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Mol Ther. 2017 Apr 5;25(4):855-869. doi: 10.1016/j.ymthe.2017.02.013. Epub 2017 Mar 9.

Systemic AAV-Mediated β-Sarcoglycan Delivery Targeting Cardiac and Skeletal Muscle Ameliorates Histological and Functional Deficits in LGMD2E Mice.

Author information

1
Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH 43210, USA; Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
2
Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
3
Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH 43210, USA; Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA; Department of Pediatrics and Neurology, The Ohio State University, Columbus, OH 43210, USA.
4
Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH 43210, USA; Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA; Department of Pediatrics and Neurology, The Ohio State University, Columbus, OH 43210, USA. Electronic address: louise.rodino-klapac@nationwidechildrens.org.

Abstract

Limb-girdle muscular dystrophy type 2E (LGMD2E), resulting from mutations in β-sarcoglycan (SGCB), is a progressive dystrophy with deteriorating muscle function, respiratory failure, and cardiomyopathy in 50% or more of LGMD2E patients. SGCB knockout mice share many of the phenotypic deficiencies of LGMD2E patients. To investigate systemic SGCB gene transfer to treat skeletal and cardiac muscle deficits, we designed a self-complementary AAVrh74 vector containing a codon-optimized human SGCB transgene driven by a muscle-specific promoter. We delivered scAAV.MHCK7.hSGCB through the tail vein of SGCB-/- mice to provide a rationale for a clinical trial that would lead to clinically meaningful results. This led to 98.1% transgene expression across all muscles that was accompanied by improvements in histopathology. Serum creatine kinase (CK) levels were reduced following treatment by 85.5%. Diaphragm force production increased by 94.4%, kyphoscoliosis of the spine was significantly reduced by 48.1%, overall ambulation increased by 57%, and vertical rearing increased dramatically by 132% following treatment. Importantly, no adverse effects were seen in muscle of wild-type mice injected systemically with scAAV.hSGCB. In this well-defined model of LGMD2E, we have demonstrated the efficacy and safety of systemic scAAV.hSGCB delivery, and these findings have established a path for clinically beneficial AAV-mediated gene therapy for LGMD2E.

KEYWORDS:

AAV; LGMD2E; gene therapy; limb-girdle muscular dystrophy; muscular dystrophy; β-sarcoglycan

PMID:
28284983
PMCID:
PMC5383645
DOI:
10.1016/j.ymthe.2017.02.013
[Indexed for MEDLINE]
Free PMC Article

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