RNAi-based inhibitors of stat3 for psoriasis treatment

描述（由申请人提供）：牛皮癣是一种使人衰弱和毁容的皮肤病，影响约2%的人口。现有的治疗方法有明显的副作用，或者，就新兴的生物制剂而言，价格昂贵，只能作为全身治疗，必须注射，并且可能有严重的副作用。我们的目标是开发基于rna的治疗方法，可以局部应用于特异性抑制被认为参与维持银屑病斑块的基因的表达。局部治疗应该相对没有副作用，需要的药物量应该少得多，而且比全身治疗更容易让患者自我管理。在初步实验中，我们已经证明了在活体小鼠皮肤内注射小发夹rna （shRNAs）后，内源性基因的显著敲除。在这个项目中，我们将鉴定靶向关键蛋白Stat3的shrna， Stat3在角化细胞中的表达最近被令人信服地认为与牛皮癣有关。这些抑制剂将在培养的角质形成细胞和小鼠皮肤中测试其敲除Stat3的能力。我们还将测试这些抑制剂逆转牛皮癣样特征的能力，这些特征是由组成性表达Stat3的转基因小鼠表现出来的，包括表皮增生。确定将抑制剂输送到人体皮肤的最佳方法将是该SBIR项目第二阶段的重点，但一些局部配方将在第一阶段进行评估，同时使用胶带剥离和/或皮内注射来证明概念的有效性。这项工作将与md安德森癌症中心的John DiGiovanni博士合作，他发现了stat3 -牛皮癣之间的联系。银屑病是一种使人衰弱和毁容的皮肤病，影响约2%的人口，10-30%的患者也有一种影响关节的疾病（银屑病关节炎）。现有的治疗方法有明显的副作用，或者非常昂贵，只能作为有风险的全身治疗。我们的目标是用基于rna的药物来治疗受影响的皮肤，以抑制已知或怀疑参与维持银屑病斑块的基因的表达。

DESCRIPTION (provided by applicant): Psoriasis is a debilitating and disfiguring skin disease affecting about 2% of the population. Existing treatments have significant side effects or, in the case of emerging biologics, are expensive and available only as systemic treatments that have to be injected and have potentially severe side-effects. Our goal is to develop RNA-based treatments that can be applied topically to inhibit specifically the expression of genes believed to be involved in the maintenance of psoriatic plaques. Topical treatment should be relatively free of side-effects and should require far lower amounts of drug and be easier for patients to self-administer than systemic treatments. In preliminary experiments, we have demonstrated dramatic knock-down of endogenous genes in the skin of living mice following intradermal injection of small hairpin RNAs (shRNAs). In this project, we will identify shRNAs targeting a key protein, Stat3, whose expression in keratinocytes has recently been convincingly implicated in psoriasis. These inhibitors will be tested for their ability to knock down Stat3 in cultured keratinocytes and in mouse skin. We will also test for the ability of these inhibitors to reverse the psoriasis-like features exhibited by a transgenic mouse that constitutively expresses Stat3, including epiderdermal hyperplasia. Identifying optimal methods for delivering the inhibitors to human skin will be a focus of Phase II of this SBIR project, but some topical formulations will be evaluated in Phase I along with the use of tape-stripping and/or intradermal injection to demonstrate proof of concept. This work will be collaboration with Dr. John DiGiovanni of M.D. Anderson Cancer Center, who discovered the Stat3-psoriasis connection. Psoriasis is a debilitating and disfiguring skin disease affecting about 2% of the population, and 10-30% of patients also have a form of the disease that affects the joints (psoriatic arthritis). Existing treatments have significant side effects cases or are very expensive and available only as systemic treatments that have risks of their own. Our goal is to treat affected skin with RNA-based drugs to inhibit the expression of genes known or suspected to be involved in the maintenance of psoriatic plaques.