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To enhance \u03b1\u2010Gal A expression and secretion for recombinant adeno\u2010associated viral (rAAV) gene therapy, the signal peptide was engineered in HepG2 cells. Among 22 heterogeneous signal peptides, sp21 was identified and validated for this purpose. The enzyme activity of\n                    <jats:italic>GLA<\/jats:italic>\n                    with sp21 in conditioned media was 2.3 times higher than that with the wild\u2010type signal peptide. Furthermore, the human\n                    <jats:italic>GLA<\/jats:italic>\n                    gene was codon optimized (hGLAco), aiming to achieve increased hepatic expression and prevent gene silencing. The secreted \u03b1\u2010Gal A activity of hGLAco increased approximately 4\u2010fold in\u00a0vitro. Finally, the hGLAco transgene with sp21 driven by a liver\u2010specific promoter was packaged in rAAV8 vectors and injected into Fabry mice. Compared with the wild\u2010type cDNA, the engineered\n                    <jats:italic>GLA<\/jats:italic>\n                    gene resulted in a 6.9\u2010fold increase in secreted \u03b1\u2010Gal A activity in Fabry mice, and toxic Lyso\u2010Gb3 accumulation in plasma and key tissues was effectively cleared. These findings demonstrate a promising strategy to develop a more efficient rAAV gene therapy for Fabry disease.\n                  <\/jats:p>","DOI":"10.1002\/jimd.70168","type":"journal-article","created":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T00:14:39Z","timestamp":1773101679000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Signal Peptide Engineering and Codon Optimization to Enhance \u03b1\u2010Gal A Activity for\n                    <scp>rAAV<\/scp>\n                    Gene Therapy of Fabry Disease"],"prefix":"10.1002","volume":"49","author":[{"given":"Siwu","family":"He","sequence":"first","affiliation":[{"name":"National Clinical Research Center for Geriatrics and State Key Laboratory of Biotherapy, West China Hospital Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Yang","sequence":"additional","affiliation":[{"name":"National Clinical Research Center for Geriatrics and State Key Laboratory of Biotherapy, West China Hospital Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Wan","sequence":"additional","affiliation":[{"name":"Department of Geriatrics and National Clinical Research Center for Geriatrics West China Hospital, Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoyue","family":"Zheng","sequence":"additional","affiliation":[{"name":"Sichuan Real &amp; Best Biotech Co., Ltd.  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