Background: Limb-girdle muscular dystrophy type 2E (LGMD2E) is caused by mutations in the β-sarcoglycan (SGCB) gene that result in loss of functional protein affecting other structural components of the dystrophin-associated protein complex. Clinically, LGMD2E usually manifests with progressive hip/shoulder muscle weakness and often includes cardiac involvement and elevated creatine kinase (CK). We designed a self-complementary (sc) rAAVrh74.MHCK7.hSGCB construct to restore functional SGCB to muscles. Here we report initial findings of a Phase 1/2 clinical gene transfer trial of rAAVrh74.MHCK7.hSGCB (SRP-9003) in patients with LGMD2E.
Methods: In this first-in-human, single-center, open-label, systemic gene delivery, Phase 1/2 study (NCT03652259), 6 patients with LGMD2E received SRP-9003 in escalating doses. Eligible patients: age 4−15 years, SGCB gene mutation (both alleles), negative for rAAVrh74 antibodies, >40% on 100-meter timed test. Cohort 1 (n=3) received single IV infusion of 5×1013 vg/kg; Cohort 2 (n=3) received single IV infusion of 2×1014 vg/kg. For all patients, prednisone 1 mg/kg/day was initiated 1 day before treatment (tapering after 30–60 days). Primary endpoint: safety. Secondary endpoint: change in SGCB expression from baseline to week 8. Other endpoints: CK decrease; functional endpoints (North Star Assessment of Limb-girdle Muscular Dystrophies [NSAD] and timed functional tests [100-meter walk/run, 10-meter walk/run, 4-stair climb, and time to rise]).
Results: Systemic administration of rAAVrh74.MHCK7.hSGCB is well tolerated with no unexpected immunological responses observed. Results show efficient transduction and robust SGCB protein expression in all patients post-infusion, leading to reconstitution of the sarcoglycan complex and reductions in CK. Six months after rAAVrh74.MHCK7.hSGCB infusion, patients from both cohorts experienced improvements in functional measures compared with baseline. For Cohort 1, data up to 18 months post-infusion are available and demonstrate improvements in NSAD and timed tests maintained over baseline.
Conclusion: These data suggest the long-term efficacy of rAAVrh74.MHCK7.hSGCB gene transfer therapy, supporting advancement of the clinical development program.