Inhibitors of PI3K-delta for Treatment of Skin Inflammation

描述(由申请人提供)： 系统性红斑狼疮(SLE)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。皮肤变异型狼疮(CLE)的发生率是SLE本身的2-3倍，虽然没有那么严重，但往往会导致严重的工作残疾和生活质量低下。CLE治疗难度大，少数有效的治疗方法有明显的毒副作用。血浆细胞样树突状细胞(PDC)前体细胞和B细胞的自身核酸激活天然受体TLR7和TLR9在SLE的发病机制中起关键作用，因为这会导致产生I型干扰素，产生抗DNA和抗RNP免疫复合体。同样，在CLE中，PDC大量渗透到皮损皮肤并产生I型IFN，它在建立推动疾病的自我永久化炎症环路中发挥重要作用。我们最近发现PI3K-Delta(PI3K4)是PDC产生干扰素-1的TLR7&9途径的关键信号分子，并表明这种内部合成的基于小分子的抑制剂在体外和体内实验中都非常有效。此外，我们还建立了小鼠皮肤炎症模型，在该模型中，内源性TLR7和9配体通过渗透PDC产生干扰素-1在疾病的发生和发展中发挥了重要作用。我们有新的初步数据表明，在我们的模型中，PI3K4的抑制剂可以减少皮肤炎症。这项建议包括几个相关的活动，以评估PI3K4抑制剂在血浆细胞样树突状细胞激活和干扰素-1产生介导的皮肤自身免疫中的有效性。这些研究包括：“剂量和路线研究”“作用机制的定义”对PI3K4在CLE小鼠模型中的临床前评估最终目标是开发一种用于治疗自身免疫性皮肤病的PI3K4抑制剂的局部配方。由于易于评估症状，皮肤红斑狼疮等疾病可能被证明在临床开发的早期阶段特别有用。 公共卫生相关性： 皮肤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。我们建议开发一种新药来抑制干扰素-α的产生，这是这种疾病的关键因素，作为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): Systemic lupus erythematosus (SLE) is an autoimmune disease that affects over a million people in the United States, disproportionately affecting women of childbearing age. The cutaneous variant of lupus (CLE) is 2-3 times more frequent then SLE itself and, although less severe, often leads to severe disability for work and poor quality of life. CLE is difficult to treat, and the few effective therapies have significant toxicities and side effects. Triggering of the innate receptors TLR7 and TLR9 by self nucleic acids in plasmacytoid dendritic cell (PDC) precursors and B cells is key in the pathogenesis of SLE, because this leads to the production of type I IFN and the production of anti-DNA and anti-RNP immune complexes, respectively. In CLE, as well, PDC massively infiltrate the lesional skin and produce type I IFNs, which play a major role in establishing a self- perpetuating inflammatory loop driving the disease. We have recently identified PI3K-delta (PI3K4) as a key signaling molecule of the TLR7&9 pathway for the production of IFN-1 by PDC, and have shown that this in-house synthesized small-molecule-based inhibitor is extremely efficient in both in vitro and in vivo assays. In addition, we have developed and fully characterized mouse models of skin inflammation in which IFN-1 production by infiltrating PDC in response to endogenous TLR7&9 ligands plays a major role in the development and progression of the disease. We have new preliminary data showing that the inhibitor of PI3K4 can reduce skin inflammation in our model. This proposal comprises several related activities to evaluate the PI3K4 inhibitor's effectiveness in cutaneous autoimmunity mediated by plasmacytoid dendritic cell activation and IFN-1 production. These studies include: " Dose and route-finding studies " Definition of the mechanism of action " Preclinical evaluation of PI3K4 in a mouse model of CLE The ultimate goal is the development of a topical formulation of an inhibitor of PI3K4 for the treatment of autoimmune skin diseases. Because of the ease in evaluating symptoms, diseases such as cutaneous lupus may prove to be particularly useful in the early phase of clinical development. PUBLIC HEALTH RELEVANCE: Cutaneous 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 production, a key factor in the disease, as a therapy for cutaneous lupus and related autoimmune diseases in the skin.