Development of an endocannabinoid microparticle formulation for the topical treatment of cutaneous manifestations of lupus erythematosus.

项目摘要/摘要 在美国，大约有50万人患有皮肤狼疮皮损(CLE)，其影响很大 到目前为止，还没有治愈的方法，治疗选择有限，FDA也没有新药-- 已被批准超过50年。84因此，CLE代表着对定向治疗的高度未得到满足的需求。 皮肤损伤是由依赖于遗传和环境因素的复杂的自身免疫反应引起的 这些病变具有共同的组织学特征，如干扰素调节的界面性皮炎。 趋化因子的表达。阿南达胺(AEA)是一种主要的内源性大麻素，参与(I)调节 先天和适应性免疫系统，(Ii)感觉输入的处理，如瘙痒和疼痛，和(Iii) 维持皮肤屏障的完整性。152,153 AEA的主要减炎途径是通过结合 CB2受体，主要由外周器官中的巨噬细胞和淋巴细胞表达 具有免疫功能，包括皮肤。164初步数据(I)显示CB2受体在 和(Ii)显示经AEA处理的CLE患者外周血单个核细胞 产生较低水平的细胞因子。 鉴于此，AEA是一种很有前途的治疗CLE的候选药物。AEA面临着各种交付挑战， 然而，包括不稳定，有限的对角质层的渗透，以及脂肪酸的快速代谢 酰胺水解酶(FAAH).134-135为了克服这些挑战，AEA被负载到一种新型的局部二氧化硅中- 衍生颗粒递送系统，已被证明提高了其他几种原料药的生物利用度。 由此产生的制剂(AEA-ZP)被证明(I)促进AEA对角质层的渗透，(Ii) 提供AEA在皮肤中的延长释放，以及(Iii)显著减少狼疮皮损的大小和严重程度 在两项小鼠狼疮研究中与对照组进行比较，包括无包膜的AEA。 在这个第一阶段的提案中，AEA-ZP原型将在一个新的小鼠模型中进行体内疗效评估， 并将获得初步的毒性数据。将使用血液进行体外作用机制研究 和人类CLE患者的皮损组织；这些数据有望为临床开发决策提供信息 与目标患者人群相关，其中特定的生物标志物配置文件可能指示患者 可能对AEA-ZP的治疗有反应。同时，更高负荷的AEA-ZP原型将在 为随后进行的剂量范围安全性和有效性研究做准备，并进行加速稳定性测试。

Project Summary/Abstract Approximately 500,000 people in the U.S. suffer from cutaneous lupus lesions (CLE), with a significant impact on quality of life.4 Yet, there is no cure, the treatment options are limited, and no new drug has been FDA- approved for over 50 years.84 As such, CLE represents a high unmet need for directed therapeutics. Skin lesions are caused by a complex autoimmune response dependent on genetic and environmental factors.80 These lesions have common histological features such as interface dermatitis with interferon-regulated chemokines expression.19 Anandamide (AEA) is a primary endocannabinoid involved in (i) modulation of the innate and the adaptive immune system, (ii) processing of sensory input such as pruritus and pain, and (iii) maintenance of skin barrier integrity.152,153 AEA’s primary pathway for decreasing inflammation is through binding to CB2 receptors, which are predominantly expressed by macrophages and lymphocytes in peripheral organs with immune function, including the skin.164 Preliminary data (i) demonstrate upregulation of CB2 receptors in lesional human CLE tissue and (ii) show that AEA-treated peripheral blood mononuclear cells from CLE patients produce lower levels of cytokines. Given all this, AEA is a promising drug candidate for treatment of CLE. AEA faces a variety of delivery challenges, however, including instability, limited penetration into the stratum corneum, and rapid metabolism by fatty acid amide hydrolase (FAAH).134-135 To overcome these challenges, AEA was loaded into a novel topical silica- derived particle delivery system that has been demonstrated to enhance bioavailability of several other APIs. The resulting formulation (AEA-ZP) was shown to (i) enhance penetration of AEA into the stratum corneum, (ii) provide extended release of AEA in the skin, and (iii) significantly reduce the size and severity of lupus lesions in two murine lupus studies as compared to controls, including unencapsulated AEA. During this Phase I proposal, the AEA-ZP prototype will be evaluated for efficacy in vivo in a new mouse model, and preliminary toxicity data will be obtained. In vitro mechanism-of-action studies will be conducted using blood and lesional tissue from human CLE patients; such data is expected to inform clinical development decisions relating to target patient populations in which specific biomarker profiles might indicate patients that are more likely to respond to treatment with AEA-ZP. In parallel, higher loaded AEA-ZP prototypes will be developed in preparation for dose-ranging safety and efficacy studies to follow, and accelerated stability testing performed.