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

• Published in: The Journal of clinical investigation 2011-01, Vol.121 (1), p.410
• Main Authors: Zibert, John R, Wallbrecht, Katrin, Schon, Margarete, Mir, Lluis M, Jacobsen, Grete K, Trochon-Joseph, Veronique, Bouquet, Celine, Villadsen, Louise S, Cadossi, Ruggero, Skov, Lone, Schon, Michael P
• Format: Article
• Language: English
• Subjects: Care and treatment; Gene therapy; Genetic aspects; Health aspects; Neovascularization; Psoriasis
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JC141295

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.