Inhibitors of Toll-like receptors 7 & 9 for treatment of skin inflammation

描述（由申请人提供）：狼疮是一种自身免疫性疾病，在美国影响超过一百万人，不成比例地影响育龄妇女。治疗困难，有效的治疗方法不多，毒副作用明显。B淋巴细胞和浆细胞样树突状细胞这两种免疫系统细胞的异常激活在疾病的发病机制中是重要的。这两种细胞类型的慢性激活似乎是由于通过先天免疫受体TLR 7和TLR 9作用的DNA和RNA的刺激。我们已经开发了一系列合成的寡核苷酸（称为IRS）的序列基序强烈抑制TLR 7和TLR 9信号。先导IRS分子DV 056已被证明在系统性红斑狼疮小鼠模型中具有活性，并且正在进行IND使能研究以支持系统性红斑狼疮的适应症。最近的证据表明，浆细胞样树突状细胞在皮肤狼疮和一系列相关的皮肤自身免疫性疾病，包括扁平苔藓皮肌炎，硬化性苔藓和皮肤GVHD中的作用。我们的初步证据表明，这种由自身DNA和RNA触发的炎症途径可以通过重复胶带剥离正常小鼠的皮肤来激活。该建议包括几个相关的活动，以开发一个临床前模型的皮肤自身免疫介导的浆细胞样树突状细胞活化和IFN-1的生产。这些研究包括：“关键细胞类型和信号通路在小鼠胶带剥离引起的炎症中的作用的定义“使用易患自身免疫性疾病的小鼠开发慢性炎症模型”IRS作为胶带剥离诱导的自身免疫性炎症抑制剂的初步临床前评价。最终目标是利用这项工作的结果来支持IRS用于主要涉及皮肤的自身免疫性疾病的发展。由于易于评估症状，皮肤狼疮等疾病可能被证明对IRS的早期临床发展特别有用。公共卫生相关性：狼疮是一种严重的自身免疫性疾病，在美国影响超过100万人，主要是女性。目前对这种疾病的治疗有严重的副作用;然而，最近的发现表明新的治疗方法可能更安全，更有效。我们建议开发一种抑制干扰素-α的新药，干扰素-α是皮肤狼疮和相关皮肤自身免疫性疾病的治疗方法。

DESCRIPTION (provided by applicant): Lupus is an autoimmune disease that affects over a million people in the United States, disproportionately affecting women of childbearing age. It is difficult to treat and the few effective therapies have significant toxicities and side effects. The abnormal activation of two types of immune system cells, B lymphocytes and plasmacytoid dendritic cells are important in the pathogenesis of the disease. The chronic activation of both cell types appears due to stimulation by DNA and RNA acting through the innate immune receptors, TLR7 and TLR9. We have developed a series of synthetic oligonucleotides (termed IRS) with sequence motifs strongly inhibitory for both TLR7 and TLR9 signaling. The lead IRS molecule, DV056, has been proven active in mouse models of systemic lupus erythematosus and IND-enabling studies are underway to support an indication in systemic lupus. Recent evidence now points to a role for plasmacytoid dendritic cells in cutaneous lupus and in a series of related cutaneous autoimmune diseases, including lichen planus dermatomyositis, lichen sclerosus and cutaneous GVHD. Our preliminary evidence suggests that this pathway of inflammation triggered by self DNA and RNA can be activated by repeated tape stripping of skin in normal mice. This proposal comprises several related activities to develop a preclinical model of cutaneous autoimmunity mediated by plasmacytoid dendritic cell activation and IFN-1 production. These studies include: " Definition of the role of key cell types and signaling pathways in inflammation caused by tape stripping in mice " Development of a chronic inflammation model using mice predisposed to autoimmune disease " Initial preclinical evaluation of IRS as an inhibitor of autoimmune inflammation induced by tape-stripping. The ultimate goal is to use the results of this work to support the development of IRS for autoimmune diseases with primary involvement in the skin. Because of the ease in evaluating symptoms, diseases such as cutaneous lupus may prove to be particularly useful for in the early clinical development of IRS. PUBLIC HEALTH RELEVANCE: Lupus is a serious autoimmune disease affecting over 1 million people in the U.S., primarily women. Current treatments for this disease have serious side effects; however recent discoveries suggest new methods of treatment that may be safer and more effective. We propose to develop a novel drug that inhibits Interferon-alpha, a key factor in the disease as a therapy for cutaneous lupus and related autoimmune diseases in the skin.