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Topical c-Jun Silencing to Prevent Photoaging
Lisa H. Hwang, MD, Yee C. Low, MD, Marc Soares, MD, Maria Ham, MD, Obinna Ezeamuzie, MD, Sara Immerman, MD, Daniel Ceradini, MD, Pierre B. Saadeh, MD.
NYU Langone Medical Center, New York, NY, USA.

Background: With the increase in life expectancy of Americans today, the aging face is a growing topic of interest in the study of both cosmesis and carcinogenesis. Skin cancer is occurring with rising incidence and is the most common cancer in the United States, presenting frequently on the aging face. Photoaging develops, in part, by UV-induced activation of the transcription factor c-Jun and downstream matrix metalloproteinases (MMPs), which cause dermal matrix degradation. Damage induced by UV radiation manifests histologically as the disorganization of collagen fibrils that constitute the majority of skin connective tissue and accumulation of abnormal elastin-containing material, producing skin wrinkling. Current modes of treatment include non-invasive methods, such as topical retinoids, antioxidants, and α-hydroxy acids, and invasive methods, such as dermabrasion, chemical peeling, collagen and botulinum toxin injections, laser re-surfacing, and face-lift; however, there are no gene-specific therapies. We investigated the impact of cutaneous c-Jun silencing on photoaging.
Methods: After c-Jun siRNA transfection, UV-radiated 3T3 fibroblasts were assayed for c-Jun and MMP (RT-PCR / Western Blot). In a mouse model of photoaging, chronic silencing was achieved throughout the three-week course of UV radiation (weekly siRNA application). The impact of topically applied c-Jun siRNA was determined by the following: c-Jun and MMP (RT-PCR / Western Blot), dermal thickness (H&E), collagen content and organization (picrosirius red birefringence), scar index quantification (high density photoanalysis), solar elastosis (Verhoeff stain), and skin elasticity and tensile strength (tensiometry). Non-radiated and non-sense siRNA groups were controls.
Results: in vitro, UV radiation induced a 7-fold increase of c-Jun mRNA. c-Jun siRNA-transfected 3T3 cells yielded 98±9% and 99.9±0.03% knockdown of c-Jun and MMP mRNA respectively (p<0.01). in vivo, UV radiation induced 20-fold and 15-fold increases (p<0.01), while topical c-Jun silencing resulted in 95±12% and 97±0.06% knockdown (p<0.01). Protein analysis was consistent with mRNA data. Chronically silenced irradiated skin retained features of non-irradiated skin, displaying markedly decreased signs of photoaging compared to controls, as measured by decreased dermal thickness (164 vs. 278 microns, p<0.01), increased collagen and fibrillar organization, decreased scar index (3.9 vs. 13.8, p<0.01), decreased solar elastosis and tissue breaking strength (0.34±0.01 kg vs. 0.47±0.02 kg, p<0.05), and increased skin elasticity.
Conclusion: Photoaging is a rising problem in today’s aging population, predisposing individuals to the development of skin cancer. We aim to interrupt the photoaging pathway without expressing any other untoward effects by targeting c-Jun. This study demonstrates preclinical efficacy of topical c-Jun silencing in preventing the development of clinical features of photoaging. Cutaneous siRNA delivery prevented UV induction of c-Jun and MMP expression and associated changes to collagen, skin elasticity, and tensile strength, ultimately retaining features of non-irradiated skin. This novel, gene-specific strategy to prevent photoaging may be rapidly translatable to clinical use.


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