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Mol Ther Methods Clin Dev. 2017 Jul 27;6:216-230. doi: 10.1016/j.omtm.2017.06.006. eCollection 2017 Sep 15.

A Five-Repeat Micro-Dystrophin Gene Ameliorated Dystrophic Phenotype in the Severe DBA/2J-mdx Model of Duchenne Muscular Dystrophy.

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Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, MO 65212, USA.
National Center for Advancing Translational Sciences (NCATS), Bethesda, MD 20892, USA.
Department of Bioengineering, University of Missouri, Columbia, MO 65212, USA.
Department of Neurology, Wellstone Muscular Dystrophy Research Center, University of Washington, Seattle, WA 98105, USA.
Solid Biosciences, LLC, Cambridge, MA 02142, USA.
Department of Neurology, School of Medicine, University of Missouri, Columbia, MO 65212, USA.
Department of Biomedical Sciences, College of Veterinary Medicine, University of Missouri, Columbia, MO 65212, USA.


Micro-dystrophins are highly promising candidates for treating Duchenne muscular dystrophy, a lethal muscle disease caused by dystrophin deficiency. Here, we report robust disease rescue in the severe DBA/2J-mdx model with a neuronal nitric oxide synthase (nNOS)-binding micro-dystrophin vector. 2 × 1013 vector genome particles/mouse of the vector were delivered intravenously to 10-week-old mice and were evaluated at 6 months of age. Saturated micro-dystrophin expression was detected in all skeletal muscles and the heart and restored the dystrophin-associated glycoprotein complex and nNOS. In skeletal muscle, therapy substantially reduced fibrosis and calcification and significantly attenuated inflammation. Centronucleation was significantly decreased in the tibialis anterior (TA) and extensor digitorum longus (EDL) muscles but not in the quadriceps. Muscle function was normalized in the TA and significantly improved in the EDL muscle. Heart histology and function were also evaluated. Consistent with the literature, DBA/2J-mdx mice showed myocardial calcification and fibrosis and cardiac hemodynamics was compromised. Surprisingly, similar myocardial pathology and hemodynamic defects were detected in control DBA/2J mice. As a result, interpretation of the cardiac data proved difficult due to the confounding phenotype in control DBA/2J mice. Our results support further development of this microgene vector for clinical translation. Further, DBA/2J-mdx mice are not good models for Duchenne cardiomyopathy.


AAV; DBA/2J; DMD; Duchenne muscular dystrophy; adeno-associated virus; cardiomyopathy; mdx; micro-dystrophin; nNOS; systemic gene therapy

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