title: Collagen VII Half-Life at the Dermal-Epidermal Junction Zone: Implications for Mechanisms and Therapy of Genodermatoses.
abstract: The tissue half-life of proteins largely determines treatment frequency of non-gene-editing-based therapies targeting the cause of genodermatoses. Surprisingly, such knowledge is missing for a vast number of proteins involved in pathologies. The dermal-epidermal junction zone is believed to be a rather static structure, but to our knowledge no detailed analysis of the stability of proteins within this zone has been performed. Here, we addressed the in vivo half-life of collagen type VII using genetic ablation of its expression and therapeutic introduction of exogenous collagen VII in a preclinical model. A similar in vivo stability of collagen VII was observed in the skin, tongue, and esophagus, with a half-life of about 1 month. Collagen VII expressed by intradermally injected mesenchymal stromal cells also exhibited a similar half-life. Our study provides key information needed for the development of protein replacement or cell-based therapies for dystrophic epidermolysis bullosa caused by genetic deficiency of collagen VII. Moreover, by showing what we define as an intermediate half-life of collagen VII, our study challenges the view of the dermal-epidermal junction zone as a static structure with very slow turnover.
authors.affiliation: Department of Dermatology, Medical Center-University of Freiburg, 79104 Freiburg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Kühl
authors.affiliation: University Children's Hospital, Department of General Paediatrics, Oncology/Haematology, Eberhard Karls University, 72076 Tuebingen, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Mezger
authors.affiliation: EM lab, Institute of Pathology, University Clinic Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Hausser
authors.affiliation: Shire, Lexington, Massachusetts, USA.
authors.forename: Lin T
authors.initials: LT
authors.lastname: Guey
authors.affiliation: University Children's Hospital, Department of General Paediatrics, Oncology/Haematology, Eberhard Karls University, 72076 Tuebingen, Germany.
authors.forename: Rupert
authors.initials: R
authors.lastname: Handgretinger
authors.affiliation: Department of Dermatology, Medical Center-University of Freiburg, 79104 Freiburg, Germany.
authors.forename: Leena
authors.initials: L
authors.lastname: Bruckner-Tuderman
authors.affiliation: Department of Dermatology, Medical Center-University of Freiburg, 79104 Freiburg, Germany. Electronic address: alexander.nystroem@uniklinik-freiburg.de.
authors.forename: Alexander
authors.initials: A
authors.lastname: Nyström
mesh_terms: D000818:Animals; D015153:Blotting, Western; D064987:Cell- and Tissue-Based Therapy / Q000379:methods; D002478:Cells, Cultured; D024143:Collagen Type VII / Q000627:therapeutic use*; D020405:Dermis / Q000378:metabolism; D004195:Disease Models, Animal; D004817:Epidermis / Q000378:metabolism; D016108:Epidermolysis Bullosa Dystrophica / Q000235:genetics / Q000628:therapy*; D005347:Fibroblasts / Q000166:cytology; D015316:Genetic Therapy / Q000379:methods*; D006207:Half-Life; D006801:Humans; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D051379:Mice; D018345:Mice, Knockout; D011897:Random Allocation; D012873:Skin Diseases, Genetic / Q000235:genetics / Q000628:therapy
chemical_list: D024143:Collagen Type VII