GENE THERAPY FOR DERMATOSES USING EPIDERMAL VECTORS

这项提议是开发基因药物的计划的一部分 利用新型DNA治疗牛皮癣等皮肤病 可定向高水平组织特异性的表达载体(HK1) 角质形成细胞在表皮中的表达。HK1载体包含 来源于人类K1的转录和翻译调控元件 吉恩。在转基因动物中，这种载体引导高水平的基因 在增殖性基底细胞中特异表达，以及 表皮分化的超基底层细胞。第一阶段研究将 重点论证表达治疗产品的可行性 直接给药后的正常皮肤和增生性皮肤 通过粒子轰击进入表皮。我们会研究 标记基因β-半乳糖苷酶和转化生长因子-β的表达 生长调节因子，可能有助于抑制 牛皮癣等疾病中的过度增殖。我们将研究基因 正常小鼠和转基因HK-1-转化生长因子-α小鼠的表达 基因工程诱导的转化生长因子-α的过度表达 类似的皮肤增厚、过度增殖和过度角化 与牛皮癣的情况相同。第二阶段的研究将集中在开发 一种新颖的皮肤基因传递方法，在人的表皮中表达 模型，以及治疗癌症的新基因药物的开发 银屑病的特点是过度增殖和炎症。

This proposal is part of a program to develop gene medicines for treatment of dermatoses such as psoriasis utilizing a novel DNA expression vector (HK1) capable of directing high-level tissue-specific expression from keratinocytes in the epidermis. The HK1 vector contains transcription and translation control elements derived from the human K1 gene. In transgenic animals, this vector directs high levels of gene expression specifically in proliferative basal cells, as well as differentiated supra-basal cells of the epidermis. Phase-I studies will focus on demonstrating the feasibility of expressing therapeutic products in normal and hyperplastic skin after direct administration of the HK1 vector into the epidermis by particle bombardment. We will study expression of a marker gene beta-galactosidase as well as TGF-beta, a growth regulating factor which may be useful in inhibiting hyperproliferation in diseases such as psoriasis. We will study gene expression in normal mice and in the transgenic HK-1-TGF-alpha mouse where genetically engineered overexpression of TGF-alpha induces thickening, hyperproliferation, and hyperkeratosis of the skin similar to that seen in psoriasis. Phase-II studies will focus on developing novel, methods for gene delivery to skin, expression in human epidermal models, and the development of new gene medicines for treating the hyperproliferation and inflammation characteristic of psoriasis.