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Development of a One-Stage Transdermal Gene Delivery System
Meredith Wetterau1, Stelios Wilson1, Caroline Szpalski, MD1, Oriana Cohen1, Lisa Hwang, MD1, Stephen M. Warren, MD1, Stavroula Sofou, PhD2, Pierre B. Saadeh, MD1.
1NYU Langone Medical Center, New York, NY, USA, 2NYU Polytechnic Institute, Brooklyn, NY, USA.

Background
RNAi poses a unique gene specific therapeutic option for cutaneous disease. The application of RNAi has had limited success due to the difficulty in creating a carrier molecule that could both disrupt the stratum corneum and provide a mechanism for intracellular delivery. Targeting a ubiquitously expressed gene (MAPK), we aimed to develop a novel lipid nanoparticle-based gene delivery system designed to penetrate the stratum corneum and suppress targeted gene expression.
Methods
siRNA was complexed with preformed DOTAP-containing lipid nanoparticles (NP) under vigorous vortexing at the mole ratio of 1:10 (siRNA:DOTAP). The size and zeta potential of complexes were monitored over several days. Complex suspensions were applied to the dorsum of mice. Treated sections were harvested at 0, 24, 72, 96, 120 and 168 hrs after application and analyzed (mRNA, protein, and immunohistochemistry (IHC). ANOVA determined significance (p<.05).
Results
600-800nm siRNA-DOTAP particle size with a postive zeta potential provided optimal gene delivery. RT-PCR demonstrated 20% knockdown of MAPK beginning at 6 hrs, 70% knockdown at 24 hrs, with return of protein expression to baseline (Day 0) at 168 hrs. Targeted mRNA suppression led to similar protein suppression at 24hours (p<0.05). IHC demonstrated highly specific and limited knockdown of the target gene confined to the treatment area. No off-target effects were noted.
Conclusion
We developed a novel liposome-based transdermal gene delivery system. This application could be utilized for off the shelf targeted gene suppression to treat cutaneous disease.


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