CN116437898A - 包含plvap作为活性成分的用于预防或治疗视网膜或脉络膜疾病的药物组合物 - Google Patents
包含plvap作为活性成分的用于预防或治疗视网膜或脉络膜疾病的药物组合物 Download PDFInfo
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- CN116437898A CN116437898A CN202180070383.8A CN202180070383A CN116437898A CN 116437898 A CN116437898 A CN 116437898A CN 202180070383 A CN202180070383 A CN 202180070383A CN 116437898 A CN116437898 A CN 116437898A
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Abstract
本发明涉及一种用于预防或治疗视网膜疾病的药物组合物,其包含PLVAP作为活性成分,并且基于PLVAP的减少可通过引起脉络膜血管的超微结构改变而导致视网膜变性,本发明的发明人确认,对视网膜疾病动物模型施用PLVAP质粒DNA具有增加窗孔的作用,这对于维持脉络膜血管的正常功能,同时维持脉络膜血管的结构和功能是重要的。因此,预期PLVAP蛋白或基因可有效用于治疗视网膜或脉络膜疾病。
Description
技术领域
本发明涉及一种用于预防或治疗视网膜或脉络膜疾病的药物组合物,其包含PLVAP等作为活性成分。
本申请要求于2020年10月13日向韩国知识产权局提交的No.10-2020-0131953韩国专利申请的优先权及其权益,该申请的说明书和附图所公开的全部内容均包含在本申请中。
背景技术
位于眼内视网膜中心的神经组织被称为黄斑,由于大部分对光刺激有反应的视细胞都聚集在黄斑处,并且形成物体图像的地方也位于黄斑中心,因此黄斑在视觉中起着非常重要的作用。年龄相关性黄斑变性(AMD)是一种慢性疾病,其特征在于视网膜色素上皮细胞、布鲁赫膜和黄斑脉络膜毛细血管的变性。在解剖学上,神经感觉视网膜位于视网膜色素上皮细胞的前面,并依赖于视网膜色素上皮细胞的营养、支持、再循环和废物处理。布鲁赫膜是在脉络膜和视网膜色素上皮之间的五层结构。最内层是视网膜色素上皮细胞的基底膜,最外层是脉络膜毛细血管内皮细胞的基底膜。也就是说,AMD是一种在视网膜色素上皮细胞、布鲁赫膜和脉络膜毛细血管复合体中发展的退行性疾病。
这种疾病主要发生在50岁以上的人群中,在西方,这种疾病已经是60岁以上人群失明的主要原因,在韩国也有增加的趋势。尽管AMD的病因尚不清楚,但除了吸烟这一最受关注的环境因素外,还有年龄(尤其是75岁以后急剧增加)、高血压、肥胖、遗传易感性、紫外线照射过度、血清抗氧化浓度低等已知的风险因素。
黄斑变性有两种类型,即干性(非渗出性)黄斑变性和湿性(渗出性)黄斑变性。在干性黄斑变性(干性AMD、非渗出性AMD、非新生血管性AMD)的情况下,废产物在视网膜下形成称为玻璃膜疣的黄色沉积物,当这种沉积物积聚时,它会干扰血液流向视网膜,尤其是黄斑,导致视力模糊和视力障碍。虽然干性黄斑变性不会导致视力突然丧失,但它可能会发展为湿性黄斑变性(湿性AMD、渗出性AMD、新生血管性AMD)。在视网膜下方,嵌入纤维组织内的血管聚集是由视网膜下方脉络膜区域中新血管的生长引起的。当脆弱的新生血管破裂时,会导致出血或渗出,引起视网膜黄斑区的退化,从而导致视力障碍。已知湿性黄斑变性进展迅速,导致视力在数周内迅速恶化,并在两个月至三年内导致失明。
同时,作为迄今为止已知的黄斑变性治疗方法,已使用光动力疗法(PDT)和抗血管内皮生长因子抗体(抗VEGF)注射。PDT是一种通过用特殊的激光照射眼睛来选择性破坏新血管的方法,这种激光仅当维替泊芬(visudyene,其是光敏材料)通过血管注射然后在预定时间后到达视网膜的新血管时对光敏材料产生反应。然而,即使治疗后复发的情况也很多,因此存在很多情况下必须重复治疗的缺点,并且视网膜本身也可能受到损伤。
抗VEGF注射是一种直接注射抗体(抗VEGF)的方法(玻璃体内注射),该抗体通过选择性结合血管内皮生长因子(VEGF)来抑制新血管的形成和增殖,VEGF是新血管生成和发展的重要因素。用于抗VEGF注射的蛋白抗体的示例包括Lucentis(ranibizumab)、Eylea(aflibercept)、Beovu(brolucizumab)和Avastin(bevacizumab),Lucentis、Eylea和Beovu是FDA批准作为湿性黄斑变性的治疗剂,Avastin是一种批准用于治疗癌症的药物,用于治疗眼部疾病。然而蛋白治疗法价格昂贵,并且药物直接注射进入眼内,因为药物不能点滴或施加于眼,需要大约每1至3个月定期施用一次,因此存在出血、感染、视网膜脱离等风险。
此外,脉络膜血管通过内皮细胞的窗孔向视网膜提供氧和营养,并将视网膜中产生的代谢物排入脉络膜,脉络膜血管的窗孔主要朝向视网膜,以帮助排泄废物。然而,抗血管内皮生长因子抗体治疗有效抑制血管生成,但研究结果表明,该治疗通过减少窗孔而加剧视网膜变性,窗孔对于维持脉络膜血管的正常功能很重要。因此,需要开发一种治疗疾病的新技术,同时保持脉络膜血管的超微结构和功能。
糖尿病视网膜病变是年轻人最常见的失明原因,是慢性高血糖引起的血管并发症。这种糖尿病性视网膜病的发生由于血管周围细胞的损失而引起毛细血管的闭合,并且由于新血管的增殖而引起视网膜出血和脱离,从而通过引起视网膜神经功能的丧失而导致失明。虽然包括Lucentis在内的抑制血管内皮生长因子(VEGF)的抗体注射疗法已被用于治疗糖尿病视网膜病变,但需要反复注射,难以恢复基本的血管系统和功能。糖尿病性脉络膜视网膜病变是在存在或不存在此类糖尿病性视网膜病变的情况下都可能发生的疾病,其特征在于脉络膜血管扩张、脉络膜血管渗漏增加以及脉络膜组织炎症和缺血。这种由糖尿病引起的脉络膜变化导致视网膜色素上皮细胞的退化,从而导致视细胞损失和视力退化。由于缺乏对糖尿病性脉络膜视网膜病变的病因和治疗靶点的研究,因此需要开发一种新技术,因为还没有能够治愈或预防糖尿病性脉络膜视网膜病变的有效治疗药物。
此外,还没有尝试改变脉络膜血管的超微结构来治疗视网膜或脉络膜疾病,包括年龄相关性黄斑变性和糖尿病性脉络膜视网膜病变。
【技术问题】
因此,作为构建表达PLVAP的重组质粒DNA并将重组质粒视网膜下注射到年龄相关性黄斑变性和糖尿病性脉络膜视网膜病变小鼠模型的结果,本发明人通过补充PLVAP,不仅脉络膜血管的超微结构极性可以正常化,而且通过恢复内皮细胞窗孔的结构和功能,排泄废物的效果是显著的,因此产生了改善视网膜结构和改善视觉功能的效果,从而完成了本发明。
因此,本发明的一个目的是提供一种用于预防或治疗视网膜或脉络膜疾病的药物组合物,该药物组合物包含质膜囊泡相关蛋白(PLVAP)蛋白、该蛋白的表达或活性激活剂,或编码PLVAP蛋白的核苷酸序列作为活性成分。
本发明的另一个目的是提供一种用于预防或治疗视网膜或脉络膜疾病的准药物组合物,该准药物组合物包含质膜囊泡相关蛋白(PLVAP)蛋白、该蛋白的表达或活性激活剂,或编码PLVAP蛋白的核苷酸序列作为活性成分。
本发明的又一个目的是提供一种用于改善脉络膜血管超微结构的药物组合物,其包含质膜囊泡相关蛋白(PLVAP)蛋白、该蛋白的表达或活性激活剂、或编码PLVAP蛋白的分离的核苷酸序列作为活性成分。
然而,本发明所要解决的技术问题并不局限于上述问题,本领域技术人员从以下描述中可以清楚地理解未提及的其他问题。
发明内容
为实现上述目的,本发明提供了一种用于预防或治疗视网膜或脉络膜疾病的药物组合物,该药物组合物包含质膜囊泡相关蛋白(PLVAP)蛋白、该蛋白的表达或活性激活剂、或编码PLVAP蛋白的核苷酸序列作为活性成分。
在本发明的一个示例性实施方案中,PLVAP蛋白可包含由SEQ ID NO:25表示的氨基酸序列,或与其具有80%或以上序列同源性的氨基酸序列,但不限于此。
在本发明的另一个示例性实施方案中,PVLAP蛋白可以是PLVAP蛋白、其片段、其变体或其融合蛋白,但不限于此。
在本发明的又一示例性实施方案中,编码PLVAP蛋白的核苷酸序列可包含在重组载体中,但不限于此。
重组载体可包含启动子、增强子、内含子、报告标记序列、蛋白质纯化标签、终止序列、mRNA稳定序列、外源基因序列、细胞选择标记序列或其组合,但不限于此。
在本发明的又一个示例性实施方案中,重组载体包含诱导血管内皮细胞特异性表达的启动子,该启动子可以是选自CD144、TIE1、FLT1和EMCN中的一种或多种,但不限于此。
在本发明的又一示例性实施方案中,视网膜或脉络膜疾病可以是与血管渗透性相关的视网膜或脉络膜疾病,但不限于此。
在本发明的又一个示例性实施方案中,视网膜或脉络膜疾病可以是色素性视网膜炎(RP)、Leber先天性黑蒙(LCA)、Stargardt病、Usher综合征、无脉络膜、视锥细胞或视锥细胞营养不良、纤毛病、线粒体疾病、进行性视网膜萎缩、退行性视网膜疾病、年龄相关性黄斑变性(AMD)、湿性AMD、干性AMD、中心性浆液性脉络膜视网膜病变、厚脉络膜疾病谱、退行性近视、结节性脉络膜病变、脉络膜视网膜炎、脉络膜肿瘤、脉络膜新生血管形成、遗传性脉络膜疾病、地图样萎缩、家族性或获得性黄斑病变、视网膜光感受器疾病、视网膜色素上皮性疾病、糖尿病性视网膜病变、糖尿病性脉络膜视网膜病变、黄斑囊样水肿、葡萄膜炎、视网膜脱离、外伤性视网膜损伤、医源性视网膜损伤、黄斑裂孔、黄斑毛细血管扩张症、神经节细胞疾病、视神经细胞疾病、青光眼、视神经病变、缺血性视网膜疾病、早产儿视网膜病变、视网膜血管阻塞、家族性视网膜动脉大动脉瘤、视网膜血管疾病、眼部血管疾病、视网膜神经细胞变性、由于青光眼引起的视网膜神经细胞变性、缺血性视神经病变或其组合,但不限于此。
在本发明的又一示例性实施方案中,核苷酸序列可包含由SEQ ID NO:1表示的碱基序列,或与其具有80%或以上同源性的碱基序列,但不限于此。
在本发明的又一个示例性实施方案中,药物组合物可以配制为通过一种或多种选自:口服、皮下、腹膜内、肺内、鼻内、肌内、静脉内、动脉内和局部眼部施用的途径施用于受试者,但不限于此。
在本发明的又一个示例性实施方案中,局部眼部施用可以是结膜内施用、玻璃体内施用、视网膜下施用、脉络膜上腔施用、结膜下施用、Tenon囊下施用或其组合,但不限于此。
在本发明的又一示例性实施方案中,药物组合物还可包含选自药学上可接受的载体、赋形剂和稀释剂中的一种或多种,但不限于此。
在本发明的又一个示例性实施方案中,药物组合物可以恢复内皮细胞的窗孔,但不限于此。
在本发明的又一示例性实施方案中,药物组合物还可以包含抗VEGF剂,但不限于此。
在本发明的又一个示例性实施方案中,药物组合物可以与抗VEGF剂同时或依次施用,但不限于此。
此外,本发明提供一种用于预防或治疗视网膜或脉络膜疾病的准药物组合物,该准药物组合物包含质膜囊泡相关蛋白(PLVAP)蛋白质、该蛋白质的表达或活性激活剂,或编码PLVAP蛋白的核苷酸序列作为活性成分。
此外,本发明提供了一种预防、改善或治疗视网膜或脉络膜疾病的方法,该方法包括:将包含质膜囊泡相关蛋白(PLVAP)蛋白、该蛋白的表达或活性激活剂、或编码PLVAP蛋白的核苷酸序列作为活性成分的药物组合物施用于受试者。
在本发明的示例性实施方案中,受试者可以是需要治疗视网膜或脉络膜疾病的受试者,但不限于此。
在本发明的示例性实施方案中,药物组合物可以与抗VEGF剂同时或依次施用,但不限于此。
此外,本发明提供包含质膜囊泡相关蛋白(PLVAP)蛋白、该蛋白的表达或活性激活剂、或编码PLVAP蛋白的核苷酸序列作为活性成分的药物组合物用于预防、改善或治疗视网膜或脉络膜疾病的用途。
此外,本发明提供质膜囊泡相关蛋白(PLVAP)蛋白、该蛋白的表达或活性激活剂、或编码PLVAP蛋白的核苷酸序列在制备用于预防或治疗视网膜或脉络膜疾病的药物中的用途。
此外,本发明还提供了质膜囊泡相关蛋白(PLVAP)蛋白、该蛋白的表达或活性激活剂、或编码该PLVAP蛋白的核苷酸序列,其特征在于改善脉络膜血管的超微结构。
此外,本发明提供了一种用于改善脉络膜血管超微结构的药物组合物,该药物组合物包含质膜囊泡相关蛋白(PLVAP)蛋白、该蛋白的表达或活性激活剂、或编码PLVAP蛋白的分离的核苷酸序列作为活性成分。
此外,本发明提供了一种改善脉络膜血管超微结构的方法,该方法包括:将包含质膜囊泡相关蛋白(PLVAP)蛋白、该蛋白的表达或活性激活剂、或编码PLVAP蛋白的分离的核苷酸作为活性成分的组合物施用于受试者。
此外,本发明提供包含质膜囊泡相关蛋白(PLVAP)蛋白、该蛋白的表达或活性激活剂、或编码PLVAP蛋白的分离的核苷酸序列作为活性成分的组合物用于改善脉络膜血管的超微结构的用途。
【有益效果】
基于PLVAP的减少可能通过引起脉络膜血管超微结构的变化而导致视网膜变性,本发明人确认,将PLVAP质粒DNA施用于视网膜或脉络膜疾病的动物模型具有增加窗孔的效果,这对于维持脉络膜血管的正常功能很重要,同时维持脉络膜血管的结构和功能。因此,预期PLVAP蛋白或基因可有效用于治疗视网膜或脉络膜疾病。
附图说明
图1示出了根据本发明示例性实施方案的PLVAP质粒DNA的结构和组成元件。
图2示出了根据本发明示例性实施方案的根据启动子和整合酶的类型PLVAP质粒DNA处理人脉络膜内皮细胞的PLVAP表达结果。
图3示出了根据本发明示例性实施方案的根据启动子的类型将PLVAP质粒DNA视网膜下注射到小鼠中后72小时PLVAP的表达率。
图4示出了根据本发明示例性实施方案的在年龄相关性黄斑变性的小鼠模型中确认脉络膜血管的超微结构变形的结果。
图5示出了根据本发明示例性实施方案的干性年龄相关性黄斑变性的小鼠模型中脉络膜血管中的窗孔数量和不定向的窗孔数量。
图6示出根据本发明示例性实施方案的干性年龄相关性黄斑变性的小鼠模型中视网膜下空间和布鲁赫膜中视网膜代谢废物排泄模式的确认结果。
图7示出了根据本发明示例性实施方案的确认其中脉络膜血管中的窗孔数量增加并且隔膜由于将PLVAP质粒DNA施用至干性年龄相关性黄斑变性小鼠模型而恢复的模式的结果。
图8A和8B示出了根据本发明的示例性实施方案的确认由于将PLVAP质粒DNA施用于干性年龄相关性黄斑变性的小鼠模型而导致脂质代谢物被良好排泄并且脂滴和积累几乎完全消失的结果。
图9A和9B示出了根据本发明示例性实施方案的通过眼底照相确认由于将PLVAP质粒DNA施用于干性年龄相关性黄斑变性小鼠模型导致的黄斑变性进展程度的结果。
图10A和10B示出了根据本发明示例性实施方案的通过眼底照相和脉络膜血管造影确认由于将PLVAP质粒DNA施用于干性年龄相关性黄斑变性小鼠模型而导致的黄斑变性进展程度的结果。
图11示出了根据本发明示例性实施方案的通过视网膜电图确认由于将PLVAP质粒DNA施用于干性年龄相关性黄斑变性的小鼠模型而导致恢复退化的视觉功能的结果。
图12示出了根据本发明示例性实施方案的确认由于将PLVAP质粒DNA施用于湿性年龄相关性黄斑变性小鼠模型而导致抑制脉络膜新生血管形成的结果。
图13示出根据本发明示例性实施方案的确认糖尿病性脉络膜视网膜病变小鼠模型中脉络膜血管超微结构变形的结果。
图14A和14B示出了根据本发明示例性实施方案的糖尿病性脉络膜视网膜病变小鼠模型中脉络膜血管的窗孔数量、不定向窗孔数量以及其中横膈膜丢失的异常窗孔的比例。
图15示出了根据本发明示例性实施方案的确认脉络膜血管的窗孔数量由于将PLVAP质粒DNA施用于糖尿病性脉络膜视网膜病变的小鼠模型而导致增加的结果。
图16示出了根据本发明示例性实施方案的通过眼底照相确认由于将PLVAP质粒DNA施用于糖尿病性脉络膜视网膜病变小鼠模型而导致的黄斑变性进展程度的结果。
图17示出了根据本发明示例性实施方案的通过视网膜电图确认由于将PLVAP质粒DNA施用于糖尿病性脉络膜视网膜病变小鼠模型而导致恢复恶化的视觉功能的结果。
图18示出了根据本发明示例性实施方案的PLVAP哺乳动物质粒载体的结构和组成元件。
图19A和19B示出了根据本发明的示例性实施方案的确认由于将PLVAP质粒DNA施用于PLVAPECKO小鼠模型而导致的脉络膜血管的窗孔数量增加并且脉络膜血管的极性归一化的结果。
图20显示了根据本发明示例性实施方案的在注射PLVAP质粒后年龄相关性黄斑变性/糖尿病性脉络膜视网膜病变脉络膜血管超微结构的变化。
图21A至21E是根据本发明示例性实施方案确认脉络膜血管极性的结果,确认PLVAP因老化或糖尿病而减少,并且脉络膜血管的超微结构因PLVAP减少而改变。
具体实施方案
【最佳模式】
本发明涉及一种用于预防或治疗视网膜或脉络膜疾病的药物组合物,该药物组合物包含质膜囊泡相关蛋白(PLVAP)蛋白、该蛋白的表达或活性激活剂、或编码PLVAP蛋白的核苷酸序列作为活性成分。
此外,本发明还涉及一种质膜囊泡相关蛋白(PLVAP)蛋白、该蛋白的表达或活性激活剂、或编码该PLVAP蛋白的核苷酸序列,其特征在于改善脉络膜血管的超微结构。
以下,对本发明进行详细说明。
在本发明中,PLVAP也称为质膜囊泡相关蛋白或PV-1,是指天然存在的或内源性的PLVAP(例如哺乳动物、人)蛋白质,其氨基酸序列为与天然存在的或内源性PLVAP蛋白(例如,重组蛋白、合成蛋白)相同或基本相同。因此,在本文中可互换使用的术语PLVAP,包括通过例如在哺乳动物(例如,人类)中自然发生的选择性剪接或其他细胞过程产生的PLVAP蛋白的多态或等位基因变体和其他亚型。在本发明中,PLVAP蛋白可以包含或由NCBI参考序列:NP_112600.1的氨基酸序列组成,但不限于此。
在本发明中,编码PLVAP蛋白的核苷酸序列可以包含SEQ ID NO:1所示的碱基序列,但不限于此。如本文所用,“编码PLVAP蛋白的核苷酸序列”可以包含由SEQ ID NO:1表示的核苷酸序列,并且优选地可以由SEQ ID NO:1表示的核苷酸序列组成。此外,核苷酸变体包括在本发明的范围内。具体地,所述核苷酸序列可以包括与SEQ ID NO:1的碱基序列具有80%或更高、优选90%或更高序列同源性的核苷酸序列。例如,所述核苷酸序列包括具有80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%的序列同源性的多核苷酸。
在本发明中,PLVAP蛋白可以包含SEQ ID NO:25所示的氨基酸序列,但不限于此。如本文所用,“PLVAP蛋白”可以包含由SEQ ID NO:25表示的氨基酸序列,并且优选地可以由SEQ ID NO:25表示的碱基序列组成。此外,PLVAP蛋白、其片段、其变体或其融合蛋白包含在本发明的范围内。具体地,蛋白可包含与SEQ ID NO:25的氨基酸序列具有80%或更多、优选90%或更多序列同源性的氨基酸序列。例如,蛋白包含具有80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%和100%的序列同源性的蛋白。
在本发明中,编码PLVAP蛋白的核苷酸序列可以包含在重组载体中,但不限于此。
在本发明中,“表达载体”是指能够表达由插入载体中的外源核酸编码的肽或蛋白质的载体,优选为表达PLVAP蛋白而制备的重组表达载体。“载体”是指用于在体外、离体或体内在宿主细胞中引入和/或转移碱基的任何介质,并且可以是复制子,另一个DNA片段可以与其结合以实现结合片段的复制,“复制子”是指在体内作为DNA复制的自主单位起作用的任何遗传单位(例如,质粒、噬菌体、粘粒、染色体、病毒等),也就是说,它能够在自己的控制下进行复制。本发明的重组表达载体可优选包含作为RNA聚合酶结合的转录起始因子的启动子、用于调节转录的任何操纵子序列、编码合适的mRNA核糖体结合位点的序列和用于调节转录和翻译的终止的序列,终止子等,还可以进一步包含用于选择转化体的抗生素抗性基因等选择标记基因。
在本发明中,编码PLVAP蛋白的核苷酸序列可以通过一个或多个核酸碱基的取代、缺失、插入或其组合进行修饰,只要它编码具有与PLVAP相当的活性的蛋白即可。这种核酸分子的序列可以是单链的也可以是双链的,可以是DNA分子也可以是RNA(mRNA)分子。
在本发明中,载体包括脂质体、质粒载体、粘粒载体、噬菌体载体、病毒载体等,但不限于此。在本发明中,优选的病毒载体的实例包括腺病毒、腺伴随病毒、逆转录病毒、慢病毒、单纯疱疹病毒、α病毒等。在本发明中,载体可以包含启动子、增强子、内含子、报告标记序列、蛋白质纯化标签、终止序列、mRNA稳定序列、外源基因序列、细胞选择标记序列,或它们的组合。本发明的重组载体可包含编码PLVAP的核酸和用于其转录或翻译的调控序列。特别是,一个重要的调节序列像启动子和增强子一样调节转录起始。此外,重要的调节序列可以包括由起始密码子、终止密码子、聚腺苷酸化信号、Kozak序列、增强子、用于膜靶向和分泌的信号序列、内部核糖体进入位点(IRES)等组成的调节序列。这种调节序列和编码PLVAP的核酸需要可操作地连接。
在本发明中,增强子可以包括CMV增强子、RSV增强子、甲胎蛋白增强子、TTR最小启动子/增强子、TH结合球蛋白启动子/α-微球蛋白/双枯宁增强子(LSP)、APB增强子、ABPS增强子、α-mic/bik增强子、TTR增强子、en34或ApoE,但不限于此。
在本发明中,内含子可选自CBA、人β珠蛋白、IVS2、SV40、bGH、α-球蛋白、β-球蛋白、胶原蛋白、卵清蛋白、p53或其片段,但不限于此。
在本发明中,报告标记序列包括各种已知的报告标记序列,可以优选为绿色荧光蛋白(GFP)基因、eGFP基因、荧光素酶基因、β-半乳糖苷酶基因、氯霉素乙酰转移酶基因、人生长激素基因或分泌性胎盘碱性磷酸酶基因,但不限于此。
在本发明中,编码本发明的PLVAP蛋白的核苷酸序列可以以下形式施用,其中包含该多核苷酸的重组DNA分子可操作地连接至调节表达的核酸序列,例如,以表达载体的形式,使得重组DNA分子在待治疗的患者中表达。优选地,该载体包含合适的转录调控信号,该信号包含能够表达编码序列的启动子位点,并且该启动子在待治疗的患者中是可操作的。因此,启动子是一个术语,它不仅包含将RNA聚合酶引导至人类基因治疗的转录起始位点所需的序列,而且包括包含增强子的其他操作或调节序列,如果合适的话,可以包含pEMU启动子、MAS启动子、组蛋白启动子、Clp启动子、花椰菜花叶病毒衍生的35S启动子、花椰菜花叶病毒衍生的19S RNA启动子、植物肌动蛋白启动子、泛素蛋白启动子、巨细胞病毒(CMV)启动子、猴病毒40(SV40)启动子、呼吸道合胞病毒(RSV)启动子、延伸因子-1α(EF-1α)启动子等,并且可以优选地是来自人基因的人启动子序列或来自通常在人类中表达的基因的人启动子序列,例如来自人类CMV的启动子。
在本发明中,载体可以由图1或图18中公开的切割图表示,但不限于此。
在本发明中,重组载体还可以包含在选自CD144、TIE1、FLT1和EMCN的一种或多种血管内皮细胞中特异性表达的启动子,优选包含CD144,但不限于此。
在本发明中,重组载体可包含内部核糖体进入位点(IRES)或2A肽,但不限于此。
在本发明中,“肽”是指小的(18-22个氨基酸)肽序列,其允许在单个编码序列中高效一致地表达单个蛋白质产物。任何方便的2A肽,例如,来自病毒(例如口蹄疫病毒(F2A)、马鼻炎A病毒、猪teschovirus-1(P2A)或Thoesa asigna病毒(T2A))的2A肽,或任何一种在Szymczak-Workman,A.等人,"Design and Construction of 2A Peptide-LinkedMulticistronic Vectors"中描述的2A肽中的任何一种,可用于靶向载体。文献[GeneTransfer:Delivery and Expression of DNA and RNA(编辑Friedmann和Rossi).CSHLPress,Cold Spring Harbor,NY,USA,2007],其公开内容通过引用并入本文。
在本发明中,视网膜或脉络膜疾病可以是与血管通透性相关的视网膜或脉络膜疾病,但不限于此。“血管通透性相关性视网膜或脉络膜疾病”是由于血管通透性的正常调节被破坏而引起的视网膜疾病,通常是指由于血管的变化导致通透性增加而引起出血、水肿和炎症的视网膜或脉络膜疾病。
在本发明中,所述视网膜或脉络膜疾病可以是选自视网膜或脉络膜疾病可以是色素性视网膜炎(RP)、Leber先天性黑蒙(LCA)、Stargardt病、亚瑟氏综合征、无脉络膜、视锥细胞或视锥细胞营养不良、纤毛病、线粒体疾病、进行性视网膜萎缩、退行性视网膜疾病、年龄相关性黄斑变性(AMD)、湿性AMD、干性AMD、中心性浆液性脉络膜视网膜病变、厚脉络膜疾病谱、退行性近视、结节性脉络膜病变、脉络膜视网膜炎、脉络膜肿瘤、脉络膜新生血管形成、遗传性脉络膜疾病、地图样萎缩、家族性或获得性黄斑病变、视网膜光感受器疾病、视网膜色素上皮性疾病、糖尿病性视网膜病变、糖尿病性脉络膜视网膜病变、黄斑囊样水肿、葡萄膜炎、视网膜脱离、外伤性视网膜损伤、医源性视网膜损伤、黄斑裂孔、黄斑毛细血管扩张症、神经节细胞疾病、视神经细胞疾病、青光眼、视神经病变、缺血性视网膜疾病、早产儿视网膜病变、视网膜血管阻塞、家族性视网膜动脉大动脉瘤、视网膜血管疾病、眼部血管疾病、视网膜神经细胞变性、由于青光眼引起的视网膜神经细胞变性、缺血性视神经病变或其组合中的一种或多种,但不限于此。
在本发明中,“年龄相关性黄斑变性(AMD)”是指视网膜黄斑随着年龄的增长而发生各种变化引起的疾病,视网膜黄斑在视力中起着非常重要的作用。在本发明中,年龄相关性黄斑变性可以包括干性(非渗出性)AMD或湿性(渗出性)AMD。“干性AMD”是指视网膜出现玻璃膜疣或视网膜色素上皮萎缩等病变的病例,占AMD的近90%。由于存在于黄斑部的视细胞逐渐萎缩,随着时间的推移,视力逐渐恶化,AMD可能发展成湿型。在“湿性AMD”中,脉络膜新生血管在视网膜下生长,这种新生血管本身或血管的出血、渗出等,正在或可能造成严重的视力障碍,并可能在发病后数月至数年内因盘状萎缩而导致失明、严重出血等。
在本发明中,“糖尿病性视网膜病变”是糖尿病发生的微血管并发症之一,是由于毛细血管的功能和形态改变而发生的,例如由于高血糖以及伴随而来的各种生化变化引起的血管通透性增加的缺血和视网膜的新生血管形成。在本发明中,糖尿病性视网膜病变可包括非增殖性或增殖性视网膜病变,但不限于此。“非增殖性视网膜病变”是指视网膜小血管变弱导致血清渗漏或堵塞,从而中断营养供应的病症。众所周知,“增殖性视网膜病变”是由于血液循环不畅的部位形成新血管而引起,除非给予适当的治疗,否则新血管出血会在5年内导致失明。
在本发明中,“糖尿病性脉络膜视网膜病变(糖尿病脉络膜病变)”是糖尿病脉络膜血管中发生的微血管并发症之一,由于慢性高血糖抑制脉络膜毛细血管层的窗孔和内皮转运而发生,大分子在脉络膜和视网膜之间的内皮运输受到糖尿病的损害。此外,血管周围细胞的损失和变性还伴随着脉络膜大血管(如动脉和静脉)的结构和功能变化,导致脉络膜组织炎症和缺血。糖尿病性脉络膜视网膜病变可能是由于脉络膜结构和功能异常的诱导导致视力下降的疾病,这导致视网膜营养不良和代谢废物的积累。
在本发明中,“脉络膜”是位于巩膜和视网膜之间的眼球壁之一,是眼球后部富含血管和黑素细胞的薄膜。已知脉络膜起到防止从外部入射的光散射的作用,在眼睛的后部充当脉络膜,在眼睛的前部充当虹膜。
在本发明中,“脉络膜血管的超微结构”可以指包括视网膜下空间、布鲁赫膜、视网膜色素上皮、脉络膜血管、脉络膜血管内皮细胞、内皮细胞的窗孔,以及上述成分的整体结构中的一种或多种,但不限于此。超微结构可通过眼底照相、脉络膜血管造影、视网膜电图等方式确认,但不限于此。
在本发明中,“脉络膜血管超微结构的改善”是指所有降低症状严重程度的行为,包括与脉络膜血管超微结构变形相关的参数,例如窗孔数量的减少,窗孔极性的变化,内皮细胞厚度的变化,内皮细胞中视网膜废物的积累,以及窗孔隔膜的损失。
在本发明中,药物组合物可以增加或恢复内皮细胞的窗孔,但不限于此。在本发明中,窗孔的恢复可以将内皮细胞的窗孔方向从巩膜侧恢复到视网膜侧,使窗孔朝向视网膜侧的极性正常化,增加窗孔的数量,或者抑制或减少窗孔隔膜的损失,但不限于此。
在本发明中,药物组合物还可以包含抗VEGF剂,但不限于此。在本发明中,抗VEGF剂例如可以为选自贝伐珠单抗、雷珠单抗、培加他尼、帕唑帕尼、舒尼替尼、索拉非尼、瑞戈非尼、卡博替尼、乐伐替尼、普纳替尼、阿昔替尼、替沃扎尼、雷莫芦单抗、凡德他尼、布罗鲁珠单抗、法利昔单抗和阿法西普中的一种或多种,但不限于此。此外,抗VEGF剂可包含结合血管表皮生长因子(VEGF)以防止或减少与其受体结合的肽、结合VEGF的抗体、能够结合VEGF的核酸等,但不限于此。
在本发明中,药物组合物可以与抗VEGF剂同时或依次施用,但不限于此。在本发明中,包含质膜囊泡相关蛋白(PLVAP)蛋白、该蛋白的表达或活性激活剂、或编码PLVAP蛋白的核苷酸序列作为活性成分的组合物可以被配制成以与抗VEGF剂的混合物的形式存在于一个容器中,并且可以被配制成存在于单独的容器中并且同时或依次施用。此外,包含质膜囊泡相关蛋白(PLVAP)蛋白、该蛋白的表达或活性激活剂或编码PLVAP蛋白的核苷酸序列作为活性成分的组合物可以在用抗VEGF剂治疗后作为二次治疗施用,但不限于此。
本发明组合物中质膜囊泡相关蛋白(PLVAP)蛋白、该蛋白的表达或活性激活剂、或编码PLVAP蛋白的核苷酸序列的含量可根据疾病的症状、症状的进展程度、患者的状况等适当调整,并且可以是,例如,基于组合物的总重量的0.0001至99.9wt%,或0.001至50wt%,但不限于此。含量比是基于除去溶剂的干燥量的值。
本发明的药物组合物还可以包括适当的载体、赋形剂和稀释剂,它们通常用于制备药物组合物。赋形剂可以是例如选自由稀释剂、粘合剂、崩解剂、润滑剂、吸附剂、保湿剂、薄膜包衣材料和控释添加剂中的一种或多种。
本发明的药物组合物可以制成散剂、颗粒剂、缓释颗粒剂、肠溶颗粒剂、液体剂、滴眼液、酏剂、乳剂、混悬剂、烈酒、锭剂、芳香水、柠檬水、片剂、缓释片、肠溶片、舌下片、硬胶囊、软胶囊、缓释胶囊、肠溶胶囊、丸剂、酊剂、软提取剂、干提取剂、液体提取剂、注射剂、胶囊、灌注剂、外用制剂如膏药、洗剂、糊剂、喷雾剂、吸入剂、贴剂、无菌注射液,或气雾剂,外用制剂可以有霜剂、凝胶剂、贴剂、喷雾剂、软膏剂、硬膏剂、洗剂、搽剂、糊剂或巴布剂等形式。
可包含在根据本发明的组合物中的载体、赋形剂或稀释剂的实例包括乳糖、右旋糖、蔗糖、寡糖、山梨糖醇、甘露糖醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、阿拉伯胶、藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、微晶纤维素、聚乙烯吡咯烷酮、水、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石粉、硬脂酸镁和矿物油。
在制备药物组合物时,使用稀释剂或赋形剂制备药物组合物,例如通常使用的填充剂、增量剂、粘合剂、润湿剂、崩解剂和表面活性剂。
作为根据本发明的片剂、散剂、颗粒剂、胶囊剂、丸剂和锭剂的添加剂,可以使用赋形剂例如玉米淀粉、马铃薯淀粉、小麦淀粉、乳糖、蔗糖、葡萄糖、果糖、D-甘露醇、沉淀碳酸钙、合成硅酸铝、磷酸氢钙、硫酸钙、氯化钠、碳酸氢钠、纯化羊毛脂、微晶纤维素、糊精、海藻酸钠、甲基纤维素、羧甲基纤维素钠、高岭土、尿素、胶体硅胶、羟丙基淀粉、羟丙基甲基纤维素(HPMC)、HPMC 1928、HPMC 2208、HPMC 2906、HPMC 2910、丙二醇、酪蛋白、乳酸钙和羧甲基淀粉钠(Primojel);粘合剂,例如明胶、阿拉伯树胶、乙醇、琼脂粉、醋酸邻苯二甲酸纤维素、羧甲基纤维素、羧甲基纤维素钙、葡萄糖、纯净水、酪蛋白酸钠、甘油、硬脂酸、羧甲基纤维素钠、甲基纤维素钠、甲基纤维素、微晶纤维素、糊精、羟纤维素、羟丙基淀粉、羟甲基纤维素、纯化紫胶、淀粉、羟丙基纤维素、羟丙基甲基纤维素、聚乙烯醇和聚乙烯吡咯烷酮;崩解剂,例如羟丙基甲基纤维素、玉米淀粉、琼脂粉、甲基纤维素、膨润土、羟丙基淀粉、羧甲基纤维素钠、海藻酸钠、羧甲基纤维素钙、柠檬酸钙、十二烷基硫酸钠、硅酸酐、1-羟丙基纤维素、葡聚糖、离子交换树脂、聚乙酸乙烯酯、甲醛处理酪蛋白和明胶、海藻酸、直链淀粉、瓜尔胶、碳酸氢钠、聚乙烯吡咯烷酮、磷酸钙、凝胶淀粉、阿拉伯树胶、支链淀粉、果胶、聚磷酸钠、乙基纤维素、蔗糖、硅酸镁铝、D-山梨糖醇溶液和轻质无水硅酸;以及润滑剂,例如硬脂酸钙、硬脂酸镁、硬脂酸、氢化植物油、滑石粉、石松粉、高岭土、凡士林、硬脂酸钠、可可脂、水杨酸钠、水杨酸镁、聚乙二醇4000、PEG 6000、液体石蜡、氢化大豆油(Lubriwax)、硬脂酸铝、硬脂酸锌、十二烷基硫酸钠、氧化镁、聚乙二醇、合成硅酸铝、硅酸酐、高级脂肪酸、高级醇、硅油、石蜡油、聚乙二醇脂肪酸醚、淀粉、氯化钠、乙酸钠、油酸钠、dl-亮氨酸和轻质无水硅酸。
作为用于根据本发明的液体制剂的添加剂,可以使用水、稀盐酸、稀硫酸、柠檬酸钠、蔗糖单硬脂酸酯、聚氧乙烯山梨糖醇脂肪酸酯(吐温酯)、聚氧乙烯单烷基醚、羊毛脂醚、羊毛脂酯、乙酸、盐酸、氨水、碳酸铵、氢氧化钾、氢氧化钠、醇溶谷蛋白、聚乙烯吡咯烷酮、乙基纤维素、羧甲基纤维素钠等。
在根据本发明的糖浆中,可以使用蔗糖溶液、其他糖或甜味剂等,并且如果需要,可以使用香料、着色剂、防腐剂、稳定剂、悬浮剂、乳化剂、增稠剂等。
根据本发明的乳液可以使用纯化水,并且如果需要,可以使用乳化剂、防腐剂、稳定剂、香料等。
在根据本发明的助悬剂中,可以使用例如阿拉伯胶、黄蓍胶、甲基纤维素、羧甲基纤维素、羧甲基纤维素钠、微晶纤维素、海藻酸钠、羟丙基甲基纤维素、HPMC 1828、HPMC2906和HPMC 2910之类助悬剂,并且如果需要可以使用表面活性剂、防腐剂、着色剂和香料。
根据本发明的注射剂可以包括:溶剂,例如注射用蒸馏水、0.9%氯化钠注射液、林格注射液、葡萄糖注射液、葡萄糖+氯化钠注射液、聚乙二醇、乳酸林格注射液、乙醇、丙二醇、非挥发油—芝麻油、棉籽油、花生油、玉米油、油酸乙酯、肉豆蔻酸异丙酯和苯甲酸苯;增溶剂,例如苯甲酸钠、水杨酸钠、乙酸钠、尿素、氨基甲酸酯、单乙基乙酰胺、丁唑烷、丙二醇、吐温、烟酰胺、六胺和二甲基乙酰胺等;缓冲剂,例如弱酸或其盐(乙酸、乙酸钠)、弱碱及其盐(氨、乙酸铵)、有机化合物、蛋白质、白蛋白、蛋白胨、树胶等;等渗剂如氯化钠;稳定剂,例如亚硫酸氢钠(NaHSO3)、二氧化碳气体、焦亚硫酸钠(Na2S2O5)、亚硫酸钠(Na2SO3)、氮气(N2)和乙二胺四乙酸;抗氧剂,例如0.1%硫化氢钠、甲醛次硫酸氢钠、硫脲、乙二胺四乙酸二钠和丙酮亚硫酸氢钠;镇痛剂,例如苯甲醇、氯丁醇、盐酸普鲁卡因、葡萄糖和葡萄糖酸钙;和悬浮剂,例如羧甲基纤维素钠、海藻酸钠、吐温80和单硬脂酸铝。
在根据本发明的栓剂中,可以使用基质例如可可脂、羊毛脂、Witepsol、聚乙二醇、甘油明胶、甲基纤维素、羧甲基纤维素、硬脂酸盐和油酸盐的混合物、Subanal、棉籽油、花生油、棕榈油、可可脂+胆固醇、卵磷脂、Lanette蜡、甘油单硬脂酸酯、吐温或Span、Imhausen、monolen(丙二醇单硬脂酸酯)、甘油、Adeps solidus、Buytyrum Tego-G、Cebes Pharma 16、hexalide base 95、Cotomar、Hydrokote SP、S-70-XXA、S-70-XX75(S-70-XX95)、Hydrokote25、Hydrokote 711、Idroppostal、Massa estrarium、A、AS、B、C、D、E、I、T)、Mass-MF、Masupol、Masupol-15、neosuppostal-N、paramount-B、supposiro(OSI、OSIX、A、B、C、D、H、L)、栓剂碱基IV型(AB、B、A、BC、BBG、E、BGF、C、D、299)、Suppostal(N、Es)、Wecoby(W、R、S、M、Fs)和Tegester甘油三酯碱(TG-95、MA、57).
用于口服施用的固体制剂包括片剂、丸剂、散剂、颗粒剂、胶囊剂等,并且该固体制剂通过混合至少一种赋形剂(例如淀粉、碳酸钙、蔗糖或乳糖、明胶等)与提取物来制备固体制剂。此外,除单纯的赋形剂外,还使用如硬脂酸镁和滑石粉等润滑剂。
用于口服施用的液体制剂对应于混悬液、内服液、乳剂、糖浆等,液体制剂除了水和液体石蜡这些简单常用的稀释剂外,还可以包括各种赋形剂,例如,润湿剂、甜味剂、香料、防腐剂等。用于肠胃外施用的制剂的示例包括无菌水溶液、非水溶剂、混悬剂、乳剂、冻干制剂和栓剂。作为非水溶剂和悬浮液,可以使用丙二醇、聚乙二醇、如橄榄油之类的植物油、如油酸乙酯之类的可注射酯等。
根据本发明的药物组合物以药物有效量施用。在本发明中,“药学有效量”是指足以以适用于医疗的合理收益/风险比治疗疾病的量,有效剂量水平可根据患者的疾病类型、疾病的严重程度、药物活性、对药物的敏感性、施用时间、施用途径、排泄率、治疗持续时间、以及医学领域众所周知的其他参数在内的参数确定。
根据本发明的药物组合物可以作为单独的治疗剂或与其他治疗剂组合施用,可以与相关领域的治疗剂顺序或同时施用,并且可以单剂量或多剂量施用。考虑到所有上述参数,重要的是以没有任何副作用的最小剂量获得最大效果,并且这样的剂量可以由本发明所属领域的普通技术人员容易地确定。
本发明的药物组合物可以通过多种途径施用于有需要的受试者。可以预期所有施用方法,药物组合物可以通过例如口服施用、皮下注射、腹膜内施用、静脉内注射、肌肉内注射、椎旁间隙(硬膜内)注射、舌下施用、口腔施用、直肠内插入、阴道内注射、眼部施用、耳部施用、鼻腔施用、吸入、经口或鼻喷雾、皮肤施用、透皮施用等来施用。
在本发明中,药物组合物可以通过一种或多种途径施用,所述途径选自口服、皮下、腹膜内、肺内、鼻内、肌内、静脉内、动脉内和局部眼部施用,但不限于此。在本发明中,局部眼部施用可以是选自结膜内施用、玻璃体内施用、视网膜下施用、脉络膜上腔施用、结膜下施用和Tenon囊下施用中的一种,但不限于此。
本发明的药物组合物取决于作为活性成分的药物的类型以及各种相关参数,例如要治疗的疾病、施用途径、患者的年龄、性别和体重以及疾病的严重程度。
如本文所用,“受试者”是指需要治疗目标疾病的对象,更具体地,可以是哺乳动物如人或非人灵长类动物、小鼠、大鼠、狗、猫、马和牛,但不限于此。受试者可以是需要治疗视网膜或脉络膜疾病的受试者,但不限于此。
如本文所用,“施用”是指通过任何合适的方法将本发明的预定组合物提供给有需要的受试者。
本文所使用的“预防”是指抑制或延缓目标疾病发作的所有作用,“治疗”是指通过施用本发明的药物组合物减轻或有益改变目标疾病及其引起的代谢异常的所有行为,并且“改善”是指通过施用根据本发明的组合物降低目标疾病和相关参数(例如症状的严重程度)的所有作用。
此外,本发明提供一种用于预防或治疗视网膜或脉络膜疾病的准药物组合物,该准药物组合物包含质膜囊泡相关蛋白(PLVAP)蛋白质、该蛋白质的表达或活性激活剂,或编码PLVAP蛋白的核苷酸序列作为活性成分。
准药物组合物是指在以诊断、治疗、改善、减轻、治疗或预防人类或动物疾病为目的的物品中,其作用比药物温和的物品,例如,根据药品事务法(Pharmaceutical AffairsAct),准药物是指不用于医药目的的物品,包括用于治疗和预防人类和动物疾病的纤维和橡胶产品,对人体几乎没有或没有直接影响的产品,并且类似于非仪器或机器的产品,以及预防传染病的杀菌杀虫剂等等。
在本发明中,准药物组合物可以通过配制成眼科组合物的剂型来使用,例如,可以作为选自滴眼液、洗眼剂、眼药膏、注射剂和洗眼液中的一种或多种制剂使用,但不限于此。
由于本发明可以被修改成各种形式并且包括各种示例性实施方案,因此具体示例性实施方案将在附图中示出并在详细描述中详细描述。然而,本说明书并不旨在将本发明限制于特定的示例性实施方案,应当理解,属于本发明的精神和技术范围的所有改变、等同物和替换都包含在本发明中。当确定在描述本发明时对相关公知技术的详细描述可能模糊本发明的要点时,将省略其详细描述。
【发明方式】
在下文中,将建议有助于理解本发明的优选实施例。然而,提供以下实施例只是为了使本发明更容易理解,本发明的内容不受以下实施例限制。
【实施例】
实施例1.表达PLVAP的最佳质粒DNA的构建
1-1.表达PLVAP的最佳质粒DNA的构建
PLVAP质粒DNA是使用在巨细胞病毒(CMV)或血管内皮细胞中特异性表达的启动子作为非特异性细胞表达启动子构建的。在血管内皮细胞中特异性表达的启动子如下:CD144(VE钙粘蛋白)、TIE1、FLT1(VEGFR1)或EMCN(内粘蛋白)。将eGFP作为报告基因插入PLVAP序列的上游,以确认质粒插入和基因表达的成功。在这种情况下,根据质粒的大小使用整合连接子,如下所示:attB1/2、内部核糖体进入位点(IRES)和Thosea asigna病毒2A肽(T2A)。为了过表达PLVAP,使用以下方法构建启动子eGFP-PLVAP质粒DNA。使用可从VectorBuilder商购的Design Vector Studio工具构建基础质粒的骨架,并将CMV、CD144、TIE1、FLT1或EMCN启动子的碱基序列插入其中。此后,将eGFP的碱基序列插入开放阅读框1(ORF1),将PLVAP的碱基序列插入开放阅读框架2(ORF2),并且将作为允许eGFP和PLVAP两者的表达的整合接头(用于连续表达并自动切割两种多肽)的碱基序列的attB1/2、IRES或T2A插入ORF1和ORF2之间。在ORF2末端插入SV40晚期mRNA多腺苷酸化信号序列,并插入CMV启动子和抗生素抗性基因。然后,使用相应的质粒图谱定制载体。所构建的载体的结构如图1所示。
表1
1-2.质粒DNA在人脉络膜血管内皮细胞中表达的确认
将经人源材料研究ICF同意下捐赠用于角膜移植的眼球中采集的原代培养人脉络膜血管内皮细胞用质粒DNA处理,以检查实施例1-1中构建的质粒DNA是否在血管内皮细胞中良好表达。向质粒DNA中添加LipofectamineTM 3000,其为可从Invitrogen商购的体外转染试剂,使得质粒DNA的最终浓度变为2μg/mL。用质粒处理人脉络膜血管内皮细胞。2天后更换培养基,再培养2天,检查PLVAP质粒是否表达。
如图2所示,所有质粒DNA均有效导入人脉络膜血管内皮细胞,确认PLVAP在转染后在血管内皮细胞中表达。其中,含有CD144作为启动子的质粒DNA具有最高的表达水平。
1-3.质粒DNA在小鼠视网膜和脉络膜中表达的确认
将质粒DNA视网膜下注射入野生型C57BL/6小鼠中,并进行RT-PCR以检测实施例1-1中构建的包含CD144和IRES的质粒DNA中的PLVAP基因是否在小鼠视网膜和脉络膜中良好表达。GAPDH用作管家基因。根据制造商的说明使用RNeasy Plus Mini试剂盒(Qiagen,Hilden,德国)提取总RNA,并使用PrimeScriptTM第一链cDNA合成试剂盒(Takara,Shiga,日本)逆转录成cDNA。使用实时PCR检测系统(Bio-Rad TM CFX96;Bio-Rad Laboratories,Inc.,Hercules,美国加利福尼亚州)使用SsoAdvanced Universal SYBR Green Supermix(Bio-Rad,美国加利福尼亚州)以及表2中列出的引物进行定量实时PCR(RT-PCR)。使用扩增软件(Bio-Rad CFX Manager;Bio-Rad Laboratories,Inc.)分析RT-PCR数据。
表2
RT-PCR引物
如图3所示,所有质粒DNA均显著诱导PLVAP表达。其中,包含CMV和CD144启动子的质粒DNA具有显著高的表达水平。
实施例2.通过注射表达PLVAP的质粒DNA对对年龄相关性黄斑变性的治疗效果的确认
2-1.年龄相关性黄斑变性小鼠模型的构建
通过将PLVAP flox小鼠与VE-cadherin-creERT2小鼠交配以特异性消耗小鼠血管内皮细胞中的PLVAP来构建年龄相关性黄斑变性模型。具体来说,使用VE-cadherin-creERT2;PLVAP flox(VEcad-CreERT2;PLVAPflox/flox;以下称为PLVAPiECKO)基因型小鼠,其是通过将对应于小鼠品系1的VE-cadherin-creERT2小鼠与对应于小鼠品系2的PLVAP flox小鼠交配而组合的诱导型内皮细胞特异性敲除小鼠。当将他莫昔芬药物引入PLVAPiECKO,将位于PLVAP基因外显子上游和下游的FLOX盒连接成环状结构,并且一部分存在于盒之间的PLVAP激活基因被移除,以利用用于防止PLVAP基因被正常转录的系统时,会产生由他莫昔芬诱导型雌激素受体(ERT2)激活的环状重组酶(Cre)。
如图4和5所示,在本发明的AMD模型中引起脉络膜毛细血管窗孔总数的减少和窗孔方向性的改变,并且窗孔的隔膜消失。这些结果与在人类黄斑变性中观察到的组织学发现一致。
此外,如图6所示,视网膜中的代谢废物积聚在视网膜下空间和布鲁赫膜中,因为由于脉络膜毛细血管的变化,代谢废物不能正常通过脉络膜血管,其具有类似于干性黄斑变性患者中发现的脂滴或玻璃膜疣的模式。因此,确认了使用转基因小鼠作为年龄相关性黄斑变性动物模型是合适的。
2-2.通过在年龄相关性黄斑变性小鼠模型中施用质粒DNA对脉络膜毛细血管结构的改善的确认
当PLVAP质粒DNA被施用于实施例2-1所示的AMD模型的视网膜下空间时,确认脉络膜毛细血管的结构是否恢复。使用购自Polyplus Transfection的体内jetPEI产品在体内递送质粒DNA。将4μg质粒DNA(包含实施例1-1的CMV和CD144启动子)与0.4μL体内转染试剂混合在10μL 5%葡萄糖溶液中获得的试剂,使用38G微针(Incyto Co.,Ltd.)以4μL的体积一次注射到PLVAPECKO小鼠模型的视网膜下空间。作为对照,将不含质粒的5%葡萄糖溶液和体内转染试剂的混合物的载体注射到视网膜下空间一次。
如图7所示,确认随着减少的窗孔数量恢复,脉络膜毛细血管恢复为正常的脉络膜毛细血管,并且构成窗孔的膜在构建的动物模型中恢复。
结果表明,本发明的PLVAP质粒DNA使年龄相关性黄斑变性小鼠的脉络膜毛细血管结构正常化。
2-3.通过施用质粒DNA对预防和治疗年龄相关性黄斑变性的机制的确认
根据实施例2-2的方法施用PLVAP质粒。当将PLVAP质粒施用于AMD模型时,确认作为干性黄斑变性患者症状的脂滴和玻璃膜疣是否得到改善,以及视网膜中的代谢废物是否得到良好排出。
如图8A和8B所示,AMD模型中布鲁赫膜中积聚的脂滴全部消失。基于该结果,确认了由PLVAP质粒DNA诱导的脉络膜毛细血管结构的变化促进了脂质代谢物从视网膜中的排泄。具体而言,已确认黑色素脂褐素、颗粒和脂滴是视网膜色素上皮细胞(RPE)的代表性脂质代谢物,从脉络膜毛细血管和布鲁赫膜掺入内皮细胞(EC)。
因此,通过施用PLVAP质粒DNA,可以通过防止年龄相关性黄斑变性中玻璃膜疣和布鲁赫膜之间的基底沉积来预防和治疗年龄相关性黄斑变性。
2-4.施用质粒DNA对年龄相关性黄斑变性的发病和早期进展的抑制作用的确认
评估了施用PLVAP质粒DNA对年龄相关性黄斑变性的发生和早期进展的抑制作用。根据实施例2-2的方法施用PLVAP质粒。在8周龄的小鼠中诱导黄斑变性,同时将包含CMV和CD144启动子的PLVAP质粒DNA注射到年龄相关性黄斑变性模型的眼睛中,随后孵育2周以允许有足够的时间使PLVAP质粒DNA充分表达。通过超广角眼底照相分析视网膜变性的进展。
如图9A和9B所示,与对照相比,施用PLVAP质粒的眼睛中视网膜变性的进展受到抑制。具体而言,确认了视网膜色素上皮细胞(RPE)的变性被显著抑制并且涡静脉的扩张显著减少。
这表明,在年龄相关性黄斑变性的早期阶段使用PLVAP质粒具有预防和抑制疾病的发生和发展的效果。
2-5.施用质粒DNA对年龄相关性黄斑变性的治疗效果的确认
同时,为了验证治疗效果,诱导了年龄相关性黄斑变性。2周后,黄斑变性的症状得到充分表达,然后向其中施用PLVAP质粒。表达时间设定为注射后2周。根据实施例2-2的方法施用PLVAP质粒。
如图10A和10B所示,当施用PLVAP质粒时,视网膜变性的进展被抑制。另外,脉络膜血管造影(indocyanine green angiography,ICGA)的结果显示涡静脉的扩张减少,脉络膜血管的渗漏减少。根据这些结果,可以预期PLVAP质粒对干性和湿性年龄相关性黄斑变性均具有治疗效果。
实施例3.PLVAP质粒DNA对受损视功能恢复效果的确认
为了评估干性年龄相关性黄斑变性模型的视觉功能,进行了视网膜电图(ERG)。视网膜电图(ERG)在诊断和研究视网膜功能异常方面起着重要作用。在暗适应下观察到a波和b波的振幅降低。这里,a波的振幅减小表示感光体的故障,b波的振幅减小表示双极细胞的故障。如[Documenta Ophthalmologica第130卷,第1-12页(2015)]中的描述进行视网膜电图方法。在将PLVAP质粒DNA注入年龄相关性黄斑变性模型的眼球后4周进行视网膜电图。
如图11所示,确认了与对照组相比,在年龄相关性黄斑变性模型中视网膜下施用PLVAP质粒的实验组中,a波和b波的振幅增加并且潜伏期减少以恢复视觉细胞的功能。这表明本发明的PLVAP质粒DNA在恢复由年龄相关性黄斑变性引起的视觉功能受损方面是有效的。
实施例4.PLVAP质粒DNA对湿性(渗出性)年龄相关性黄斑变性影响的确认
根据实施例的结果,确认PLVAP质粒DNA对脉络膜血管具有正常化作用。基于该结果,使用激光诱导的脉络膜新生血管形成模型检查了对湿性年龄相关性黄斑变性的抗血管生成作用。在7周龄时,以与实施例2-2中使用的PLVAP质粒溶液的制备和注射相同的方式,将4μL的PLVAP质粒溶液注射到模型的眼睑内。一周后,通过对8周大的小鼠应用激光,构建了模拟湿性黄斑变性的脉络膜新生血管模型。激光照射后,将2周设定为新血管形成充分进行的时间。此后,收集小鼠眼球以进行组织学检查。
如图12所示,确认了当施用PLVAP质粒DNA时,与对照相比,PLVAP质粒DNA抑制脉络膜新生血管形成,表明PLVAP质粒在治疗湿性年龄相关性黄斑变性方面是有效的。
实施例5.注射表达PLVAP的质粒DNA对糖尿病视网膜病变/脉络膜视网膜病变的治疗效果的确认
5-1.糖尿病性脉络膜视网膜病变小鼠模型的构建
糖尿病性脉络膜视网膜病变是由于长期糖尿病引起的脉络膜血管结构和功能改变而引起视网膜变性从而导致视力下降的疾病。据报道,在糖尿病性脉络膜视网膜病变中观察到脉络膜血管的各种变化,例如脉络膜血管扩张、脉络膜毛细血管损失等。其中,脉络膜毛细血管的变化对于维持视网膜的功能最为重要。为了构建糖尿病性脉络膜视网膜病变动物模型,首先,以200mg/kg的剂量对7至8周龄雄性C57BL6/J小鼠进行腹膜内施用链脲佐菌素(STZ;Sigma)。一周后,测量血糖以检查是否诱发高血糖症。选取血糖诱导至400mg/dL以上的小鼠用于后续实验。STZ施用后约8周,糖尿病性脉络膜视网膜病变的早期症状开始出现。
如图13所示,诱导糖尿病的实验动物显示出脉络膜血管以与年龄相关性黄斑变性动物模型相似的方式扩张的现象。
此外,如图14A和14B所示,观察到糖尿病性脉络膜视网膜病变的特征,例如脉络膜毛细血管中的窗孔总数减少和隔膜丢失的窗孔比例增加。结果证实该动物模型适合用作糖尿病性脉络膜视网膜病变动物模型。
5-2.通过施用质粒DNA对糖尿病性脉络膜视网膜病变小鼠模型中脉络膜毛细血管结构的改善的确认
将包含CMV和CD144启动子的PLVAP质粒DNA以与实施例2-2中溶液的制备和注射方法相同的方式视网膜下注射到实施例5-1的16周龄的糖尿病性脉络膜视网膜病变模型中,并且四周后确认了脉络膜毛细血管的结构。
如图15所示,与阴性对照相比,PLVAP质粒施用组中脉络膜毛细血管窗孔数量增加并恢复到正常水平。
结果表明,本发明的PLVAP质粒DNA使患有糖尿病性脉络膜视网膜病变的小鼠的年龄相关性黄斑变性和脉络膜毛细血管结构正常化。
5-3.施用质粒DNA对糖尿病性脉络膜视网膜病变的发病和进展的抑制作用的确认
在实施例5-1的糖尿病性脉络膜视网膜病变模型中,以与实施例2-2中使用的PLVAP质粒溶液的制备和注射相同的方式将PLVAP质粒视网膜下注射到16周龄小鼠中。通过眼底照相和脉络膜血管造影分析视网膜变性的进展。
如图16所示,根据眼底照相的结果确认,在对照的视网膜中与棉絮点相同的位置(红色虚线区域)观察到脉络膜血管的扩张和渗漏。此外,还确认在不同部位也观察到表明脉络膜组织中的炎症和视网膜微动脉瘤的脉络膜高荧光斑点,它们是糖尿病性视网膜病变的代表性医学特征。相反,在注射了PLVAP质粒的实验组的情况下,确认在眼底照相中没有观察到棉绒斑。另外,从ICGA的结果确认,未发现脉络膜血管的扩张和渗漏,微动脉瘤或高荧光点显著减少。
因此,确认了PLVAP质粒的视网膜下施用在预防和治疗糖尿病性视网膜病变和糖尿病性脉络膜视网膜病变方面是有效的。
5-4.PLVAP质粒DNA对受损视功能恢复的作用的确认
从16周龄起,将PLVAP质粒视网膜下注射到实施例5-1中使用的糖尿病性脉络膜视网膜病变模型中。进行视网膜电图(ERG)以评估糖尿病性脉络膜视网膜病变模型的视觉功能。
如图17所示,从视觉功能分析的结果确认,与对照相比,在糖尿病性视网膜病变/糖尿病性脉络膜模型中视网膜下施用PLVAP质粒的实验组中,a波和b波的振幅增加并且潜伏期减少以恢复视觉细胞的功能。
这表明本发明的PLVAP质粒DNA在恢复由糖尿病性视网膜病变/脉络膜视网膜病变引起的受损视觉功能方面是有效的。
实施例6.使用CMV启动子表达PLVAP的哺乳动物质粒载体的效果的确认6-1.表达PLVAP的哺乳动物质粒载体的构建
如图18所示,插入能够表达PLVAP蛋白质的DNA序列、作为哺乳动物共表达启动子的CMV启动子和整合接头attB1/2以构建具有约7,500bp的总大小的质粒DNA。构建这种质粒的方法如上述实施例1-1中所述。
6-2.表达PLVAP的哺乳动物质粒载体对年龄相关性黄斑变性的治疗效果的确认
以与实施例2-2中相同的方式使用实施例6-1的PLVAP质粒DNA在体内递送的细节。注射后6周,检查脉络膜毛细血管结构。通过脉络膜血管造影分析脉络膜血管渗漏和扩张。
如图19A和19B所示,确认在使用CMV作为启动子注射PLVAP质粒DNA后1个月,通过补充PLVAP,脉络膜血管中的窗孔数量增加并且极性朝向视网膜归一化,并且视网膜废物得到很好的排出。此外,已确认无隔膜窗孔的数量通过PLVAP的补充而减少。此外,已确认注射PLVAP质粒DNA后,年龄相关性黄斑变性模型中脉络膜血管的渗漏和扩张显著减少。
因此,揭示了CMV启动子-PLVAP具有改善视力的治疗效果,因为通过施用CMV启动子-PLVAP改善了视网膜变性的症状。
此外,从图20可以看出,通过注射PLVAP质粒恢复了脉络膜血管的超微结构。
实施例7.PLVAP在衰老和糖尿病患者中表达的确认
通过检查供体眼球中基础疾病的病历并使用从患者获得的眼球,检查PLVAP在衰老和糖尿病患者中的表达。仅使用无眼科和代谢基础疾病的供体眼球,根据年龄将患者分为20至40岁的青年和60岁以上的老年。仅在青年组上进行了确认窗孔方向的实验。糖尿病患者捐献的眼球未按年龄单独划分,而是使用40岁以上和70岁以下的所有患者对应的年龄组捐献的眼球作为对照。来自参与研究的患者的数据被用作糖尿病患者的超广角眼底照相和OCT照相结果。
如图21A所示,可以看出在正常人脉络膜毛细血管中窗孔均匀分布。
此外,如图21B和21C所示,确认了窗孔的绝对数量随着老年人脉络膜毛细血管内皮细胞中PLVAP表达的减少而减少,并且由于窗孔指向巩膜而不是视网膜(这是相反的方向)而导致毛细血管中窗孔的极性发生变化。由于超微结构的这种变化,确认废物不是从视网膜排出而是积累在视网膜中引起炎症,并且黄斑变性是由视网膜功能受损引起的。
此外,如图21D和21E所示,确认糖尿病患者的脉络膜毛细血管内皮细胞中的PLVAP表达降低。
结果支持,脉络膜血管的PLVAP补充因衰老和糖尿病而减少显示了对包括年龄相关性黄斑变性和糖尿病性脉络膜视网膜病变的视网膜疾病的治疗效果。
对本发明的上述描述是为了说明的目的,本发明所属领域的技术人员将理解,在不改变本发明的技术精神或本质特征的情况下,可以容易地将本发明修改为其他具体形式。因此,应当理解,上述示例在所有方面仅是示例性的而不是限制性的。
【工业适用性】
基于PLVAP的减少可能通过引起脉络膜血管超微结构的变化而导致视网膜变性,本发明人确认,将PLVAP质粒DNA施用于视网膜或脉络膜疾病的动物模型具有增加窗孔的效果,这对于维持脉络膜血管的正常功能很重要,同时维持脉络膜血管的结构和功能。因此,PLVAP蛋白或基因可有效用于治疗视网膜或脉络膜疾病,因而具有工业实用性。
<110> 财团法人峨山社会福祉财团
蔚山大学校产学协力团
<120> 包含PLVAP作为活性成分的用于预防或治疗视网膜或脉络膜疾病的药物组合物
<130> 2301871FWN
<150> KR 10-2020-0131953
<151> 2020-10-13
<160> 25
<170> KoPatentIn 3.0
<210> 1
<211> 1329
<212> DNA
<213> 人工序列
<220>
<223> hPLVAP
<400> 1
atgggtctgg ccatggagca cggagggtcc tacgctcggg cggggggcag ctctcggggc 60
tgctggtatt acctgcgcta cttcttcctc ttcgtctccc tcatccaatt cctcatcatc 120
ctggggctcg tgctcttcat ggtctatggc aacgtgcacg tgagcacaga gtccaacctg 180
caggccaccg agcgccgagc cgagggccta tacagtcagc tcctagggct cacggcctcc 240
cagtccaact tgaccaagga gctcaacttc accacccgcg ccaaggatgc catcatgcag 300
atgtggctga atgctcgccg cgacctggac cgcatcaatg ccagcttccg ccagtgccag 360
ggtgaccggg tcatctacac gaacaatcag aggtacatgg ctgccatcat cttgagtgag 420
aagcaatgca gagatcaatt caaggacatg aacaagagct gcgatgcctt gctcttcatg 480
ctgaatcaga aggtgaagac gctggaggtg gagatagcca aggagaagac catttgcact 540
aaggataagg aaagcgtgct gctgaacaaa cgcgtggcgg aggaacagct ggttgaatgc 600
gtgaaaaccc gggagctgca gcaccaagag cgccagctgg ccaaggagca actgcaaaag 660
gtgcaagccc tctgcctgcc cctggacaag gacaagtttg agatggacct tcgtaacctg 720
tggagggact ccattatccc acgcagcctg gacaacctgg gttacaacct ctaccatccc 780
ctgggctcgg aattggcctc catccgcaga gcctgcgacc acatgcccag cctcatgagc 840
tccaaggtgg aggagctggc ccggagcctc cgggcggata tcgaacgcgt ggcccgcgag 900
aactcagacc tccaacgcca gaagctggaa gcccagcagg gcctgcgggc cagtcaggag 960
gcgaaacaga aggtggagaa ggaggctcag gcccgggagg ccaagctcca agctgaatgc 1020
tcccggcaga cccagctagc gctggaggag aaggcggtgc tgcggaagga acgagacaac 1080
ctggccaagg agctggaaga gaagaagagg gaggcggagc agctcaggat ggagctggcc 1140
atcagaaact cagccctgga cacctgcatc aagaccaagt cgcagccgat gatgccagtg 1200
tcaaggccca tgggccctgt ccccaacccc cagcccatcg acccagctag cctggaggag 1260
ttcaagagga agatcctgga gtcccagagg ccccctgcag gcatccctgt agccccatcc 1320
agtggctga 1329
<210> 2
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<212> DNA
<213> 人工序列
<220>
<223> mPLVAP
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tggtactacc tgcgctattt cttcctcttc gtgtcgctca ttcagttcct catcatcctg 120
ggcctggtcc tcttcatgat ctatggcaat gtgcacgcca ccactgagtc cagcctgcgc 180
gccacggaga tccgcgccga cagcctgtac agccaggtgg ttggactatc ggcctcacag 240
gctaacctga gcaaacagct gaacatcagc ttgcttgtca aggaaacagt catgcagcaa 300
ctgttgacta cgcgacgtga gatggagcgc atcaacgcca gcttccgcca gtgccaaggc 360
gacctgatca cctacataaa ctataatcgc ttcatcgccg ctatcatcct gagcgagaag 420
cagtgccagg aacagctgaa ggaggtcaac aagacctgcg aagctttact cttcaagctg 480
ggagaaaaag ttaagacact ggagatggag gtggccaagg agaaggcagt gtgctccaag 540
gacaaggaga gcctgctggc aggaaagcgg cagacggaag agcagctgga ggcctgtggc 600
aaagcacgcg aaaggcaaca gcaggagcag caggtgaccg aggagaacct gcgcaaggtg 660
cagtccctgt gcatcccact ggaccaggag aagttccagg cggacgtgct gagtgcgtgg 720
cgggactcgc tgatctaccg taccttggaa accctgccct accactacca gctgatgccg 780
gagtacgcgt ccctccgtcg gacctgcgag agcctgcccg ggatcatgac caccaagata 840
gaagagctgg cccgcgggct gcgcgccggc attgagcgcg tgacccgtga gaatgcagaa 900
ctgcggcgcc agaagttgga gctagagcgc gcggcacagg cggcgcagga ggcgcgggcg 960
cgcgccggga ccgaggcgca ggcgcgagaa acccagctac gggcggagtg cgcgcgccag 1020
acgcagctgg ctctggagga gaaggcggcg ctgcgcgcgc agcgggacaa cctagagcgc 1080
gagctggagg cgcgtaagcg ggagctggag caactgcgca ccgaggtgga tgtgcgcatt 1140
agcgcgctgg acacctgcgt caaggccaag tcgctgccag ccgtcccgcc gagagtctca 1200
ggcccacccc cgaaccctcc acccattgat ccagctagcc tggaggaatt caagaaaagg 1260
atcctggagt ctcagcggct ccctgtagtc aaccctgctg cccaacccag cggttga 1317
<210> 3
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<213> 人工序列
<220>
<223> h/mCMV
<400> 3
gacattgatt attgactagt tattaatagt aatcaattac ggggtcatta gttcatagcc 60
catatatgga gttccgcgtt acataactta cggtaaatgg cccgcctggc tgaccgccca 120
acgacccccg cccattgacg tcaataatga cgtatgttcc catagtaacg ccaataggga 180
ctttccattg acgtcaatgg gtggagtatt tacggtaaac tgcccacttg gcagtacatc 240
aagtgtatca tatgccaagt acgcccccta ttgacgtcaa tgacggtaaa tggcccgcct 300
ggcattatgc ccagtacatg accttatggg actttcctac ttggcagtac atctacgtat 360
tagtcatcgc tattaccatg gtgatgcggt tttggcagta catcaatggg cgtggatagc 420
ggtttgactc acggggattt ccaagtctcc accccattga cgtcaatggg agtttgtttt 480
ggcaccaaaa tcaacgggac tttccaaaat gtcgtaacaa ctccgcccca ttgacgcaaa 540
tgggcggtag gcgtgtacgg tgggaggtct atataagcag agct 584
<210> 4
<211> 1559
<212> DNA
<213> 人工序列
<220>
<223> hCD144
<400> 4
catccatgcc catggcctca gatgccagcc ataagctgtt gggttccaaa cctcgactcc 60
aggctggact cacccctgtc tcccccacca gcctgacacc tccacctggg tatctaacga 120
gcatctcaaa ctcaacctgc ctgagacaga ggaatcacta tcccctcctc ctccaaaaat 180
atccttccat cacactcccc atcttgtgct ctgatttact aaacggccct gggccctctc 240
tttctcaggg tctctgcttg cccagctata taataaaaca agtttgggac ttcccaacca 300
ttcacccatg gaaaaacaga agcaactctt caaaggacag attcccagga tctgccctgg 360
gagattccaa atcagttgat ctggggtgag cccagtcctc tgtagttttt agaagctcct 420
cctatgtctc tcctggtcag cagaatcttg gcccctccct tccccccagc ctcttggttc 480
ttctgggctc tgatccagcc tcagcgtcac tgtcttccac gcccctcttt gattctcgtt 540
tatgtcaaaa gccttgtgag gatgaggctg tgattatccc cattttacag atgaggaaac 600
tgtggctcca ggatgacaca actggccaga ggtcacatca gaagcagagc tgggtcactt 660
gactccaccc aatatcccta aatgcaaaca tcccctacag accgaggctg gcaccttaga 720
gctggagtcc atgcccgctc tgaccaggag aagccaacct ggtcctccag agccaagagc 780
ttctgtccct ttcccatctc ctgaagcctc cctgtcacct ttaaagtcca ttcccacaaa 840
gacatcatgg gatcaccaca gaaaatcaag ctctggggct aggctgaccc cagctagatt 900
tttggctctt ttatacccca gctgggtgga caagcacctt aaacccgctg agcctcagct 960
tcccgggcta taaaatgggg gtgatgacac ctgcctgtag cattccaagg agggttaaat 1020
gtgatgctgc agccaagggt ccccacagcc aggctctttg caggtgctgg gttcagagtc 1080
ccagagctga ggccgggagt aggggttcaa gtggggtgcc ccaggcaggg tccagtgcca 1140
gccctctgtg gagacagcca tccggggccg aggcagccgc ccaccgcagg gcctgcctat 1200
ctgcagccag cccagccctc acaaaggaac aataacagga aaccatccca gggggaagtg 1260
ggccagggcc agctggaaaa cctgaagggg aggcagccag gcctccctcg ccagcggggt 1320
gtggctcccc tccaaagacg gtcggctgac aggctccaca gagctccact cacgctcagc 1380
cctggacgga caggcagtcc aacggaacag aaacatccct cagcccacag gcacggtgag 1440
tgggggctcc cacactcccc tccaccccaa acccgccacc ctgcgcccaa gatgggaggg 1500
tcctcagctt ccccatctgt agaatgggca tcgtcccact cccatgacag agaggctcc 1559
<210> 5
<211> 2510
<212> DNA
<213> 人工序列
<220>
<223> mCD144
<400> 5
ctagtagcag aaacaaggtc ctctggaaga gcaactgatg ctcttaggta ctgaagcatc 60
atcctgcccc agagaccact cgcatatgaa gcacacatat tcagtctgcc ttacttgtgt 120
taatgattgc cagtgtccct ctgacctcct agccctgaaa agtgtggcct gaaggtcatt 180
tcagagacgg ggagagctgc tcagagaagc caatcggcga gtctaggaca cacagacagg 240
atctagtccc agagttcgct agcctaggtg agcgtcccct ggccccttat accacttcct 300
tctccagctt gcatctaatc tgctctggca gaccatcgtg tttcctgtct tcctggcagc 360
ctccagcacg ctcagtgcta ctccctgcgc atgcgccctc ctcccagtac cttctctgac 420
tccagtgggc ttggagtgcg aggaggaagg gtgaggaagg ggtgaaatca ggtattggat 480
ccacaggggg tctgaagagc actagcctgg ccttttggga ctgaacttct gctatgaaga 540
cctccactgc catccctgga gtccggggca catccaaggc ttgctgtcca tcgtttactg 600
tttacagatg acaacaatga ctgtgttcgg ggcagaaata tccaccaggg ctagagtaca 660
aaaggagttt gcattgatgg ccggacaggc cctgtccctg gcagcctgcc agcgctgagt 720
atgagaccca gcgggaagtg ctaccctggc agacgtgtcc actgagtaca cagaccacca 780
aggcaggcag ctctcgggga agctgtctat gctgggccag cccaccttga gggcagggaa 840
cagaacagat tgtggcagag aggaaaatgt ggagcttctg tttgttcaca gacacacgca 900
ctcgcccacg cacgcacgca cgcacgcacg cacgcacgaa tgcacgcacg cagtagttga 960
atgctatgga ttccgctcag agctgagaac agccccagcg acagttccct ggcctctctc 1020
cttactctga tgtcctcatc tgtcttcaca tggtctcagg acgctaatac tccatcctaa 1080
tgtacactcc tttccctggg cctccgttcc agttcagttc tcagaggacc tggagggagt 1140
gattggctac accaactttg ctttcgttca ccaagcccat gtctctactt gggtgtctaa 1200
tgggcatctc caacattacc taccccaaac agaaaaccct ttcttccccc caaccacacc 1260
ccaccctacc cccacagtat tttctccatg cccggaaaga tctgctctct tatggtccct 1320
ctttgcctca ctgaaaagca ggacaagttg gggacttccc aaacttttat gcatgaagaa 1380
acccaggcaa tttgccaaaa ggtacactct gggggtctgt catttactct gagccagaac 1440
cctgaaattt ttactaaccc atcacataat gaatgaagag aatctttttc tttttttttt 1500
tttttctttt tttttggttt ttcgagacag ggtttctctg tatagccctg gctatcctgg 1560
aacacactct gtagaccagg ctggcctcga actcagaaat ccacctgcct ctgcctcccg 1620
agtgctggga ttaaaggcgt gcgccaccac gcctggctga atgaagagaa tcttgacctc 1680
atctccccag cctcttggtc ctgagggacc ctggtctacc tactgctttg ctgtcttctt 1740
agctcttctt acttttttgc tgactcagac ctatggctat ctccattata cagatgagga 1800
gactgaggca tggatccctg gttggtccat ggtcacgtga agcccatcac ccagtatttg 1860
taaagtgaga tgggccaggc tggtaccttg gaactgaaac tcacactgcc ctacctggaa 1920
gaatctgaca ggcaaaatct gctgctgaaa gtgattgtct gtcacgtttc tcagctgccc 1980
gactctgaga actccacagc cccctttcgt tccaccatac tacagagtcg ccacggaaag 2040
ccggctctgt ggagaagctg aggtagctgg gtttctgtct gggttactct gtccagcgag 2100
gaaacaagta ccttagaccc actaagcctc tgctttctga actgtaaagt gggggatatg 2160
acacctgcct cccagggatg gctgaatgct ctggcagaag cttagagccc ccacagctac 2220
ccctaggctc acagctcctc cgatgagacc tagaattgag gtatgagttg aataccccag 2280
gcaggtccaa ggcttccacg ggcccaggct gaccaagctg aggccgccca ccgtagggct 2340
tgcctatctg caggcagctc acaaaggaac aataacagga aaccatcccg aggggaagtg 2400
ggccagggcc agttggaaaa cctgcctccc tcccagcctg ggtgtggctc ccctctcccc 2460
tcctgaggca atcaactgtg ctctccacaa agctcggccc tggacagact 2510
<210> 6
<211> 2527
<212> DNA
<213> 人工序列
<220>
<223> hTIE1
<400> 6
atttcctctt cctccccagc accgacccac actgaccaac acaggctgag cagtcaggcc 60
cacagcatct gaccccaggc ccagctcgtc ctggctggcc tgggtcggcc tctggagtat 120
ggtctggcgg gtgccccctt tcttgctccc catcctcttc ttggcttctc atgtgggcgc 180
ggcggtggac ctgacgctgc tggccaacct gcggctcacg gacccccagc gcttcttcct 240
gacttgcgtg tctggggagg ccggggcggg gaggggctcg gacgcctggg gcccgcccct 300
gctgctggag aaggacgacc gtatcgtgcg caccccgccc gggccacccc tgcgcctggc 360
gcgcaacggt tcgcaccagg tcacgcttcg cggcttctcc aagccctcgg acctcgtggg 420
cgtcttctcc tgcgtgggcg gtgctggggc gcggcgcacg cgcgtcatct acgtgcacaa 480
cagccctgga gcccacctgc ttccagacaa ggtcacacac actgtgaaca aaggtgacac 540
cgctgtactt tctgcacgtg tgcacaagga gaagcagaca gacgtgatct ggaagagcaa 600
cggatcctac ttctacaccc tggactggca tgaagcccag gatgggcggt tcctgctgca 660
gctcccaaat gtgcagccac catcgagcgg catctacagt gccacttacc tggaagccag 720
ccccctgggc agcgccttct ttcggctcat cgtgcggggt tgtggggctg ggcgctgggg 780
gccaggctgt accaaggagt gcccaggttg cctacatgga ggtgtctgcc acgaccatga 840
cggcgaatgt gtatgccccc ctggcttcac tggcacccgc tgtgaacagg cctgcagaga 900
gggccgtttt gggcagagct gccaggagca gtgcccaggc atatcaggct gccggggcct 960
caccttctgc ctcccagacc cctatggctg ctcttgtgga tctggctgga gaggaagcca 1020
gtgccaagaa gaccggatcc cccagatcct caacatggcc tcagaactgg agttcaactt 1080
agagacgatg ccccggatca actgtgcagc tgcagggaac cccttccccg tgcggggcag 1140
catagagcta cgcaagccag acggcactgt gctcctgtcc accaaggcca ttgtggagcc 1200
agagaagacc acagctgagt tcgaggtgcc ccgcttggtt cttgcggaca gtgggttctg 1260
ggagtgccgt gtgtccacat ctggcggcca agacagccgg cgcttcaagg tcaatgtgaa 1320
agtgcccccc gtgcccctgg ctgcacctcg gctcctgacc aagcagagcc gccagcttgt 1380
ggtctccccg ctggtctcgt tctctgggga tggacccatc tccactgtcc gcctgcacta 1440
ccggccccag gacagtacca tggactggtc gaccattgtg gtggacccca gtgagaacgt 1500
gacgttaatg aacctgaggc caaagacagg atacagtgtt cgtgtgcagc tgagccggcc 1560
aggggaagga ggagaggggg cctgggggcc tcccaccctc atgaccacag actgtcctga 1620
gcctttgttg cagccgtggt tggagggctg gcatgtggaa ggcactgacc ggctgcgagt 1680
gagctggtcc ttgcccttgg tgcccgggcc actggtgggc gacggtttcc tgctgcgcct 1740
gtgggacggg acacgggggc aggagcggcg ggagaacgtc tcatcccccc aggcccgcac 1800
tgccctcctg acgggactca cgcctggcac ccactaccag ctggatgtgc agctctacca 1860
ctgcaccctc ctgggcccgg cctcgccccc tgcacacgtg cttctgcccc ccagtgggcc 1920
tccagccccc cgacacctcc acgcccaggc cctctcagac tccgagatcc agctgacatg 1980
gaagcacccg gaggctctgc ctgggccaat atccaagtac gttgtggagg tgcaggtggc 2040
tgggggtgca ggagacccac tgtggataga cgtggacagg cctgaggaga caagcaccat 2100
catccgtggc ctcaacgcca gcacgcgcta cctcttccgc atgcgggcca gcattcaggg 2160
gctcggggac tggagcaaca cagtagaaga gtccaccctg ggcaacgggc tgcaggctga 2220
gggcccagtc caagagagcc gggcagctga agagggcctg gatcagcagc tgatcctggc 2280
ggtggtgggc tccgtgtctg ccacctgcct caccatcctg gctgcccttt taaccctggt 2340
gtgcatccgc agaagctgcc tgcatcggag acgcaccttc acctaccagt caggctcggg 2400
cgaggagacc atcctgcagt tcagctcagg gaccttgaca cttacccggc ggccaaaact 2460
gcagcccgag cccctgagct acccagtgct agagtgggag gacatcacct ttgaggacct 2520
catcggg 2527
<210> 7
<211> 1063
<212> DNA
<213> 人工序列
<220>
<223> mTIE1
<400> 7
aaaagaaaaa gaaaaacctg cagaagtatg tgccagcaga ctggaagcta agggaagagg 60
agcctgggct tggacaacct ggctctgctc ccttctaact gtatgacctt aggcaagttt 120
tgagcttttg ctccctggtt ataaaaccat catcctggaa gaggataaca ctcacctccc 180
aggacagtgt ggtcctgaaa ggacgagagc atcactaaag ggccccggca cataattgac 240
atccaataaa cattaattat tatgacagca ggaacacaag atgactctga agttagtgtc 300
tcaggtaatg ggtgttatcc tttgactcag aaagcttggg agaggtgagg gtgtagctta 360
ggaaacacag atgcaaatgc attgggagct gaaaggccac accagagcta ctgactcagg 420
ggtgacagtt aatgccgagg gagtggatga atgtgctccg tagttattac agcaaaggat 480
gtcaacttca ctggaagcca tgaggatgcc agggagaaag ggcatttggt gcccgcgagg 540
tggccaagag atgccagctt ctttggctta cgatagaccg tcaaaaatat gctaagtggc 600
atttaaatga attgatgacc tgacagctaa caggcaggga agggccaggg aaggaggggc 660
cttggaaggt ctggggtcac aggtctgaag caggctgatc acattcttct cctcggtctt 720
gcccacttca gggtacagat tttacgctcc agttgcacta gcccggggca gctcccctcc 780
ccacactaca acatttctca tacttgagcg tagggtggcc tctccctacg cctgaccttt 840
cgttcctcct cacccaagca ccttctaatg aagtttgtta tctgcatctt ttcctgtccc 900
ctttccttcc cccgcccccc tgctggttag atgttcctcc ctctgagcca acacctccat 960
ctgggaggga tgcctgtgtc tggtcctcca gcttcccaag gtagggccca gacccacctg 1020
tgtctgtgtc tctctggccc taaccgatct tcaatcccag cca 1063
<210> 8
<211> 1234
<212> DNA
<213> 人工序列
<220>
<223> hFLT1
<400> 8
gtttaagcaa tttggtagaa ccgaacagtc cattctgctc cattggcctt cgtttatagg 60
agaggcttgt aagaaatgac aagatctcct gccagatgct ttccaggatc actggtggtt 120
cctcacactc ttgggtgctg tggaaattgc atgctgctga ttaaattgct ggattttata 180
ccagattgag ggaggggaag gaaattggag gaatggggta tttgagggag ggcttgaaaa 240
gaaagcctct gacttagctc acggggctgc aggggggttc attaaggaaa cagttgcatt 300
gagtctgctg aagatagtgg actagatttc ctgcattgcc gctggggcgg atgtggggag 360
atgtcaagaa ttcctgggga tttcccatcc atcttggtaa agctggatgc ctgaaagctg 420
tttctgattg ctgctccttt cctcaatttt gagctctttg aggaacttga tcttgtctca 480
cagatacaca cacacgttgt aagagctaga tggaacctca ttgacccaat ctactcatgc 540
cagagatgag aaaaccggcc cagaggaggc cagtgctgtt tttcaaggtc aacagctggc 600
tagcggcagg cctaggaaca gaacctgatg ttcctgctac agacaacatc tcttcttcac 660
tggtgtattt cctcttcccc agacggaaga cagatgttca aatatttatt gactaacatt 720
attacagtgc taaaatttct ttcgaaatga catcttttta atatgaagtt ttcttctatt 780
ttcttaacgc acataagggg tttaaactaa gaatcaaaat gatggctgct tagtagcatg 840
ccaagagatt tgatgagaag attaactttc cttacgagca cttggtatcc ttttcctgaa 900
cagctgtggc ttacatactt gtggcttatg gtactagctt tgtctttcgc cacttctctc 960
cacacacaca ctgggttcca gctacacaaa ctctacccta gtcaaacaaa ttattccccc 1020
ttcttcagag gcgccttcac tttcatcact ctgttcatgc tgctcgtctg cctgcaagac 1080
cttttccctc cctctgtgtc tcctcctctc ctgctggcaa gatccagccc agtaatcacc 1140
atctctggga gctcctcctt gtagctccca gacagcactt gccatttctt ctgctctcct 1200
gtagccctga ggtgtactcc tccttcagta attc 1234
<210> 9
<211> 1360
<212> DNA
<213> 人工序列
<220>
<223> mFLT1
<400> 9
tggtcccatt taggagccat tttatcacgg gtatctggca ggttctattg aggctatttt 60
tcaaacctgc agtatttaca gggacaagac tgggctgctc cggggaggcc gggacgactt 120
cagccttcca gttaatggat gcataattga ggaacaacgt ggaattagtg tcatcgtaaa 180
tgatctagtg tctcaagtta atttcacccg ttttttgttc caagaacatt cgagtcagtc 240
atcttggcta gccggcttcc accaaaaaga tttgttttcc atccagcgtt tcagacctag 300
agttcaagtt cttggccctt acaagttgca ggagcgtgtc tcacgccttg gctttttttt 360
tttttttttt tttttttttt aaggtaacat gttattcctt gttttgcttc taggaagcag 420
agggttgagg aaatggcttg ggcgggtgca ttaatgcagc cgaaaaagac acagactccc 480
tcccttggga cccgcgcggc cccgcgctct ttccgaaggt gcctggcaag gcgtccggtt 540
ccctcggacg ctccgggtcc aagtgcctta agcggagggt ctctggcgcc ttccttcgct 600
gtctggcaac agtctggcgg ggtcagggac cggcgggacc gctcgggaga gggctcgact 660
gcgcctcgtt cctcggtgcc agggacaccg tcgcgggagg cgcggccagc ttccctagga 720
taagacttcc cgccccgggg gcagggcggt gcacttagac ggtcccctcc tcagtttcgg 780
gcggtcacca gagctgagta agctcggtgg agggagctgg gtaaggattt cctgagagcg 840
atgggcagga ggggctgggg cagcagagca cagagcaagg accctgaacc tgcgaacctg 900
tccggcgacc cgcgcgccta gcgccaccgc acgcgcgctc tggcccccgg gctacccgcc 960
ctcgccggcc cccgcccctc cgggaggaag aagagggtag gtggggaggc ggatgagggg 1020
tgggggaccc cttgacgtca ctggaaggag gtgccggggt aggaagtggg ctggggaaag 1080
gttataaatc gcccccgccc tcggctgcac ttcagcgagg tccttgagag gctcggagcg 1140
cggtggcgga cactcccggg aggtagtgct agtggtggtg gctgctgctc ggagcgggct 1200
ccgggactca agcgcagcgg ctagcggacg cgggacggcg aggatccccc cacaccaccc 1260
ccctcggctg caggcgcgga gaagggctct cgcggcgcca agcagaagca ggaggggacc 1320
ggctcgagcg gctgcgccgt cggcctcgga gagcgcgggc 1360
<210> 10
<211> 423
<212> DNA
<213> 人工序列
<220>
<223> hEMCN
<400> 10
acattcacta caccttttcc atttgctaat aaggccctgc caggctggga gggaattgtc 60
cctgcctgct tctggagaaa gaagatattg acaccatcta cgggcaccat ggaactgctt 120
caagtgacca ttctttttct tctgcccagt atttgcagca gtaacagcac aggtattttt 180
gtctcttatt cctctggtgg tacggattgg aaatcactag taggtgactc agcctcagtt 240
tactttcagg gatcttcccc tgacacttag atgcagcaat tcctttgatg agttgagtgt 300
ttggatgttg acttggagtg cgtggagaag gcttgagaga gacggtattt gtttctactg 360
aagggaaatg tttgcgggta cagcagcctg aaagcatgtt cgatgaaatc acaaagtact 420
gga 423
<210> 11
<211> 738
<212> DNA
<213> 人工序列
<220>
<223> mEMCN
<400> 11
aggggaatgc cagggccaag aagtgggagg gggaggggga gaggagtggg ggggtatggg 60
ggacttttgg aatagcagtg gaaatgtaaa tgaagaaaat atctaataaa aatatttaaa 120
aagaaagaaa gaaatgtctt gaaaacctct ctgggcagta ataagaggcc agcttacttc 180
ctcaagagca gaacgtgatc cagttcatac ttgtatttgc ctctagaagg tggtcttcac 240
tgacttggct tatgagttga gaagagagaa gaaatgcaat tccttgtgga ttttgtactc 300
aaatccagac cttgggaagt cacagccttt tcagccgacc tggggggcta cttggtgagg 360
tctctttaca gcttctctaa aatgcacttt caaaacaaaa gttagaaagc tctctggccc 420
tttctcaaga agggtctctt cctgttcaaa tcccatcctg acctttttgt tgaagaagag 480
taaaataatg cagtaacaaa aacacaagtg gctgccaaag gaagagagag gaaaaaaaaa 540
gaagttcctg taaggggctg aaacaataaa tctcctctct gctgacctcc caaagggagt 600
gcgtgtattt cctctagttc tttatcagaa tccccaaaat aagtaggaat gggcagcgtc 660
tgctcacagt cagtacacct ttcccatttg ctaatacggc ctggccaggc tgagaggaat 720
ccttccctgc cttaccct 738
<210> 12
<211> 25
<212> DNA
<213> 人工序列
<220>
<223> attB1
<400> 12
acaagtttgt acaaaaaagc aggct 25
<210> 13
<211> 25
<212> DNA
<213> 人工序列
<220>
<223> attB2
<400> 13
accactttgt acaagaaagc tgggt 25
<210> 14
<211> 588
<212> DNA
<213> 人工序列
<220>
<223> IRES
<400> 14
gcccctctcc ctcccccccc cctaacgtta ctggccgaag ccgcttggaa taaggccggt 60
gtgcgtttgt ctatatgtta ttttccacca tattgccgtc ttttggcaat gtgagggccc 120
ggaaacctgg ccctgtcttc ttgacgagca ttcctagggg tctttcccct ctcgccaaag 180
gaatgcaagg tctgttgaat gtcgtgaagg aagcagttcc tctggaagct tcttgaagac 240
aaacaacgtc tgtagcgacc ctttgcaggc agcggaaccc cccacctggc gacaggtgcc 300
tctgcggcca aaagccacgt gtataagata cacctgcaaa ggcggcacaa ccccagtgcc 360
acgttgtgag ttggatagtt gtggaaagag tcaaatggct ctcctcaagc gtattcaaca 420
aggggctgaa ggatgcccag aaggtacccc attgtatggg atctgatctg gggcctcggt 480
gcacatgctt tacatgtgtt tagtcgaggt taaaaaaacg tctaggcccc ccgaaccacg 540
gggacgtggt tttcctttga aaaacacgat gataatatgg ccacaacc 588
<210> 15
<211> 63
<212> DNA
<213> 人工序列
<220>
<223> T2A
<400> 15
ggaagcggag agggcagggg aagtcttcta acatgcgggg acgtggagga aaatcccggc 60
ccc 63
<210> 16
<211> 717
<212> DNA
<213> 人工序列
<220>
<223> eGFP
<400> 16
atggtgagca agggcgagga gctgttcacc ggggtggtgc ccatcctggt cgagctggac 60
ggcgacgtaa acggccacaa gttcagcgtg tccggcgagg gcgagggcga tgccacctac 120
ggcaagctga ccctgaagtt catctgcacc accggcaagc tgcccgtgcc ctggcccacc 180
ctcgtgacca ccctgaccta cggcgtgcag tgcttcagcc gctaccccga ccacatgaag 240
cagcacgact tcttcaagtc cgccatgccc gaaggctacg tccaggagcg caccatcttc 300
ttcaaggacg acggcaacta caagacccgc gccgaggtga agttcgaggg cgacaccctg 360
gtgaaccgca tcgagctgaa gggcatcgac ttcaaggagg acggcaacat cctggggcac 420
aagctggagt acaactacaa cagccacaac gtctatatca tggccgacaa gcagaagaac 480
ggcatcaagg tgaacttcaa gatccgccac aacatcgagg acggcagcgt gcagctcgcc 540
gaccactacc agcagaacac ccccatcggc gacggccccg tgctgctgcc cgacaaccac 600
tacctgagca cccagtccaa gctgagcaaa gaccccaacg agaagcgcga tcacatggtc 660
ctgctggagt tcgtgaccgc cgccgggatc actctcggca tggacgagct gtacaag 717
<210> 17
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> hGAPDH 正向
<400> 17
cctccaagga gtaagacccc 20
<210> 18
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> hGAPDH 反向
<400> 18
aggggtctac atggcaactg 20
<210> 19
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> hPLVAP 正向
<400> 19
agaactcaga cctccaacgc 20
<210> 20
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> hPLVAP 反向
<400> 20
tctccacctt ctgtttcgcc 20
<210> 21
<211> 19
<212> DNA
<213> 人工序列
<220>
<223> mGAPDH 正向
<400> 21
tgtccgtcgt ggatctgac 19
<210> 22
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> mGAPDH 反向
<400> 22
cctgcttcac caccttcttg 20
<210> 23
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> mPLVAP 正向
<400> 23
gctggtacta cctgcgctat t 21
<210> 24
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> mPLVAP 反向
<400> 24
cctgtgaggc agatagtcca 20
<210> 25
<211> 442
<212> PRT
<213> 人工序列
<220>
<223> 质膜囊泡相关蛋白[人类]
<400> 25
Met Gly Leu Ala Met Glu His Gly Gly Ser Tyr Ala Arg Ala Gly Gly
1 5 10 15
Ser Ser Arg Gly Cys Trp Tyr Tyr Leu Arg Tyr Phe Phe Leu Phe Val
20 25 30
Ser Leu Ile Gln Phe Leu Ile Ile Leu Gly Leu Val Leu Phe Met Val
35 40 45
Tyr Gly Asn Val His Val Ser Thr Glu Ser Asn Leu Gln Ala Thr Glu
50 55 60
Arg Arg Ala Glu Gly Leu Tyr Ser Gln Leu Leu Gly Leu Thr Ala Ser
65 70 75 80
Gln Ser Asn Leu Thr Lys Glu Leu Asn Phe Thr Thr Arg Ala Lys Asp
85 90 95
Ala Ile Met Gln Met Trp Leu Asn Ala Arg Arg Asp Leu Asp Arg Ile
100 105 110
Asn Ala Ser Phe Arg Gln Cys Gln Gly Asp Arg Val Ile Tyr Thr Asn
115 120 125
Asn Gln Arg Tyr Met Ala Ala Ile Ile Leu Ser Glu Lys Gln Cys Arg
130 135 140
Asp Gln Phe Lys Asp Met Asn Lys Ser Cys Asp Ala Leu Leu Phe Met
145 150 155 160
Leu Asn Gln Lys Val Lys Thr Leu Glu Val Glu Ile Ala Lys Glu Lys
165 170 175
Thr Ile Cys Thr Lys Asp Lys Glu Ser Val Leu Leu Asn Lys Arg Val
180 185 190
Ala Glu Glu Gln Leu Val Glu Cys Val Lys Thr Arg Glu Leu Gln His
195 200 205
Gln Glu Arg Gln Leu Ala Lys Glu Gln Leu Gln Lys Val Gln Ala Leu
210 215 220
Cys Leu Pro Leu Asp Lys Asp Lys Phe Glu Met Asp Leu Arg Asn Leu
225 230 235 240
Trp Arg Asp Ser Ile Ile Pro Arg Ser Leu Asp Asn Leu Gly Tyr Asn
245 250 255
Leu Tyr His Pro Leu Gly Ser Glu Leu Ala Ser Ile Arg Arg Ala Cys
260 265 270
Asp His Met Pro Ser Leu Met Ser Ser Lys Val Glu Glu Leu Ala Arg
275 280 285
Ser Leu Arg Ala Asp Ile Glu Arg Val Ala Arg Glu Asn Ser Asp Leu
290 295 300
Gln Arg Gln Lys Leu Glu Ala Gln Gln Gly Leu Arg Ala Ser Gln Glu
305 310 315 320
Ala Lys Gln Lys Val Glu Lys Glu Ala Gln Ala Arg Glu Ala Lys Leu
325 330 335
Gln Ala Glu Cys Ser Arg Gln Thr Gln Leu Ala Leu Glu Glu Lys Ala
340 345 350
Val Leu Arg Lys Glu Arg Asp Asn Leu Ala Lys Glu Leu Glu Glu Lys
355 360 365
Lys Arg Glu Ala Glu Gln Leu Arg Met Glu Leu Ala Ile Arg Asn Ser
370 375 380
Ala Leu Asp Thr Cys Ile Lys Thr Lys Ser Gln Pro Met Met Pro Val
385 390 395 400
Ser Arg Pro Met Gly Pro Val Pro Asn Pro Gln Pro Ile Asp Pro Ala
405 410 415
Ser Leu Glu Glu Phe Lys Arg Lys Ile Leu Glu Ser Gln Arg Pro Pro
420 425 430
Ala Gly Ile Pro Val Ala Pro Ser Ser Gly
435 440
Claims (26)
1.一种用于预防或治疗视网膜或脉络膜疾病的药物组合物,所述药物组合物包含质膜囊泡相关蛋白(PLVAP)蛋白、所述蛋白的表达或活性激活剂、或编码所述PLVAP蛋白的核苷酸序列作为活性成分。
2.如权利要求1所述的药物组合物,其中所述PLVAP蛋白包含SEQ ID NO:25所示的氨基酸序列,或与SEQ ID NO:25具有80%或以上序列同源性的氨基酸序列。
3.如权利要求1所述的药物组合物,其中所述PVLAP蛋白是PLVAP蛋白、其片段、其变体或其融合蛋白。
4.如权利要求1所述的药物组合物,其中编码PLVAP蛋白的核苷酸序列包含在重组载体中。
5.如权利要求4所述的药物组合物,其中所述重组载体包含启动子、增强子、内含子、报告标记序列、蛋白质纯化标签、终止序列、mRNA稳定序列、外源基因序列、细胞选择标记序列或其组合。
6.如权利要求4所述的药物组合物,其中所述重组载体包含诱导血管内皮细胞特异性表达的启动子,所述启动子选自CD144、TIE1、FLT1和EMCN中的一种或多种。
7.如权利要求1所述的药物组合物,其中所述视网膜或脉络膜疾病是与血管渗透性相关的视网膜或脉络膜疾病。
8.如权利要求1所述的药物组合物,其中所述视网膜或脉络膜疾病是色素性视网膜炎(RP)、Leber先天性黑蒙(LCA)、Stargardt病、Usher综合征、无脉络膜、视锥细胞或视锥细胞营养不良、纤毛病、线粒体病症、进行性视网膜萎缩、退行性视网膜疾病、年龄相关性黄斑变性(AMD)、湿性AMD、干性AMD、中心性浆液性脉络膜视网膜病变、厚脉络膜疾病谱、退行性近视、结节性脉络膜病变、脉络膜视网膜炎、脉络膜肿瘤、脉络膜新生血管、遗传性脉络膜疾病、地图样萎缩、家族性或获得性黄斑病变、视网膜光感受器疾病、基于视网膜色素上皮的疾病、糖尿病性视网膜病变、糖尿病性脉络膜视网膜病变、黄斑囊样水肿、葡萄膜炎、视网膜脱离、外伤性视网膜损伤、医源性视网膜损伤、黄斑裂孔、黄斑毛细血管扩张症、神经节细胞疾病、视神经细胞疾病、青光眼、视神经病变、缺血性视网膜疾病、早产儿视网膜病变、视网膜血管阻塞、家族性视网膜动脉大动脉瘤、视网膜血管疾病、眼血管疾病、视网膜神经细胞变性、由于青光眼引起的视网膜神经细胞变性、缺血性视神经病变或其组合。
9.如权利要求1所述的药物组合物,其中,所述核苷酸序列包括SEQ ID NO:1所示的碱基序列,或与SEQ ID NO:1具有80%或以上序列同源性的碱基序列。
10.如权利要求1所述的药物组合物,所述药物组合物被配制成通过一种或多种选自口服、皮下、腹膜内、肺内、鼻内、肌内、静脉内、动脉内和局部眼部施用的途径施用于受试者。
11.如权利要求10所述的药物组合物,其中所述局部眼部施用为结膜内施用、玻璃体内施用、视网膜下施用、脉络膜上腔施用、结膜下施用、Tenon囊下施用或其组合。
12.如权利要求1所述的药物组合物,其中所述药物组合物还包含选自药学上可接受的载体、赋形剂和稀释剂中的一种或多种。
13.如权利要求1所述的药物组合物,其中所述药物组合物恢复内皮细胞的窗孔。
14.如权利要求1所述的药物组合物,其中所述药物组合物还包含抗VEGF剂。
15.一种用于预防或治疗视网膜或脉络膜疾病的准药物组合物,所述准药物组合物包含质膜囊泡相关蛋白(PLVAP)蛋白、所述蛋白的表达或活性激活剂、或编码所述PLVAP蛋白的核苷酸序列作为活性成分。
16.一种预防、改善或治疗视网膜或脉络膜疾病的方法,所述方法包括:将包含质膜囊泡相关蛋白(PLVAP)蛋白、所述蛋白的表达或活性激活剂、或编码所述PLVAP蛋白的核苷酸序列作为活性成分的药物组合物施用于受试者。
17.如权利要求16所述的方法,其中所述核苷酸序列包括SEQ ID NO:1所示的核碱基序列、或与SEQ ID NO:1具有80%或以上序列同源性的碱基序列。
18.如权利要求16所述的方法,其中所述药物组合物通过一种或多种选自口服、皮下、腹膜内、肺内、鼻内、肌内、静脉内、动脉内和局部眼部施用的途径施用于受试者。
19.如权利要求16所述的对象,其中所述受试者是需要治疗视网膜或脉络膜疾病的受试者,并且
其中所述视网膜或脉络膜疾病是色素性视网膜炎(RP)、Leber先天性黑蒙(LCA)、Stargardt病、Usher综合征、无脉络膜、视锥细胞或视锥细胞营养不良、纤毛病、线粒体病症、进行性视网膜萎缩、退行性视网膜疾病、年龄相关性黄斑变性(AMD)、湿性AMD、干性AMD、中心性浆液性脉络膜视网膜病变、厚脉络膜疾病谱、退行性近视、结节性脉络膜病变、脉络膜视网膜炎、脉络膜肿瘤、脉络膜新生血管、遗传性脉络膜疾病、地图样萎缩、家族性或获得性黄斑病变、视网膜光感受器疾病、基于视网膜色素上皮的疾病、糖尿病性视网膜病变、糖尿病性脉络膜视网膜病变、黄斑囊样水肿、葡萄膜炎、视网膜脱离、外伤性视网膜损伤、医源性视网膜损伤、黄斑裂孔、黄斑毛细血管扩张症、神经节细胞疾病、视神经细胞疾病、青光眼、视神经病变、缺血性视网膜疾病、早产儿视网膜病变、视网膜血管阻塞、家族性视网膜动脉大动脉瘤、视网膜血管疾病、眼血管疾病、视网膜神经细胞变性、由于青光眼引起的视网膜神经细胞变性、缺血性视神经病变或其组合。
20.如权利要求16所述的方法,其中所述药物组合物与所述抗VEGF剂同时或依次施用。
21.一种包含质膜囊泡相关蛋白(PLVAP)蛋白、所述蛋白的表达或活性激活剂、或编码所述PLVAP蛋白的核苷酸序列作为活性成分的药物组合物用于预防、改善或治疗视网膜或脉络膜疾病的用途。
22.一种质膜囊泡相关蛋白(PLVAP)蛋白、所述蛋白的表达或活性激活剂、或编码所述PLVAP蛋白的核苷酸序列,用于生产预防或治疗视网膜或脉络膜疾病的药物的用途。
23.一种质膜囊泡相关蛋白(PLVAP)蛋白、所述蛋白的表达或活性激活剂、或分离的编码所述PLVAP蛋白的核苷酸序列,其特征在于改善脉络膜血管的超微结构。
24.一种用于改善脉络膜血管的超微结构的药物组合物,所述药物组合物包含质膜囊泡相关蛋白(PLVAP)蛋白、所述蛋白的表达或活性激活剂、或分离的编码所述PLVAP蛋白的核苷酸序列作为活性成分。
25.一种用于改善脉络膜血管的超微结构的方法,所述方法包括:将包含质膜囊泡相关蛋白(PLVAP)蛋白、所述蛋白的表达或活性激活剂、或分离的编码所述PLVAP蛋白的核苷酸序列作为活性成分的组合物施用于受试者。
26.包含质膜囊泡相关蛋白(PLVAP)蛋白、所述蛋白的表达或活性激活剂、或分离的编码所述PLVAP蛋白的核苷酸序列作为活性成分的组合物用于改善脉络膜血管的超微结构的用途。
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PCT/KR2021/014090 WO2022080847A1 (ko) | 2020-10-13 | 2021-10-13 | Plvap를 유효성분으로 포함하는 망막 또는 맥락막 질환의 예방 또는 치료용 약학적 조성물 |
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