Research Question: Limb girdle muscular dystrophies (LGMD) typically manifest with progressive hip/shoulder
muscle weakness that subsequently extends to other muscles. LGMD2E (due to β-sarcoglycan
deficiency) includes cardiac involvement and elevated creatine kinase (CK). We present
findings of an ongoing, phase 1 multiple ascending-dose clinical gene transfer trial
of up to 9 patients, delivering rAAVrh74.MHCK7.SGCB to patients with LGMD2E (NCT03652259).
Material and Method: Participants included patients 4–15 years of age who were confirmed with β-sarcoglycan
mutation (both alleles); were negative for antibodies against AAVrh74; and had ≥40%
of predicted time for age-, height-, and weight-matched healthy controls on 100-meter
timed test. Patients received a single IV infusion of 5x10^13 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% β-sarcoglycan-positive fibers (Day 60 muscle biopsy)
and safety. Secondary endpoints were CK decrease and functional endpoints, including
motor and pulmonary assessments.
Results: For the first 3 patients enrolled (age 13, n = 2; age 4; n = 1), robust β-sarcoglycan
expression was observed by immunohistochemistry (IHC), with a mean of 51% β-sarcoglycan-positive
fibers (range 42–63%) expressing a mean 47% intensity (range 38–57%). Co-localization
with α-sarcoglycan was observed by IHC. Western blot showed a mean 36.1% β-sarcoglycan
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 were observed.
Discussion: Systemic treatment of 3 LGMD2E patients with scAAVrh74.MHCK7.SGCB led to robust and
consistent expression of β-sarcoglycan in muscle fibers 60 days post gene transfer.
Co-localization of β-sarcoglycan with α-sarcoglycan suggests that scAAVrh74.MHCK7.SGCB
restores the sarcoglycan complex.
Conclusion: 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 that promotes
protein production of a transgene delivered using rAAVrh74 vector and regulation driven
by the MHCK7 promoter, demonstrating potential benefits of a rationally designed delivery
system.
