Background: Limb-girdle muscular dystrophy type 2E/R4 (LGMD2E/R4) is caused by mutations in the ?-sarcoglycan gene (SGCB), resulting in loss of SGCB protein and, subsequently, an absence of the dystrophin-associated protein complex (DAPC) at the sarcolemma. LGMD 2E/R4 manifests as progressive hip/shoulder muscle weakness.
Objective: This first-in-human, phase 1/2 trial (NCT03652259) evaluated SRP-9003, a self-complementary rAAVrh74.MHCK7.hSGCB construct designed to restore SGCB protein production.
Methods: Patients aged 4–15 years with SGCB mutation (both alleles) received 1 SRP-9003 IV infusion: Cohort 1 (n=3), 1.85×10^13 vg/kg; Cohort 2 (n=3), 7.41×10^13 vg/kg. Endpoints included safety (primary), SGCB protein expression (secondary), and function (North Star Assessment for Limb-girdle Type Muscular Dystrophies [NSAD], time to rise [TTR], 4-stair climb [4-sc], 100-meter timed test [100m], 10-meter timed test [10m]).
Results: Previously reported results: Year 1 (Y1) for Cohort 2 and Year 2 (Y2) for Cohort 1 showed that as of January 2021, SRP-9003 was well tolerated; adverse events occurred early and were manageable. Immunofluorescence showed robust SGCB expression and correct sarcolemmal localization post treatment, leading to DAPC reconstitution, maintained to Y2 (Cohort 1). SRP-9003–treated patients showed functional improvements, maintained at Y2 in Cohort 1 (NSAD, +5.7 points; TTR, -0.6 s; 4-sc, -0.3 s; 100m, -2.8 s; 10m, -0.2 s) and Y1 in Cohort 2 (NSAD, +4 points; TTR, -1.1 s; 4-sc, -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, Y2; 95% CI, 3.2?15.1). An update with 3-year functional data for Cohort 1 and 2-year protein expression and functional data for Cohort 2 will be presented.
Conclusions: These data suggest long-term efficacy of SRP-9003 therapy, supporting advancement of the clinical development program.