A nonpsychoactive cannabinoid receptor-2 agonist to treat itch and inflammation in dermatomyositis

一种非精神活性大麻素受体 2 激动剂，用于治疗皮肌炎的瘙痒和炎症

• 批准号: 10437840
• 负责人: VICTORIA P WERTH
• 金额: $ 40.18万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10437840
• 关键词: Afferent Neurons; Aftercare; Agonist; Anti Inflammatory Analgesics; Area; Autoimmune Diseases; Biopsy; CD4 Positive T Lymphocytes; CNR2 gene; Cancer Etiology; Cannabinoids; Cells; Clinical; Clinical Research; Cutaneous; Cytokine Signaling; Cytometry; Data; Dendritic Cells; Dermal; Dermatomyositis; Development; Disease; Double-Blind Method; Down-Regulation; Flow Cytometry; Funding; Gene Expression; Genetic Transcription; Goals; IL4 gene; IRF3 gene; In Vitro; Inflammation; Inflammatory; Innate Immune Response; Interferon Type II; Interferon-alpha; Interferon-beta; Interferons; Interleukins; International; Label; Lead; Lesion; Light; Lupus; Malignant Neoplasms; Measures; Messenger RNA; Molecular; Mus; Myelogenous; Nerve; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Peripheral Blood Mononuclear Cell; Phase; Placebo Control; Production; Pruritus; Quality of life; Randomized; Randomized Controlled Trials; Refractory; Regulation; Reporting; Resolution; Risk; Role; Sampling; Scientific Advances and Accomplishments; Signal Transduction; Skin; Stains; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Th1 Cells; Therapeutic; Time; Tissues; United States National Institutes of Health; Work; arm; cell type; cytokine; effective therapy; in vivo; knock-down; laser capture microdissection; novel; novel therapeutic intervention; novel therapeutics; peripheral blood; personalized therapeutic; phase II trial; phase III trial; placebo group; primary outcome; programs; receptor; response; safety study; secondary outcome; skin disorder; skin lesion; transcription factor; treatment duration

Abstract Dermatomyositis (DM) is a multiorgan autoimmune disease that causes significant skin activity and severe pruritus, both of which worsen the patients’ quality of life (QoL). Despite its clinical importance, however, the pathogenesis of skin activity and itch in DM remains poorly understood. Accordingly, no new therapies for DM have been approved in the last 70 years. Currently available off-label therapies are frequently ineffective or have significant risks. We recently completed a successful NIH-funded phase 2 randomized controlled trial of lenabasum, a novel nonpsychoactive CB2 inverse agonist, to treat skin-predominant DM. Lenabasum produced significant improvements in skin disease activity, itch, and key QoL measures. Mechanistic studies performed in our lab using the limited number of biopsies of lesional skin from the trial demonstrated that lenabasum decreased the numbers of dermal CD4+ T-cells and dermal staining areas for interferon (IFN)ß, IFNγ, and interleukin (IL)31. None of these four parameters changed in the placebo group. The first three of these changes significantly correlated with improvement in skin disease activity. The decreases in dermal staining for IFNγ and IL31 each significantly correlated with improvement in itch. Our recent work demonstrates prominent myeloid dendritic cells (mDCs) in the skin of patients with DM, in contrast to the predominance of plasmacytoid DCs (pDCs) and the IFNα signature in the skin of many lupus patients. Given the prominent IFNß signal in skin previously reported in DM and the decrease in IFNß and skin disease activity in response to lenabasum, we now propose to evaluate the role of mDCs in the production of IFNß in DM. We have an opportunity to expand the scientific advances we made in the phase 2 trial in an upcoming phase 3 international trial of lenabasum for DM. We hypothesize that lenabasum, acting through the CB2 receptor on mDCs, decreases mDC expression of IFNß through effects on IRF-3, -5, and -7. We also hypothesize that lenabasum, either through the downregulation of IFNß from mDCs or by direct effects on T cells, decreases production of IFNγ and IL31 in skin. In DM patients treated with lenabasum in the phase 3 trial, we will identify cellular and molecular changes in pathways relevant to skin disease activity and itch that predict or correlate with clinical improvements. We will also perform mechanistic studies of pathways promoting activity and itch in DM and the improvement with lenabasum. Our proposed studies utilizing samples from the upcoming phase 3 trial will enhance our understanding of how lenabasum works, thereby shedding light on key disease mechanisms and possibly providing a basis for additional novel therapeutic approaches.

抽象的 皮肌炎 (DM) 是一种多器官自身免疫性疾病，会导致显着的皮肤活动 和严重的瘙痒，这两者都会恶化患者的生活质量（QoL）。尽管其临床 然而，对于 DM 中皮肤活动和瘙痒的发病机制仍知之甚少。 明白了。因此，过去 70 年来没有新的 DM 疗法获得批准。 目前可用的标签外疗法常常无效或存在重大风险。我们 最近成功完成了一项由 NIH 资助的 lenabasum 2 期随机对照试验， 一种新型非精神活性 CB2 反向激动剂，用于治疗皮肤为主的 DM。莱纳巴苏姆 皮肤病活动、瘙痒和关键生活质量指标显着改善。 我们的实验室使用有限数量的病变皮肤活检进行了机理研究 试验表明，lenabasum 减少了真皮 CD4+ T 细胞的数量， 干扰素 (IFN)ß、IFNγ 和白细胞介素 (IL)31 的真皮染色区域。这四个都没有 安慰剂组的参数发生了变化。其中前三个变化显着 与皮肤病活动的改善相关。真皮 IFNγ 染色减少 和 IL31 均与瘙痒的改善显着相关。我们最近的工作表明 与正常人相比，DM 患者皮肤中存在明显的髓系树突状细胞 (mDC) 许多狼疮皮肤中浆细胞样 DC (pDC) 和 IFNα 特征占主导地位 患者。鉴于先前在 DM 中报道的皮肤中显着的 IFNβ 信号以及 IFNß 和皮肤病活性对 lenabasum 的反应，我们现在建议评估其作用 mDC 在 DM 中产生 IFNβ 的作用。我们有机会拓展科学领域 我们在即将进行的 lenabasum 国际试验第 3 阶段的第 2 阶段试验中取得的进展 对于DM。我们假设 lenabasum 通过 mDC 上的 CB2 受体作用，减少 mDC 通过影响 IRF-3、-5 和 -7 表达 IFNβ。我们还假设 lenabasum，通过 mDC 的 IFNβ 下调或直接影响 T 细胞，减少皮肤中 IFNγ 和 IL31 的产生。在接受 lenabasum 治疗的 DM 患者中 在第三阶段试验中，我们将识别与皮肤相关的通路中的细胞和分子变化 预测或与临床改善相关的疾病活动和瘙痒。我们还将 对促进 DM 活动和瘙痒的途径及其改善进行机制研究 与莱纳巴苏姆。我们提出的利用即将到来的第三阶段试验样本的研究将 增强我们对 lenabasum 工作原理的理解，从而揭示关键疾病 机制，并可能为其他新的治疗方法提供基础。