Development of RNA-based topical psoriasis inhibitors

基于 RNA 的局部银屑病抑制剂的开发

• 批准号: 6935527
• 负责人: ROGER L KASPAR
• 金额: $ 28.59万
• 依托单位: SOMAGENICS, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6935527
• 关键词: RNA interference; biotechnology; drug design /synthesis /production; fluorescence microscopy; genetic disorder; psoriasis; reporter genes; skin disorder chemotherapy; small interfering RNA; topical drug application; transfection; tumor necrosis factor alpha

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.

描述（由申请人提供）：牛皮癣是一种毁容和使人衰弱的疾病，不存在标准治疗。现有的局部处理是有效的，但副作用不可接受，随着时间的推移有效性降低，不便可阻止长期使用。有效生物学的出现，例如抗TNF和抗LFA抑制剂，为许多牛皮癣患者提供了卓越的治疗选择，但担心免疫反应下调引起的副作用的担忧会缓解其热情使用。该提案的目的是开发基于RNA的疗法，该治疗剂专门抑制牛皮癣发病机理中重要的基因，这些基因可以局部应用于皮肤受影响的区域。局部应用允许递送更高浓度的药物，并且对副作用的担忧减少。第一阶段建立在最近开发的制剂上，以表明核酸可以有效地递送到小鼠皮肤上，并且报告基因和TNF（经过验证的牛皮癣药物靶标）可以通过特异性，可靠的RNA抑制剂阻止。要开发和测试的RNA抑制剂包括Somagenics1专有套索，该拉索具有特殊结合并在mRNA靶标周围和共价循环，以及通过RNA干扰机制起作用的小发夹RNA。第二阶段的目的是针对其他相关的牛皮癣基因靶标开发这些RNA抑制剂，并在人体皮肤器官模型中显示其有效性，以准备1阶段的临床试验。包含有效牛皮癣抑制剂的局部构造的发展将满足目前未满足的医疗需求。