title: Phase 1 gene therapy for Duchenne muscular dystrophy using a translational optimized AAV vector.
abstract: 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.
authors: Department of Surgery, Division of Surgical Sciences, Duke University Medical Center, Durham, North Carolina, USA.
authors: Dawn E
authors: DE
authors: Bowles
authors: Scott W J
authors: SW
authors: McPhee
authors: Chengwen
authors: C
authors: Li
authors: Steven J
authors: SJ
authors: Gray
authors: Jade J
authors: JJ
authors: Samulski
authors: Angelique S
authors: AS
authors: Camp
authors: Juan
authors: J
authors: Li
authors: Bing
authors: B
authors: Wang
authors: Paul E
authors: PE
authors: Monahan
authors: Joseph E
authors: JE
authors: Rabinowitz
authors: Joshua C
authors: JC
authors: Grieger
authors: Lakshmanan
authors: L
authors: Govindasamy
authors: Mavis
authors: M
authors: Agbandje-McKenna
authors: Xiao
authors: X
authors: Xiao
authors: R Jude
authors: RJ
authors: Samulski
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D000914:Antibodies, Viral / Q000276:immunology; D036022:Capsid Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D000229:Dependovirus / Q000235:genetics* / Q000502:physiology; D016189:Dystrophin / Q000235:genetics / Q000378:metabolism; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000378:metabolism; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D011487:Protein Conformation; D016415:Sequence Alignment; D013601:T-Lymphocytes / Q000276:immunology; D014161:Transduction, Genetic; D056189:Viral Tropism
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D036022:Capsid Proteins; D016189:Dystrophin