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

Toll 样受体抑制剂 7

• 批准号: 7671622
• 负责人: Franck Barrat
• 金额: $ 35.94万
• 依托单位: DYNAVAX TECHNOLOGIES CORPORATION
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7671622
• 关键词: Acute; Adverse effects; Affect; Animal Model; Antibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Award; B-Lymphocytes; Biopsy Specimen; Cells; Chronic; Clinical; Clinical Trials; Complement; Cutaneous; DNA; Data; Dendritic Cells; Dendritic cell activation; Dermatomyositis; Development; Disease; Disease model; Evaluation; Female of child bearing age; Funding; Genes; Goals; Human; Immune system; Immunologic Receptors; In Vitro; Infiltration; Inflammation; Interferon-alpha; Interferons; Lead; Lesion; Lichen Planus; Lichen Sclerosus et Atrophicus; Lupus; Mediating; Methods; Modeling; Mus; Nucleic Acids; Oligonucleotides; Organ; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Pre-Clinical Model; Procedures; Production; R44 grant; RNA; Role; Safety; Series; Signal Pathway; Signal Transduction; Skin; Symptoms; Systemic Lupus Erythematosus; Systemic disease; TLR7 gene; Therapeutic; Tissues; Toll-like receptors; Toxic effect; Treatment Protocols; United States; Woman; Work; cell type; clinical efficacy; effective therapy; graft vs host disease; human TLR7 protein; inhibitor/antagonist; lupus prone mice; man; mouse development; mouse model; neutrophil; novel; pre-clinical; preclinical evaluation; public health relevance; receptor; synthetic construct

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.

描述（由申请人提供）：狼疮是一种自身免疫性疾病，在美国影响超过100万人，对育龄妇女的影响不成比例。该病治疗困难，少数有效的治疗方法有明显的毒副作用。两种免疫系统细胞，B淋巴细胞和浆细胞样树突状细胞的异常活化在疾病的发病机制中起重要作用。这两种细胞类型的慢性激活是由于DNA和RNA通过先天免疫受体TLR7和TLR9的刺激而出现的。我们已经开发了一系列合成的寡核苷酸（称为IRS），其序列基序对TLR7和TLR9信号传导都有强烈的抑制作用。IRS的先导分子DV056已被证明在系统性红斑狼疮的小鼠模型中具有活性，ind的研究正在进行中，以支持系统性狼疮的适应症。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（包括扁平苔藓、皮肌炎、硬化苔藓和皮肤GVHD）中的作用。我们的初步证据表明，这种由自身DNA和RNA触发的炎症途径可以通过反复剥离正常小鼠的皮肤来激活。本研究旨在建立一个由浆细胞样树突状细胞激活和IFN-1产生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胶带剥离引起的炎症中的作用的定义”，“使用易患自身免疫性疾病的小鼠建立慢性炎症模型”，“IRS作为胶带剥离引起的自身免疫性炎症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IRS治疗主要累及皮肤的自身免疫性疾病的发展。由于易于评估症状，诸如皮肤红斑狼疮等疾病可能被证明对IRS的早期临床发展特别有用。公共卫生相关性：狼疮是一种严重的自身免疫性疾病，在美国影响超过100万人，主要是女性。目前对这种疾病的治疗有严重的副作用；然而，最近的发现提出了可能更安全、更有效的新治疗方法。我们建议开发一种抑制干扰素- α的新药，作为治疗皮肤狼疮和相关皮肤自身免疫性疾病的一种关键因素。