Halting angiogenesis by non-viral somatic gene therapy alleviates psoriasis and murine psoriasiform skin lesions.
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.
Department of Dermato-Allergology, University of Copenhagen, Gentofte Hospital, Hellerup, Denmark.
John R
JR
Zibert
Katrin
K
Wallbrecht
Margarete
M
Schön
Lluis M
LM
Mir
Grete K
GK
Jacobsen
Veronique
V
Trochon-Joseph
Céline
C
Bouquet
Louise S
LS
Villadsen
Ruggero
R
Cadossi
Lone
L
Skov
Michael P
MP
Schön
D051722:ADAM Proteins / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000502:physiology; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D011565:Psoriasis / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D011993:Recombinant Fusion Proteins / Q000235:genetics; D014183:Transplantation, Heterologous
D008565:Membrane Proteins; D011993:Recombinant Fusion Proteins; D051722:ADAM Proteins; C098660:ADAM15 protein, human; C490902:Adam15 protein, mouse