PMID- 22278411
OWN - NLM
STAT- MEDLINE
DCOM- 20130528
LR  - 20121211
IS  - 1476-5462 (Electronic)
IS  - 0969-7128 (Linking)
VI  - 19
IP  - 12
DP  - 2012 Dec
TI  - AAV-based shRNA silencing of NF-kappaB ameliorates muscle pathologies in mdx mice.
PG  - 1196-204
LID - 10.1038/gt.2011.207 [doi]
AB  - Chronic inflammation, promoted by an upregulated NF-kappa B (NF-kappaB) pathway, has 
      a key role in Duchenne muscular dystrophy (DMD) patients' pathogenesis. Blocking 
      the NF-kappaB 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-kappaB/p65 (p65-shRNA), the major subunit of NF-kappaB associated with chronic 
      inflammation in mdx mice. We examined whether i.m. AAV9-mediated delivery of 
      p65-shRNA could decrease NF-kappaB activation, allowing for amelioration of muscle 
      pathologies in 1- and 4-month-old mdx mice. At 1 month after treatment, NF-kappaB/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-kappaB/p65 activity.
FAU - Yang, Q
AU  - Yang Q
AD  - Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA 
      15219, USA.
FAU - Tang, Y
AU  - Tang Y
FAU - Imbrogno, K
AU  - Imbrogno K
FAU - Lu, A
AU  - Lu A
FAU - Proto, J D
AU  - Proto JD
FAU - Chen, A
AU  - Chen A
FAU - Guo, F
AU  - Guo F
FAU - Fu, F H
AU  - Fu FH
FAU - Huard, J
AU  - Huard J
FAU - Wang, B
AU  - Wang B
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120126
PL  - England
TA  - Gene Ther
JT  - Gene therapy
JID - 9421525
RN  - 0 (NF-kappa B)
RN  - 0 (RNA, Small Interfering)
SB  - IM
MH  - Animals
MH  - Dependovirus/genetics
MH  - Male
MH  - Mice
MH  - Mice, Inbred mdx
MH  - Muscle, Skeletal/*pathology
MH  - Muscular Dystrophy, Duchenne/*genetics/pathology
MH  - NF-kappa B/*genetics/metabolism
MH  - RNA, Small Interfering
MH  - Regeneration/genetics
EDAT- 2012/01/27 06:00
MHDA- 2013/05/29 06:00
CRDT- 2012/01/27 06:00
PHST- 2012/01/27 06:00 [entrez]
PHST- 2012/01/27 06:00 [pubmed]
PHST- 2013/05/29 06:00 [medline]
AID - gt2011207 [pii]
AID - 10.1038/gt.2011.207 [doi]
PST - ppublish
SO  - Gene Ther. 2012 Dec;19(12):1196-204. doi: 10.1038/gt.2011.207. Epub 2012 Jan 26.