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(申请人提供)：系统性硬化症(SSC；硬皮病)是一种原因不明的复杂的多系统自身免疫性疾病，与早期一过性炎症和血管损伤相关，随后累及皮肤和内脏；最常见的是食道、肾脏、心脏和肺(I)。早期炎症浸润以单核细胞和活化的T淋巴细胞为主。纤维化是SSc患者的组织病理学特征，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)阳性的肌成纤维细胞的聚集。进行性纤维化通常会导致器官功能障碍，包括衰弱的食道功能障碍和肺纤维化，这是SSC患者的主要死亡原因。现有数据虽然可变，但表明美国的发病率为9-19例/百万/年，患病率为28-253例/百万(2)。目前的治疗是有限的，10年存活率为55%。导致成纤维细胞活化和随后过度产生细胞外基质的机制尚不清楚。观察到(3)胶原生成、活化的成纤维细胞位于炎性浸润物附近，这支持了白细胞参与SSC早期纤维化启动的观点。细胞因子和生长因子如转化生长因子和结缔组织生长因子激活成纤维细胞并诱导其向肌成纤维细胞分化，导致结缔组织的聚集。由于肌成纤维细胞增加ECM的硬度，产生促纤维化的细胞因子，并抵抗细胞凋亡，它们在组织中的积聚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发挥重要调节作用的自然系统。阿魏酸(AJA)是一种非精神性内源性大麻素类似物，已被证明在止痛、炎症和最近的纤维化疾病模型中非常有效。该方案中的实验旨在进一步表征AJA在两种不同的硬皮病小鼠模型中的抗纤维化作用的有效性和机制，这两种模型的炎症和纤维化在疾病过程中的贡献不同。我们将使用这些模型来确定AJA预防或抑制硬皮病模型中进行性纤维化的具体机制，目的是将这一信息转化为 在SSc患者中检测AJA的临床试验。这项提案的成功完成将有助于开发一种新的药物类别，该药物具有潜在的新机制，用于治疗纤维性疾病，特别是硬皮病。 公共卫生相关性：JB治疗公司组建了一个特殊的科学团队，研究其新型非精神药物大麻素治疗硬皮病的药理和作用机制。我们最近在体外和体内获得了概念验证数据，即一种非精神药物纳米分子CB1/CB2激动剂，在预防博莱霉素硬皮病小鼠模型的皮肤和肺纤维化方面非常有效，并抑制硬皮病患者真皮成纤维细胞产生细胞外基质。JB治疗公司是围绕菊花酸及其用途的IP的唯一所有者，并计划将一天两次的配方推进到临床试验中，用于治疗硬皮病患者，硬皮病是一种威胁生命的疾病。拟议中的实验将在动物模型中确定菊酸(AJA)的抗纤维化作用的有效性和作用机制。