CN117159718A - 治疗青光眼的Wnt5a的调节 - Google Patents
治疗青光眼的Wnt5a的调节 Download PDFInfo
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Abstract
通过向有此需要的眼睛局部施用Wnt5a抑制剂的制剂来治疗青光眼或致病眼内压。
Description
本申请为申请日为2018年8月14日、发明名称为“治疗青光眼的Wnt5a的调节”的PCT国际申请PCT/US2018/046578于2020年2月13日进入中国国家阶段、申请号为201880052621.0的中国发明专利申请的分案申请。
本发明是在美国国立卫生研究院授予的基金号EY017392和EY028995的政府支持下完成的。政府拥有本发明的某些权利。
介绍
青光眼是主要的健康问题，其影响超过300万美国人和全世界6000万人。据估计，到2040年，全世界将有1.118亿人受到这种疾病的影响。这种疾病的主要危险因素是眼内压(IOP)升高，如果不进行治疗，它会损害视神经并引起永久性失明。目前，尚无治愈青光眼的方法。现有的滴眼剂或口服药物疗效有限，具有许多副作用，并且手术通常会因瘢痕形成和纤维化而失败。
房水是填充眼睛的前房和后房的透明无色液体。它由睫状体在后房产生，并经由小梁网和施莱姆氏管通过常规途径离开前房角，以及经由葡萄膜巩膜外流通过非常规途径离开前房角。在正常的眼睛中，房水的产生和排出之间存在动态平衡，从而将IOP维持在正常范围内。
施莱姆氏管(SC)是位于眼前房中的虹膜角膜角的圆周通道。它是常规房水流出系统的一部分，占人排出眼的总房水的70-90％。施莱姆氏管的内皮细胞内衬是抵抗房水排出的主要部位之一，并且是IOP的主要决定因素。当管阻力随着年龄的增长或在病理情况下增加时，IOP升高，导致青光眼，并伴有不可逆的视神经损害和视力丧失。因此，它是青光眼治疗的重要靶标。最近，我们提供了施莱姆氏管表达淋巴形成的主要控制基因Prox-1的首个证据(Truong TN,Li H,Hong YK,Chen L.Novel characterization and live imaging ofSchlemm's canal expressing Prox-1.PLoS One.2014；9(5):e98245)。
Wnt5a属于Wnt家族，其在哺乳动物中包含配体和受体。
这里我们公开了Wnt5a在施莱姆氏管上表达，并且其表达响应于剪切应力变化而被调节。此外，通过抑制Wnt5a，我们可以有效地在体内降低IOP。
发明概述
本发明提供了用于局部治疗青光眼或致病眼内压的方法和组合物。
一方面，本发明提供了一种治疗青光眼或致病眼内压的方法，该方法包括向有此需要的眼睛局部施用Wnt5a抑制剂。
在实施方案中：
-施用步骤包括通过滴眼剂或通过前房内、结膜下注射或玻璃体内注射递送；
-所述抑制剂选自抗体、siRNA、小干扰肽和小分子抑制剂；
-通过病毒载体如AAV或慢病毒递送所述抑制剂；和/或
-施用是局部的，并且所述抑制剂以局部眼用凝胶、软膏、混悬剂或溶液的形式施用。
另一方面，本发明提供了Wnt5a特异性抑制剂的眼用制剂，所述抑制剂选自抗体、siRNA、小干扰肽和小分子抑制剂，所述制剂为用于治疗青光眼或致病眼内压的单位剂型。
在实施方案中：
-所述制剂为局部眼用凝胶、软膏、混悬剂或溶液的形式，如眼用润滑剂；
-所述剂型为负载抑制剂的接触镜、滴眼剂、长效制剂(depot)或单次推注剂型(bollus)；
-所述制剂包装在滴眼剂分配器中；
-所述制剂装载在配置用于前房内注射、结膜下注射或玻璃体内注射的注射器中；和/或
-所述制剂还包含适用于直接、局部递送到眼睛的赋形剂和/或特征，其例如选自眼科上适合的澄清度、pH缓冲剂、张力、粘度、稳定性和无菌性。
本发明包括本文叙述的具体实施方案的所有组合。方法可以用包括特定实施方案的所有公开的组合物实施。
发明的具体实施方式的描述
本文描述的实例和实施方案是出于说明性目的，并且按照其的各种修改或改变对于本领域技术人员而言将是显而易见的，并将被包括在本发明中。本领域技术人员将认识到可以改变或修改各种非关键参数以产生基本相似的结果。本发明可以排除本文未要求或公开的任何化合物、组分、要素或步骤，或在本文未要求或公开的任何化合物、组分、要素或步骤不存在的情况下实施。除非有相反指示或另外说明，否则在这些描述和整个说明书中，术语“一个(a)”和“一个(an)”表示一个或多个。出于所有目的将本文引用的所有出版物、专利和专利申请，包括其中的引文通过引用整体并入。
公开的Wnt5a抑制方法可以是基因操纵和/或施用小干扰RNA(siRNA)、抗体、小分子等，其中许多可从诸如Applied Biological Materials Inc.(ABM,Richmond BC)、LifeTechnologies(ThermoFisher Scientific)、Sigma-Aldrich等的来源商购获得。该方法可单独使用以降低眼内压和预防或治疗青光眼，和/或与其他治疗方法，如滴眼剂、药物、激光、植入装置和手术等组合使用，以预防或治疗青光眼。
典型实施例
Wnt5a在培养物中的人原代SC细胞上表达和在小鼠SC上体内表达。Wnt5a表达随剪切应力变化而被调节，如通过实时定量PCR分析来分析。我们还证明了Wnt5a特异性siRNA可以下调人SC细胞中的Wnt5a表达，这也影响SC细胞功能。与对照同窝小鼠相比，在青光眼模型中诱导的SC特异性Wnt5a基因条件性敲除小鼠IOP升高显著降低。在敲除小鼠和对照同窝小鼠之间的基线IOP中未发现显著差异。与在研究的所有时间点均具有IOP升高的对照同窝小鼠相比，Wnt5a敲除小鼠仅在早期(24小时内)显示出IOP升高，而在后来的时间点没有显示IOP升高，表明Wnt5a干预下IOP升高是不可持续的。我们还证明了wnt5a干预可有效保护视网膜神经纤维层并增加SC渗透性，这是增强通过常规流出系统的房水运动来管理高眼压的靶标(例如Tam等人,Scientific Reports 7:40717,DOI:10.1038/srep40717)。这些实验表明，Wnt5a是用于青光眼管理的有效治疗靶标。使用Huang等人的方法，通过CRISPR基因编辑对Wnt5a的选择性抑制进一步证明了这些结果(Nature Communications,2017；8(1)DOI:10.1038/s41467-017-00140-3)。
接下来，我们开发了实验方案来证明Wnt5a siRNA抑制剂治疗降低IOP的功效。对于这些方案，可商业获得Wnt5a特异性siRNA(人WNT5AsiRNA,Life Technologies；Anastas等人，J.Clin.Investig.2014,124,2877-2890)。在一种方案中，如Yuen等人所述进行siRNA的结膜下注射(2014,Invest Ophthalmol Vis Sci.2014；55:3320-3327)。随机选择小鼠接受5uL(0.2lg/uL)siRNA或对照的结膜下注射，每周两次，持续2周。在第二方案中，如Tam等人所述进行siRNA的前房内注射(2017,Scientific Reports 7,40717)。通过腹膜内注射麻醉小鼠，并扩大瞳孔。首先使用牵引的钝头微玻璃针刺穿角膜，以抽出房水。穿刺后，立即将连接到10μl注射器的牵引的钝头微玻璃针通过穿孔插入，并将1.5μl含1μg siRNA的PBS施加到前房中。对侧眼睛接受包含相同浓度的乱序siRNA的1.5μl的相同注射。这些实验证明通过结膜下注射或前房内注射局部递送的Wnt5a特异性抑制剂siRNA是用于致病IOP的有效疗法。
为了评估通过滴眼剂递送的siRNA对IOP的作用，我们基于Martinez等人的方法(Mol Ther.2014Jan；22(l):81-91)开发了另一种方案，其中新西兰白兔在连续4天的期间内接受局部施用20nmol/天的siRNA或磷酸盐缓冲盐水(PBS)。与溶媒处理组相比，处理的眼睛显示显著的IOP降低。第一次施用后2天可检测到siRNA对IOP的作用，直到最后一次施用后约2天，其值仍在基础水平以下。我们还调整了新西兰白兔的口服水过载模型，以评价Wnt5a siRNA在例如青光眼中观察到的病理状态下降低IOP的作用。最初施用四个不同剂量的siRNA(10nmol、20nmol、40nmol和60nmol/眼/天)，共三次：诱发压力过高前48、24和2小时。所有处理均在双眼中实施，并在诱发压力过高之前以及口服过载后每20分钟至最长120分钟测量IOP。结果分析表明，在所有测试剂量下，Wnt5a siRNA均提供显著保护，防止IOP升高。
为了证实Wnt5a siRNA对IOP的功效和特异性，在连续4天的期间内，以40nmol/眼/天的剂量处理一个较大组的动物；在第四天，通过水负载诱导高眼压。对照结果证明，在用PBS处理的动物中，在诱发高眼压后的第一小时期间，水负载导致IOP升高。通过比较每个时间点的IOP值进行的分析表明，与PBS处理的动物相比，用siRNA处理在第一小时内显著降低了ΔΙΟΡ值。由于使用乱序siRNA的处理对IOP没有作用，所以该作用具有特异性。
我们接下来开发了实验方案以证明Wnt5a特异性抗体抑制剂治疗降低IOP的功效。这些方案使用两种不同的抗体：在兔纯化的免疫球蛋白缓冲水溶液中产生的抗人WNT5A抗体(Sigma-Aldrich SAB 1411396)和在小鼠克隆6F2腹水中产生的抗人WNT5A单克隆抗体(Sigma-Aldrich SAB5300183)，但也可以使用其他Wnt5a抗体，例如Hanaki等人,MolCancer Ther 11(2)Feb2012；He等人，Oncogene.2005,24(18):3054-3058。使用小鼠和兔模型(同上)，这些实验证明通过滴眼剂局部递送的Wnt5a特异性抗体抑制剂是用于致病IOP的有效疗法。
在示例性模型系统中，在野生型正常小鼠的右眼(OD)中诱发了眼内高压，并施用Wnt5a中和抗体以评估其对IOP和青光眼的其他参数的治疗效果，所述青光眼的其他参数包括角膜水肿、视网膜神经节细胞(RGC)死亡和RNFL变薄。与在小鼠右眼中IOP显著升高的对照组相比，在Wnt5a抗体处理的眼睛中，IOP显著更低并保持在基线水平。如通过OCT在体内由中央角膜厚度所测量的，Wnt5a干预减少了角膜水肿。在IOP增加之后，在对照组中观察到角膜厚度增加，但在Wnt5a抗体处理的眼睛中未观察到。Wnt5a干预减少了处理的眼睛中的RGC死亡以及RNFL变薄。这些分别通过免疫染色和OCT检测。这些结果证实，在青光眼小鼠模型中，局部Wnt5a抗体干预显著降低IOP并保护角膜和视网膜。
我们接下来设计实验方案以证明Wnt5a特异性拮抗剂肽和小分子抑制剂处理以降低IOP的功效。这些方案采用了叔丁氧羰基修饰的Wnt5a衍生的六肽(Box5)，其充当Wnt5a的强效拮抗剂(Jenei等人,PNAS USA,106(46),19473-8)，和6,7-二氢-10α-羟基根赤壳菌素，其为一种强效WNT-5A表达抑制剂，具有相对低的毒性和优异的稳定性(Shinonaga等人，Bioorg Med Chem.2009Jul l；17(13):4622-35)。这些实验再次使用小鼠和兔模型两者(同上)证明，由滴眼剂局部递送的Wnt5a特异性修饰的肽抑制剂和Wnt5a表达的小分子抑制剂是用于致病IOP的有效疗法。
Claims (24)
1.Wnt5a抑制剂在制备用于预防或治疗青光眼或致病眼内压紊乱的药物中的用途，其中所述Wnt5a抑制剂被局部施用至有此需要的眼睛。
2.根据权利要求1所述的用途，其中所述Wnt5a抑制剂是小干扰肽。
3.根据权利要求2所述的用途，其中所述小干扰肽是叔丁氧羰基修饰的Wnt5a衍生的六肽(Box5)。
4.根据权利要求1所述的用途，其中所述Wnt5a抑制剂是小分子。
5.根据权利要求4所述的用途，其中所述小分子是6,7-二氢-10α-羟基根赤壳菌素。
6.根据权利要求1所述的用途，其中所述Wnt5a抑制剂包括通过CRISPR基因编辑对Wnt5a的选择性抑制。
7.根据权利要求1所述的用途，其中所述Wnt5a抑制剂通过病毒载体递送。
8.根据权利要求7所述的用途，其中所述病毒载体选自AAV或慢病毒。
9.根据权利要求1所述的用途，其中所述Wnt5a抑制剂通过滴眼剂或选自前房内注射、结膜下注射或玻璃体内注射的注射施用。
10.根据权利要求9所述的用途，其中所述Wnt5a抑制剂通过结膜下注射施用。
11.根据权利要求9所述的用途，其中所述Wnt5a抑制剂通过前房内注射施用。
12.根据权利要求9所述的用途，其中所述Wnt5a抑制剂通过玻璃体内注射施用。
13.根据权利要求9所述的用途，其中所述Wnt5a抑制剂通过滴眼剂施用。
14.根据权利要求1所述的用途，其中所述Wnt5a抑制剂以眼用凝胶、软膏、混悬剂或溶液的形式施用。
15.根据权利要求1所述的用途，其产生的一种或多种治疗效果选自降低的IOP、增加的施莱姆氏管渗透性、减少的角膜水肿、保持的角膜厚度、减少的视网膜神经节细胞(RGC)死亡、减少的视网膜神经纤维层(RNFL)变薄或其组合。
16.根据权利要求1所述的用途，其进一步包括施用选自滴眼剂疗法、药物疗法、激光疗法、植入装置疗法或手术疗法的一种或多种另外的治疗方法。
17.一种药物组合物，其包含Wnt5a抑制剂和一种或多种赋形剂，所述药物组合物为配置用于局部施用至眼睛的单位剂型。
18.权利要求17所述的药物组合物，其中所述Wnt5a抑制剂包含一种或多种小干扰肽。
19.权利要求17所述的药物组合物，其中所述Wnt5a抑制剂包含一种或多种小分子。
20.权利要求17所述的药物组合物，其中所述单位剂型选自眼用凝胶、软膏、混悬剂或溶液。
21.权利要求17所述的药物组合物，其中所述单位剂型选自负载的接触镜、滴眼剂制剂、长效制剂或单次推注剂型。
22.权利要求17所述的药物组合物，其中所述单位剂型为滴眼剂制剂。
23.权利要求17所述的药物组合物，其中所述单位剂型被配置用于前房内注射、结膜下注射或玻璃体内注射。
24.权利要求17所述的药物组合物，其进一步包含适用于局部递送到眼睛的特征，其选自眼科上适合的澄清剂、pH缓冲剂、张力剂、粘度剂、稳定剂或无菌剂。
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