1. ¹Molecular Imaging Program at Stanford (MIPS), Stanford University School of Medicine, Stanford, CA, USA
2. ²Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
3. ³Department of Radiology, Stanford University School of Medicine, Stanford, CA, USA
4. ⁴Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA
5. ⁵Department of Electrical Engineering, Stanford University, Stanford, CA, USA
6. ⁶TransDerm Inc., Santa Cruz, CA, USA
7. ⁷NECTEC, Pathumthani, Thailand
8. ⁸Thermo Fisher Scientific, Dharmacon Products, Lafayette, CO, USA
9. ⁹Centre for Cutaneous Research, Cancer Research UK, Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, Whitechapel, London, UK

Correspondence: Dr RL Kaspar, TransDerm Inc., 2161 Delaware Avenue, Suite D, Santa Cruz, CA 95060, USA. E-mail: Roger.Kaspar@TransDermInc.com

Received 23 September 2008; Revised 22 March 2009; Accepted 13 April 2009; Published online 28 May 2009.

Abstract

Small interfering RNAs (siRNAs) can be designed to specifically and potently target and silence a mutant allele, with little or no effect on the corresponding wild-type allele expression, presenting an opportunity for therapeutic intervention. Although several siRNAs have entered clinical trials, the development of siRNA therapeutics as a new drug class will require the development of improved delivery technologies. In this study, a reporter mouse model (transgenic click beetle luciferase/humanized monster green fluorescent protein) was developed to enable the study of siRNA delivery to skin; in this transgenic mouse, green fluorescent protein reporter gene expression is confined to the epidermis. Intradermal injection of siRNAs targeting the reporter gene resulted in marked reduction of green fluorescent protein expression in the localized treatment areas as measured by histology, real-time quantitative polymerase chain reaction and intravital imaging using a dual-axes confocal fluorescence microscope. These results indicate that this transgenic mouse skin model, coupled with in vivo imaging, will be useful for development of efficient and 'patient-friendly' siRNA delivery techniques and should facilitate the translation of siRNA-based therapeutics to the clinic for treatment of skin disorders.