Background: Limb girdle muscular dystrophies (LGMD) usually manifest with progressive hip/shoulder muscle weakness extending to other muscles. LGMD2E (due to β-sarcoglycan [SGCB] deficiency) includes cardiac involvement and elevated creatine kinase (CK).
Objective: We present initial findings of an ongoing, phase 1 multiple ascending-dose clinical gene transfer trial of ≤9 patients with LGMD2E who received rAAVrh74.MHCK7.SGCB (NCT03652259).
Approach: Participants were patients 4-15 y with confirmed SGCB mutation (both alleles), negative for antibodies against rAAVrh74, and >40%n on 100-meter timed test. Patients received single IV infusion of 5×10^13 vg/kg rAAVrh74.MHCK7.SGCB. Prednisone 1 mg/kg/day was initiated 1 day before gene delivery, tapering after 30 days. Primary endpoints were ≥20% SGCB-positive fibers (Day 60 muscle biopsy) and safety. Secondary endpoints were CK decrease and functional endpoints.
Results: For the first 3 patients enrolled (age 13, n=2; age 4; n=1), robust SGCB expression was observed by immunohistochemistry (IHC), with a mean of 51% SGCB positive fibers (range 42-63%) expressing a mean 47% intensity (range 38-57%). Co-localization of α-sarcoglycan was observed by IHC. Western blot showed a mean 36.1% SCGB expression vs normal (range 34-39%). Mean CK levels were reduced by 90% (range 83-97%), suggesting slowed muscle destruction. Two patients had elevated liver enzymes (1 serious) and 1 had elevated bilirubin following oral steroid taper, which subsequently returned to baseline. Two patients had transient mild nausea, corresponding with increased steroid dosing. No other clinically significant lab findings.
Conclusions: Gene transfer in patients with LGMD2E following an infusion of rAAVrh74.MHCK7.SGCB was positive for the defined endpoints. This is the second gene therapy inducing protein production post transgene delivery with rAAVrh74 vector and MHCK7 promoter, demonstrating potential benefits of a rationally designed delivery system.