Jacob Giehm Mikkelsen

Is TNF-a-targeted short hairpin RNA (shRNA) a novel potential therapeutic tool in psoriasis treatment?

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisKonferenceabstrakt i tidsskriftForskning

  • Dermato-Venerologisk Afdeling S
  • Institut for Human Genetik
 

TNF-α is a well known target in psoriasis treatment and biological treatments targeting TNF-a are already clinically used against psoriasis and psoriasis arthritis. Attention is however given to a novel therapeutic tool: RNA interference that controls gene silencing. This study investigates the efficiency of targeting TNF-a with specific short hairpin RNA (shRNA) and explores its potential in treating psoriasis.

ShRNAs targeting human TNF-α mRNA were generated. Their efficiency in down-regulating TNF-a protein expression was evaluated using a Renilla luciferase screening-assay and a transient co-transfection assay. The expression cassette encoding the most efficient TNF-a shRNA was inserted into a lentiviral vector, allowing proficient gene delivery. The lentiviral vector is integrated into the host genome and establishes life-long infection and persistent shRNA expression.

The lentiviral vector expressing TNF-a shRNA was used to transduce HEK293 cells and verify vector-derived TNF-a knockdown in vitro. In vivo, psoriasis skin was exposed to lentiviral TNF-a shRNAs by a single intra-dermal injection. Psoriasis skin for the in vivo study was obtained from psoriatic plaque skin biopsies that were transplanted onto SCID mice employing the psoriasis xenograft model. Three weeks after exposure, biopsies were taken and the epidermal thickness as an endpoint for evaluating psoriasis and the levels of TNF-a mRNA were measured.

The lentiviral TNF-a shRNAs down-regulated the TNF-a expression in vitro and in vivo by 50% and, most interestingly, the epidermal thickness of the psoriatic plaques was reduced.

In conclusion, our results demonstrate that lentiviral TNF-a shRNAs have the potential to down-regulate TNF-a production in vitro and in vivo. The decreased epidermal thickness suggests a potential role for TNF-a shRNAs as a new therapeutic agent in psoriasis treatment.

OriginalsprogEngelsk
TidsskriftJournal of Investigative Dermatology
Vol/bind128
Nummersuppl 1
Sider (fra-til)113 no 674
Antal sider1
ISSN0022-202X
StatusUdgivet - 2008
BegivenhedInternational Investigative Dermatology - Kyoto, Japan
Varighed: 14 maj 200817 maj 2008

Konference

KonferenceInternational Investigative Dermatology
LandJapan
ByKyoto
Periode14/05/200817/05/2008

Bibliografisk note

Udgivelsesdato: April

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