CN110325185A - 用于治疗神经退行性疾病和/或自身免疫性疾病的专门的促消退脂质介质 - Google Patents
用于治疗神经退行性疾病和/或自身免疫性疾病的专门的促消退脂质介质 Download PDFInfo
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Abstract
本发明涉及一种专门的促消退脂质介质，该专门的促消退脂质介质包含巨噬素、D系列消退素、E系列消退素、保护素或脂氧素、或其组合，用于治疗神经退行性疾病和/或自身免疫性疾病。
Description
技术领域
本发明涉及神经退行性疾病和/或自身免疫性疾病领域。更具体地讲，本发明涉及专门的促消退脂质介质，优选地是巨噬素(maresin)，以及包含这些介质的组合物，用于治疗神经退行性疾病和/或自身免疫性疾病，优选地多发性硬化症(MS)和肌萎缩侧索硬化症(ALS)。
背景技术
神经退行性疾病是一系列主要影响人脑神经元的病症的涵盖性术语。神经元是包括脑和脊髓的神经系统的基石。神经元通常不会自我复制或替换，因此当它们受损或死亡时，它们不能被身体替换。神经退行性疾病的实例包括帕金森氏症、阿尔茨海默氏症、肌萎缩侧索硬化症和亨廷顿舞蹈病。神经退行性疾病是无法治愈且会使人衰弱的病症，这些病症导致神经细胞的进行性退化和/或死亡。这会导致运动问题(称为共济失调)或心理功能问题(称为痴呆)。
同样地，免疫系统障碍或自身免疫性疾病导致免疫系统具有异常低的活性或过度的活性。免疫缺陷疾病降低身体抵抗入侵者的能力，从而导致易受感染。在免疫系统具有过度活性的情况下，身体会攻击并损坏其自身的组织。自身免疫性疾病就是这种情况，在这种情况下，免疫系统产生抗体，这些抗体不是去抵抗感染，而是攻击身体自身的组织元素。自身免疫性疾病的治疗通常集中在降低免疫系统活性上。自身免疫性疾病的实例包括：类风湿性关节炎、系统性红斑狼疮(狼疮)、炎症性肠病(IBD)、多发性硬化症(MS)、1型糖尿病、格林-巴利综合征、慢性炎症性脱髓鞘性多发性神经病、牛皮癣、格雷夫斯氏病、桥本氏甲状腺炎、重症肌无力、血管炎。
尽管神经退行性和自身免疫性疾病具有不同的病因，但众所周知，位于中枢神经系统中的炎症反应对于这些疾病的发病机理具有至关重要的作用。
如今，世界各地有许多研究小组在寻找针对长清单的这些疾病的完全治疗或姑息治疗方案，因为受这些疾病影响的人群在不断增长，特别是由于目前更长的预期寿命。
有了这个目标，本发明人惊奇地发现一些称为“专门的促消退脂质介质”或“SPM”的分子可用于治疗此类疾病。
“专门的促消退脂质介质”(SPM，也称为专门的促消退介质)是一大类且不断增多的细胞信号传导分子，这些分子通过多不饱和脂肪酸(PUFA)被脂氧合酶、环氧合酶和细胞色素P450单加氧酶之一或其组合进行的代谢而在细胞中形成。主要在动物模型和人体组织中进行的临床前研究表明SPM起到协调炎症消退的作用。这些研究表明，对代谢失活具有抗性的合成SPM有望成为临床上有用的药理学工具，用于预防和解决多种多样的病理性炎症反应以及这些反应引起的组织破坏和发病。这些分子包括巨噬素、D系列消退素、E系列消退素、保护素和脂氧素。脂氧素来源于花生四烯酸，E系列消退素来源于长链n-3脂肪酸二十碳五烯酸(EPA)，以及D系列消退素、保护素/神经保护素和巨噬素都来源于n-3脂肪酸二十二碳六烯酸(DHA)。有越来越多的证据证明这些化合物在炎症过程中的作用。
例如，WO 2012/170791披露了用于治疗或预防炎症过程的二十二碳六烯酸(DHA)的单羟基和二羟基类似物。WO 2010/033509披露了用于治疗或预防炎症过程的二十二碳六烯酸(DHA)的14-羟基类似物。WO 2012/135032披露了至少部分地由细胞衍生的微粒产生的颗粒具有抗炎特性并且可以用作药物递送系统以治疗例如炎症、伤口或疼痛，所述颗粒是消退素、脂氧素、巨噬素和保护素等。Serhan等人,“Pro-resolving lipid mediators areleads for resolution physiology”[促消退脂质介质是消退生理学的引领者],Nature[自然],第10卷,第92-101页,2014年6月5日披露了SPM及其在炎症过程中的影响。WO 2013/170006披露了从天然来源(油)获得的专门的促消退介质(SPM)和SPM前体，以及它们在营养补充剂和药物及化妆品配制品中用于改善炎症和具有炎性成分的疾病的用途。
如上所示，众所周知使用SPM作为抗炎剂，但本发明人惊奇地发现这些分子，特别是巨噬素，也可用于治疗神经退行性疾病和/或自身免疫性疾病，特别是治疗多发性硬化症和肌萎缩侧索硬化症。这是非常有利的，因为目前用作抗炎药物的药剂对患有神经退行性疾病和/或自身免疫性疾病，特别是多发性硬化症和肌萎缩侧索硬化症的患者无用或甚至会产生负面影响。其实例是(依那西普)或(塞来昔布)，并且还在以下文章中找到了进一步的证据：“TNF neutralization in MS Results of a randomized,placebo-controlled multicenter study”[在随机、安慰剂对照多中心研究的MS结果中的TNF中和]，由来那西普多发性硬化症研究小组(The Lenercept Multiple SclerosisStudy Group)和不列颠哥伦比亚大学MS/MRI分析小组(The University of BritishColumbia MS/MRI Analysis Group)开发并在Neurology[神经学](1999,第457-507页)中发表；以及“Trial of Celecoxib in Amyotrophic Lateral Sclerosis”[塞来昔布在肌萎缩侧索硬化症中的试验],Cudkowicz等人,Ann.Neurol.[神经病学年鉴]2006；60:22-31。
因此，未在文献中发现对将这些化合物直接用于本文披露的目的的提及。
附图说明
图1.巨噬素在实验性自身免疫性脑脊髓炎(EAE)中的治疗作用，EAE是一种多发性硬化症的小鼠模型。(A)评估EAE小鼠随时间的运动丧失。注意，在疾病发作时用巨噬素治疗导致运动缺陷的显著改善(对比媒介物*p<0.05；使用邦费罗尼(Bonferroni)事后检验的双向重复测量ANOVA)。(B)从罗克沙尔固蓝(luxol fast blue)染色的组织切片对脊髓中的髓磷脂损失进行组织学评估。巨噬素对脱髓鞘产生了显著的保护作用(对比媒介物*p<0.037；t检验)。
图2.巨噬素的给予赋予了对ALS中的功能丧失的显著保护。(A)电生理学试验显示在胫骨前肌(TA)中保留复合肌肉动作电位(CMAP)。注意，巨噬素在4周内延迟了CMAP振幅的丧失(对比媒介物*p<0.05；使用邦费罗尼事后检验的双向重复测量ANOVA)(B)使用巨噬素治疗导致由转棒试验评估的功能结局的显著保留(*p＝0.017；Matel-Cox检验)。
图3.口服巨噬素在实验性自身免疫性脑脊髓炎(EAE)中的治疗作用，EAE是一种多发性硬化症的小鼠模型。(A)评估EAE小鼠随时间的运动丧失。注意，在疾病发作时用巨噬素治疗导致运动缺陷的显著改善(对比媒介物*p<0.05；使用邦费罗尼事后检验的双向重复测量ANOVA)。
发明内容
本发明涉及一种专门的促消退脂质介质，该专门的促消退脂质介质包括巨噬素、D系列消退素、E系列消退素、保护素或脂氧素或其组合，用于治疗神经退行性疾病和/或自身免疫性疾病。
本发明进一步涉及一种包含选自由巨噬素、D系列消退素、E系列消退素、保护素和脂氧素或其组合组成的组的专门的促消退脂质介质的组合物，用于治疗神经退行性疾病和/或自身免疫性疾病。
具体实施方式
本发明涉及一种化合物，该化合物是如本文所定义的专门的促消退脂质介质，该专门的促消退脂质介质包括巨噬素、D系列消退素、E系列消退素、保护素或脂氧素或其组合，用于治疗神经退行性疾病和/或自身免疫性疾病。
本发明进一步涉及一种化合物，该化合物是如本文所定义的专门的促消退脂质介质，该专门的促消退脂质介质选自由巨噬素、D系列消退素、E系列消退素、保护素和脂氧素或其组合组成的组，用于治疗神经退行性疾病和/或自身免疫性疾病。
在优选的实施例中，所述巨噬素是巨噬素-1或巨噬素-2；所述D系列消退素是消退素D1、D2、D3或D4；所述E系列消退素是消退素E1或E2；所述保护素是保护素D1或神经保护素D1；并且所述脂氧素是脂氧素A4或阿司匹林诱生型脂氧素。在更优选的实施例中，用于治疗神经退行性疾病和/或自身免疫性疾病的所述专门的促消退脂质介质是巨噬素-1或巨噬素-2。在本申请的上下文中，术语“巨噬素”包括巨噬素-1和/或巨噬素-2。
巨噬素1(7(R)-MaR1)是由外源性提供给用酵母聚糖A活化的常驻腹腔小鼠巨噬细胞的14(S)-氢过氧化DHA形成的7,14-二羟基DHA。巨噬素2(MaR2)是由与DHA共温育的重组人巨噬细胞12-脂氧合酶和可溶性环氧化物水解酶形成的13R,14S-二羟基DHA。消退素E1(RvE1)是5S,12R,18R-三羟基-二十碳-6Z,8E,10E,14Z,16E-五烯酸。消退素E2(RvE2)是5S,18-二羟基-二十碳-6E,8Z,11Z,14Z,16E-五烯酸。保护素D1(PD1)是10R,17S-二羟基-二十二碳-4Z,7Z,11E,13E,15Z,19Z-六烯酸。消退素D1(RvD1)是7S,8R,17S-三羟基-二十二碳-4Z,9E,11E,13Z,15E,19Z-六烯酸。消退素D2(RvD2)是7S,16R,17S-三羟基-二十二碳-4Z,8E,10Z,12E,14E,19Z-六烯酸。消退素D3(RvD3)是4S,11R,17S-三羟基-二十二碳-5Z,7E,9E,13Z,15E,19Z-六烯酸。消退素D4(RvD4)是4S,5,17S-三羟基-二十二碳-6E,8E,10Z,13Z,15E,19Z-六烯酸。脂氧素A4(LXA4)是5S,6R,15S-三羟基-二十碳-7E,9E,11Z,13E-四烯酸。
如本文所用并在背景技术章节中所定义，“专门的促消退脂质介质”(SPM，也称为专门的促消退介质)是一大类且不断增多的细胞信号传导分子，这些分子通过多不饱和脂肪酸(PUFA)被脂氧合酶、环氧合酶和细胞色素P450单加氧酶之一或其组合进行的代谢而在细胞中形成。
在特定实施例中，所述专门的促消退脂质介质呈互变异构体、溶剂化物、水合物或其药学上可接受的盐的形式，条件是这些化合物的化学结构允许以这些形式存在。
如本文所用的“药学上可接受的盐”是指衍生自相应化合物的盐适于给予给受试者以实现本文所述的治疗，鉴于疾病的严重性和治疗的必要性，没有过度有害的副作用。然而，非药学上可接受的酸和碱的盐也可用于例如制备或纯化药学上可接受的化合物。所有盐，无论是否是药学上可接受的，均包括在本发明的范围内。如上文所提及的药学上可接受的酸和碱加成盐意在包括如本文所披露的化合物能够形成的治疗活性的无毒酸和碱加成盐形式。药学上可接受的酸加成盐可以通过用这种适当的酸处理碱形式而方便地获得。合适的酸包括例如无机酸，诸如氢卤酸，例如盐酸或氢溴酸、硫酸、硝酸、磷酸等酸；或有机酸，例如乙酸、丙酸、羟基乙酸、乳酸、丙酮酸、草酸(即乙二酸)、丙二酸、琥珀酸(即丁二酸)、马来酸、富马酸、苹果酸(即羟基丁二酸)、酒石酸、柠檬酸、甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、环拉酸、水杨酸、对氨基水杨酸、扑酸等酸。
反过来，所述盐形式可通过用适当的碱处理而转化成游离碱形式。
合适的碱盐形式包括例如铵盐、碱金属盐和碱土金属盐，例如锂盐、钠盐、钾盐、镁盐、钙盐等；与有机碱形成的盐，例如苄星青霉素盐、N-甲基-D-葡糖胺盐、海巴明(hydrabamine)盐；以及与氨基酸形成的盐，例如精氨酸盐、赖氨酸盐等。
在另一个优选的实施例中，所述神经退行性疾病和/或自身免疫性疾病选自由多发性硬化症、肌萎缩侧索硬化症、阿尔茨海默氏病、帕金森氏病、HIV痴呆、癫痫、精神分裂症、抑郁症、躁狂抑郁症、神经发育障碍、自闭症、中风、亨廷顿舞蹈病、炎症性肠病、牛皮癣、类风湿性关节炎和系统性红斑狼疮组成的组。在更优选的实施例中，所述疾病是多发性硬化症(MS)。在另一个更优选的实施例中，所述疾病是肌萎缩侧索硬化症(ALS)。
在另一个实施例中，根据前述实施例中任一项所述使用的专门的促消退脂质介质包含在组合物中。在优选的实施例中，将所述组合物配制成化妆品组合物、药物组合物、食品配方、食品成分或补充剂、功能食品、营养补充剂、营养药物组合物(nutraceuticalcomposition)或在天然产物的提取物中。在更优选的实施例中，所述组合物是药物组合物。在另一个更优选的实施例中，所述组合物是食品。
如上所述的“食品”或“食品成分或补充剂”、“功能食品”或“营养补充剂”的组合物原则上可采用适于人或动物消耗的任何形式。
此外，包含SPM的组合物可以包含其他成分。例如，将包含SPM的组合物混合、溶解、乳化(例如，在油/水、水/油或双重乳液中)或悬浮在基质或基料中。基质或基料可以是例如食用油，例如含ω-3PUFA的油，含有高水平EPA、或DELA、或EPA和DELA的混合物的ω-3PUFA浓缩物，或适于消耗或给予的另一种食用油。基质或基料也可以是水或水性缓冲液。包含SPM的组合物也可以在脂质体、纳米颗粒或微粒中制备。
为了延长保质期，组合物还可以含有一种或多种稳定剂，包括抗氧化剂，诸如一种或多种生育酚、抗坏血酸和抗坏血酸-脂肪酸衍生物，以及常用于稳定膳食油的其他抗氧化剂，诸如迷迭香提取物。此外，该组合物可以包装在容器中，这些容器使暴露于氧气、热量和入射光最小化。这些条件将通过防止或限制双键的氧化和异构化来特定地增强SPM的稳定性。由于SPM溶解在具有显著水平的对氧化敏感的PUFA的油中，因此本体油或配制油的稳定性也将受益于这些条件。
这些组合物还可包含一种或多种活性成分，诸如阿司匹林、其他非甾体抗炎药、维生素、抗氧化剂、黄酮类、矿物质、微量元素、脂肪酸、番茄红素、S-腺苷甲硫氨酸、刺激醛(oleocanthal)、白藜芦醇、紫檀茋、生物活性蛋白质和肽诸如菠萝蛋白酶、低聚糖、硫代葡萄糖苷以及植物提取物，诸如齿叶乳香树(Boswellia serrata)、山竹、辣椒、姜黄、姜、茶、印楝和/或柳树皮提取物。成分不限于这里提及的实例。
可以制备特定的营养补充剂以支持特定的健康状况，这些营养补充剂包括补充有包含SPM的组合物的鱼油、磷虾油、或长链ω-3PUFA浓缩物，连同用于关节炎的葡糖胺和软骨素，或连同用于眼睛健康的锌、叶黄素和玉米黄质。
包含SPM的其他营养补充剂是多维生素制剂、运动营养品、强化鱼油胶囊、口腔保健产品诸如牙膏和漱口水，以及用作食品如涂抹酱、调味品、烹调油、零食、营养饮料、软凝胶、口香糖和婴儿配方食品的特定油。
营养药物可以定义为通过增加重要营养素的总膳食摄入量来补充膳食的天然产品。这个定义包括营养补充剂，诸如维生素、矿物质、草药提取物、抗氧化剂、氨基酸和蛋白质补充剂。营养药品适用于由F.D.A在1994年的Dietary Supplement Act[膳食补充剂法案]中确立的新创建的“膳食补充剂”产品类别。该法案特别定义了膳食补充剂包括：维生素、矿物质、草药或其他植物性药材、抗氧化剂、氨基酸或通过增加每日总摄入量来补充膳食的其他膳食物质。“营养药物组合物”在本文中定义为用能够产生健康益处的成分强化的食品组合物。在本发明的上下文中，这样的组合物也可以表示为特殊膳食用途的食品；医疗食品；和膳食补充剂。例如，食品或补充剂可以有助于预防或减轻与炎性病症诸如过敏(例如枯草热)等相关的症状。与药物组合物一样，食品或食品添加剂中活性成分的量将取决于多个因素。食品通常包含的浓度足以在消耗食品的常规(例如每日)部分时向消费者提供有效量的活性成分。本领域技术人员将认识到，技术人员可以容易地确定用于实现本文所述的药物组合物、食品或食品补充剂的治疗效果的各个剂量的最佳量和间隔。
药物组合物的剂量范围可以按照治疗个体患者的需要和根据所治疗的具体病症而调整。许多合适的药物配制品中的任一种都可以用作给予本发明组合物的媒介物，并且可能有多种给予途径。所选的特定模式当然将取决于所选的特定配制品，所治疗的疾病、障碍或病症的严重性和治疗功效所需的剂量。
包含根据前述实施例中任一项所述使用的专门的促消退脂质介质的组合物将通过口服、直肠、局部、阴道、肠胃外(例如，皮下、肌内、皮内、吸入或静脉内)、鞘内、透皮、腹膜内、肺内和鼻内途径但不限于这些途径给予。优选地，所述组合物将通过口服或肠胃外途径给予，但在任何给定情况下最合适的途径将取决于所治疗的病症的性质和严重性以及所用的特定活性产品的性质。适于口服给予的配制品可以以离散单位存在，诸如胶囊剂、扁囊剂、锭剂、滴剂或片剂，它们各自含有预定量的活性化合物；作为粉末或颗粒存在；作为水性或非水性液体中的溶液或悬浮液存在；或作为水包油或油包水乳液存在。此类配制品可通过任何合适的药学方法制备，该方法包括使活性化合物与合适的载体(该载体可含有一种或多种如上所述的辅助成分)结合的步骤。
通常，本发明的配制品通过将活性化合物与液体或细碎的固体载体或两者均匀且紧密地配混，然后如果需要使所得混合物成型来制备。例如，片剂可以通过压制或模制含有活性化合物、任选地具有一种或多种辅助成分的粉末或颗粒来制备。压缩片剂可以通过在合适的机器中压制呈自由流动形式的化合物来制备，诸如任选地与粘合剂、润滑剂、惰性稀释剂和/或表面活性剂/分散剂混合的粉末或颗粒。模制片剂可以通过在合适的机器中模制用惰性液体粘合剂润湿的粉末化合物来制备。
适于肠胃外给予的本发明的配制品方便地包括活性化合物的无菌水性配制品，这些配制品优选与预期接受者的血液等渗。这些制剂可以通过皮下、静脉内、肌内、吸入或皮内注射而给予。此类制剂可以方便地通过将化合物与水或甘氨酸缓冲液配混并使得到的溶液无菌且与血液等渗来制备。
本发明的配制品特别适合局部施用于皮肤，并且优选地采用软膏、乳膏、洗剂、糊剂、凝胶、喷雾剂、气溶胶或油的形式。可以使用的载体包括凡士林、羊毛脂、聚乙二醇、醇、透皮增强剂以及它们中两种或更多种的组合。
适合透皮给予的配制品也可以作为适于与接受者的表皮保持长时间紧密接触的医用绷带或离散贴剂存在。适合透皮给予的配制品也可以通过离子电渗疗法(小电流流过以将带电离子“注入”皮肤；也称为电动力给药(EMDA))通过皮肤递送。
本披露内容还涉及治疗受试者中的如上所定义的神经退行性疾病和/或自身免疫性疾病的方法，该方法包括向所述受试者给予治疗有效量的如上所定义的专门的促消退脂质介质。优选地，受试者是人类受试者。此外，本发明还涉及治疗受试者中的如上所定义的神经退行性疾病和/或自身免疫性疾病的方法，该方法包括向所述受试者给予治疗有效量的如上所定义的包含专门的促消退脂质介质的组合物。短语“治疗有效量”是指以适用于任何治疗的合理的效益/风险比产生一些所需的局部或全身作用的物质的量。这种物质的治疗有效量将根据受试者和所治疗的疾病状况、受试者的体重和年龄、疾病状况的严重性、给予方式等而变化，这可以由本领域的普通技术人员容易地确定。例如，本披露内容的某些组合物可以以足以产生适用于这种治疗的合理的效益/风险比的量给予。
应该注意的是，所有先前的实施例均可以彼此独立地实践或者与本文披露的任何其他实施例组合。
现在通过参考以下实例进一步说明本发明，这些实例无意限制本发明的范围。
实例
实例1：实验性自身免疫性脑脊髓炎(EAE)，多发性硬化症(MS)的小鼠模型
EAE诱导和功能评估：
在雌性成年(8周龄)C57Bl/6小鼠中进行主动免疫。简而言之，皮下注射300μg髓鞘少突胶质细胞糖蛋白(MOG)35-55肽(MEVGWYRSPFSRVVHLYRNGK)，该肽在补充有4mg结核杆菌(micobacterioum tuberculosis)H37RA(迪夫科实验室(DIFCO Laboratories))的完全弗氏佐剂中乳化。在第0天和第2天，还给小鼠腹膜内(i.p.)注射500ng百日咳毒素(立斯特生物实验室(List Biological Laboratories))。每天监测动物的EAE迹象，评分系统如下：0＝没有临床症状；0.5＝部分软尾，1＝软尾；2＝轻度后肢无力(快速翻正反射)；3＝严重后肢无力(缓慢翻正反射)；3.5＝后肢无力或一条后肢瘫痪；4＝双后肢瘫痪，4.5＝前肢无力；5＝前肢瘫痪；6＝奄奄一息。一旦动物显示出最初几个迹象，便每天向小鼠腹膜内注射巨噬素(在200μl盐水中1μg)，直到实验结束(免疫后第21天)。对照小鼠按照相同的治疗方案接受含有200μl盐水的溶液。在免疫后第21天，用4％多聚甲醛溶液灌注小鼠，取出脊髓并切割连续冷冻切片(15μm厚)。然后用罗克沙尔固蓝对组织切片染色以评估脱髓鞘面积。
结果：
我们发现小鼠在免疫后第10-13天之间显示出疾病的最初几个迹象(图1A)。随着时间的推移，在注射盐水的小鼠中功能缺陷出现进展，在免疫后第18天达到平台期。在这个时间点，注射盐水的小鼠的临床评分为约4.5，这表明双后肢瘫痪和前肢无力(图1A)。这一评分在随访结束前没有变化。有趣的是，巨噬素的给予导致功能障碍得到显著改善，在疾病高峰期显示出临床评分为约2.5(图1A)。该评分表明小鼠没有表现出后肢瘫痪，但它们显示出轻微或严重的后肢无力，但前肢没有。脊髓的组织病理学切片还揭示，与用盐水治疗的那些小鼠相比，巨噬素治疗使脱髓鞘区面积减小约50％(图1B)。该数据提供了明确的证据，即巨噬素治疗在多发性硬化症的临床前模型中赋予对功能丧失和髓磷脂损失的保护。
实例2：肌萎缩侧索硬化症
动物：
在从美国缅因州巴港杰克逊实验室Jackson Laboratory(Bar Harbor，ME，USA)获得并从萨拉戈萨大学(University of Zaragoza)维持的群体提供的携带G93A人SOD1突变的雌性转基因小鼠(B6-Tg[SOD1-G93A]1Gur)中进行实验。通过对从尾部样品中提取的DNA进行PCR扩增来鉴定半合子转基因小鼠，然后将这些小鼠保持在当地设施中。将小鼠圈养在22℃±2℃的室温和12:12-h光-暗循环下，随意提供食物和水。当翻正反射丧失超过30s时，认为动物达到了疾病终点。在8周龄时(在治疗开始之前)，对动物进行电生理学测试以获得基线水平。然后在以下平衡组中根据动物的起源、体重和电生理学基线值在不同的实验组中分配动物：巨噬素治疗的或盐水治疗的SOD1G93A小鼠。从8周龄开始，在周一、周三和周五腹膜内给予巨噬素(在200μl盐水中1μg)。
功能测试：
使用转棒试验20评估动物的运动协调、平衡和强度。所有小鼠每周训练三次，在以14rpm的恒定速度旋转的棒(直径3.4cm的旋转圆柱体)上最多180秒以达到基线表现水平。然后以相同的速度从第8至16周每周测试动物，并测量每只动物可以保持在旋转棒上的时间。考虑在旋转棒上保持180s的任意最长时间。
从8周龄到20周龄每2周进行运动神经传导试验(n＝12只用媒介物治疗的SOD1G93A，n＝13只用巨噬素治疗的SODG93A)。通过放置在坐骨神经切口处的一对针电极，借助0.02ms持续时间的单次脉冲(Grass S88)，经皮刺激坐骨神经。从胫骨前肌(TA)记录复合肌肉动作电位(CMAP，M波)。在数字示波器(Tektronix 450S)上以适于测量从基线到最大负峰的振幅的设置放大和显示所有电位。使用显微镜放置记录针并由解剖学标志引导，以确保在所有动物上的针位置的再现性。在试验期间，使用恒温控制的加热垫将小鼠皮肤温度保持在34℃与36℃之间。所有评估者都对实验组不知情。
结果：
我们发现通过复合肌肉动作电位(CMAP)在电生理学上评估的胫骨前肌的神经肌肉完整性在SOD1G93A中从8周龄到20周龄小鼠逐渐降低(图2A)。然而，在第14周观察到在转棒试验中评估的明显运动丧失的最初几个迹象，但在盐水治疗的ALS小鼠中的中位疾病发作为16周(图2B)。有趣的是，用巨噬素治疗在约4周内延迟了电生理损失(图2A)。与电生理学数据一致，我们观察到巨噬素治疗也在3周内延迟了基于转棒试验的疾病发作(中位疾病发作为19周)(图2B)。这些数据提供了明确的证据，即巨噬素在ALS的小鼠模型中提供显著的治疗效果。
在说明书和权利要求书中，术语“包括”和“包含”是开放式术语，并且应该被解释为表示“包括但不限于......”。这些术语涵盖更具限制性的术语“基本上由......组成”和“由......组成”。必须注意的是，除非上下文另外明确指示，否则如本文和所附权利要求中所使用，单数形式“一个/种”和“该”包括复数提及物。
实例3：实验性自身免疫性脑脊髓炎(EAE)，口服治疗中的多发性硬化(MS)小鼠模型
EAE诱导和功能评估：
在雌性成年(8周龄)C57Bl/6小鼠中进行主动免疫。简而言之，皮下注射300μg髓鞘少突胶质细胞糖蛋白(MOG)35-55肽(MEVGWYRSPFSRVVHLYRNG K)，该肽在补充有4mg结核杆菌(micobacterioum tuberculosis)H37RA(迪夫科实验室(DIFCO Laboratories))的完全弗氏佐剂中乳化。在第0天和第2天，还给小鼠腹膜内(i.p.)注射500ng百日咳毒素(立斯特生物实验室(Lis t Biological Laboratories))。每天监测动物的EAE迹象，评分系统如下：0＝没有临床症状；0.5＝部分软尾，1＝软尾；2＝轻度后肢无力(快速翻正反射)；3＝严重后肢无力(缓慢翻正反射)；3.5＝后肢无力或一条后肢瘫痪；4＝双后肢瘫痪，4.5＝前肢无力；5＝前肢瘫痪；6＝奄奄一息。一旦动物显示出疾病的最初几个迹象，小鼠便每天接受巨噬素(在200μl盐水中1μg)口服治疗，直到实验结束(免疫后第21天)。对照小鼠按照相同的治疗方案接受200μl盐水。
结果：
我们发现小鼠在免疫后第9-12天之间显示出疾病的最初几个迹象(图3)。随着时间的推移，在注射盐水的小鼠中功能缺陷出现进展，在免疫后第20天达到平台期。在这个时间点，注射盐水的小鼠的临床评分为约4，这表明双后肢瘫痪(图3)。这一评分在随访结束前没有变化。有趣的是，巨噬素的口服给予导致功能障碍得到显著改善，在疾病高峰期显示出临床评分为约2.5(图3)。该评分表明小鼠没有表现出后肢瘫痪，但它们显示出轻微或严重的后肢无力。
Claims (14)
1.一种专门的促消退脂质介质，其包含巨噬素、D系列消退素、E系列消退素、保护素或脂氧素、或其组合，用于治疗神经退行性疾病和/或自身免疫性疾病。
2.根据权利要求1所述使用的专门的促消退脂质介质，其中所述巨噬素是巨噬素-1或巨噬素-2；所述D系列消退素是消退素D1、D2、D3或D4；所述E系列消退素是消退素E1或E2；所述保护素是保护素D1或神经保护素D1；并且所述脂氧素是脂氧素A4或阿司匹林诱生型脂氧素。
3.根据权利要求2所述使用的专门的促消退脂质介质，该专门的促消退脂质介质是巨噬素-1或巨噬素-2。
4.根据前述权利要求中任一项所述使用的专门的促消退脂质介质，其中所述神经退行性疾病和/或自身免疫性疾病选自由多发性硬化症、肌萎缩侧索硬化症、阿尔茨海默氏病、帕金森氏病、HIV痴呆、癫痫、精神分裂症、抑郁症、躁狂抑郁症、神经发育障碍、自闭症、中风、亨廷顿舞蹈病、炎症性肠病、牛皮癣、类风湿性关节炎和系统性红斑狼疮组成的组。
5.根据前述权利要求中任一项所述使用的专门的促消退脂质介质，其中所述疾病是多发性硬化症。
6.根据前述权利要求中任一项所述使用的专门的促消退脂质介质，其中所述疾病是肌萎缩侧索硬化症。
7.根据前述权利要求中任一项所述使用的专门的促消退脂质介质，该专门的促消退脂质介质包括在组合物中。
8.根据权利要求7所述使用的专门的促消退脂质介质，其中所述组合物被配制成药物组合物、食品、功能食品、食品成分或补充剂、营养补充剂、营养药物组合物或医疗食品，或者在天然产物的提取物或化妆品组合物中。
9.根据权利要求8所述使用的专门的促消退脂质介质，其中所述组合物是药物组合物。
10.根据权利要求8所述使用的专门的促消退脂质介质，其中所述组合物是食品、功能食品或食品成分或补充剂。
11.根据权利要求8所述使用的专门的促消退脂质介质，其中所述组合物是营养药物组合物或医疗食品。
12.根据权利要求8所述使用的专门的促消退脂质介质，其中所述组合物是化妆品组合物。
13.根据权利要求7-12中任一项所述使用的专门的促消退脂质介质，其中所述组合物通过口服、静脉内、皮下、肌内、直肠、局部、阴道、肠胃外、透皮、腹膜内、肺内、鞘内和鼻内途径给予。
14.根据权利要求13所述使用的专门的促消退脂质介质，其中所述组合物通过口服或肠胃外途径给予。
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| CN (1) | CN110325185A (zh) |
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| CN115969830A (zh) * | 2023-02-28 | 2023-04-18 | 武汉大学人民医院（湖北省人民医院） | 保护素d1在制备缓解和/或治疗高血压病及其并发症药物中的应用 |
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| US11583511B2 (en) | 2017-07-20 | 2023-02-21 | Universitat Autonoma De Barcelona | Maresins for use in the treatment of CNS injuries |
| GB202108485D0 (en) * | 2021-06-14 | 2021-07-28 | Univ London Queen Mary | Treatment of inflammatory conditions or diseases |
| CA3222844A1 (en) * | 2021-06-25 | 2022-12-29 | Rene Maltais | Derivatives of the protectin 10s,17s-dihda (pdx) and use thereof as antiviral, anti-inflammatory, and anti-diabetic agents |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5441951A (en) * | 1994-06-15 | 1995-08-15 | Brigham & Women's Hospital | Lipoxin compounds |
| WO2005013908A2 (en) * | 2003-08-05 | 2005-02-17 | Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College | Neuroprotection protects against cellular apoptosis, neural stroke damage, alzheimer’s disease and retinal degeneration |
| US20130302343A1 (en) * | 2011-01-04 | 2013-11-14 | Charité Universitätsmedizin Berlin | Modulators of il-12 and/or il-23 for the prevention or treatment of alzheimer's disease |
| CN104684389A (zh) * | 2012-05-10 | 2015-06-03 | 索卢泰克斯Na有限责任公司 | 含有天然专门促消退介质及其前体的具有抗炎活性的油 |
| CN105338826A (zh) * | 2013-06-27 | 2016-02-17 | 飞鱼有限公司 | 包含鱼油和果汁的组合物用于治疗炎症的用途 |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2390272T3 (es) * | 2003-12-01 | 2012-11-08 | Cambridge Enterprise Limited | Agentes antiinflamatorios |
| GB2452696B (en) * | 2007-08-02 | 2009-09-23 | Cambridge Entpr Ltd | 3-(2',2'-dimethylpropanoylamino)-tetrahydropyridin-2-one and its use in pharmaceutical compositions |
| ES2569371T3 (es) | 2008-09-16 | 2016-05-10 | The Brigham And Women's Hospital Inc. | Compuestos del ácido 7,14-dihidroxidocosahexaenoico |
| CN102021075A (zh) | 2009-09-09 | 2011-04-20 | 朱述兴 | 一种胖大海香精 |
| WO2012135032A2 (en) | 2011-03-25 | 2012-10-04 | The Brigham And Women's Hospital, Inc. | Anti-inflammatory particles |
| US9416118B2 (en) | 2011-06-10 | 2016-08-16 | The Brigham And Women's Hospital, Inc. | Docosahexaenoyl ethanolamides |
| US20150018417A1 (en) * | 2012-02-03 | 2015-01-15 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | Fatty acids as anti-inflammatory agents |
| EP2814479B1 (en) * | 2012-02-15 | 2019-09-04 | Anida Pharma Inc. | Methods of treating amyotrophic lateral sclerosis |
| US9463177B2 (en) | 2012-09-10 | 2016-10-11 | The Regents Of The University Of California | Compounds and methods for modulating vascular injury |
| US10653703B2 (en) | 2015-09-03 | 2020-05-19 | Solutex Na Llc | Compositions comprising omega-3 fatty acids, 17-HDHA and 18-HEPE and methods of using same |
| US11583511B2 (en) | 2017-07-20 | 2023-02-21 | Universitat Autonoma De Barcelona | Maresins for use in the treatment of CNS injuries |
-
2018
- 2018-01-17 EP EP18701301.6A patent/EP3570827A1/en active Pending
- 2018-01-17 CA CA3050572A patent/CA3050572A1/en active Pending
- 2018-01-17 CN CN201880012411.9A patent/CN110325185A/zh active Pending
- 2018-01-17 AU AU2018209681A patent/AU2018209681B2/en active Active
- 2018-01-17 US US16/478,740 patent/US11484520B2/en active Active
- 2018-01-17 IL IL268144A patent/IL268144B2/en unknown
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-
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5441951A (en) * | 1994-06-15 | 1995-08-15 | Brigham & Women's Hospital | Lipoxin compounds |
| WO2005013908A2 (en) * | 2003-08-05 | 2005-02-17 | Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College | Neuroprotection protects against cellular apoptosis, neural stroke damage, alzheimer’s disease and retinal degeneration |
| US20130302343A1 (en) * | 2011-01-04 | 2013-11-14 | Charité Universitätsmedizin Berlin | Modulators of il-12 and/or il-23 for the prevention or treatment of alzheimer's disease |
| CN104684389A (zh) * | 2012-05-10 | 2015-06-03 | 索卢泰克斯Na有限责任公司 | 含有天然专门促消退介质及其前体的具有抗炎活性的油 |
| CN105338826A (zh) * | 2013-06-27 | 2016-02-17 | 飞鱼有限公司 | 包含鱼油和果汁的组合物用于治疗炎症的用途 |
Non-Patent Citations (2)
| Title |
|---|
| JOAN CLÀRIA ETAL.: "Diversity of lipid mediators in human adipose tissue depots", 《AM J PHYSIOL CELL PHYSIOL》, 30 January 2013 (2013-01-30), pages 1 - 31 * |
| 朱兴族: "神经退行性疾病病变机理及药物作用新靶点", 《世界科技研究与发展》, vol. 21, no. 6, 31 December 1999 (1999-12-31), pages 42 - 46 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115969830A (zh) * | 2023-02-28 | 2023-04-18 | 武汉大学人民医院（湖北省人民医院） | 保护素d1在制备缓解和/或治疗高血压病及其并发症药物中的应用 |
Also Published As
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|---|---|
| JP2020505385A (ja) | 2020-02-20 |
| EP3570827A1 (en) | 2019-11-27 |
| AU2018209681A1 (en) | 2019-08-08 |
| IL268144B2 (en) | 2024-05-01 |
| US11484520B2 (en) | 2022-11-01 |
| IL268144B1 (en) | 2024-01-01 |
| IL268144A (en) | 2019-09-26 |
| WO2018134230A1 (en) | 2018-07-26 |
| AU2018209681B2 (en) | 2023-11-16 |
| JP2023123871A (ja) | 2023-09-05 |
| US20200038356A1 (en) | 2020-02-06 |
| CA3050572A1 (en) | 2018-07-26 |
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