PMID- 19568223
OWN - NLM
STAT- MEDLINE
DCOM- 20100105
LR  - 20211020
IS  - 1525-0024 (Electronic)
IS  - 1525-0016 (Print)
IS  - 1525-0016 (Linking)
VI  - 17
IP  - 10
DP  - 2009 Oct
TI  - Amelioration of psoriasis by anti-TNF-alpha RNAi in the xenograft transplantation 
      model.
PG  - 1743-53
LID - 10.1038/mt.2009.141 [doi]
AB  - Tumor necrosis factor-alpha (TNF-alpha) is upregulated in psoriatic skin and 
      represents a prominent target in psoriasis treatment. The level of 
      TNF-alpha-encoding mRNA, however, is not increased in psoriatic skin, and it 
      remains unclear whether intervention strategies based on RNA interference (RNAi) 
      are therapeutically relevant. To test this hypothesis the present study describes 
      first the in vitro functional screening of a panel of short hairpin RNAs (shRNAs) 
      targeting human TNF-alpha mRNA and, next, the transfer of the most potent 
      TNF-alpha shRNA variant, as assessed in vitro, to human skin in the psoriasis 
      xenograft transplantation model by the use of lentiviral vectors. TNF-alpha shRNA 
      treatment leads to amelioration of the psoriasis phentotype in the model, as 
      documented by reduced epidermal thickness, normalization of the skin morphology, 
      and reduced levels of TNF-alpha mRNA as detected in skin biopsies 3 weeks after a 
      single vector injection of lentiviral vectors encoding TNF-alpha shRNA. Our data 
      show efficient lentiviral gene delivery to psoriatic skin and therapeutic 
      applicability of anti-TNF-alpha shRNAs in human skin. These findings validate 
      TNF-alpha mRNA as a target molecule for a potential persistent RNA-based 
      treatment of psoriasis and establish the use of small RNA effectors as a novel 
      platform for target validation in psoriasis and other skin disorders.
FAU - Jakobsen, Maria
AU  - Jakobsen M
AD  - Department of Human Genetics, University of Aarhus, Aarhus DK-8000, Denmark.
FAU - Stenderup, Karin
AU  - Stenderup K
FAU - Rosada, Cecilia
AU  - Rosada C
FAU - Moldt, Brian
AU  - Moldt B
FAU - Kamp, Soren
AU  - Kamp S
FAU - Dam, Tomas N
AU  - Dam TN
FAU - Jensen, Thomas G
AU  - Jensen TG
FAU - Mikkelsen, Jacob Giehm
AU  - Mikkelsen JG
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20090630
PL  - United States
TA  - Mol Ther
JT  - Molecular therapy : the journal of the American Society of Gene Therapy
JID - 100890581
RN  - 0 (Tumor Necrosis Factor-alpha)
SB  - IM
MH  - Animals
MH  - Cell Line
MH  - Disease Models, Animal
MH  - Genetic Vectors/genetics
MH  - Humans
MH  - Lentivirus/genetics
MH  - Mice
MH  - Mice, SCID
MH  - Polymerase Chain Reaction
MH  - Psoriasis/genetics/*therapy
MH  - RNA Interference/*physiology
MH  - Transplantation, Heterologous
MH  - Tumor Necrosis Factor-alpha/*genetics
PMC - PMC2835022
EDAT- 2009/07/02 09:00
MHDA- 2010/01/06 06:00
PMCR- 2010/10/01
CRDT- 2009/07/02 09:00
PHST- 2009/07/02 09:00 [entrez]
PHST- 2009/07/02 09:00 [pubmed]
PHST- 2010/01/06 06:00 [medline]
PHST- 2010/10/01 00:00 [pmc-release]
AID - S1525-0016(16)32138-4 [pii]
AID - 10.1038/mt.2009.141 [doi]
PST - ppublish
SO  - Mol Ther. 2009 Oct;17(10):1743-53. doi: 10.1038/mt.2009.141. Epub 2009 Jun 30.