RNAi-based inhibitors of stat3 for psoriasis treatment

描述（由申请人提供）：银屑病是一种使人衰弱和毁容的皮肤病，影响约2%的人口。现有的治疗方法具有显著的副作用，或者在新兴生物制剂的情况下，昂贵且仅作为必须注射且具有潜在严重副作用的全身治疗方法提供。我们的目标是开发基于RNA的治疗方法，可以局部应用，以特异性抑制被认为参与银屑病斑块维持的基因的表达。局部治疗应相对无副作用，需要的药物量应远低于全身治疗，患者更容易自我管理。在初步的实验中，我们已经证明了显着的敲低内源性基因在活小鼠皮肤皮内注射后的小发夹RNA（shRNA）。在这个项目中，我们将鉴定靶向一个关键蛋白Stat 3的shRNA，该蛋白在角质形成细胞中的表达最近被令人信服地与银屑病有关。将测试这些抑制剂在培养的角质形成细胞和小鼠皮肤中敲低Stat 3的能力。我们还将测试这些抑制剂逆转组成型表达Stat 3的转基因小鼠所表现出的银屑病样特征（包括表皮增生）的能力。确定将抑制剂递送至人体皮肤的最佳方法将是该SBIR项目的第II阶段的重点，但将在第I阶段沿着使用胶带剥离和/或皮内注射对一些局部制剂进行评价，以证明概念验证。这项工作将与医学博士John DiGiovanni博士合作。安德森癌症中心，他发现了Stat 3与牛皮癣的联系。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%的患者还患有影响关节的疾病（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，只能作为具有自身风险的系统性治疗方法。我们的目标是用基于RNA的药物治疗受影响的皮肤，以抑制已知或怀疑参与银屑病斑块维持的基因的表达。

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.