Gentamicin induces functional type VII collagen in recessive dystrophic epidermolysis bullosa patients
Gentamicin induces functional type VII collagen in recessive dystrophic epidermolysis bullosa patients
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DOI：
10.1172/jci92707
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发表时间：
2017-08-01
影响因子：
15.9
通讯作者：
Chen, Mei
中科院分区：
文献类型：
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作者：
Woodley, David T.;Cogan, Jon;Chen, Mei
背景资料。隐性营养不良性大疱性表皮松解症(RDEB)是一种不治之症，是由II型胶原基因突变引起的，II型胶原是锚定纤维(AF)的主要成分。我们先前证明庆大霉素在含有无义突变的RDEB细胞中产生功能性的III型胶原。在这里，我们确定了局部或皮内注射庆大霉素是否会在RDEB患者中诱导VII型胶原和AFS。方法：一项双盲、安慰剂对照的先导试验评估了5例无意义突变的RDEB患者局部和皮内注射庆大霉素的安全性和有效性。外用试验组每天在2个开放的糜烂部位测试0.1%庆大霉素软膏或安慰剂3次，持续2周。在5名患者中，有4名患者每天在2个完整的皮肤部位皮内注射庆大霉素溶液(8 Mg)或安慰剂2天。主要结果是在试验部位诱导出III型胶原和AFS，并进行安全性评估。结果：局部和皮内注射庆大霉素均可在治疗部位的真皮-表皮交界处诱导VII型胶原和AFS。新生成的III型胶原蛋白的表达水平为正常人皮肤的20%~165%，并持续3个月。外用庆大霉素可纠正真皮-表皮分离，改善伤口闭合，减少水泡的形成。庆大霉素治疗没有任何不良副作用。VII型胶原诱导不会在患者的血液或皮肤中产生抗VII型胶原自身抗体。结论：局部和皮内注射庆大霉素可抑制RDEB患者的无义突变，并诱导VII型胶原和AFS。庆大霉素治疗可能为无义突变的RDEB患者提供一种现成的治疗方法。
BACKGROUND. Recessive dystrophic epidermolysis bullosa (RDEB) is an incurable disease caused by mutations in the gene encoding type VII collagen, the major component of anchoring fibrils (AF). We previously demonstrated that gentamicin produced functional type VII collagen in RDEB cells harboring nonsense mutations. Herein, we determined whether topical or intradermal gentamicin administration induces type VII collagen and AFs in RDEB patients.METHODS. A double-blind, placebo-controlled pilot trial assessed safety and efficacy of topical and intradermal gentamicin in 5 RDEB patients with nonsense mutations. The topical arm tested 0.1% gentamicin ointment or placebo application 3 times daily at 2 open erosion sites for 2 weeks. The intradermal arm tested daily intradermal injection of gentamicin solution (8 mg) or placebo into 2 intact skin sites for 2 days in 4 of 5 patients. Primary outcomes were induction of type VII collagen and AFs at the test sites and safety assessment. A secondary outcome assessed wound closure of topically treated erosions.RESULTS. Both topical and intradermal gentamicin administration induced type VII collagen and AFs at the dermal-epidermal junction of treatment sites. Newly created type VII collagen varied from 20% to 165% of that expressed in normal human skin and persisted for 3 months. Topical gentamicin corrected dermal-epidermal separation, improved wound closure, and reduced blister formation. There were no untoward side effects from gentamicin treatments. Type VII collagen induction did not generate anti-type VII collagen autoantibodies in patients' blood or skin.CONCLUSION. Topical and intradermal gentamicin suppresses nonsense mutations and induces type VII collagen and AFs in RDEB patients. Gentamicin therapy may provide a readily available treatment for RDEB patients with nonsense mutations.