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.)

Generation of keratinocytes from normal and recessive dystrophic epidermolysis bullosa-induced pluripotent stem cells

“…RDEB has been the subject of intense research over the past 20 y, and because it is a monogenic disorder, a cure would rely upon on the normal production of type VII collagen. Therefore, several current research approaches aim to restore collagen VII, including cell therapy (11,12,(18)(19)(20), gene therapy (11,12,(18)(19)(20), and, more recently, bone marrow transplantation (21,22). However, long-term success in treating RDEB is limited by the low proliferative capacity of keratinocytes and by the low efficiency of targeting the keratinocyte stem cell pool.…”

“…If we can establish iPSCs from such revertant patches of skin, then the gene correction step can be eliminated altogether, and a source of spontaneously corrected iPSCs can be generated and differentiated into skin. Building on the use of bone marrow transplantation in skin diseases such as RDEB (21,22), patientspecific iPSCs could be administered topically as well as systemically to ameliorate skin disease using an outside-in as well as an inside-out approach aimed at corrective therapy for RDEB.…”

PDGFRα-positive cells in bone marrow are mobilized by high mobility group box 1 (HMGB1) to regenerate injured epithelia

“…With regard to skin injury, both embryonic and postnatal transplantation of BM cells into mice lacking the skin protein, type VII collagen (Col 7) as well as postnatal studies in mice lacking type XVII collagen, basement membrane components that normally help secure adhesion between the epidermal and dermal skin layers, have demonstrated the capacity of BM to promote skin wound healing and to correct the intrinsic basement membrane defect (18)(19)(20). Most recently, a clinical trial of allogeneic whole BMT in humans lacking Col 7 (who have the inherited blistering skin disorder, recessive dystrophic epidermolysis bullosa, RDEB; OMIM226600) (21) has demonstrated that BM cells can repair fragile skin and restore Col 7 expression in skin basement membrane (22).…”

Early intra-amniotic gene transfer using lentiviral vector improves skin blistering phenotype in a murine model of Herlitz junctional epidermolysis bullosa

“…Recently, several molecular therapies are being investigated for the treatment of patients with different subtypes of EB, including ex vivo gene therapy, 1 protein replacement 2 and cellular therapy. [3][4][5][6][7] Herlitz junctional epidermolysis bullosa (HJEB) is one of the most severe variants of EB characterized by extensive mucocutaneous blistering and erosions at birth leading to early lethality. 8,9 HJEB, an autosomal recessive disease, is caused by mutations in any of the genes encoding the subunit polypeptides laminin-a3, laminin-b3 or laminin-w2 of the heterotrimeric laminin-332 protein.…”