Assessment of Systemic Delivery of rAAVrh74.MHCK7.micro-dystrophin in Children With Duchenne Muscular Dystrophy

作者：Jerry R. Mendell, Zarife Sahenk, Kelly J. Lehman, C. Nease, Linda Lowes, N. Miller, M. Iammarino, Lindsay N. Alfano, Amanda Nicholl, Samiah Al-Zaidy, Sarah Lewis, Kathleen Church, Richard Shell, Linda Cripe, Rachael A. Potter, Danielle A. Griffin, Eric R. Pozsgai, A. Dugar, Mark Hogan, Louise R. Rodino‐Klapac · 发表于：JAMA Neurology · 年份：2020 · DOI：10.1001/jamaneurol.2020.1484 · 被引用次数：402 · 研究领域：Muscle Physiology and Disorders、Mesenchymal stem cell research、Virus-based gene therapy research

Importance: Micro-dystrophin gene transfer shows promise for treating patients with Duchenne muscular dystrophy (DMD) using recombinant adeno-associated virus serotype rh74 (rAAVrh74) and codon-optimized human micro-dystrophin driven by a skeletal and cardiac muscle-specific promoter with enhanced cardiac expression (MHCK7). Objective: To identify the 1-year safety and tolerability of intravenous rAAVrh74.MHCK7.micro-dystrophin in patients with DMD. Design, Setting, and Participants: This open-label, phase 1/2a nonrandomized controlled trial was conducted at the Nationwide Children's Hospital in Columbus, Ohio. It began on November 2, 2017, with a planned duration of follow-up of 3 years, ending in March 2021. The first 4 patients who met eligibility criteria were enrolled, consisting of ambulatory male children with DMD without preexisting AAVrh74 antibodies and a stable corticosteroid dose (≥12 weeks). Interventions: A single dose of 2.0 × 1014 vg/kg rAAVrh74.MHCK7.micro-dystrophin was infused through a peripheral limb vein. Daily prednisolone, 1 mg/kg, started 1 day before gene delivery (30-day taper after infusion). Main Outcomes and Measures: Safety was the primary outcome. Secondary outcomes included micro-dystrophin expression by Western blot and immunohistochemistry. Functional outcomes measured by North Star Ambulatory Assessment (NSAA) and serum creatine kinase were exploratory outcomes. Results: Four patients were included (mean [SD] age at enrollment, 4.8 [1.0] ye...