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

描述(申请人提供)：狼疮是一种自身免疫性疾病，在美国影响着100多万人，对育龄妇女的影响不成比例。它很难治疗，而且少数有效的治疗方法有明显的毒副作用。B淋巴细胞和浆细胞样树突状细胞两种免疫细胞的异常激活在该病的发病机制中起重要作用。这两种细胞的慢性激活是由于DNA和RNA通过先天免疫受体TLR7和TLR9作用而产生的刺激。我们已经开发了一系列对TLR7和TLR9信号具有强烈抑制作用的序列基序的人工合成寡核苷酸(称为IRS)。先导IRS分子DV056已被证明在系统性红斑狼疮小鼠模型中具有活性，支持IND的研究正在进行中，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中发挥作用，包括扁平苔藓皮肌炎、硬化性苔藓和皮肤移植物抗宿主病。我们的初步证据表明，这种由自身DNA和RNA引发的炎症途径可以通过反复剥离正常小鼠的皮肤胶带来激活。这项建议包括几个相关的活动，以建立一个由浆细胞样树突状细胞激活和产生干扰素-1介导的皮肤自身免疫的临床前模型。这些研究包括：“关键细胞类型和信号通路在小鼠磁带剥离引起的炎症中的作用的定义”“利用易患自身免疫性疾病的小鼠建立慢性炎症模型”“IRS作为磁带剥离引起的自身免疫性炎症的抑制剂的初步临床前评估”。最终目标是利用这项工作的结果来支持针对主要累及皮肤的自身免疫性疾病的IRS的开发。由于易于评估症状，皮肤红斑狼疮等疾病在IRS的早期临床发展中可能被证明特别有用。与公共卫生相关：狼疮是一种严重的自身免疫性疾病，在美国有100多万人受到影响，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和更有效。我们建议开发一种抑制干扰素-α的新药，干扰素-α是导致这种疾病的关键因素，用于治疗皮肤狼疮和相关的皮肤自身免疫性疾病。

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.