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

Molecular Therapy: Methods & Clinical Development

Gang Yao¹  Nalinda B. Wasala²  Chady H. Hakim²  Kasun Kodippili²  Yongping Yue²  Dongsheng Duan²  Keqing Zhang²  Xiufang Pan²  Brittney Haffner²  Sean X. Duan²  Julian Ramos³  Jeffrey S. Chamberlain³  N. Nora Yang⁴  Joel S. Schneider⁵ 

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

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

DOI  :  10.1016/j.omtm.2017.06.006

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown