Bone marrow transplantation for recessive dystrophic epidermolysis bullosa.
Bone marrow transplantation for recessive dystrophic epidermolysis bullosa.
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DOI：
10.1056/nejmoa0910501
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发表时间：
2010-08-12
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影响因子：
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通讯作者：
Tolar J
中科院分区：
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作者：
Wagner JE;Ishida-Yamamoto A;McGrath JA;Hordinsky M;Keene DR;Woodley DT;Chen M;Riddle MJ;Osborn MJ;Lund T;Dolan M;Blazar BR;Tolar J
隐性营养不良大疱性表皮松解症是由编码VII型胶原蛋白（C7）的基因COL7A1突变引起的一种无法治愈的、通常是致命的粘膜皮肤起疱性疾病。基于临床前数据显示col7 - / -小鼠的生化校正和延长生存期，我们假设异体骨髓中含有能够改善人类隐性营养不良大泡性表皮溶解症表现的干细胞。在2007年10月至2009年8月间，我们对7名患有隐性营养不良大疱性表皮松解症的儿童进行了免疫清除化疗和同种异体干细胞移植。我们通过免疫荧光染色评估C7的表达，并使用透射电镜观察锚定原纤维的可视化。我们通过竞争性聚合酶链反应法测量嵌合，并使用数码摄影记录水泡形成和伤口愈合。1例患者在移植前死于心肌病。在其余6例患者中，1例有严重的方案相关皮肤毒性，所有患者在移植后30至130天内伤口愈合改善，水疱形成减少。我们观察到6个受体中有5个在真皮-表皮交界处的C7沉积增加，尽管锚定原纤维没有正常化。5名受者在移植后存活130至799天；一例在183天时因移植排斥和感染死亡。6名受者的皮肤中有相当比例的供体细胞，没有人有可检测到的抗c7抗体。同种异体骨髓移植后，隐性营养不良大疱性表皮松解症患儿皮肤中C7沉积增加，供体细胞持续存在。需要进一步的研究来评估这种治疗对这种疾病患者的长期风险和益处。（由美国国立卫生研究院资助；ClinicalTrials.gov号码，NCT00478244。）
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. 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. 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. 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.)