Topical Cyclosporin A for Dermatitis and Psoriasis

描述：（逐字逐句）皮肤的保护外层，即地层 角质层，用于排除治疗药物，如环孢菌素A（CsA）。 初步实验已经明确地确定， 精氨酸穿过小鼠和人皮肤的角质层进入 表皮和真皮组织。类似的渗透到皮肤的所有层 当精氨酸的短聚合物与CsA缀合时观察到， 未结合形式不能渗透皮肤。这些共轭物达到 在发炎皮肤的真皮中浸润T细胞。相关缀合物使用 可释放接头提供治疗活性CsA缀合物，因此 提供了一种局部递送全身毒性药物的方法， 治疗牛皮癣和皮炎，同时减轻全身性的问题， 毒性 该提案的目标是选择一种领先的CsA -转运蛋白缀合物， 进一步发展。这将需要综合和评价一系列 GsA-转运蛋白缀合物，所述缀合物包含一组转运蛋白， 组织穿透能力将对标记的子集进行组织评估 渗透性和相应的可释放子集将在体外进行评价， 测定它们抑制活化T细胞分泌IL-2的能力， 体内使用接触性皮炎的动物模型。 拟定商业应用： 目前用于皮炎和牛皮癣的局部疗法都存在根本问题。当口服时，免疫抑制剂可以是有效的，并且通过病灶内注射，CsA显著减少或清除银屑病病灶。CsA目前不用于治疗皮炎，由于全身毒性，仅用于严重的银屑病病例。预期所提出的缀合物将为特应性/接触性皮炎和银肩病提供第一种高度有效的局部治疗，这些疾病在美国总共有> 2000万患者。

DESCRIPTION: (Verbatim) The protective outer layer of the skin, the stratum corneum, serves to exclude therapeutic drugs like cyclosporin A (CsA). Preliminary experiments have unambiguously established that short polymers of arginine cross the stratum corneum of murine and human skin to enter the epidermal and dermal tissue. Similar penetration into all layers of the skin was observed when short polymers of arginine were conjugated to CsA, which in unconjugated form fails to penetrate skin. These conjugates reached infiltrating T cells in the dermis of inflamed skin. Related conjugates using a releasable linker provided therapeutically active CsA conjugates, thus providing a means of focally delivering systemically toxic drugs for the treatment of psoriasis and dermatitis while alleviating the problem of systemic toxicity. The goal of this proposal is to select a lead CsA -transporter conjugate for further development. This will entail the synthesis and evaluation of a series of GsA-transporter conjugates comprising a set of transporters with a range of tissue penetrating ability. A labeled subset will be assessed for tissue penetration and a corresponding releasable subset will be evaluated in vitro by assaying their ability to inhibit secretion of Il-2 by activated T cells and in vivo using an animal model of contact dermatitis. PROPOSED COMMERCIAL APPLICATION: Current topical therapies for dermatitis and psoriasis all have fundamental problems. When administered orally, immunosuppressants can be effective, and by, intralesional injection, CsA dramatically reduces or clears psoriatic lesions. CsA is not currently used to treat dermatitis and is used only in severe cases of psoriasis because of systemic toxicity. The proposed conjugates are expected to provide the first highly efficacious topical treatments for atopic/contact dermatitis and psoriasis, which together total >20 million US patients.