Mol Ther. 2025 Dec 24:S1525-0016(25)01062-7. doi: 10.1016/j.ymthe.2025.12.039. Online ahead of print.
ABSTRACT
Fabry disease is a rare X-linked lysosomal storage disorder caused by pathological mutations in the GLA gene which encodes α-galactosidase A (α-Gal A). The deficiency of α-Gal A leads to the accumulation of its substrates in multiple cell types, affecting various organs and resulting in a spectrum of clinical manifestations. Enzyme replacement therapy often falls short of adequately addressing the α-Gal A enzyme deficiency in critical tissues, highlighting the need for more efficacious interventions. Here, we present EXG110, an AAV-based gene therapy, engineered to enable robust and durable α-Gal A expression. EXG110 comprises a codon-optimized human GLA transgene, a synthetic dual-tissue promoter for hepatocyte and myocyte expression, and an engineered AAV9 capsid variant for efficient liver and muscle transduction. In both adult and juvenile Fabry mice, a single intravenous dose of EXG110 achieved supraphysiological plasma α-Gal A activity and near-complete clearance of accumulated substrates in key tissues. EXG110-treated juvenile Fabry mice exhibited sustained α-Gal A activity for at least 12 weeks, with the highest vector genome retention in the heart. Adult non-human primates (NHPs) treated with EXG110 showed dose-dependent plasma α-Gal A activity persisting for at least 26 weeks. These results provide proof of concept for treating Fabry disease with EXG110.
PMID:41445191 | DOI:10.1016/j.ymthe.2025.12.039