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Mol Ther. 2014 Apr;22(4):713-24. doi: 10.1038/mt.2013.246. Epub 2013 Oct 22.

Vascular Delivery of rAAVrh74.MCK.GALGT2 to the Gastrocnemius Muscle of the Rhesus Macaque Stimulates the Expression of Dystrophin and Laminin α2 Surrogates.

Author information

  • 11] Department of Pediatrics, The Ohio State University and Nationwide Children's Hospital, Columbus, Ohio, USA [2] Centers for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
  • 2Centers for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
  • 3Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
  • 41] Department of Pediatrics, The Ohio State University and Nationwide Children's Hospital, Columbus, Ohio, USA [2] Current address: Department of Radiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
  • 51] Department of Pediatrics, The Ohio State University and Nationwide Children's Hospital, Columbus, Ohio, USA [2] Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
  • 61] Department of Pediatrics, The Ohio State University and Nationwide Children's Hospital, Columbus, Ohio, USA [2] Department of Neurology, The Ohio State University and Nationwide Children's Hospital, Columbus, Ohio, USA [3] Centers for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.

Abstract

Overexpression of GALGT2 in skeletal muscle can stimulate the glycosylation of α dystroglycan and the upregulation of normally synaptic dystroglycan-binding proteins, some of which are dystrophin and laminin α2 surrogates known to be therapeutic for several forms of muscular dystrophy. This article describes the vascular delivery of GALGT2 gene therapy in a large animal model, the rhesus macaque. Recombinant adeno-associated virus, rhesus serotype 74 (rAAVrh74), was used to deliver GALGT2 via the femoral artery to the gastrocnemius muscle using an isolated focal limb perfusion method. GALGT2 expression averaged 44 ± 4% of myofibers after treatment in macaques with low preexisting anti-rAAVrh74 serum antibodies, and expression was reduced to 9 ± 4% of myofibers in macaques with high preexisting rAAVrh74 immunity (P < 0.001; n = 12 per group). This was the case regardless of the addition of immunosuppressants, including prednisolone, tacrolimus, and mycophenolate mofetil. GALGT2-treated macaque muscles showed increased glycosylation of α dystroglycan and increased expression of dystrophin and laminin α2 surrogate proteins, including utrophin, plectin1, agrin, and laminin α5. These experiments demonstrate successful transduction of rhesus macaque muscle with rAAVrh74.MCK.GALGT2 after vascular delivery and induction of molecular changes thought to be therapeutic in several forms of muscular dystrophy.

PMID:
24145553
[PubMed - in process]
PMCID:
PMC3982494
[Available on 2015/4/1]
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