title: Targeted silencing of DEFB4 in a bioengineered skin-humanized mouse model for psoriasis: development of siRNA SECosome-based novel therapies.
abstract: Psoriasis is a complex inflammatory skin disease that presents a wide variety of clinical manifestations. Human β defensin-2 (hBD-2) is highly up-regulated in psoriatic lesions and has been defined as a biomarker for disease activity. We explored the potential benefits of targeting hBD-2 by topical application of DEFB4-siRNA-containing SECosomes in a bioengineered skin-humanized mouse model for psoriasis. A significant improvement in the psoriatic phenotype was observed by histological examination, with a normalization of the skin architecture and a reduction in the number and size of blood vessels in the dermal compartment. Treatment leads to the recovery of transglutaminase activity, filaggrin expression and stratum corneum appearance to the levels similar to those found in normal regenerated human skin. The availability of a reliable skin-humanized mouse model for psoriasis in conjunction with the use of the SECosome technology may provide a valuable preclinical tool for identifying potential therapeutic targets for this disease.
authors.affiliation: Department of Dermatology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Bracke
authors.forename: Marta
authors.initials: M
authors.lastname: Carretero
authors.forename: Sara
authors.initials: S
authors.lastname: Guerrero-Aspizua
authors.forename: Eline
authors.initials: E
authors.lastname: Desmet
authors.forename: Nuria
authors.initials: N
authors.lastname: Illera
authors.forename: Manuel
authors.initials: M
authors.lastname: Navarro
authors.forename: Jo
authors.initials: J
authors.lastname: Lambert
authors.forename: Marcela
authors.initials: M
authors.lastname: Del Rio
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D057005:Bioengineering; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D020405:Dermis / Q000473:pathology; D004195:Disease Models, Animal; D053492:Elafin / Q000032:analysis; D004817:Epidermis / Q000737:chemistry / Q000473:pathology; D000091344:Filaggrin Proteins; D015870:Gene Expression / Q000187:drug effects; D020868:Gene Silencing; D006801:Humans; D007381:Intermediate Filament Proteins / Q000032:analysis; D053556:Keratin-1 / Q000032:analysis; D053537:Keratin-17 / Q000032:analysis; D019394:Ki-67 Antigen / Q000032:analysis; D039841:Leukocyte L1 Antigen Complex / Q000032:analysis; D008081:Liposomes / Q000008:administration & dosage; D051379:Mice; D058990:Molecular Targeted Therapy; D053758:Nanoparticles / Q000008:administration & dosage; D011498:Protein Precursors / Q000032:analysis; D011565:Psoriasis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000627:therapeutic use*; D000075023:S100 Calcium Binding Protein A7; D009418:S100 Proteins / Q000032:analysis; D023083:beta-Defensins / Q000235:genetics*
chemical_list: C106641:DEFB4A protein, human; D053492:Elafin; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; D053556:Keratin-1; D053537:Keratin-17; D019394:Ki-67 Antigen; D039841:Leukocyte L1 Antigen Complex; D008081:Liposomes; D011498:Protein Precursors; D034741:RNA, Small Interfering; D000075023:S100 Calcium Binding Protein A7; D009418:S100 Proteins; C089242:S100A7 protein, human; D023083:beta-Defensins; C032253:involucrin
keywords: SECosomes; hBD-2; psoriasis; siRNA; skin-humanized mouse model