Halting angiogenesis by non-viral somatic gene therapy alleviates psoriasis and murine psoriasiform skin lesions
John R. Zibert, Katrin Wallbrecht, Margarete Schön, Lluis M. Mir, Grete K. Jacobsen, Veronique Trochon-Joseph, Céline Bouquet, Louise S. Villadsen, Ruggero Cadossi, Lone Skov, Michael P. Schön
John R. Zibert, Katrin Wallbrecht, Margarete Schön, Lluis M. Mir, Grete K. Jacobsen, Veronique Trochon-Joseph, Céline Bouquet, Louise S. Villadsen, Ruggero Cadossi, Lone Skov, Michael P. Schön
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Research Article Dermatology

Halting angiogenesis by non-viral somatic gene therapy alleviates psoriasis and murine psoriasiform skin lesions

Abstract

Dysregulated angiogenesis is a hallmark of chronic inflammatory diseases, including psoriasis, a common skin disorder that affects approximately 2% of the population. Studying both human psoriasis in 2 complementary xenotransplantation models and psoriasis-like skin lesions in transgenic mice with epidermal expression of human TGF-β1, we have demonstrated that antiangiogenic non-viral somatic gene therapy reduces the cutaneous microvasculature and alleviates chronic inflammatory skin disorders. Transient muscular expression of the recombinant disintegrin domain (RDD) of metargidin (also known as ADAM-15) by in vivo electroporation reduced cutaneous angiogenesis and vascularization in all 3 models. As demonstrated using red fluorescent protein–coupled RDD, the treatment resulted in muscular expression of the gene product and its deposition within the cutaneous hyperangiogenic connective tissue. High-resolution ultrasound revealed reduced cutaneous blood flow in vivo after electroporation with RDD but not with control plasmids. In addition, angiogenesis- and inflammation-related molecular markers, keratinocyte proliferation, epidermal thickness, and clinical disease scores were downregulated in all models. Thus, non-viral antiangiogenic gene therapy can alleviate psoriasis and may do so in other angiogenesis-related inflammatory skin disorders.

Authors

John R. Zibert, Katrin Wallbrecht, Margarete Schön, Lluis M. Mir, Grete K. Jacobsen, Veronique Trochon-Joseph, Céline Bouquet, Louise S. Villadsen, Ruggero Cadossi, Lone Skov, Michael P. Schön

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Figure 2

Expression and dermal deposition of RDD fusion proteins in vivo.

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Expression and dermal deposition of RDD fusion proteins in vivo. (A) Prk...
(A) Prkdcscid mice were transfected with pVAX-RDD-RFP, pVAX-RFP, or pVAX-mock by in vivo electroporation of the tibialis cranialis muscle as indicated. After 3 days, fluorescence was detected in the transfected tibialis cranialis muscle (left panels) and the skin (right panels). Dashed lines indicate the dermo-epidermal junction. Both RFP-containing products are expressed in the muscle tissue, but only RDD-containing products are deposited in the skin. Scale bar: 20 μm. (B) The skeletal muscle of a Prkdcscid mouse transfected with pVAX-RDD-RFP (14 days after electrotransfer of the gene construct) was subjected to immunohistochemistry to allow topographic mapping of the transgene within the skeletal muscle. Arrows point to examples of positive cross-cut fibers. Original magnification, ×25. (C) High-power magnification of skin sections of a Prkdcscid mouse transfected with pVAX-RDD-RFP (left panel) and a Prkdcscid mouse transfected with pVAX-RFP (right) that were stained immunohistochemically using a RFP-directed antibody. Only blood vessels (arrows) in the mouse transfected with the RDD-containing construct, but not those of the RFP control, light up, thus indicating deposition of RDD-containing gene products in the vicinity of cutaneous blood vessels. Scale bar: 20 μm. (D) Mice were treated by somatic gene therapy using the pVAX-RFP (n = 3 mice), pVAX-RDD (n = 4 mice), or the pVAX-RDD-RFP (n = 4 mice) construct as indicated. Secreted protein was detected by Western blot analysis using an RFP-directed antibody. Only mice transfected with the pVAX-RDD-RFP construct exhibit a signal, suggesting that secretion into the circulation is dependent on the presence of the RDD sequence.