title: Bone marrow transplantation for recessive dystrophic epidermolysis bullosa.
abstract: BACKGROUND
  Recessive dystrophic epidermolysis bullosa is an incurable, often fatal mucocutaneous blistering disease caused by mutations in COL7A1, the gene encoding type VII collagen (C7). On the basis of preclinical data showing biochemical correction and prolonged survival in col7 −/− mice, we hypothesized that allogeneic marrow contains stem cells capable of ameliorating the manifestations of recessive dystrophic epidermolysis bullosa in humans.
  
  
  METHODS
  Between October 2007 and August 2009, we treated seven children who had recessive dystrophic epidermolysis bullosa with immunomyeloablative chemotherapy and allogeneic stem-cell transplantation. We assessed C7 expression by means of immunofluorescence staining and used transmission electron microscopy to visualize anchoring fibrils. We measured chimerism by means of competitive polymerase-chain-reaction assay, and documented blister formation and wound healing with the use of digital photography.
  
  
  RESULTS
  One patient died of cardiomyopathy before transplantation. Of the remaining six patients, one had severe regimen-related cutaneous toxicity, with all having improved wound healing and a reduction in blister formation between 30 and 130 days after transplantation. We observed increased C7 deposition at the dermal-epidermal junction in five of the six recipients, albeit without normalization of anchoring fibrils. Five recipients were alive 130 to 799 days after transplantation; one died at 183 days as a consequence of graft rejection and infection. The six recipients had substantial proportions of donor cells in the skin, and none had detectable anti-C7 antibodies.
  
  
  CONCLUSIONS
  Increased C7 deposition and a sustained presence of donor cells were found in the skin of children with recessive dystrophic epidermolysis bullosa after allogeneic bone marrow transplantation. Further studies are needed to assess the long-term risks and benefits of such therapy in patients with this disorder. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00478244.)
authors.affiliation: Blood and Marrow Transplant Program, Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA. wagne002@umn.edu
authors.forename: John E
authors.initials: JE
authors.lastname: Wagner
authors.forename: Akemi
authors.initials: A
authors.lastname: Ishida-Yamamoto
authors.forename: John A
authors.initials: JA
authors.lastname: McGrath
authors.forename: Maria
authors.initials: M
authors.lastname: Hordinsky
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
authors.forename: Megan J
authors.initials: MJ
authors.lastname: Riddle
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Osborn
authors.forename: Troy
authors.initials: T
authors.lastname: Lund
authors.forename: Michelle
authors.initials: M
authors.lastname: Dolan
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.forename: Jakub
authors.initials: J
authors.lastname: Tolar
mesh_terms: D000293:Adolescent; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D002648:Child; D002675:Child, Preschool; D024143:Collagen Type VII / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000648:ultrastructure; D016108:Epidermolysis Bullosa Dystrophica / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D005260:Female; D005312:Fetal Blood / Q000637:transplantation*; D005808:Genes, Recessive; D006084:Graft Rejection; D006801:Humans; D008297:Male; D046529:Microscopy, Electron, Transmission; D012155:Reticulin / Q000648:ultrastructure; D012867:Skin / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D018183:Transplantation Chimera; D019172:Transplantation Conditioning / Q000009:adverse effects; D014184:Transplantation, Homologous
chemical_list: D024143:Collagen Type VII; D012155:Reticulin
references.citation: Nat Med. 2004 Jul;10(7):693-5
references.pmid: 15195089
references.citation: Blood. 2007 Oct 15;110(8):3064-70
references.pmid: 17569820
references.citation: Int J Dermatol. 2007 Aug;46(8):795-800
references.pmid: 17651159
references.citation: Hum Gene Ther. 2002 Sep 1;13(13):1655-62
references.pmid: 12228020
references.citation: J Invest Dermatol. 1985 May;84(5):374-7
references.pmid: 4039741
references.citation: J Invest Dermatol. 2003 Nov;121(5):1021-8
references.pmid: 14708601
references.citation: Br J Nurs. 2008 Mar 27-Apr 9;17(6):S6, S8, S10 passim
references.pmid: 18521993
references.citation: Clin Dermatol. 2005 Jul-Aug;23(4):430-6
references.pmid: 16023940
references.citation: Expert Opin Biol Ther. 2006 Apr;6(4):367-78
references.pmid: 16548763
references.citation: J Cell Sci. 1999 Nov;112 ( Pt 21):3641-8
references.pmid: 10523500
references.citation: J Am Acad Dermatol. 2009 Feb;60(2):203-11
references.pmid: 19026465
references.citation: J Wound Care. 2008 Nov;17(11):482, 484-6, 488 passim
references.pmid: 18978687
references.citation: Exp Dermatol. 2008 Jul;17(7):553-68
references.pmid: 18558993
references.citation: J Am Acad Dermatol. 2003 Jun;48(6):886-92
references.pmid: 12789180
references.citation: Matrix Biol. 1999 Feb;18(1):29-42
references.pmid: 10367729
references.citation: J Invest Dermatol. 2005 Apr;124(4):863-6
references.pmid: 15816848
references.citation: Mol Ther. 2007 Mar;15(3):628-35
references.pmid: 17245357
references.citation: J Invest Dermatol. 1984 Dec;83(6):448-53
references.pmid: 6209345
references.citation: N Engl J Med. 1994 Mar 24;330(12):827-38
references.pmid: 8114836
references.citation: Blood. 2009 Jan 29;113(5):1167-74
references.pmid: 18955559
references.citation: J Clin Invest. 2008 May;118(5):1669-79
references.pmid: 18382769
references.citation: Br J Dermatol. 2009 Jul;161(1):19-24
references.pmid: 19466960
references.citation: Nat Genet. 2002 Dec;32(4):670-5
references.pmid: 12426566
references.citation: J Am Acad Dermatol. 2008 Jun;58(6):931-50
references.pmid: 18374450
references.citation: Br J Nurs. 2008 Mar 13-26;17(5):292-6
references.pmid: 18414291
references.citation: J Invest Dermatol. 1997 Jan;108(1):68-72
references.pmid: 8980290
references.citation: Hum Gene Ther. 2004 Oct;15(10):921-33
references.pmid: 15585108
references.citation: Nat Med. 2002 Oct;8(10):1166-70
references.pmid: 12244305
references.citation: J Invest Dermatol. 2008 Sep;128(9):2179-89
references.pmid: 18385758
references.citation: J Invest Dermatol. 1996 Jan;106(1):119-24
references.pmid: 8592061
references.citation: J Biol Chem. 2008 Jun 27;283(26):17838-45
references.pmid: 18450758
references.citation: J Clin Invest. 2003 Jan;111(2):251-5
references.pmid: 12531881
references.citation: Mol Ther. 2004 Aug;10(2):318-26
references.pmid: 15294178
references.citation: Mol Ther. 2009 Jan;17(1):26-33
references.pmid: 19018253