Inhibitors of PI3K-delta for Treatment of Skin Inflammation

用于治疗皮肤炎症的 PI3K-delta 抑制剂

• 批准号: 8303202
• 负责人: Cristiana Guiducci
• 金额: $ 29.24万
• 依托单位: DYNAVAX TECHNOLOGIES CORPORATION
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-18 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8303202
• 关键词: Acute; Adverse effects; Affect; Animal Model; Antigen-Antibody Complex; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Automobile Driving; B-Lymphocytes; Biological Assay; Blood; Cellular Infiltration; Chronic; Clinical; Cutaneous; DNA; Data; Dendritic Cells; Dendritic cell activation; Dermatitis; Dermatomyositis; Development; Disease; Disease Progression; Dose; Drug Formulations; Effectiveness; Female of child bearing age; Genes; Goals; Histologic; Housing; Human; IC 87114; In Vitro; Inflammation; Inflammatory; Interferon-alpha; Interferons; Kidney; Lesion; Leukocytes; Lichen Planus; Lichen Sclerosus et Atrophicus; Ligands; Lupus; Mediating; Methods; Modeling; Monoclonal Antibodies; Mus; Names; Nucleic Acids; Oligonucleotides; Onset of illness; Organ; PIK3CG gene; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phosphatidylinositols; Phosphotransferases; Play; Production; Quality of life; RNA; Reporting; Role; Route; Series; Signaling Molecule; Skin; Source; Steroids; Symptoms; Systemic Lupus Erythematosus; TLR7 gene; Therapeutic; Time; Topical application; Toxic effect; United States; Variant; Woman; Work; base; cell type; disability; effective therapy; human TLR7 protein; in vivo; inhibitor/antagonist; lupus cutaneous; lupus prone mice; man; mouse model; novel; preclinical evaluation; prevent; research study; response; skin disorder; skin lesion; small molecule

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.

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，在美国影响超过一百万人，不成比例地影响育龄妇女。皮肤型狼疮（CLE）的发病率是SLE本身的2-3倍，虽然不太严重，但往往导致严重的工作残疾和生活质量低下。CLE难以治疗，并且少数有效的疗法具有显著的毒副作用。浆细胞样树突状细胞（PDC）前体和B细胞中的自身核酸触发先天受体TLR 7和TLR 9是SLE发病机制的关键，因为这导致I型IFN的产生以及抗DNA和抗RNP免疫复合物的产生。分别。同样，在CLE中，PDC大量渗入病变皮肤并产生I型IFN，其在建立驱动疾病的自我持续炎性循环中起主要作用。我们最近已经鉴定了PI 3 K-delta（PI 3 K4）作为用于通过PDC产生IFN-1的TLR 7和9途径的关键信号传导分子，并且已经表明这种内部合成的基于小分子的抑制剂在体外和体内测定中都非常有效。此外，我们已经开发并充分表征了皮肤炎症的小鼠模型，其中响应于内源性TLR 7和9配体通过浸润PDC产生IFN-1在疾病的发展和进展中起主要作用。我们有新的初步数据表明，PI 3 K4抑制剂可以减少我们模型中的皮肤炎症。该提案包括几项相关活动，以评估PI 3 K4抑制剂在由浆细胞样树突状细胞活化和IFN-1产生介导的皮肤自身免疫中的有效性。这些研究包括：“剂量和途径探索研究“作用机制的定义“CLE小鼠模型中PI 3 K4的临床前评价最终目标是开发用于治疗自身免疫性皮肤病的PI 3 K4抑制剂的局部制剂。由于易于评估症状，皮肤狼疮等疾病可能在临床发展的早期阶段特别有用。