Mendell 2020 — Phase 1/2 Trial of rAAVrh74.MHCK7.micro-dystrophin in DMD Children
Citation: Mendell JR, et al. (2020). “Assessment of Systemic Delivery of rAAVrh74.MHCK7.micro-dystrophin in Children With Duchenne Muscular Dystrophy: A Nonrandomized Controlled Trial.” JAMA Neurology, 77(9), 1122–1131.
DOI: 10.1001/jamaneurol.2020.1484
PMC: PMC7296461
File: ~/BookLibrary/incoming/Mendell_2020_rAAVrh74-micro-dystrophin-DMD-phase1-2_JAMA-Neurol.pdf
Key Findings
- First human Phase 1/2 trial of systemic AAV gene therapy for DMD
- 4 patients aged 3-7 years, IV infusion 2×10^14 vg/kg
- Safety: manageable immune responses (corticosteroid protocol), no serious AAV-related adverse events
- Efficacy: micro-dystrophin expression in muscle (up to 74% of fibers), functional improvements at 12 months
- Serotype rAAVrh74 chosen for low pre-existing immunity + efficient muscle transduction
Safety Profile (Critical for STRC Planning)
- Dose-limiting concern: elevated liver enzymes (transient, steroid-managed)
- T-cell response to AAV capsid — managed with prophylactic immunosuppression
- No antibody seroconversion leading to loss of expression at 12 months
- Pediatric safety profile better than adults (lower pre-existing immunity)
Clinical Trial Design Lessons
- Start with lowest safe dose, escalate
- Prophylactic corticosteroids (prednisone 1 mg/kg starting day of infusion)
- Monitor: LFTs, CBC, CMV, AAV antibodies
- Endpoint: protein expression (immunofluorescence + Western), functional tests (motor for DMD, ABR/DPOAE for hearing)
- Efficacy at 1 year = basis for accelerated approval
Relevance to STRC/DFNB16
- Cochlear delivery is local (not systemic) → likely lower immunogenic load
- But pediatric age window matters: Misha is ~4-5 now → ideally in trial by age 7-10 before OHC structural changes
- rAAVrh74 not optimal for cochlea (vs. Anc80L65) but immunogenicity data is valuable
- STRC Phase 1 trial design will likely mirror this: 3-5 patients, local cochlear injection, ABR+DPOAE endpoints
Connections
- Duan_2018_micro_dystrophin_AAV [see-also]
- STRC Gene Therapy Landscape 2026 [applies]
- Misha [applies]
- Jeffrey Holt [see-also]