期刊
GENE THERAPY
卷 17, 期 12, 页码 1476-1483出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/gt.2010.110
关键词
AAV; NF-kappa B; DMD; muscle regeneration
类别
资金
- Department of Defense [W81XWH-06-1-0406]
- Pittsburgh Foundation
- Department of Orthopaedic Surgery, University of Pittsburgh
The I kappa B kinase (IKK alpha, beta and the regulatory subunit IKK gamma) complex regulates nuclear factor of kappa B (NF-kappa B) transcriptional activity, which is upregulated in many chronic inflammatory diseases. NF-kappa B signaling promotes inflammation and limits muscle regeneration in Duchenne muscular dystrophy (DMD), resulting in fibrotic and fatty tissue replacement of muscle that exacerbates the wasting process in dystrophic muscles. Here, we examined whether dominant-negative forms of IKK alpha (IKK alpha-dn) and IKK beta (IKK beta-dn) delivered by adeno-associated viral (AAV) vectors to the gastrocnemius (GAS) and tibialis anterior (TA) muscles of 1, 2 and 11-month-old mdx mice, a murine DMD model, block NF-kappa B activation and increase muscle regeneration. At 1 month post-treatment, the levels of nuclear NF-kappa B in locally treated muscle were decreased by gene transfer with either AAV-CMV-IKK alpha-dn or AAV-CMV-IKK beta-dn, but not by IKK wild-type controls (IKK alpha and beta) or phosphate-buffered saline (PBS). Although treatment with AAV-IKK alpha-dn or AAV-IKK beta-dn vectors had no significant effect on muscle regeneration in young mdx mice treated at 1 and 2 months of age and collected 1 month later, treatment of old (11 months) mdx with AAV-CMV-IKK alpha-dn or AAV-CMV-IKK beta-dn significantly increased levels of muscle regeneration. In addition, there was a significant decrease in myofiber necrosis in the AAVIKK alpha-dn- and AAV-IKK beta-dn-treated mdx muscle in both young and old mice. These results demonstrate that inhibition of IKK alpha or IKK beta in dystrophic muscle reduces the adverse effects of NF-kappa B signaling, resulting in a therapeutic effect. Moreover, these results clearly demonstrate the therapeutic benefits of inhibiting NF-kappa B activation by AAV gene transfer in dystrophic muscle to promote regeneration, particularly in older mdx mice, and block necrosis. Gene Therapy (2010) 17, 1476-1483; doi:10.1038/gt.2010.110; published online 19 August 2010
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