Development of a Nonpsychotropic Cannabinoid Agonist for the Treatment of Sclerod

描述（由申请人提供）：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，随后是影响皮肤和内脏器官的进行性纤维化;最常见的是食道、肾脏、心脏和肺（I）。单核细胞和活化的T淋巴细胞占主导地位的早期炎性浸润。纤维化是SSc患者的特征性组织病理学，包括胶原蛋白和其他细胞外基质（ECM）组分的产生增加，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，包括使人衰弱的食管功能障碍和肺纤维化，这是SSc患者死亡的主要原因。现有的数据，虽然变量，表明在美国的发病率为9至19例/百万/年，患病率范围从28至253例/百万（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ECM过度产生的机制尚不清楚。观察结果（3），产生胶原的活化成纤维细胞位于炎性浸润物附近，支持白细胞参与SSc病程早期纤维化的起始的观点。细胞因子和生长因子如转化生长因子（TGF-β）和结缔组织生长因子（CTGF）激活成纤维细胞并诱导其分化为肌成纤维细胞，导致结缔组织的积累。由于肌成纤维细胞增强ECM的硬度，产生促纤维化细胞因子，并且对细胞凋亡具有抗性，因此认为它们在组织中的积累促进纤维化的进展。内源性大麻素系统（endocannabinoid system，ECS）是一个在中枢神经系统和免疫系统调节中起重要作用的天然系统。Ajulemic acid（AJA）是一种非精神性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。本提案中的实验旨在进一步表征AJA在2种不同硬皮病小鼠模型中的抗纤维化作用的功效和机制，所述硬皮病小鼠模型在炎症和纤维化对疾病过程的贡献方面不同。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药物设计。 在SSc患者中测试AJA的临床试验。该提案的成功完成将有助于开发一类具有潜在新机制的新药物，以治疗一般纤维化疾病，特别是硬皮病。 公共卫生相关性：JB Therapeutics组建了一支杰出的科学团队，研究其新型非精神类大麻素治疗硬皮病的药理学和作用机制。我们最近获得了体外和体内概念验证数据，即阿佳酸（一种非精神药物纳摩尔CB 1/CB 2激动剂）在硬皮病小鼠博来霉素模型中预防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 Therapeutics是围绕阿佳酸及其用途的知识产权的唯一拥有者，并计划将一种每天两次的制剂推进临床试验，用于治疗硬皮病患者，硬皮病是一种危及生命的疾病。拟议的实验将在动物模型中确定阿佳酸（AJA）抗纤维化作用的有效性和作用机制。

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).