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Current treatments such as enzyme replacement therapy (ERT) and chaperone therapy are noncurative and have limitations. Gene therapy is an interesting alternative approach that may overcome most of these limitations, and different approaches are currently being tested. Here, we developed a gene therapy approach using rAAV2\/8 vectors, delivered intravenously, that target the liver to produce and secrete functional \u03b1\u2010Gal A into circulation. This enzyme is then captured by organs expressing mannose\u20106\u2010phosphate receptors, reducing glycosphingolipid accumulation in affected tissues. We generated a codon\u2010optimized\n                    <jats:italic>GLA<\/jats:italic>\n                    cDNA with enhanced translatability that was expressed under a strong liver\u2010specific promoter. In a dose escalation study in juvenile\n                    <jats:italic>Gla<\/jats:italic>\n                    knock\u2010out (ko) mice, the lowest dose (3.0E11vg\/kg) resulted in 85%\u201395% clearance of lyso\u2010Gb3 in plasma and tissues, while doses of 3.0E12 vg\/kg and higher showed 98%\u2013100% clearance of the glycosphingolipid. All AAV doses were more effective than systemic \u03b1\u2010Gal A administration (ERT). Long\u2010term treatment showed normal levels of lyso\u2010Gb3 in plasma and tissues, and corrected neuropathic involvement, as shown in the hot plate test. This study provides a proof\u2010of\u2010concept showing that the tested liver\u2010specific gene therapy vector is capable of preventing disease progression in juvenile Fabry mice at relatively low doses and shows potential in treating both early\u2010 and late\u2010onset FD in patients.\n                  <\/jats:p>","DOI":"10.1002\/jimd.70188","type":"journal-article","created":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T09:36:45Z","timestamp":1777282605000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Liver Gene Therapy in Fabry Disease Mice With Low Doses of\n                    <scp>rAAV2<\/scp>\n                    \/8 Expressing a Codon\u2010Optimized\n                    <scp>h<\/scp>\n                    <i>GLA<\/i>\n                    <scp>cDNA<\/scp>\n                    Results in Long\u2010Term Disease Correction"],"prefix":"10.1002","volume":"49","author":[{"given":"Himanshi","family":"Saxena","sequence":"first","affiliation":[{"name":"International Centre for Genetic Engineering and Biotechnology  Trieste Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rossana","family":"Domenis","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pathology, Department of Laboratory Medicine University Hospital of Udine  Udine Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Romano","sequence":"additional","affiliation":[{"name":"International Centre for Genetic Engineering and Biotechnology  Trieste Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Biasizzo","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pathology, Department of Laboratory Medicine University Hospital of Udine  Udine 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