AAV micro-dystrophin gene therapy alleviates stress-induced cardiac death but not myocardial fibrosis in >21-m-old mdx mice, an end-stage model of Duchenne muscular dystrophy cardiomyopathy.

Journal of Molecular and Cellular Cardiology
Brian BostickDongsheng Duan

Abstract

Duchenne muscular dystrophy (DMD) is a fatal genetic disease caused by the absence of the sarcolemmal protein dystrophin. Dilated cardiomyopathy leading to heart failure is a significant source of morbidity and mortality in DMD. We recently demonstrated amelioration of DMD heart disease in 16 to 20-m-old dystrophin-null mdx mice using adeno-associated virus (AAV) mediated micro-dystrophin gene therapy. DMD patients show severe heart disease near the end of their life expectancy. Similarly, mdx mice exhibit profoundly worsening heart disease when they reach beyond 21 months of age. To more rigorously test micro-dystrophin therapy, we treated mdx mice that were between 21.2 and 22.7-m-old (average, 22.1 ± 0.2 months; N=8). The ∆R4-23/∆C micro-dystrophin gene was packaged in the cardiotropic AAV-9 virus. 5×10(12) viral genome particles/mouse were delivered to mdx mice via the tail vein. AAV transduction, myocardial fibrosis and heart function were examined 1.7 ± 0.2 months after gene therapy. Efficient micro-dystrophin expression was observed in the myocardium of treated mice. Despite the robust dystrophin expression, myocardial fibrosis was not mitigated. Most hemodynamic parameters were not improved either. However, ECG abnormal...Continue Reading

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Citations

Aug 12, 2014·Molecular Therapy. Methods & Clinical Development·Chady H HakimDongsheng Duan
Jan 15, 2014·Nature Reviews. Cardiology·Josef Finsterer, Linda Cripe
Apr 29, 2014·BioMed Research International·Ashling Holland, Kay Ohlendieck
Jun 25, 2016·Expert Opinion on Orphan Drugs·Yongping YueDongsheng Duan
Mar 29, 2013·Muscle & Nerve·Drielen De Oliveira MoreiraMaria Julia Marques
Jul 28, 2016·Current Opinion in Virology·Dongsheng Duan
Aug 21, 2016·Human Genetics·Jacqueline N Robinson-Hamm, Charles A Gersbach
Apr 12, 2017·Wiley Interdisciplinary Reviews. Nanomedicine and Nanobiotechnology·Michael E NanceDongsheng Duan
Aug 22, 2013·Journal of the American Heart Association·Mattia QuattrocelliMaurilio Sampaolesi
Aug 24, 2013·Journal of the American Heart Association·Louise R Rodino-Klapac
Sep 7, 2016·F1000Research·Hayder Abdul-RazakGeorge Dickson
Aug 31, 2019·EMBO Molecular Medicine·Andrea GrundJoerg Heineke
May 16, 2015·Journal of Biomolecular Screening·Yuval Blat, Shachar Blat
Nov 21, 2020·American Journal of Physiology. Heart and Circulatory Physiology·Satvik MareeduGopal J Babu
Jan 25, 2020·Cell Stem Cell·Hesham SolimanFabio M V Rossi
Aug 11, 2018·Molecular Therapy : the Journal of the American Society of Gene Therapy·Dongsheng Duan
Sep 22, 2017·Molecular Therapy. Methods & Clinical Development·Chady H HakimDongsheng Duan
Mar 6, 2015·Disease Models & Mechanisms·Joe W McGreevyDongsheng Duan
Jan 8, 2020·Molecular Therapy. Methods & Clinical Development·Buel D RodgersJoseph W Maricelli
Sep 15, 2021·Endocrine Reviews·Buel D Rodgers, Christopher W Ward
Nov 16, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Angus LindsayAaron P Russell

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