Development of a Nonpsychotropic Cannabinoid Agonist for the Treatment of Sclerod

开发用于治疗硬化症的非精神药物大麻素激动剂

• 批准号: 8353713
• 负责人: ROBERT B ZURIER
• 金额: $ 29.44万
• 依托单位: JB THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-17 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8353713
• 关键词: 9-deoxy-delta-9-prostaglandin D2; Absence of pain sensation; Acids; Affect; Agonist; Animal Model; Apoptosis; Applications Grants; Autoimmune Diseases; Bleomycin; Cannabinoids; Cause of Death; Characteristics; Clinical; Clinical Treatment; Clinical Trials; Collagen; Complex; Connective Tissue; Cutaneous; Data; Dermal; Development; Disease; Drug Formulations; Eicosanoids; Endocannabinoids; Esophageal; Esophagus; Extracellular Matrix; Fibroblasts; Fibrosis; Functional disorder; Gene Expression; Goals; Grant; Growth Factor; Heart; Histopathology; Human; Immune response; Immune system; In Vitro; Incidence; Inflammation; Inflammation Mediators; Inflammatory Infiltrate; Injury; Interleukin-1; Interleukin-6; Kidney; Leukocytes; Life; Lung; Modeling; Mus; Myofibroblast; Organ; PPAR gamma; Patients; Pharmaceutical Preparations; Pharmacology; Play; Prevalence; Prevention; Process; Production; Pulmonary Fibrosis; Regulation; Resistance; Role; Scleroderma; Signal Transduction; Skin; Small Business Innovation Research Grant; Smooth Muscle Actin Staining Method; System; Systemic Scleroderma; T-Lymphocyte; TLR4 gene; Testing; Therapeutic; Therapeutic Agents; Tissues; Transforming Growth Factor beta; Transforming Growth Factors; Translating; Treatment Efficacy; United States; ajulemic acid; connective tissue growth factor; cytokine; design; genome-wide; in vivo; lipoxin A4; mimetics; monocyte; mortality; mouse model; novel; prevent; research study; vascular inflammation

DESCRIPTION (provided by applicant): Systemic sclerosis (SSc; scleroderma) is a complex multisystem autoimmune disease of unknown cause associated with early transient inflammation and vascular injury followed by progressive fibrosis affecting skin and internal organs; most frequently esophagus, kidneys, heart, and lungs (I). Monocytes and activated T lymphocytes dominate the early inflammatory infiltrates. Fibrosis, the characteristic histopathology in patients with SSc, includes increased production of collagen and other extracellular matrix (ECM) components, and accumulation of alpha smooth muscle actin (ASMA) positive myofibroblasts. The progressive fibrosis often leads to organ dysfunction including debilitating esophageal dysfunction and pulmonary fibrosis, the leading cause of death for SSc patients. Available data, while variable, indicate an incidence in the United States of 9 t 19 cases /million/year, and prevalence rates ranging from 28 to 253 cases/million (2). Current therapy is limited, with 10 year survival of 55%. The mechanisms leading to activation of fibroblasts and the subsequent over production of ECM are not clear. The observation (3) that collagen producing, activated fibroblasts are localized adjacent to inflammatory infiltrates supports the notion that leucocytes are involved in initiation of fibrosis early in the course of SSc. Cytokines and growth factors such as transforming growth factor (TGF-Beta) and connective tissue growth factor (CTGF) activate fibroblasts and induce their differentiation to myofibroblasts, leading to accumulation of connective tissue. Because myofibroblasts enhance the stiffness of the ECM, produce profibrotic cytokines, and are resistant to apoptosis, their accumulation in tissue is believed to promote progression of fibrosis. The endocannabinoid system (ECS) is a natural system that plays an important role in the regulation of the CNS and immune system. Ajulemic acid (AJA), a non-psychotropic endocannabinoid mimetic has been shown to be highly effective in models of analgesia, inflammation and most recently fibrotic diseases. Experiments in this proposal are designed to further characterize the efficacy and mechanisms of the anti fibrotic action of AJA in 2 different murine models of scleroderma which differ in the contribution of inflammation and fibrosis to the disease process. We will use these models to determine the specific mechanism by which AJA prevents or suppresses progressive fibrosis in models of scleroderma, with the goal of translating this information into the design of a clinical trial to test AJA in patients with SSc. Successful completion of this proposal will facilitate development of a new class of drug with a potentially new mechanism to treat fibrotic disease in general and scleroderma in particular. PUBLIC HEALTH RELEVANCE: JB Therapeutics has assembled an exceptional scientific team to study the pharmacology and mechanism of action of its novel non-psychotropic cannabinod in the treatment of scleroderma. We have recently obtained in vitro and in vivo proof-of-concept data that ajulemic acid, a non-psychotropic nanomolar CB1/ CB2 agonist is highly effective in preventing skin and lung fibrosis in a mouse bleomycin model of scleroderma and inhibits extracellular matrix production by dermal fibroblasts from patients with scleroderma. JB Therapeutics is the sole owner of the IP around ajulemic acid and its uses, and is planning to advance a twice-a-day formulation into clinical trials for the treatment of patients with scleroderma, a life-threatening disease. The proposed experiments will determine in animal models the efficacy and mechanisms of action responsible for the antifibrotic effects of ajulemic acid (AJA).

描述（由申请人提供）：系统性硬化症（SSc; scleroderma）是一种病因不明的复杂多系统自身免疫性疾病，与早期短暂性炎症和血管损伤相关，随后进行性纤维化影响皮肤和内脏器官；最常见的是食道、肾脏、心脏和肺(1)。单核细胞和活化T淋巴细胞在早期炎症浸润中占主导地位。纤维化是SSc患者的特征性组织病理学，包括胶原和其他细胞外基质（ECM）成分的产生增加，以及α平滑肌肌动蛋白（ASMA）阳性肌成纤维细胞的积累。进行性纤维化通常导致器官功能障碍，包括食道功能障碍和肺纤维化，这是SSc患者死亡的主要原因。现有数据虽然不一致，但表明美国的发病率为9至19例/百万人/年，患病率为28至253例/百万人(2)。目前的治疗是有限的，10年生存率为55%。导致成纤维细胞活化和随后过度产生ECM的机制尚不清楚。产生胶原的活化成纤维细胞位于炎性浸润附近的观察结果(3)支持了白细胞参与SSc早期纤维化起始的观点。转化生长因子（tgf - β）、结缔组织生长因子（CTGF）等细胞因子和生长因子激活成纤维细胞，诱导成纤维细胞向肌成纤维细胞分化，导致结缔组织积累。由于肌成纤维细胞增强ECM的硬度，产生促纤维化细胞因子，并且抵抗细胞凋亡，它们在组织中的积累被认为促进了纤维化的进展。内源性大麻素系统（ECS）是一种在中枢神经系统和免疫系统中起重要调节作用的天然系统。阿菊酸（AJA）是一种非精神药物内源性大麻素模拟物，已被证明在镇痛、炎症和最近的纤维化疾病模型中非常有效。本实验旨在进一步表征AJA在两种不同硬皮病小鼠模型中抗纤维化作用的疗效和机制，这两种硬皮病小鼠模型在炎症和纤维化对疾病过程的贡献不同。我们将使用这些模型来确定AJA在硬皮病模型中预防或抑制进行性纤维化的具体机制，目的是将这些信息转化为设计