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

项目总结/摘要 在美国大约有50万人患有皮肤狼疮病变（CLE）， 4然而，没有治愈的方法，治疗选择有限，没有新药被FDA- 因此，CLE代表了对定向治疗的高度未满足的需求。 皮肤病变是由依赖于遗传和环境因素的复杂自身免疫反应引起的。 这些病变具有共同的组织学特征，例如干扰素调节的界面皮炎。 Anandamide（AEA）是一种主要的内源性大麻素，参与（i）调节趋化因子的表达。 先天性和适应性免疫系统，（ii）感觉输入如瘙痒和疼痛的处理，和（iii） 维持皮肤屏障的完整性。152，153 AEA减少炎症的主要途径是通过结合 CB 2受体，其主要由外周器官中的巨噬细胞和淋巴细胞表达 164初步数据（i）表明，在免疫系统中， （ii）显示来自CLE患者经AEA处理的外周血单核细胞 产生较低水平的细胞因子。 鉴于这一切，AEA是一个有前途的候选药物治疗CLE。AEA面临着各种交付挑战， 然而，包括不稳定性、有限地渗透到角质层中以及通过脂肪酸的快速代谢 为了克服这些挑战，将AEA装载到新型局部二氧化硅-聚酰胺水解酶（FAAH）中。 衍生的颗粒递送系统已被证明可以提高其他几种API的生物利用度。 所得制剂（AEA-ZP）显示出⑴增强AEA渗透到角质层中，（ii） 提供AEA在皮肤中的延长释放，以及（iii）显着减少狼疮病变的大小和严重程度 在两项小鼠狼疮研究中，与对照组相比，包括未包封的AEA。 在该I期提案期间，将在新的小鼠模型中评估AEA-ZP原型的体内功效， 并获得初步毒性数据。将使用血液进行体外作用机制研究 和人类CLE患者的病变组织;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谱可能表明患者更容易 可能对AEA-ZP治疗有反应。与此同时，更高负荷的AEA-ZP原型将在 准备后续的剂量范围安全性和有效性研究，并进行加速稳定性试验。

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.