Vascular delivery of rAAVrh74.MCK.GALGT2 to the gastrocnemius muscle of the rhesus macaque stimulates the expression of dystrophin and laminin α2 surrogates.

Autor:	Chicoine LG; 1] 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., Rodino-Klapac LR; 1] 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., Shao G; Centers for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA., Xu R; Centers for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA., Bremer WG; Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA., Camboni M; Centers for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA., Golden B; Centers for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA., Montgomery CL; Centers for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA., Shontz K; Centers for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA., Heller KN; Centers for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA., Griffin DA; Centers for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA., Lewis S; Centers for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA., Coley BD; 1] 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., Walker CM; 1] 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., Clark KR; 1] 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., Sahenk Z; 1] 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., Mendell JR; 1] 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., Martin PT; 1] 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.
Jazyk:	angličtina
Zdroj:	Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2014 Apr; Vol. 22 (4), pp. 713-24. Date of Electronic Publication: 2013 Oct 22.
DOI:	10.1038/mt.2013.246
Abstrakt:	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.
Databáze:	MEDLINE
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