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AAV-based shRNA silencing of NF-κB ameliorates muscle pathologies in mdx mice

Yang, Q and Tang, Y and Imbrogno, K and Lu, A and Proto, JD and Chen, A and Guo, F and Fu, FH and Huard, J and Wang, B (2012) AAV-based shRNA silencing of NF-κB ameliorates muscle pathologies in mdx mice. Gene Therapy, 19 (12). 1196 - 1204. ISSN 0969-7128

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Chronic inflammation, promoted by an upregulated NF-kappa B (NF-κB) pathway, has a key role in Duchenne muscular dystrophy (DMD) patients pathogenesis. Blocking the NF-κB pathway has been shown to be a viable approach to diminish chronic inflammation and necrosis in the dystrophin-defective mdx mouse, a murine DMD model. In this study, we used the recombinant adeno-associated virus serotype 9 (AAV9) carrying an short hairpin RNA (shRNA) specifically targeting the messenger RNA of NF-κB/p65 (p65-shRNA), the major subunit of NF-κB associated with chronic inflammation in mdx mice. We examined whether i.m. AAV9-mediated delivery of p65-shRNA could decrease NF-κB activation, allowing for amelioration of muscle pathologies in 1-and 4-month-old mdx mice. At 1 month after treatment, NF-κB/p65 levels were significantly decreased by AAV gene transfer of p65-shRNA in the two ages of treatment groups, with necrosis significantly decreased compared with controls. Quantitative analysis revealed that central nucleation (CN) of the myofibers of p65-shRNA-treated 1-month-old mdx muscles was reduced from 67 to 34%, but the level of CN was not significantly decreased in treated 4-month-old mdx mice. Moreover, delivery of the p65-shRNA enhanced the capacity of myofiber regeneration in old mdx mice treated at 4 months of age when the dystrophic myofibers were most exhausted; however, such p65 silencing diminished the myofiber regeneration in young mdx mice treated at 1 month of age. Taken together, these findings demonstrate that the AAV-mediated delivery of p65-shRNA has the capacity to ameliorate muscle pathologies in mdx mice by selectively reducing NF-κB/p65 activity. © 2012 Macmillan Publishers Limited.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Yang, Q
Tang, Y
Imbrogno, K
Lu, A
Proto, JD
Chen, A
Guo, F
Fu, FHffu@pitt.eduFFU
Huard, J
Wang, Bbingwang@pitt.eduBINGWANG
Date: 6 December 2012
Date Type: Publication
Journal or Publication Title: Gene Therapy
Volume: 19
Number: 12
Page Range: 1196 - 1204
DOI or Unique Handle: 10.1038/gt.2011.207
Schools and Programs: School of Medicine > Orthopaedic Surgery
Refereed: Yes
ISSN: 0969-7128
MeSH Headings: Animals; Dependovirus--genetics; Male; Mice; Mice, Inbred mdx; Muscle, Skeletal--pathology; Muscular Dystrophy, Duchenne--genetics; Muscular Dystrophy, Duchenne--pathology; NF-kappa B--genetics; NF-kappa B--metabolism; RNA, Small Interfering; Regeneration--genetics
PubMed ID: 22278411
Date Deposited: 04 Apr 2014 15:43
Last Modified: 02 Feb 2019 16:56


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