A Five-Repeat Micro-Dystrophin Gene Ameliorated Dystrophic Phenotype in the Severe DBA/2J-mdx Model of Duchenne Muscular Dystrophy
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 ×...
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| Format: | Article |
| Language: | English |
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Elsevier
2017-09-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050117300815 |
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| author | Chady H. Hakim Nalinda B. Wasala Xiufang Pan Kasun Kodippili Yongping Yue Keqing Zhang Gang Yao Brittney Haffner Sean X. Duan Julian Ramos Joel S. Schneider N. Nora Yang Jeffrey S. Chamberlain Dongsheng Duan |
| author_facet | Chady H. Hakim Nalinda B. Wasala Xiufang Pan Kasun Kodippili Yongping Yue Keqing Zhang Gang Yao Brittney Haffner Sean X. Duan Julian Ramos Joel S. Schneider N. Nora Yang Jeffrey S. Chamberlain Dongsheng Duan |
| author_sort | Chady H. Hakim |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T12:08:21Z |
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| id | doaj.art-a968d82e3a484f8cb6cd48ebc8ad7bec |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-04-13T12:08:21Z |
| publishDate | 2017-09-01 |
| publisher | Elsevier |
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| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-a968d82e3a484f8cb6cd48ebc8ad7bec2022-12-22T02:47:33ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012017-09-016C21623010.1016/j.omtm.2017.06.006A Five-Repeat Micro-Dystrophin Gene Ameliorated Dystrophic Phenotype in the Severe DBA/2J-mdx Model of Duchenne Muscular DystrophyChady H. Hakim0Nalinda B. Wasala1Xiufang Pan2Kasun Kodippili3Yongping Yue4Keqing Zhang5Gang Yao6Brittney Haffner7Sean X. Duan8Julian Ramos9Joel S. Schneider10N. Nora Yang11Jeffrey S. Chamberlain12Dongsheng Duan13Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, MO 65212, USADepartment of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, MO 65212, USADepartment of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, MO 65212, USADepartment of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, MO 65212, USADepartment of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, MO 65212, USADepartment of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, MO 65212, USADepartment of Bioengineering, University of Missouri, Columbia, MO 65212, USADepartment of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, MO 65212, USADepartment of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, MO 65212, USADepartment of Neurology, Wellstone Muscular Dystrophy Research Center, University of Washington, Seattle, WA 98105, USASolid Biosciences, LLC, Cambridge, MA 02142, USANational Center for Advancing Translational Sciences (NCATS), Bethesda, MD 20892, USADepartment of Neurology, Wellstone Muscular Dystrophy Research Center, University of Washington, Seattle, WA 98105, USADepartment of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, MO 65212, USAMicro-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.http://www.sciencedirect.com/science/article/pii/S2329050117300815AAVDMDmicro-dystrophinmdxDBA/2JnNOScardiomyopathysystemic gene therapyDuchenne muscular dystrophyadeno-associated virus |
| spellingShingle | Chady H. Hakim Nalinda B. Wasala Xiufang Pan Kasun Kodippili Yongping Yue Keqing Zhang Gang Yao Brittney Haffner Sean X. Duan Julian Ramos Joel S. Schneider N. Nora Yang Jeffrey S. Chamberlain Dongsheng Duan 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 AAV DMD micro-dystrophin mdx DBA/2J nNOS cardiomyopathy systemic gene therapy Duchenne muscular dystrophy adeno-associated virus |
| title | A Five-Repeat Micro-Dystrophin Gene Ameliorated Dystrophic Phenotype in the Severe DBA/2J-mdx Model of Duchenne Muscular Dystrophy |
| title_full | A Five-Repeat Micro-Dystrophin Gene Ameliorated Dystrophic Phenotype in the Severe DBA/2J-mdx Model of Duchenne Muscular Dystrophy |
| title_fullStr | A Five-Repeat Micro-Dystrophin Gene Ameliorated Dystrophic Phenotype in the Severe DBA/2J-mdx Model of Duchenne Muscular Dystrophy |
| title_full_unstemmed | A Five-Repeat Micro-Dystrophin Gene Ameliorated Dystrophic Phenotype in the Severe DBA/2J-mdx Model of Duchenne Muscular Dystrophy |
| title_short | A Five-Repeat Micro-Dystrophin Gene Ameliorated Dystrophic Phenotype in the Severe DBA/2J-mdx Model of Duchenne Muscular Dystrophy |
| title_sort | five repeat micro dystrophin gene ameliorated dystrophic phenotype in the severe dba 2j mdx model of duchenne muscular dystrophy |
| topic | AAV DMD micro-dystrophin mdx DBA/2J nNOS cardiomyopathy systemic gene therapy Duchenne muscular dystrophy adeno-associated virus |
| url | http://www.sciencedirect.com/science/article/pii/S2329050117300815 |
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