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 4

RDD gene therapy prevents the development of psoriasis in the hu/SCID xenotransplantation model.

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RDD gene therapy prevents the development of psoriasis in the hu/SCID xe...
(A) Uninvolved skin from psoriasis patients was transplanted onto immunodeficient Prkdcscid mice, and recipient mice were injected intraperitoneally with PBS (left panel) or 107 activated PBMCs from the same donors to induce psoriasis (middle and right panels). Two days prior to injection of PBMCs, the mice were subjected to gene therapy with pVAX-mock or pVAX-RDD. The macroscopic aspect of the blood vessels on the underside of the skin transplants demonstrates that gene therapy with RDD markedly reduced cutaneous vascularization. Original magnification, ~×3 (B) Prkdcscid mice were treated as described in A, and the transplanted human skin was analyzed by immunohistochemistry using the indicated reagents detecting blood vessels. Somatic gene therapy with pVAX-RDD, but not that with pVAX-mock or pVAX-RFP, reduces number and size of cutaneous blood vessels of both human (CD31 and αSMA) and murine (BS-1) origin. Scale bar: 50 μm. (C) Human skin transplants from Prkdcscid mice were further analyzed by H&E staining (left panels) and by immunohistochemistry using the indicated antibodies detecting proliferating cells (Ki67) or T cells (CD3). Both the epidermal thickness and the number of proliferating epidermal keratinocytes are reduced in transplants from mice treated by RDD gene therapy. Scale bar: 50 μm. (D) Quantitative morphometric analysis of transplants from Prkdcscid mice. The top graph depicts epidermal thickness as determined by blinded measurements. The bottom graph shows the number of proliferating epidermal cells in mice subjected to RDD gene therapy compared with that of the controls. ***P < 0.001. Values represent mean ± SD.