycogen from a deficiency in acid alpha-glucosidase (GAA). Replacement of the missing enzyme is available by repeated protein infusions; however, efficacy is limited by immune response and inability to restore enzymatic function in the central nervous system. An alternative therapeutic option is adeno-associated virus (AAV)-mediated gene therapy, which results in widespread gene transfer and prolonged transgene expression. Both enzyme replacement therapy (ERT) and gene therapy can elicit anti-GAA immune reactions that dampen their effectiveness and pose life-threatening risks to patient safety. To modulate the immune responses related to gene therapy, we show that a human codon-optimized GAA (coGAA) driven by a liver-specific promoter (LSP) using AAV9 is capable of promoting immune tolerance in a\n                    <jats:italic toggle=\"yes\">Gaa<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mouse model. Copackaging AAV9-LSP-coGAA with the tissue-restricted desmin promoter (AAV9-DES-coGAA) demonstrates the necessary cell autonomous expression in cardiac muscle, skeletal muscle, peripheral nerve, and the spinal cord. Simultaneous high-level expression in liver led to the expansion of GAA-specific regulatory T-cells (T\n                    <jats:sub>regs<\/jats:sub>\n                    ) and induction of immune tolerance. Transfer of T\n                    <jats:sub>regs<\/jats:sub>\n                    into na\u00efve recipients prevented pathogenic allergic reactions after repeated ERT challenges. Copackaged AAV9 also attenuated preexisting humoral and cellular immune responses, which enhanced the biochemical correction. Our data present a therapeutic design in which simultaneous administration of two copackaged AAV constructs may provide therapeutic benefit and resolve immune reactions in the treatment of multisystem disorders.\n                  <\/jats:p>","DOI":"10.1089\/hum.2015.103","type":"journal-article","created":{"date-parts":[[2015,11,25]],"date-time":"2015-11-25T05:09:33Z","timestamp":1448428173000},"page":"43-59","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":50,"title":["Copackaged AAV9 Vectors Promote Simultaneous Immune Tolerance and Phenotypic Correction of Pompe Disease"],"prefix":"10.1177","volume":"27","author":[{"given":"Phillip A.","family":"Doerfler","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Powell Gene Therapy Center, University of Florida, Gainesville, Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian G.","family":"Todd","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Powell Gene Therapy Center, University of Florida, Gainesville, Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Cl\u00e9ment","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Powell Gene Therapy Center, University of Florida, Gainesville, Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darin J.","family":"Falk","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Powell Gene Therapy Center, University of Florida, Gainesville, Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sushrusha","family":"Nayak","sequence":"additional","affiliation":[{"name":"Department of Medicine, Center for Infectious Medicine, Karolinska Institute, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland W.","family":"Herzog","sequence":"additional","affiliation":[{"name":"University of Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barry J.","family":"Byrne","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Powell Gene Therapy Center, University of Florida, Gainesville, Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2015,11,4]]},"reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-01-306647"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(08)61555-X"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2011.02.004"},{"key":"e_1_3_3_5_2","first-page":"132","article-title":"Recombinant human acid alpha-glucosidase enzyme therapy for infantile glycogen storage disease type II: Results of a phase I\/II clinical trial","volume":"3","author":"Amalfitano A","year":"2001","unstructured":"Amalfitano A, , Bengur AR, , Morse RP, et al. 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