title: AAV.Dysferlin Overlap Vectors Restore Function in Dysferlinopathy Animal Models.
abstract: OBJECTIVE
  Dysferlinopathies are a family of untreatable muscle disorders caused by mutations in the dysferlin gene. Lack of dysferlin protein results in progressive dystrophy with chronic muscle fiber loss, inflammation, fat replacement, and fibrosis; leading to deteriorating muscle weakness. The objective of this work is to demonstrate efficient and safe restoration of dysferlin expression following gene therapy treatment.
  
  
  METHODS
  Traditional gene therapy is restricted by the packaging capacity limit of adeno-associated virus (AAV), however, use of a dual vector strategy allows for delivery of over-sized genes, including dysferlin. The two vector system (AAV.DYSF.DV) packages the dysferlin cDNA utilizing AAV serotype rh.74 through the use of two discrete vectors defined by a 1 kb region of homology. Delivery of AAV.DYSF.DV via intramuscular and vascular delivery routes in dysferlin deficient mice and nonhuman primates was compared for efficiency and safety.
  
  
  RESULTS
  Treated muscles were tested for dysferlin expression, overall muscle histology, and ability to repair following injury. High levels of dysferlin overexpression was shown for all muscle groups treated as well as restoration of functional outcome measures (membrane repair ability and diaphragm specific force) to wild-type levels. In primates, strong dysferlin expression was demonstrated with no safety concerns.
  
  
  CONCLUSIONS
  Treated muscles showed high levels of dysferlin expression with functional restoration with no evidence of toxicity or immune response providing proof of principle for translation to dysferlinopathy patients.
authors: Center for Gene Therapy, Nationwide Children's Hospital Columbus, Ohio.
authors: Patricia C
authors: PC
authors: Sondergaard
authors: Center for Gene Therapy, Nationwide Children's Hospital Columbus, Ohio.
authors: Danielle A
authors: DA
authors: Griffin
authors: Center for Gene Therapy, Nationwide Children's Hospital Columbus, Ohio ; Biomedical Sciences Graduate Program, The Ohio State University Columbus, Ohio.
authors: Eric R
authors: ER
authors: Pozsgai
authors: Center for Gene Therapy, Nationwide Children's Hospital Columbus, Ohio.
authors: Ryan W
authors: RW
authors: Johnson
authors: Center for Gene Therapy, Nationwide Children's Hospital Columbus, Ohio.
authors: William E
authors: WE
authors: Grose
authors: Center for Gene Therapy, Nationwide Children's Hospital Columbus, Ohio.
authors: Kristin N
authors: KN
authors: Heller
authors: Center for Gene Therapy, Nationwide Children's Hospital Columbus, Ohio.
authors: Kim M
authors: KM
authors: Shontz
authors: Center for Gene Therapy, Nationwide Children's Hospital Columbus, Ohio.
authors: Chrystal L
authors: CL
authors: Montgomery
authors: Center for Gene Therapy, Nationwide Children's Hospital Columbus, Ohio.
authors: Joseph
authors: J
authors: Liu
authors: Center for Gene Therapy, Nationwide Children's Hospital Columbus, Ohio ; Biomedical Sciences Graduate Program, The Ohio State University Columbus, Ohio.
authors: Kelly Reed
authors: KR
authors: Clark
authors: Center for Gene Therapy, Nationwide Children's Hospital Columbus, Ohio ; Department of Pediatrics, The Ohio State University Columbus, Ohio ; Department of Neurology, The Ohio State University Columbus, Ohio.
authors: Zarife
authors: Z
authors: Sahenk
authors: Center for Gene Therapy, Nationwide Children's Hospital Columbus, Ohio ; Department of Pediatrics, The Ohio State University Columbus, Ohio ; Department of Neurology, The Ohio State University Columbus, Ohio.
authors: Jerry R
authors: JR
authors: Mendell
authors: Center for Gene Therapy, Nationwide Children's Hospital Columbus, Ohio ; Biomedical Sciences Graduate Program, The Ohio State University Columbus, Ohio ; Department of Pediatrics, The Ohio State University Columbus, Ohio.
authors: Louise R
authors: LR
authors: Rodino-Klapac