Injection of Recombinant Human Type VII Collagen Corrects the Disease Phenotype in a Murine Model of Dystrophic Epidermolysis Bullosa
Injection of Recombinant Human Type VII Collagen Corrects the Disease Phenotype in a Murine Model of Dystrophic Epidermolysis Bullosa
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DOI：
10.1038/mt.2008.234
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发表时间：
2009-01-01
影响因子：
12.4
通讯作者：
Chen, Mei
中科院分区：
文献类型：
--
作者：
Remington, Jennifer;Wang, Xinyi;Chen, Mei
隐性营养不良性大疱性表皮病（RDEB）患者由于编码VII型胶原蛋白（C7）的基因突变而具有无法治愈的皮肤脆性、起泡和瘢痕，VII型胶原蛋白（C7）介导人类皮肤中的真皮-表皮粘附。我们先前表明，皮内注射重组C7到移植的人DEB皮肤等同物中稳定地恢复了基底膜区（BMZ）的C7表达，并逆转了RDEB疾病的特征。在这项研究中，我们评估了C7基因敲除小鼠（Col 7a 1（-/-））的蛋白质治疗的可行性，该小鼠概括了人类RDEB的特征。我们将纯化的人C7皮内注射到DEB小鼠中，发现注射的人C7稳定地掺入小鼠BMZ中，形成锚定原纤维，并纠正DEB小鼠表型，如通过降低皮肤脆性、减少新水疱形成和显著延长存活所证明的。4周后，治疗的DEB小鼠产生循环抗人C7抗体。最令人惊讶的是，这些抗C7抗体既不直接结合小鼠的BMZ，也不阻止新注射的人C7掺入BMZ。通过用抗CD 40 L单克隆抗体MR 1处理小鼠来防止抗C7抗体的产生。我们的结论是，蛋白质治疗可能是可行的，用于治疗人类患者的RDEB。
Patients with recessive dystrophic epidermolysis bullosa (RDEB) have incurable skin fragility, blistering, and scarring due to mutations in the gene that encodes for type VII collagen (C7) that mediates dermal-epidermal adherence in human skin. We showed previously that intradermal injection of recombinant C7 into transplanted human DEB skin equivalents stably restored C7 expression at the basement membrane zone (BMZ) and reversed the RDEB disease features. In this study, we evaluated the feasibility of protein therapy in a C7 null mouse (Col7a1(-/-)) which recapitulates the features of human RDEB. We intradermally injected purified human C7 into DEB mice and found that the injected human C7 stably incorporated into the mouse BMZ, formed anchoring fibrils, and corrected the DEB murine phenotype, as demonstrated by decreased skin fragility, reduced new blister formation, and markedly prolonged survival. After 4 weeks, treated DEB mice developed circulating anti-human C7 antibodies. Most surprisingly, these anti-C7 antibodies neither bound directly to the mouse's BMZ nor prevented the incorporation of newly injected human C7 into the BMZ. Anti-C7 antibody production was prevented by treating the mice with an anti-CD40L monoclonal antibody, MR1. We conclude that protein therapy may be feasible for the treatment of human patients with RDEB.