Phase 1 gene therapy for duchenne muscular dystrophy using a translational optimized AAV vector

Dawn E. Bowles, Scott W.J. McPhee, Chengwen Li, Steven J. Gray, Jade J. Samulski, Angelique S. Camp, Juan Li, Bing Wang, Paul E. Monahan, Joseph E. Rabinowitz, Joshua C. Grieger, Lakshmanan Govindasamy, Mavis Agbandje-Mckenna, Xiao Xiao, R. Jude Samulski

Research output: Contribution to journalArticlepeer-review

290 Scopus citations


Efficient and widespread gene transfer is required for successful treatment of Duchenne muscular dystrophy (DMD). Here, we performed the first clinical trial using a chimeric adeno-associated virus (AAV) capsid variant (designated AAV2.5) derived from a rational design strategy. AAV2.5 was generated from the AAV2 capsid with five mutations from AAV1. The novel chimeric vector combines the improved muscle transduction capacity of AAV1 with reduced antigenic crossreactivity against both parental serotypes, while keeping the AAV2 receptor binding. In a randomized double-blind placebo-controlled phase I clinical study in DMD boys, AAV2.5 vector was injected into the bicep muscle in one arm, with saline control in the contralateral arm. A subset of patients received AAV empty capsid instead of saline in an effort to distinguish an immune response to vector versus minidystrophin transgene. Recombinant AAV genomes were detected in all patients with up to 2.56 vector copies per diploid genome. There was no cellular immune response to AAV2.5 capsid. This trial established that rationally designed AAV2.5 vector was safe and well tolerated, lays the foundation of customizing AAV vectors that best suit the clinical objective (e.g., limb infusion gene delivery) and should usher in the next generation of viral delivery systems for human gene transfer.

Original languageEnglish (US)
Pages (from-to)443-455
Number of pages13
JournalMolecular Therapy
Issue number2
StatePublished - Feb 2012

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery


Dive into the research topics of 'Phase 1 gene therapy for duchenne muscular dystrophy using a translational optimized AAV vector'. Together they form a unique fingerprint.

Cite this