title: Patient-specific naturally gene-reverted induced pluripotent stem cells in recessive dystrophic epidermolysis bullosa.
abstract: Spontaneous reversion of disease-causing mutations has been observed in some genetic disorders. In our clinical observations of severe generalized recessive dystrophic epidermolysis bullosa (RDEB), a currently incurable blistering genodermatosis caused by loss-of-function mutations in COL7A1 that results in a deficit of type VII collagen (C7), we have observed patches of healthy-appearing skin on some individuals. When biopsied, this skin revealed somatic mosaicism resulting in the self-correction of C7 deficiency. We believe this source of cells could represent an opportunity for translational 'natural' gene therapy. We show that revertant RDEB keratinocytes expressing functional C7 can be reprogrammed into induced pluripotent stem cells (iPSCs) and that self-corrected RDEB iPSCs can be induced to differentiate into either epidermal or hematopoietic cell populations. Our results give proof-of-principle that an inexhaustible supply of functional patient-specific revertant cells can be obtained--potentially relevant to local wound therapy and systemic hematopoietic cell transplantation. This technology may also avoid some of the major limitations of other cell therapy strategies, e.g., immune rejection and insertional mutagenesis, which are associated with viral- and nonviral-mediated gene therapy. We believe this approach should be the starting point for autologous cellular therapies using 'natural' gene therapy in RDEB and other diseases.
authors: Department of Pediatrics, Blood and Marrow Transplant, Medical School, University of Minnesota, Minneapolis, Minnesota, USA; Stem Cell Institute, University of Minnesota, Minneapolis, Minnesota, USA. Electronic address: tolar003@umn.edu.
authors: Jakub
authors: J
authors: Tolar
authors: St John's Institute of Dermatology, King's College London (Guy's Campus), London, UK.
authors: John A
authors: JA
authors: McGrath
authors: Department of Pediatrics, Blood and Marrow Transplant, Medical School, University of Minnesota, Minneapolis, Minnesota, USA.
authors: Lily
authors: L
authors: Xia
authors: Department of Pediatrics, Blood and Marrow Transplant, Medical School, University of Minnesota, Minneapolis, Minnesota, USA.
authors: Megan J
authors: MJ
authors: Riddle
authors: Department of Pediatrics, Blood and Marrow Transplant, Medical School, University of Minnesota, Minneapolis, Minnesota, USA.
authors: Chris J
authors: CJ
authors: Lees
authors: Department of Pediatrics, Blood and Marrow Transplant, Medical School, University of Minnesota, Minneapolis, Minnesota, USA.
authors: Cindy
authors: C
authors: Eide
authors: Microimaging Center, Shriners Hospital for Children, Portland, Oregon, USA.
authors: Douglas R
authors: DR
authors: Keene
authors: St John's Institute of Dermatology, King's College London (Guy's Campus), London, UK.
authors: Lu
authors: L
authors: Liu
authors: Department of Pediatrics, Blood and Marrow Transplant, Medical School, University of Minnesota, Minneapolis, Minnesota, USA.
authors: Mark J
authors: MJ
authors: Osborn
authors: Department of Pediatrics, Blood and Marrow Transplant, Medical School, University of Minnesota, Minneapolis, Minnesota, USA.
authors: Troy C
authors: TC
authors: Lund
authors: Department of Pediatrics, Blood and Marrow Transplant, Medical School, University of Minnesota, Minneapolis, Minnesota, USA.
authors: Bruce R
authors: BR
authors: Blazar
authors: Department of Pediatrics, Blood and Marrow Transplant, Medical School, University of Minnesota, Minneapolis, Minnesota, USA.
authors: John E
authors: JE
authors: Wagner
mesh_terms: D002454:Cell Differentiation / Q000502:physiology; D002648:Child; D024143:Collagen Type VII / Q000235:genetics*; D016108:Epidermolysis Bullosa Dystrophica / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D044127:Epigenesis, Genetic / Q000502:physiology; D005808:Genes, Recessive; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000502:physiology*; D015603:Keratinocytes / Q000502:physiology; D008297:Male; D009030:Mosaicism; D012867:Skin / Q000473:pathology
chemical_list: C569053:COL7A1 protein, human; D024143:Collagen Type VII