Corrective gene transfer in the human skin disorder lamellar ichthyosis
Corrective gene transfer in the human skin disorder lamellar ichthyosis
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DOI：
10.1038/nm1196-1263
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发表时间：
1996-11-01
期刊：
影响因子：
82.9
通讯作者：
Khavari, PA
中科院分区：
文献类型：
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作者：
Choate, KA;Medalie, DA;Khavari, PA
板层鱼鳞病（LI）是一种以表皮分化异常和皮肤屏障功能缺陷为特征的毁容皮肤病（1,2）。LI与角化细胞转谷氨酰胺酶1 （TGase1）的丧失有关（3,4），这种酶被认为是角化表皮屏障正常形成所必需的。利用LI作为治疗性皮肤基因传递的原型，我们使用人类皮肤/免疫缺陷小鼠异种移植模型来纠正LI患者皮肤在体内的分子、组织学和功能异常。我们利用来自LI患者的缺乏TGase1的原代角质形成细胞，结合功能性TGase1的高效转移，在免疫缺陷小鼠上再生工程化的人LI表皮。工程LI表皮在体内表现出正常的TGase1表达，而非工程LI表皮缺乏TGase1。表皮结构也因TGase1的恢复而恢复正常，表皮分化标志聚丝蛋白的表达也恢复正常。工程LI皮肤显示皮肤屏障功能恢复到正常皮肤患者角质形成细胞再生表皮的水平，表明LI的原发性病理生理缺陷在体内得到了功能纠正。这些结果证实了TGase1在表皮分化中的主要作用，并展示了在人类皮肤中治疗性基因传递的潜在未来方法。
Lamellar ichthyosis (LI) is a disfiguring skin disease characterized by abnormal epidermal differentiation and defective cutaneous barrier function(1,2). LI has been associated with loss of keratinocyte transglutaminase 1 (TGase1)(3,4) an enzyme believed necessary for normal formation of the cornified epidermal barrier. Using LI as a prototype for therapeutic cutaneous gene delivery, we have used the human skin/immunodeficient mouse xenograft model to correct the molecular, histologic and functional abnormalities of LI patient skin in vivo. We have used TGase1-deficient primary keratinocytes from LI patients combined with high-efficiency transfer of functional TGase1 to regenerate engineered human LI epidermis on immunodeficient mice. Engineered LI epidermis displayed normal TGase1 expression in vivo, unlike unengineered LI epidermis where TGase1 was absent. Epidermal architecture was also normalized by TGase1 restoration, as was expression of the epidermal differentiation marker filaggrin. Engineered LI skin demonstrated restoration of cutaneous barrier function measures to levels seen in epidermis regenerated by keratinocytes from patients with normal skin, indicating functional correction in vivo of the proposed primary pathophysiologic defect in LI. These results confirm a major role for TGase1 in epidermal differentiation and demonstrate a potential future approach to therapeutic gene delivery in human skin.