title: NBD delivery improves the disease phenotype of the golden retriever model of Duchenne muscular dystrophy.
abstract: BACKGROUND
  Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene and afflicts skeletal and cardiac muscles. Previous studies showed that DMD is associated with constitutive activation of NF-κB, and in dystrophin-deficient mdx and utrophin/dystrophin (utrn (-/-) ;mdx) double knock out (dko) mouse models, inhibition of NF-κB with the Nemo Binding Domain (NBD) peptide led to significant improvements in both diaphragm and cardiac muscle function.
  
  
  METHODS
  A trial in golden retriever muscular dystrophy (GRMD) canine model of DMD was initiated with four primary outcomes: skeletal muscle function, MRI of pelvic limb muscles, histopathologic features of skeletal muscles, and safety. GRMD and wild type dogs at 2 months of age were treated for 4 months with NBD by intravenous infusions. Results were compared with those collected from untreated GRMD and wild type dogs through a separate, natural history study.
  
  
  RESULTS
  Results showed that intravenous delivery of NBD in GRMD dogs led to a recovery of pelvic limb muscle force and improvement of histopathologic lesions. In addition, NBD-treated GRMD dogs had normalized postural changes and a trend towards lower tissue injury on magnetic resonance imaging. Despite this phenotypic improvement, NBD administration over time led to infusion reactions and an immune response in both treated GRMD and wild type dogs.
  
  
  CONCLUSIONS
  This GRMD trial was beneficial both in providing evidence that NBD is efficacious in a large animal DMD model and in identifying potential safety concerns that will be informative moving forward with human trials.
authors: Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA ; Department of Neurology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA ; The Gene Therapy Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA ; Department of Veterinary Integrative Biosciences, College of Veterinary Medicine, Texas A&M University, Mail Stop 4458, College Station, TX, USA.
authors: Joe N
authors: JN
authors: Kornegay
authors: Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA.
authors: Jennifer M
authors: JM
authors: Peterson
authors: Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA ; The Gene Therapy Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
authors: Daniel J
authors: DJ
authors: Bogan
authors: Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA.
authors: William
authors: W
authors: Kline
authors: Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA ; The Gene Therapy Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
authors: Janet R
authors: JR
authors: Bogan
authors: Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA ; The Gene Therapy Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
authors: Jennifer L
authors: JL
authors: Dow
authors: Department of Neurology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
authors: Zheng
authors: Z
authors: Fan
authors: Department of Psychiatry, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
authors: Jiahui
authors: J
authors: Wang
authors: Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC 27599, USA.
authors: Mihye
authors: M
authors: Ahn
authors: Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC 27599, USA.
authors: Hongtu
authors: H
authors: Zhu
authors: Department of Psychiatry, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA ; Department of Computer Science, University of North Carolina, Chapel Hill, NC 27599, USA.
authors: Martin
authors: M
authors: Styner
authors: Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA ; The Ohio State University College of Medicine, 460W. 12th Avenue, Columbus, OH 43210, USA.
authors: Denis C
authors: DC
authors: Guttridge