Development of RNA-based topical psoriasis inhibitors

描述（由申请人提供）：牛皮癣是一种毁容和使人衰弱的疾病，没有标准的治疗方法。现有的局部治疗方法是有效的，但不可接受的副作用，随着时间的推移效果降低和不便阻止长期使用。诸如抗肿瘤坏死因子和抗lfa抑制剂等有效生物制剂的出现，为许多牛皮癣患者提供了优越的治疗选择，但对免疫反应下调导致的副作用的担忧使其使用热情降低。本提案的目的是开发基于rna的治疗方法，特异性抑制银屑病发病机制中重要的基因，可以局部应用于皮肤的受影响区域。局部应用允许输送更高浓度的药物，减少对副作用的担忧。第一阶段是建立在最近开发的配方基础上，表明核酸可以有效地递送到小鼠皮肤上，报告基因和TNF（一种经过验证的牛皮癣药物靶点）可以被特异性的、强大的RNA抑制剂阻断。待开发和测试的RNA抑制剂包括SomaGenics1专有的Lassos，其特异性结合并在mRNA靶标周围共价循环，以及通过RNA干扰机制起作用的小发夹RNA。II期的目标是开发这些RNA抑制剂针对其他相关银屑病基因靶点，并在人体皮肤器官模型中显示其有效性，为1期临床试验做准备。局部形成含有有效的银屑病抑制剂的发展将填补目前未满足的医疗需求。

DESCRIPTION (provided by applicant): Psoriasis is a disfiguring and debilitating disease for which no standard treatment exists. Existing topical treatments are effective, but unacceptable side-effects, diminished effectiveness over time and inconvenience prevent long-term usage. The emergence of effective biologies, such as anti-TNF and anti-LFA inhibitors, offer superior treatment options for many psoriasis patients, but concerns over the side-effects resulting from down-regulation of the immune response temper their enthusiastic use. The purpose of this proposal is to develop RNA-based therapeutics that specifically inhibits genes important in psoriasis pathogenesis, which can be applied topically to affected areas of the skin. Topical application allows delivery of higher concentrations of drug with diminished concerns regarding side-effects. Phase I builds on recently developed formulations to show that nucleic acids can be effectively delivered to mouse skin and that a reporter gene and TNF (a validated psoriasis drug target) can be blocked by specific, robust RNA inhibitors. The RNA inhibitors to be developed and tested include SomaGenics1 proprietary Lassos, which specifically bind to and covalently circularize around an mRNA target, and small hairpin RNAs that work through an RNA interference mechanism. Phase II aims to develop these RNA inhibitors against additional relevant psoriasis gene targets and show their effectiveness in a human skin organ model in preparation for a Phase 1 clinical trial. The development of a topical formation containing effective psoriasis inhibitors would fill a currently unmet medical need.