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• W4205274892 abstract "Limb-girdle muscular dystrophy type 2E/R4 (LGMD2E/R4) is caused by mutations in the β-sarcoglycan gene (SGCB), resulting in loss of SGCB protein and other components of the dystrophin-associated protein complex (DAPC). LGMD2E/R4 manifests as progressive hip/shoulder muscle weakness and elevated creatine kinase (CK). This first-in-human, Phase 1/2 gene transfer trial (NCT03652259) evaluated SRP-9003, a self-complementary rAAVrh74.MHCK7.hSGCB construct to restore SGCB. Six patients aged 4–15 years with SGCB mutation (both alleles) received a single SRP-9003 IV infusion: Cohort 1 (n=3), 1.85 × 1013 vg/kg; Cohort 2 (n=3), 7.41 × 1013 vg/kg. Prednisone 1 mg/kg/day began 1 day before treatment, tapering after 30–60 days. Endpoints included safety (primary), SGCB expression (secondary), CK level, and function (North Star Assessment of Limb-girdle Muscular Dystrophies [NSAD], 100-meter timed test [100m], 10m, 4-stair climb, time to rise). We report Year 2 (Y2; Cohort 1) and Year 1 (Y1; Cohort 2) results. As of January 2021, SRP-9003 was well tolerated with no new safety signals since the previous data cut (July 2020); adverse events occurred early and were manageable. Immunofluorescence showed robust SGCB expression post treatment, leading to increased δ- and γ-sarcoglycan expression, demonstrating DAPC reconstitution. SGCB expression was maintained to Y2 (Cohort 1). CK decreased by 77% in Cohort 1 (Y2) and 74% in Cohort 2 (Y1). SRP-9003–treated patients showed functional improvements, maintained at Y2 in Cohort 1 (NSAD, +5.7 points; time to rise, -0.6 s; 4-stair climb, -0.3 s; 100m, -2.8 s; 10m, -0.2 s) and Y1 in Cohort 2 (NSAD, +4 points; time to rise, -1.1 s; 4-stair climb, -0.4 s; 100m, -7.9 s; 10m, -0.6 s). Post hoc analysis showed improved NSAD outcomes versus untreated natural history cohort (9.2-point difference at Y2; 95% CI, 3.2−15.1). These data suggest long-term efficacy of SRP-9003 therapy, supporting advancement of the clinical development program." @default.
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• W4205274892 date "2021-10-01" @default.
• W4205274892 modified "2023-10-05" @default.
• W4205274892 title "LGMD" @default.
• W4205274892 doi "https://doi.org/10.1016/j.nmd.2021.07.210" @default.
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