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: 10656390
• 负责人: VICTORIA P WERTH
• 金额: $ 40.24万
• 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 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656390
• 关键词: Afferent Neurons; Aftercare; Agonist; Analgesics; Anti-Inflammatory Agents; Area; Autoimmune Diseases; Biopsy; CD4 Positive T Lymphocytes; CNR2 gene; Cancer Etiology; Cannabinoids; Cells; Clinical; Clinical Research; Cutaneous; 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; Light; Lupus; Malignant Neoplasms; Measures; Messenger RNA; Molecular; Mus; Myelogenous; Nerve; Organ; Pathogenesis; Pathway interactions; 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; Sorting; Specific qualifier value; Stains; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Th1 Cells; Therapeutic; Time; United States National Institutes of Health; Work; arm; cell type; cytokine; effective therapy; improved; 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; tissue fixing; 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.

摘要 皮肌炎（DM）是一种多器官自身免疫性疾病，导致显着的皮肤活动 和严重瘙痒，这两种情况都使患者的生活质量（QoL）恶化。尽管其临床 然而，重要的是，DM中皮肤活动和瘙痒的发病机制仍然不清楚 明白因此，在过去的70年里，没有新的糖尿病治疗方法被批准。 目前可用的标签外治疗通常无效或具有重大风险。我们 最近完成了一项成功的NIH资助的lenabasum的第二阶段随机对照试验， 一种新的非精神活性CB 2反向激动剂，用于治疗皮肤型糖尿病。Lenabasum 在皮肤病活动性、瘙痒和关键QoL指标方面产生了显著改善。 我们实验室使用有限数量的病变皮肤活检进行的机制研究 试验表明，lenabasum减少了真皮CD 4 + T细胞的数量， 干扰素（IFN）β、IFNγ和白细胞介素（IL）的真皮染色区域31。这四个人 安慰剂组的参数发生变化。其中前三个变化显著 与皮肤病活动的改善相关。皮肤IFNγ染色减少 和IL 31均与瘙痒的改善显着相关。我们最近的研究表明 在糖尿病患者皮肤中的突出的髓样树突状细胞（mDC）， 许多狼疮患者皮肤中浆细胞样DC（pDC）和IFNα特征占优势 患者鉴于先前在DM中报告的皮肤中显著的IFN γ信号和 IFN-γ和皮肤病活动的反应lenabasum，我们现在建议评估的作用， 在DM中产生IFN γ中的mDC。我们有机会扩大科学研究 我们在即将到来的lenabasum第三阶段国际试验的第二阶段试验中取得的进展 对于DM。我们假设，通过mDC上的CB 2受体起作用的lenabasum， 通过对IRF-3、IRF-5和IRF-7的影响，表达IFN γ。我们还假设， lenabasum，通过下调mDC的IFN γ或直接作用于T细胞， 细胞，减少皮肤中IFNγ和IL 31的产生。在接受lenabasum治疗的DM患者中， 在3期试验中，我们将确定与皮肤相关的通路中的细胞和分子变化， 疾病活动性和瘙痒预测临床改善或与临床改善相关。我们还将 对DM中促进活动和瘙痒的途径进行机制研究， 关于Lenabasum我们提议的研究将利用即将到来的3期试验的样本， 提高我们对lenabasum如何工作的理解，从而阐明关键疾病 机制，并可能为其他新的治疗方法提供基础。

项目成果

Importance of collaboration of dermatology and rheumatology to advance the field for lupus and dermatomyositis.

• DOI: 10.1016/j.ijwd.2021.09.002
• 发表时间: 2021-12
• 期刊: International journal of women's dermatology
• 作者: Werth VP;Askanase AD;Lundberg IE
• 通讯作者: Lundberg IE

Highly Multiplexed Mass Cytometry Identifies the Immunophenotype in the Skin of Dermatomyositis.

• DOI: 10.1016/j.jid.2021.02.748
• 发表时间: 2021-09
• 期刊: The Journal of investigative dermatology
• 作者: Patel J;Maddukuri S;Li Y;Bax C;Werth VP
• 通讯作者: Werth VP

Safety and Efficacy of Lenabasum, a Cannabinoid Receptor Type 2 Agonist, in Patients with Dermatomyositis with Refractory Skin Disease: A Randomized Clinical Trial.

• DOI: 10.1016/j.jid.2022.03.029
• 发表时间: 2022-10
• 期刊: JOURNAL OF INVESTIGATIVE DERMATOLOGY
• 影响因子: 6.5
• 作者: Werth, Victoria P.;Hejazi, Emily;Pena, Sandra M.;Haber, Jessica;Zeidi, Majid;Reddy, Nithin;Okawa, Joyce;Feng, Rui;Bashir, Muhammad M.;Gebre, Kirubel;Jadoo, Arvin S.;Concha, Josef Symon S.;Dgetluck, Nancy;Constantine, Scott;White, Barbara
• 通讯作者: White, Barbara

Plasma-derived DNA containing-extracellular vesicles induce STING-mediated proinflammatory responses in dermatomyositis.

• DOI: 10.7150/thno.59152
• 发表时间: 2021
• 期刊: Theranostics
• 影响因子: 12.4
• 作者: Li Y;Bax C;Patel J;Vazquez T;Ravishankar A;Bashir MM;Grinnell M;Diaz D;Werth VP
• 通讯作者: Werth VP

Trial of intravenous immunoglobulin in dermatomyositis: a critically appraised research paper.

静脉注射免疫球蛋白治疗皮肌炎的试验：一篇经过严格评价的研究论文。

• DOI: 10.1093/bjd/ljad044
• 发表时间: 2023
• 期刊: The British journal of dermatology
• 作者: Pandya,Rachita;Kleitsch,Julianne;Werth,VictoriaP
• 通讯作者: Werth,VictoriaP