title: Injection of recombinant human type VII collagen corrects the disease phenotype in a murine model of dystrophic epidermolysis bullosa.
abstract: Patients with recessive dystrophic epidermolysis bullosa (RDEB) have incurable skin fragility, blistering, and scarring due to mutations in the gene that encodes for type VII collagen (C7) that mediates dermal-epidermal adherence in human skin. We showed previously that intradermal injection of recombinant C7 into transplanted human DEB skin equivalents stably restored C7 expression at the basement membrane zone (BMZ) and reversed the RDEB disease features. In this study, we evaluated the feasibility of protein therapy in a C7 null mouse (Col7a1(-/-)) which recapitulates the features of human RDEB. We intradermally injected purified human C7 into DEB mice and found that the injected human C7 stably incorporated into the mouse BMZ, formed anchoring fibrils, and corrected the DEB murine phenotype, as demonstrated by decreased skin fragility, reduced new blister formation, and markedly prolonged survival. After 4 weeks, treated DEB mice developed circulating anti-human C7 antibodies. Most surprisingly, these anti-C7 antibodies neither bound directly to the mouse's BMZ nor prevented the incorporation of newly injected human C7 into the BMZ. Anti-C7 antibody production was prevented by treating the mice with an anti-CD40L monoclonal antibody, MR1. We conclude that protein therapy may be feasible for the treatment of human patients with RDEB.
authors.affiliation: Department of Dermatology, University of Southern California, Los Angeles, California, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Remington
authors.forename: Xinyi
authors.initials: X
authors.lastname: Wang
authors.forename: Yingpin
authors.initials: Y
authors.lastname: Hou
authors.forename: Hui
authors.initials: H
authors.lastname: Zhou
authors.forename: Julie
authors.initials: J
authors.lastname: Burnett
authors.forename: Trevor
authors.initials: T
authors.lastname: Muirhead
authors.forename: Jouni
authors.initials: J
authors.lastname: Uitto
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Keene
authors.forename: David T
authors.initials: DT
authors.lastname: Woodley
authors.forename: Mei
authors.initials: M
authors.lastname: Chen
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D001485:Basement Membrane / Q000378:metabolism; D024143:Collagen Type VII / Q000008:administration & dosage* / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D016108:Epidermolysis Bullosa Dystrophica / Q000473:pathology / Q000628:therapy*; D006801:Humans; D007271:Injections, Intradermal; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D012867:Skin / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure
chemical_list: D000906:Antibodies; D024143:Collagen Type VII; D011994:Recombinant Proteins