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- W4233332011 abstract "Gene transfer therapy is promising for Duchenne muscular dystrophy (DMD). We designed an adeno-associated virus vector (rAAVrh74) containing a codon-optimized human micro-dystrophin transgene driven by a muscle-cardiac specific promoter, MHCK7. Findings from 4 patients in our open-labelled, single-dose, Phase I/IIa trial (NCT03375164) are presented. Eligible: ambulatory boys (4-7y); confirmed DMD mutations; creatine kinase (CK) elevations (>1,000 U/L); 80% predicted 100-meter timed test (100m); no AAVrh74 antibodies; stable steroid dosing (3 mo). IV infusion (2.0 × 1014 vg/kg rAAVrh74.MHCK7.micro-dystrophin) given. Prednisone (1 mg/kg/d) initiated 1d before gene delivery, tapering after 30d. Primary endpoint: safety. Secondary and exploratory endpoints: micro-dystrophin expression by western blot (WB) and immunohistochemistry (IHC); functional outcomes by North Star Ambulatory Assessment (NSAA), 100m, Time to Rise, 4-Stair Climb; CK. No serious adverse events were observed by serum chemistry. Three patients had transiently elevated gamma-glutamyl transpeptidase (resolved with steroids). No adverse immune responses observed. Robust transgene expression was observed in all: mean 81.2% muscle fibers expressing micro-dystrophin (mean intensity 96% at the sarcolemma by IHC). WB showed mean micro-dystrophin expression of 74.3% without fat/fibrosis adjustment and 95.8% when adjusted (Day 90). All patients had confirmed vector transduction and showed robust reductions in CK (mean change baseline to 1 year: -67.3%). Motor function was improved in all, measured by increased ambulatory function (100m), increased muscle strength (Time to Rise, 4-Stair Climb), and overall motor abilities (NSAA). All 4 patients demonstrated a clinically meaningful improvement on NSAA as early as Day 90. rAAVrh74.MHCK7.micro-dystrophin infusion was well-tolerated, demonstrating successful systemic delivery of micro-dystrophin transgene and targeted expression of functional micro-dystrophin protein." @default.
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- W4233332011 date "2020-10-01" @default.
- W4233332011 modified "2023-10-05" @default.
- W4233332011 title "DMD – THERAPY" @default.
- W4233332011 doi "https://doi.org/10.1016/j.nmd.2020.08.277" @default.
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