The Models Core (Core C) will provide four essential support elements for Projects 1 and 2. First, the Models Core will be responsible for breeding and maintaining mdx mice for experiments described in both projects 1 and 2. The mdx mouse model for Duchenne muscular dystrophy is essential for verifying gene therapeutic efficacy as proposed in this U54 application. Second, the Models Core will provide all physiological assessments of gene function in the mdx mouse. These consist offeree and eccentric contraction measurements of the extensor digitorum longus muscle. These measures are known to be impaired in this FDA accepted animal model for DMD, and thus will provide important criteria for each Project to demonstrate a physiologically significant clinical measure of improvement in muscle function. Such validation is critical for demonstrating efficacy. Third, the core will be responsible for the housing and care of rhesus macaque monkeys for experiments described in both projects. Non-human primate animals are essential to evaluate the immunology, distribution, and efficacy in a larger animal species for review by the FDA. Fourth, the Core will perform and optimize regional vascular delivery protocols, in both the mdx mouse and rhesus macaque, to deliver human micro-dystrophin and CT GAINAc transferase via rAAVSmediated gene delivery to the muscles of the lower limb via the femoral artery. The skills involved in this delivery system are best acquired by repeated performance. Providing this technique in the Core is essential to achieve uniformity for both projects, and is essential for consistent distribution of transgenes within the targeted muscle (gastrocnemius).

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54NS055958-04
Application #
8130725
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
2014-08-31
Budget Start
2010-09-01
Budget End
2011-08-31
Support Year
4
Fiscal Year
2010
Total Cost
$259,222
Indirect Cost
Name
Nationwide Children's Hospital
Department
Type
DUNS #
147212963
City
Columbus
State
OH
Country
United States
Zip Code
43205
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Chicoine, L G; Montgomery, C L; Bremer, W G et al. (2014) Plasmapheresis eliminates the negative impact of AAV antibodies on microdystrophin gene expression following vascular delivery. Mol Ther 22:338-347
Chicoine, Louis G; Rodino-Klapac, Louise R; Shao, Guohong et al. (2014) Vascular delivery of rAAVrh74.MCK.GALGT2 to the gastrocnemius muscle of the rhesus macaque stimulates the expression of dystrophin and laminin ?2 surrogates. Mol Ther 22:713-24
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Malik, Vinod; Rodino-Klapac, Louise R; Mendell, Jerry R (2012) Emerging drugs for Duchenne muscular dystrophy. Expert Opin Emerg Drugs 17:261-77
Rodino-Klapac, Louise R; Montgomery, Chrystal L; Mendell, Jerry R et al. (2011) AAV-mediated gene therapy to the isolated limb in rhesus macaques. Methods Mol Biol 709:287-98
Rodino-Klapac, Louise R; Montgomery, Chrystal L; Bremer, William G et al. (2010) Persistent expression of FLAG-tagged micro dystrophin in nonhuman primates following intramuscular and vascular delivery. Mol Ther 18:109-17
Chandrasekharan, Kumaran; Martin, Paul T (2010) Genetic defects in muscular dystrophy. Methods Enzymol 479:291-322
Mendell, Jerry R; Rodino-Klapac, Louise R; Rosales, Xiomara Q et al. (2010) Sustained alpha-sarcoglycan gene expression after gene transfer in limb-girdle muscular dystrophy, type 2D. Ann Neurol 68:629-38
Martin, Paul T; Xu, Rui; Rodino-Klapac, Louise R et al. (2009) Overexpression of Galgt2 in skeletal muscle prevents injury resulting from eccentric contractions in both mdx and wild-type mice. Am J Physiol Cell Physiol 296:C476-88

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