Novel Small Molecule Targeting STAT Proteins for the Management of Atopic Dermatitis

项目摘要 特应性皮炎/AD(特应性湿疹)是一种慢性炎症性疾病，导致瘙痒、炎症和肿胀 容易感染的皮肤。据国家湿疹协会估计，有 目前有3160万人受到影响，其中至少有1780万人患有中重度疾病。这个 目前的护理标准主要包括多管齐下的方法，包括皮肤护理，消除 过敏诱因和免疫抑制策略，包括使用类固醇、抗组胺药物或局部用药 免疫调节剂(TIMs)。虽然这些疗法可以在一定程度上帮助控制疾病，但不良的一面 长期使用会产生影响。因此，考虑到强加给社会的重大公共卫生负担 由于缺乏有效的治疗方法，对新的靶向疗法的需求尚未得到满足，这种疗法可以帮助 管理症状，提高AD患者的生活质量 Fannin Partners，LLC是一家专注于商业化的早期生命科学开发集团 创新是在德克萨斯医疗中心的机构中开发的。由一支经验丰富的经理团队领导， 不同的商业背景、商业化经验和强大的创业诀窍，范宁 合作伙伴与有前途的生命科学创新者合作，帮助开发有前途的疗法并将其商业化 临床采用的技术。约翰·麦克默里博士和大卫·科里博士进行的基础研究 直接导致了这一创新。我们的铅分子PM-43I是一种小分子、细胞渗透性和 针对STAT6的SH2结构域并阻止募集的磷酸酶稳定的磷酸多肽模拟物 IL-4R和随后的转录活性导致特应性皮炎表型。的关注点 该提案旨在完成将该技术转化为商业化的关键里程碑 通过对特应性皮炎市场进行体外和体内的概念验证研究。 该项目分为两个可衡量的具体目标： 1.人类STAT6磷酸化和皮肤屏障基因表达的特征 角质形成细胞在PM-43I存在下。 角质形成细胞在AD发病机制中起关键作用。它们显示上调的STAT6对IL-1的磷酸化 4和IL-13刺激。然后，磷酸化的STAT6下调氯化氯化蛋白和异伏氯化蛋白的水平，2 对皮肤屏障形成和完整性非常重要的蛋白质。我们之前对哮喘的研究表明 PM-43I能够减少肺上皮细胞中STAT6的磷酸化(数据未显示)，我们在这里 准备测试PM-43I是否也减少角质形成细胞中STAT6的磷酸化，以及随后的下调 LOR和IVL的表达。 2.研究PM-43I治疗特应性皮炎的疗效。 具体目标2a：确定动物实验用PM-43I制剂。(2个月) 这个目的是为了确定PM-43I治疗特应性皮炎的最佳外用配方 用于以下小鼠模型的疗效研究。药物的溶解度、稳定性和体外皮肤渗透性 学习。 特异目的2B：研究PM43I在特应性皮炎动物模型中的疗效(7个月) 根据从Aim 2A获得的配方，我们将使用特应性皮炎小鼠模型来研究其疗效 PM-43I在这个目标上的应用。AD临床评分将用于评估PM-43I或不使用PM-43I小鼠的症状 治疗。此外，组织学、血清细胞因子和IgE水平以及STAT6磷酸化和皮肤屏障 将检测角质形成细胞中的基因表达。这些研究将有助于证明PM-43I在体内的功能。 症状和分子水平的特应性皮炎。

Project Summary Atopic dermatitis/AD (atopic eczema) is a chronic, inflammatory disease resulting in itchy, inflamed, swollen skin that is easily susceptible to infection. It is estimated by the National Eczema association that there are currently 31.6 million people affected, and at least 17.8 million of them have moderate to severe disease. The current standard of care largely comprises of a multipronged approach involving skin care, elimination of allergic triggers and immune-suppressive strategies including the use of steroids, antihistamines, or topical immunommodulators (TIMs). While these therapies can help partly manage the disease, undesirable side effects are seen upon chronic usage. Thus, given the significant public health burden imposed on the society and the lack of effective treatments, there is an unmet need for novel targeted therapeutics that can help manage symptoms and improve the quality of life for AD patients Fannin Partners, LLC is an early-stage life sciences development group focused on commercializing innovation developed in the Texas Medical Center institutions. Led by an experienced team of managers with diverse business backgrounds, commercialization experience, and strong entrepreneurial knowhow, Fannin Partners works with promising life science innovators to help develop and commercialize promising therapeutic technologies for clinical adoption. The basic research conducted by Drs. John McMurray and David Corry directly led to this innovation. Our lead molecule, PM-43I, is a small-molecule, cell-permeable, and phosphatase-stable phosphopeptide mimetic that targets the SH2 domain of STAT6 and prevents recruitment to IL-4R and the subsequent transcriptional activity leading to the atopic dermatitis phenotype. The focus of this proposal is to accomplish key milestones that will transition this technology for commercialization for the atopic dermatitis market by conducting in vitro and in vivo proof of concept study. The project is organized into two measureable Specific Aims: 1. Characterization of STAT6 phosphorylation and skin barrier gene expression in human keratinocytes in the presence of PM-43I. Keratinocytes play a critical role in AD pathogenesis. They show upregulated STAT6 phosphorylation upon IL- 4 and IL-13 stimulation. Phosphorylated STAT6 then down-regulates the level of loricrin and ivolucrin, two proteins important for skin barrier formation and integrity. Our previous studies in asthma have demonstrated that PM-43I is able to reduce STAT6 phosphorylation in lung epithelial cells (data not shown), here we are going to test if PM-43I also reduces STAT6 phosphorylation in keratinocytes, and subsequent down-regulation of LOR and IVL expression. 2. To study the efficacy of PM-43I in atopic dermatitis management. Specific Aim 2A: To determine PM-43I formulation for animal study. (2 months) This aim is going to determine the best-performing topical formulation for PM-43I in treating atopic dermatitis for the following efficacy study in mouse models. Drug solubility, stability, and in vitro skin permeation will be studied. Specific Aim 2B: To study the efficacy of PM43I in atopic dermatitis animal models (7 months) With the formulation obtained from Aim 2A, we will employ atopic dermatitis mouse model to study the efficacy of PM-43I in this aim. AD clinical score will be used to evaluate the symptoms of mice with or without PM-43I treatment. In addition, histology, serum cytokines and IgE level, and STAT6 phosphorylation and skin barrier gene expression in keratinocytes will be examined. These studies will help to prove the function of PM-43I in atopic dermatitis on both the symptomatic and molecular level.