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

用于治疗特应性皮炎的新型小分子靶向 STAT 蛋白

• 批准号: 9348063
• 负责人: Dev Kumar Chatterjee
• 金额: $ 24.3万
• 依托单位: FANNIN PARTNERS, LLC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-16 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9348063
• 关键词: Acute; Adoption; Adult; Adverse effects; Affect; Allergic; Animal Model; Animals; Antihistamines; Asthma; Atopic Dermatitis; B-Lymphocytes; Basic Science; Binding; Biological Sciences; Businesses; Cancer Center; Cell Differentiation process; Cells; Child; Chronic; Clinical; Collaborations; Data; Dermal; Developed Countries; Developing Countries; Development; Disease; Disease Progression; Down-Regulation; Drug Targeting; Eczema; Epithelial Cells; Evaluation; Focus Groups; Formulation; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Helper-Inducer T-Lymphocyte; Histology; Human; IgE; Immune; Immune System Diseases; In Vitro; Infant; Infection; Infiltration; Inflammation; Inflammatory; Institution; Interleukin-13; Interleukin-4; Investigational New Drug Application; Janus kinase; Lead; Lung; Measures; Medical center; Medicine; Molecular; Mus; Pathogenesis; Pathology; Patients; Permeability; Pharmaceutical Preparations; Phase; Phenotype; Phosphopeptides; Phosphoric Monoester Hydrolases; Phosphorylation; Play; Prevalence; Proteins; Pruritus; Public Health; Quality of life; Recruitment Activity; Rhinitis; Role; STAT protein; STAT6 gene; Serum; Signal Pathway; Skin; Skin Care; Small Business Innovation Research Grant; Societies; Solubility; Steroids; Swelling; Symptoms; Technology; Testing; Texas; Therapeutic; Toxicology; Transcription Coactivator; Transducers; Up-Regulation; Work; college; commercialization; cytokine; design; effective therapy; efficacy study; efficacy testing; environmental allergen; experience; improved; in vivo; inhibitor/antagonist; innovation; keratinocyte; loricrin; mimetics; mouse model; new therapeutic target; novel; novel therapeutics; prevent; skin barrier; skin disorder; small molecule; src Homology Region 2 Domain; standard of care; symptom management

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.

项目概要 特应性皮炎/AD（特应性湿疹）是一种慢性炎症性疾病，会导致瘙痒、发炎、肿胀 据国家湿疹协会估计，容易受到感染的皮肤。 目前有3160万人受到影响，其中至少1780万人患有中度至重度疾病。 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 过敏触发因素和免疫抑制策略，包括使用类固醇、抗组胺药或局部用药 虽然这些疗法可以帮助一些人控制疾病，但也有不良的一面。 因此，考虑到给社会带来的巨大公共卫生负担，长期使用会产生影响。 由于缺乏有效的治疗方法，对新的靶向治疗方法的需求尚未得到满足，以帮助 管理 AD 患者的症状并提高生活质量 Fannin Partners, LLC 是一家早期生命科学开发集团，专注于商业化 德克萨斯医疗中心机构的创新由经验丰富的管理团队领导。 Fannin 拥有多元化的商业背景、商业化经验和强大的创业知识 合作伙伴与有前途的生命科学创新者合作，帮助开发有前途的治疗方法并将其商业化 约翰·麦克默里 (John McMurray) 和大卫·科里 (David Corry) 博士进行的基础研究。 我们的主导分子 PM-43I 是一种小分子、细胞渗透性且直接导致了这一创新。 磷酸酶稳定的磷酸肽模拟物，靶向 STAT6 的 SH2 结构域并防止招募 IL-4Rα 以及随后导致特应性皮炎表型的转录活性。 该提案旨在实现关键的里程碑，将这项技术转变为商业化 通过进行体外和体内概念验证研究来开拓特应性皮炎市场。 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表征 PM-43I 存在下的角质形成细胞。 角质形成细胞在 AD 发病机制中发挥着关键作用，IL-2 导致 STAT6 磷酸化上调。 4 和 IL-13 刺激后，磷酸化 STAT6 会下调 loricrin 和 ivolucrin 这两种物质的水平。 我们之前对哮喘的研究已经证明，蛋白质对于皮肤屏障的形成和完整性很重要。 PM-43I 能够减少肺上皮细胞中的 STAT6 磷酸化（数据未显示），我们在这里 将测试 PM-43I 是否也降低角质形成细胞中的 STAT6 磷酸化以及随后的下调 LOR 和 IVL 表达。 2. 研究PM-43I治疗特应性皮炎的疗效。 具体目标 2A：确定用于动物研究的 PM-43I 配方（2 个月）。 该目标是确定 PM-43I 治疗特应性皮炎的最佳外用制剂 后续将在小鼠模型中进行药物溶解度、稳定性和体外皮肤渗透性研究。 研究过。 具体目标 2B：研究 PM43I 在特应性皮炎动物模型中的功效（7 个月） 使用Aim 2A获得的配方，我们将使用特应性皮炎小鼠模型来研究功效 PM-43I的AD临床评分将用于评估有或没有PM-43I的小鼠的症状。 此外，还包括组织学、血清细胞因子和IgE水平，以及STAT6磷酸化和皮肤屏障。 这些研究将有助于证明 PM-43I 在角质形成细胞中的功能。 症状和分子水平上的特应性皮炎。