biostudies-literatureUnknown33(2)Sellier PPompe disease is a glycogen storage disorder caused by mutations in the acid α-glucosidase (GAA) gene, leading to reduced GAA activity and glycogen accumulation in heart and skeletal muscles. Enzyme replacement therapy with recombinant GAA, the standard of care for Pompe disease, is limited by poor skeletal muscle distribution and immune responses after repeated administrations. The expression of GAA in muscle with adeno-associated virus (AAV) vectors has shown limitations, mainly the low targeting efficiency and immune responses to the transgene. To address these issues, we developed AAV capsids with improved skeletal muscle targeting and reduced off-targeting. These capsids combined with codon optimization, muscle-specific <i>cis</i>-regulatory elements, and a synthetic promoter demonstrMolecular therapy. Methods & clinical development101464https://www.ebi.ac.uk/biostudies/studies/S-EPMC12415980biostudies-literatureA myotropic AAV vector combined with skeletal muscle &lt;i&gt;cis&lt;/i&gt;-regulatory elements improve glycogen clearance in mouse models of Pompe disease.PMC12415980Jimenez VPham QHRonzitti GLeon XChuah MKBenchekroun YKCollaud FDaniele NVandenDriessche TMingozzi FBosch FEl Andari JSellier PGrimm DfalseA myotropic AAV vector combined with skeletal muscle &lt;i&gt;cis&lt;/i&gt;-regulatory elements improve glycogen clearance in mouse models of Pompe disease.Pompe disease is a glycogen storage disorder caused by mutations in the acid α-glucosidase (GAA) gene, leading to reduced GAA activity and glycogen accumulation in heart and skeletal muscles. Enzyme replacement therapy with recombinant GAA, the standard of care for Pompe disease, is limited by poor skeletal muscle distribution and immune responses after repeated administrations. The expression of GAA in muscle with adeno-associated virus (AAV) vectors has shown limitations, mainly the low targeting efficiency and immune responses to the transgene. To address these issues, we developed AAV capsids with improved skeletal muscle targeting and reduced off-targeting. These capsids combined with codon optimization, muscle-specific <i>cis</i>-regulatory elements, and a synthetic promoter demonstr2025-01-01T00:00:00Z2025 Jun2026-06-02T02:29:20.823Z2026-04-13T03:12:28.123ZS-EPMC124159804092776610.1016/j.omtm.2025.101464