Gene therapy of epidermolysis bullosa.
Easy access to the organ and identification of underlying mutations in epidermolysis bullosa (EB) facilitated the first cutaneous gene therapy experiments in vitro in the mid-1990s. The leading technology was transduction of the respective cDNA carried by a retroviral vector. Using this approach, the genotypic and phenotypic hallmark features of the recessive forms of junctional EB, which are caused by loss of function of the structural proteins laminin-5 or bullous pemphigoid antigen 2/type XVII collagen of the dermo-epidermal basement membrane zone, have been corrected in vitro and in vivo using xenograft mouse models. Recently, this approach has also been shown to be feasible for the large COL7A1 gene (mutated in dystrophic EB), applying PhiC31 integrase or lentiviral vectors. Neither of these approaches has made it into a successful Phase I study on EB patients. Therefore, alternative approaches to gene correction, including modulation of splicing, are being investigated for gene therapy in EB.
Bauer
Johann W
JW
Department of Dermatology, Paracelsus Private Medical University, Muellner Hauptstrasse 48, A-5020 Salzburg, Austria. jo.bauer@salk.at
Laimer
Martin
M
D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000502:physiology; D002352:Carrier Proteins; D015815:Cell Adhesion Molecules / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D003598:Cytoskeletal Proteins; D018076:DNA, Complementary / Q000235:genetics; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D000071821:Dystonin; D004820:Epidermolysis Bullosa / Q000145:classification / Q000235:genetics / Q000628:therapy*; D018740:Genetic Heterogeneity; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use; D006801:Humans; D039663:Integrin beta4 / Q000235:genetics / Q000502:physiology; D053547:Keratin-14; D015603:Keratinocytes / Q000378:metabolism / Q000637:transplantation; D007633:Keratins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D020782:Matrix Metalloproteinases / Q000502:physiology; D051379:Mice; D008819:Mice, Nude; D009419:Nerve Tissue Proteins; D024041:Non-Fibrillar Collagens / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D011480:Protease Inhibitors / Q000627:therapeutic use; D012326:RNA Splicing; D016337:RNA, Catalytic / Q000627:therapeutic use; D019098:Telomerase / Q000235:genetics / Q000502:physiology; D000097794:Kalinin; D000097805:Collagen Type XVII
D001324:Autoantigens; D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D000071821:Dystonin; D039663:Integrin beta4; D053547:Keratin-14; D007633:Keratins; D020782:Matrix Metalloproteinases; D009419:Nerve Tissue Proteins; D024041:Non-Fibrillar Collagens; D011480:Protease Inhibitors; D016337:RNA, Catalytic; D019098:Telomerase; D000097794:Kalinin; D000097805:Collagen Type XVII; C486268:DST protein, human; C507540:KRT14 protein, human; C507446:Krt14 protein, mouse