CN115120730A - Pcsk9抑制剂在制备预防和治疗疤痕产品中的应用 - Google Patents
Pcsk9抑制剂在制备预防和治疗疤痕产品中的应用 Download PDFInfo
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Abstract
本发明属于医药生物技术领域,具体涉及前蛋白转化酶枯草杆菌转化酶(PCSK9)在促进皮肤创伤愈合,预防和治疗疤痕(瘢痕)形成中的作用,以及PCSK9抑制剂在制备促进皮肤创伤愈合,预防和治疗疤痕(瘢痕)的产品中的应用。可进一步开发出系统或外用的PCSK9抑制剂产品,用于预防和治疗疤痕(瘢痕)。这些产品疗效显著,不良反应小。
Description
技术领域
本发明属于医药技术领域,具体涉及PCSK9在治疗疤痕(瘢痕)中的作用,以及PCSK9抑制剂在制备治疗疤痕(瘢痕)产品中的应用。
背景技术
疤痕(瘢痕)是物理、生物、化学等因素的损害作用于人体皮肤软组织,导致皮肤软组织的严重损伤而不能完全自行正常修复,转由纤维组织替代修复留下的即影响外观又影响功能的症状。疤痕给患者带来的是巨大的肉体痛苦和精神痛苦,尤其是烧伤、烫伤、严重外伤后遗留的疤痕。疤痕增生期的几年时间几乎让患者苦不堪言。而后的萎缩期又使患者面目全非,功能障碍,造成患者极大的身、心双重障碍。疤痕包括多个种类:主要有增殖性(增生性)疤痕、疤痕疙瘩、浅表性疤痕、萎缩性疤痕、挛缩性疤痕和凹陷性疤痕等。
增生性瘢痕表现为突出表面,外形不规则,高低不平,潮红充血,质实韧。有灼痛及瘙痒感。增生性瘢痕的表现于环境温度增高,情绪激动,或食辛辣刺激食物时症状加重。增生瘢痕往往延续数月或几年以后,才渐渐发生退行性变化。这种疤痕的特点是:早期局部肿胀变硬充血,其组织结构为表层是一层萎缩的上皮细胞所盖,中层为血管扩张,并有炎性细胞浸润,底层为较少的胶原纤维和大量的结缔组织增生。这种疤痕高出皮肤表面,早期局部增厚变硬,毛细血管充血呈现红色或暗红色。该疤痕基底部一般不与深组织粘连,可以推动,且收缩性较小,多数不会产生严重功能障碍,但在面部及暴露部位多影响美容。
疤痕疙瘩实质上是皮肤上的一种结缔组织瘤,以具有持续性强大增生力为特点,常表现为向四周健全皮肤呈蟹足样浸润的形象,病变隆出皮面,高低不平,形状不规则,质硬韧,多感奇痒难忍。瘢痕疙瘩的发生可和常染色体显性遗传有关,外伤、感染等机械性刺激可使纤维细胞生成大量异常的胶原纤维。瘢痕好见于胸骨区,亦常见于肩部、面部、颈部、耳部等处。皮损初起为小且坚实的红色丘疹,缓慢增大,为圆形、椭圆形或不规则形,隆起于皮面,经常超过原损伤部位,呈蟹足状向外伸展,表面光滑发亮。位于面部的瘢痕影响美观,继发于烧伤,伤者可出现大面积皮损,严重者可影响受累肢体功能。
浅表性疤痕是在皮肤浅表层的一种疤痕,多由于皮肤轻度擦伤或浅表烧伤(真皮浅层)所引起,其外表稍异于正常皮肤,表面粗糙或有色素变化,一般无功能障碍,随着时间的推移,浅表性疤痕渐不明显,因此这类疤痕一般不需处理。
萎缩性疤痕是一种最不稳定的疤痕组织,又称不稳定疤痕,常见于大面积的烧伤,特别是深及脂肪层的创面,在未经植皮而仅靠周边上皮细胞生长而使创面愈合的。这种疤痕的特点是:疤痕表皮菲薄,表面平坦,局部血液循环差,呈亮白色且基底较坚硬。由于其表层仅覆盖一层萎缩的上皮细胞,经不住外力磨擦,常易破损。萎缩性疤痕易形成溃疡,一般很难愈合,经久可导致恶变。因为此类疤痕常与下面肌肉、神经、血管粘连,且有很大收缩性,故可牵拉正常组织而造成或比增殖性疤痕更为严重的功能障碍。由于这种疤痕具有很强的破坏性,故应注意预防,应早治疗。
挛缩性疤痕是以其引起的功能障碍特征命名的疤痕。多见于深度烧伤愈合后,由于疤痕收缩,常导致外形改变和功能障碍,长期的疤痕挛缩可影响骨骼、肌肉、血管、神经等组织的发育,应及早处理。临床上常见的因疤痕挛缩造成的畸形有睑外翻、唇外翻、颏胸粘连、手部疤痕挛缩畸形及各关节的屈侧或伸侧挛缩畸形等。其中在关节屈面的条索状疤痕挛缩,如经较长时间,挛缩疤痕两侧的皮肤及皮下组织可以逐渐伸长,成为蹼状的疤痕挛缩,称蹼状挛缩疤痕。此种蹼状疤痕较大者常见于颈前侧、腋窝、肘窝、踝关节等处,较小者可见于内眦角、外眦角、鼻唇沟、口角、指蹼等部位,部分在体表孔道的开口挛缩性疤痕处呈环状出现,造成其口径狭窄,影响正常功能。
凹陷性疤痕:当疤痕组织在体表造成凹陷畸形时,称之为凹陷疤痕。常见于天花、水痘或痤疮后遗留的疤痕,也可见于外伤及皮肤感染患者。简单的凹陷性疤痕仅是线状疤痕及其区域的低陷,广泛的凹陷性疤痕则可合并有皮下组织、肌肉或骨骼组织缺损。
对于瘢痕的处理难度较大,目前只能做到使发红、发硬的疤痕变软、变浅,宽的疤痕变窄,粗的疤痕变细,还不能完全彻底消除疤痕。因此在伤口愈合早期即开始进行干预非常重要,可以有效减少疤痕的形成,改善外观,纠正畸形,恢复功能。
目前常用来治疗疤痕(瘢痕)方法有:手术治疗、激光治疗、冷冻治疗和药物治疗等。常用的药物主要有:糖皮质激素和维甲酸。糖皮质激素有抗炎、抗病毒、抗休克等功能,并且有明显的抗组织纤维化的效应,去炎松-A是目前抗瘢痕功效最大的种皮质激素,众所周知糖皮质激素长期使用毒副作用多。维甲酸是维生素A在体内代谢的中间产物,是维生素A类相关药物,,维甲酸能减轻局部炎症,促进上皮细胞生长,减少胶原合成,使成纤维细胞的DNA合成减少,抑制细胞生长。维甲酸类药物浓度越大,抑制生长作用越明显。但维甲酸疗效有限,系统应用毒副作用也不少,外用对皮肤刺激明显,并随着浓度增加而增加。目前的治疗疤痕(瘢痕)的方法远不能满足临床需求,需要寻找更多疗效好、副作用少、价格便宜的新药来减少疤痕(瘢痕)的形成。
前蛋白转化酶枯草杆菌转化酶(PCSK9)是前蛋白转换酶家族中的一员,前蛋白转换酶在肝脏内作为一种不活跃酶原分泌。PCSK9基因cDNA的大小为3617bp,编码692个氨基酸组成的PCSK9蛋白。PCSK9前体在内质网内经过分子内自动催化分离其N-末端前肽,分离后的N-末端前区与催化区相连,允许成熟的PCSK9蛋白离开内质网并进入分泌途径。PCSK9分泌至细胞外后,在细胞表面的第一表皮生长因子样区域与低密度脂蛋白(LDL)受体结合,PCSK9-LDL受体复合体可进入溶酶体降解,从而导致细胞表面LDL受体下降,即PCSK9水平与LDL受体成负相关关系。而多项研究显示,PCSK9基因的突变功能丧失可使不同人种的LDL-C水平及冠心病发生率明显下降。鉴于抑制PCSK9对降低LDL-C及冠心病发生率的显著作用,已有多项治疗方案正在研发阻断PCSK9的药物,用于降低LDL-C及冠心病的发生率。
PCSK9抑制剂包括两大类:1、阻止PCSK9与LDL-R的结合,如单抗、模拟肽(多肽抑制剂)、模拟抗体蛋白药;2、抑制PCSK9分子的表达或干扰PCSK9分泌,如小分子干扰RNA、反义寡核苷酸、小分子化合物抑制剂等。单克隆抗体由于阻断效率高、靶位准确和稳定性好而成为新药研究的热点。目前,全球上市的PCSK9靶向单抗药物,均为阻止PCSK9与LDL-R结合的药物。包括安进(Amgen)和安斯泰来(Astellas)联合开发的的evolocumab(依洛尤单抗),商品名Repatha(瑞百安);赛诺菲(Sanofi)和再生元(Regeneron)联合开发的alirocumab(阿利西尤单抗,阿利珠单抗),商品名Praluent(波立达),以及Eli lilly公司的LY3015014,君实生物的重组人源化抗PCSK9单克隆抗体(JS002),和信立泰药业的重组全人源抗PCSK9单克隆抗体注射液。临床研究发现,以上药物治疗高胆固醇血症耐受性良好,安慰剂组与积极治疗组不良反应的发生率无明显区别。此外,Inclisiran是一款siRNA(小干扰RNA)药物,不同于直接与PCSK9分子结合的单抗,它可以抑制PCSK9基因的表达,使LDL受体不会因PCSK9而被降解,从而改善肝细胞对LDL颗粒的摄取,降低血液中的LDL水平。Alnylam公司的Inclisiran采用专有技术,由脂质纳米颗粒与GalNAc(N-乙酰半乳糖胺)结合而成,而GalNAc可与肝细胞表面表达的唾液酸糖蛋白受体ASGR1和ASGR2结合。该技术允许皮下给药并靶向肝脏。Affiris公司的ALN-PCS和ALN-PCSsc也属于siRNA(小干扰RNA)药物。PCSK9干扰RNAI抑制剂药物还有Alnylam公司的Inclisran,Affiris公司的ALN-PCS和ALN-PCSsc。辉瑞公司设计的一种相关的疫苗药物,以及Affiris公司的AT04A和AT06A疫苗,患者只需每年接受一次疫苗即可达到长期降低LDL的效果,可以减少使用频率。PCSK9模拟肽和PCSK9模拟抗体蛋白药药物研发包括Pieris公司的DS9001和Merck公司的1G08等。PCSK9反义寡核苷酸药物包括Santaris Pharma公司的SPC5001等。
到目前为止,尚未见到应用PCSK9抑制剂治疗疤痕(瘢痕)的相关文献、专利和产品。我们首次发现敲出PCSK9基因能够明显抑制疤痕(瘢痕)的形成,PCSK9抑制剂能够明显改善疤痕(瘢痕)。
发明内容
本发明需要解决的问题是:通过动物模型明确PCSK9基因在疤痕(瘢痕)形成机制中的作用,以及PCSK9抑制剂在制备预防和治疗疤痕(瘢痕)的产品中的应用。本发明通过建立大鼠皮肤疤痕(瘢痕)模型,发现了PCSK9基因在疤痕(瘢痕)形成机制中起关键作用,以及PCSK9抑制剂在制备预防和治疗疤痕(瘢痕)的产品中的应用价值。
本发明的技术方案
本发明通过研究发现,PSCK9基因敲出能明显促进大鼠皮肤创伤的愈合,减少疤痕(瘢痕)形成。敲出PSCK9基因也能明显抑制皮肤成纤维细胞的增殖,促进成纤维细胞凋亡,显示抑制PSCK9能通过抑制皮肤成纤维细胞增殖,促进其凋亡,来抑制疤痕(瘢痕)的形成。
本发明又在能够明显阻断PCSK9的抑制剂(阻断剂)中,分别选取了具有代表性的PCSK9单克隆抗体、PCSK9多肽抑制剂、PCSK9小分子化合物抑制剂和PCSK9小干扰RNA,通过尾静脉注射或者皮肤外用干预大鼠疤痕(瘢痕)模型,和模型组比较,结果发现,PCSK9抑制剂组的疤痕增生情况均明显好于模型组,各PCSK9抑制剂组均未出现全身不良反应,大鼠活动和觅食正常,未见呼吸和中枢神经系统异常表现。通过实验研究证实,各种PCSK9抑制剂均能促进皮肤创伤愈合,减少疤痕(瘢痕)形成,显示无论系统还是外用PCSK9抑制剂均能对皮肤疤痕(瘢痕)具有明显的预防和治疗作用,且均未见明显毒副作用。
本领域技术人员公知,基于疾病的共同发病机制和以上实验显示的结果,可以推测PCSK9抑制剂(阻断剂)对各种类型的疤痕(瘢痕)均具有预防和治疗作用。PCSK9抑制剂(阻断剂)可以单独使用,也可以联合其他药物或者治疗方法一起使用,包括传统药物和其他靶向生物制剂。
基于上述研究,本发明涉及了PCSK9抑制剂(阻断剂)在制备预防和治疗疤痕(瘢痕)的产品中的应用,其中所述PCSK9是前蛋白转化酶枯草杆菌转化酶/kexin9型(genebank序列号:255738),属前蛋白转换酶家族。
本发明所述的PCSK9抑制剂可以为常规的任何的分子生物学或者药物化学手段能够抑制PCSK9基因表达或者分泌作用的产品或方法,例如但不限于通过现有分子生物学技术对PCSK9基因进行敲除或者沉默;在一些实施例中,还可以为或者采用PCSK9抑制剂,优选的,上述PCSK9抑制剂(阻断剂)为PCSK9小分子化合物或PCSK9干扰RNAi抑制剂或PCSK9单克隆抗体或PCSK9模拟肽或PCSK9模拟抗体蛋白或PCSK9反义寡核苷酸或PCSK9疫苗。
优选的,上述PCSK9抑制剂(阻断剂)为PCSK9小分子化合物或PCSK9干扰RNA或PCSK9单克隆抗体或PCSK9模拟肽或PCSK9模拟抗体蛋白或PCSK9反义寡核苷酸或PCSK9疫苗。
在一些实例中,本发明所述的PCSK9小分子化合物包括但不限于Selleck公司产品R-IMPP,化学式:C24H27N3O2,分子量:389.49,结构式:或Selleck公司产品PF-06446846,化学式:C22H20ClN7O,分子量:433.04,结构式:或Selleck公司产品SBC-115076,化学式:C31H33N3O5,分子量:527.61,结构式:或Selleck公司产品SBC-110736,化学式:C26H27N3O2,分子量:413.51,结构式:
在一些实例中,本发明所述的PCSK9单克隆抗体抑制剂包括但不限于Abcam公司ab81041,或安进(Amgen)和安斯泰来(Astellas)联合开发的evolocumab(依洛尤单抗),或赛诺菲(Sanofi)和再生元(Regeneron)联合开发的alirocumab(阿利西尤单抗,阿利珠单抗),或君实生物的重组人源化抗PCSK9单克隆抗体(JS002),或信立泰药业的重组全人源抗PCSK9单克隆抗体注射液,或Eli lilly公司的LY3015014,或Merck公司的1G08。
在一些实例中,本发明所述的PCSK9干扰RNAI抑制剂包括但不限于Alnylam公司的Inclisran,Affiris公司的ALN-PCS和ALN-PCSsc。
在一些实例中,本发明所述的PCSK9模拟肽抑制剂和PCSK9模拟抗体蛋白抑制剂包括但不限于Pieris公司的DS9001和Merck公司的1G08等。
在一些实例中,本发明所述的PCSK9反义寡核苷酸抑制剂包括但不限于SantarisPharma公司的SPC5001。
在一些实例中,本发明所述的PCSK9疫苗抑制剂包括但不限于Affiris公司的AT04A和AT06A。
本领域技术人员公知,基于以上PCSK9的作用机制,PCSK9抑制剂(阻断剂)对各种原因引起的疤痕性疾病均具有治疗作用。
PCSK9抑制剂(阻断剂)可以单独使用,也可以联合其他药物或者治疗方法一起使用,包括传统药物和其他靶向生物制剂。
本发明还提供一种药物组合物,以本发明所述化合物或其药学上可接受的盐为活性成分或主要活性成分,辅以药学上可接受的载体组成。
本发明所述的化合物或组合物可制备为药学上允许的任何剂型,例如为适于口服、肠胃外、腹膜内、静脉内、动脉内、透皮、舌下、肌内、直肠、透颊、鼻内、吸入、阴道、眼内、局部、皮下、脂肪内、关节内、腹膜内或鞘内任意给药方式的制剂。
在一种优选的实施方式中,本发明所述的剂型为膏剂、片剂、冲剂、口服液剂、胶囊剂、滴丸剂、灌肠剂、膜剂或注射剂。
本发明与现有技术相比其有益效果是:本发明为疤痕(瘢痕)的预防和治疗提供了新的、更好的治疗方法,通过本发明的揭示可进一步制备治疗预防和治疗疤痕(瘢痕)的PCSK9抑制剂(阻断剂)产品,进而开发出包含各类PCSK9抑制剂的单体新药或复方制剂,用于预防和治疗疤痕(瘢痕)。已经有的研究结果证明此类包含PCSK9抑制剂的产品疗效显著、副作用小、耐受性好,可为市场提供一系列疗效好、安全、经济的新产品。
具体实施方式
以下通过特定的具体实例说明本发明的实施方式,本领域技术人员可由本说明书所揭露的内容轻易地了解本发明的其他优点与功效。本发明还可以通过另外不同的具体实施方式加以实施或应用,本说明书中的各项细节也可以基于不同观点与应用,在没有背离本发明的精神下进行各种修饰或改变。
在进一步描述本发明具体实施方式之前,应理解本发明的保护范围不局限于下述特定的具体实施方案;还应当理解,本发明实施例中使用的术语是为了描述特定的具体实施方案,而不是为了限制本发明的保护范围;在本发明说明书和权利要求书中,除非文中另外明确指出,单数形式“一个”、“一”和“这个”包括复数形式。
当实施例给出数值范围时,应理解,除非本发明另有说明,每个数值范围的两个端点以及两个端点之间任何一个数值均可选用。除非另外定义,本发明中使用的所有技术和科学术语与本技术领域技术人员通常理解的意义相同。除实施例中使用的具体方法、设备、材料外,根据本技术领域的技术人员对现有技术的掌握及本发明的记载,还可以使用与本发明实施例中所述的方法、设备、材料相似或等同的现有技术的任何方法、设备和材料来实现本发明,均属于本发明的保护范围。
实施例1 PSCK9基因敲出对大鼠疤痕(瘢痕)模型的影响
1.实验方法
1.1实验动物分组与造模:SPF级大鼠,PCSK9-/-SPF级大鼠(利用CRISPR基因编辑技术,敲除Pcsk9基因exon 2-3,获得Pcsk9基因敲除大鼠),体重(220±26)g,雄性。分为模型对照组和PCSK9-/-组,每组各6只。各组大鼠用2%戊巴比妥钠(120mg/kg)腹腔注射麻醉后固定于手术台上,然后在其背部左侧选择一块4×5cm的完整皮肤,8%硫化钠脱毛,用组织剪在脱毛处各剪成一直径为2.4cm圆形深达肌筋膜的伤口,破坏部分肌肉表面筋膜。为防止大鼠撕咬、舔蹭,动物分笼饲养。创面每日涂2%碘酊常规消毒,观察大鼠创面愈合情况。于第20d取材,用2%戊巴比妥钠麻醉大鼠,取创面皮缘组织约0.5cm2,用于成纤维细胞的培养和后续实验。
1.2成纤维细胞培养和鉴定
取创面组织制成1mm*1mm大小,接种于培养皿,加入0.5mlDMEM培养液。
1.3 TUNEL试剂盒检测原位细胞凋亡
TUNEL是一种检测凋亡DNA片段化的方法,广泛用于鉴定和定量凋亡细胞,或检测单个细胞中过多的DNA断裂,该测定依赖于末端脱氧核苷酸转移酶(TdT)的使用,TdT是催化用荧光染料或另一种标记物标记的脱氧核苷酸与DNA双链断裂的3'-羟基末端连接的酶,它还可以通过除凋亡过程之外的其他方式标记具有DNA损伤的细胞。将实验用的细胞悬液用MEM调节浓度至1×105/ml,接种于100ml培养瓶中,每瓶l0ml。于37℃5%CO2、95%湿度条件下培养,分别于24h、48h、72h后将培养细胞吹打成细胞溶液,收集细胞。于2500rpm离心5min,去上清,每瓶加入75%乙醇lml固定。按照TUNEL细胞凋亡检测盒要求进行染色,用手动计数器手动计算在所有视野中凋亡的成纤维细胞单元的平均分布中的表达,进行统计学比较。
1.4 MTT法检测细胞增殖
MTT化学名:3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐,商品名:噻唑蓝。检测原理:活细胞线粒体中的琥珀酸脱氢酶能使外源性MTT还原为水不溶的蓝紫色结晶甲臢(Formazan),并沉积在细胞中,而死亡细胞无此功能。二甲基亚砜(DMSO)能溶解细胞中的甲臢,用酶联免疫检测仪测定其光吸收值,可间接反映活细胞数量。在一定细胞数范围内MTT结晶形成的量与细胞数成正比。将细胞以1.0×105/ml密度接种于用48孔培养板中,每孔100μ1、37℃、5%CO2孵箱中培养至细胞贴壁。于37℃、5%CO2孵箱中培养24h、48h、72h后每孔加入MTT(5mg/ml)20μ1继续培养4h,吸弃培养基,加入DMSO裂解液100μ1,37℃5%CO2孵箱中孵育20min,紫色结晶完全溶解后在酶标仪上在570nm下测试吸光度(光密度值)。对各组的成纤维的增殖情况进行比较。
1.4统计学方法
采用SPSS 16.0统计软件进行数据分析。计量资料以均数±标准差(x±s)表示,采用单因素方差分析比较,两两数据比较采用t检验,P<0.05为差异有统计学意义,P<0.01为差异显著。
2.实验结果
2.1大鼠创面观测结果
创面每天常规消毒,第1d、3d、5d、7d、12d、20d观察大鼠创面。在观察期第3天开始PCSK9-/-组伤口恢复速度明显比模型组快,创面面积变小。到第12天时,PCSK9-/-组创面已经基本恢复,只留下少量结痂,而模型组仍有0.5cm2左右大小的创面。到第20天时,两组创面均已经基本恢复,模型对照组留下疤痕,而PCSK9-/-组只留下较少色素沉着,未见明显疤痕。
2.2 TUNEL法检测成纤维细胞凋亡
TUNEL是一种检测凋亡DNA片段化的方法,广泛用于鉴定和定量凋亡细胞。结果显示PCSK9-/-组和模型对照组中的成纤维细胞凋亡指数分别为16.816±1.012和2.151±0.563,PCSK9-/-组中的成纤维细胞凋亡显著多于模型对照组(P<0.01)。
2.3 MTT法检测成纤维细胞增殖
二甲基亚砜(DMSO)能溶解细胞中的甲臢,用酶联免疫检测仪在490nm波长处测定其光吸收值,可间接反映活细胞数量,在一定细胞数范围内,MTT结晶形成的量与细胞数成正比。结果显示:培养24h后PCSK9-/-组和模型对照组的平均吸光度值分别为0.31和0.52,培养48h后PCSK9-/-组和模型对照组的平均吸光度值分别为0.26和0.57,培养72h后PCSK9-/-组和模型对照组的平均吸光度值分别为0.21和0.66。PCSK9-/-组与模型对照组比较吸光度值在培养24h后开始明显降低,培养72h后PCSK9-/-组吸光度值降低更为明显,与模型对照组比较差距更加明显。实验结果表明PCSK9敲出能明显降低成纤维细胞的增殖活性。
3.实验结论
PSCK9基因敲出能明显促进皮肤伤口愈合,同时降低成纤维细胞增殖活性,促进成纤维细胞凋亡,减少疤痕(瘢痕)形成,显示敲出PSCK9基因对疤痕(瘢痕)具有预防和治疗作用。
实施例2各种PSCK9抑制剂对大鼠疤痕模型的影响
1.实验方法
1.1材料:
(1)PCSK9干扰RNA-1序列及修饰
基因 | 5'-3'Sense | 5'-3'Antisense |
siPCSK9-1 | GccuGGAGuuuAuucGGAAdT*dT | UUCCgAAuAAACUCcAGGCdT*dT |
siPCSK9-2 | AGGuGuAucuccuAGAcAcdT*dT | GUGUCuAGGAGAuAcACCUdT*dT |
将siPcsk9-1和2等量混合后用生理盐水稀释至20μM,取稀释后siRNA与润肤液均匀混合。
PCSK9干扰RNAi抑制剂-2:RNA序列与Alnylam公司的Inclisran同;PCSK9干扰RNAi抑制剂-3:RNA序列与Affiris公司的ALN-PCS同。
(2)PCSK9小分子化合物抑制剂1:Selleck公司产品R-IMPP,化学式:C24H27N3O2,分子量:389.49,结构式:PCSK9小分子化合物抑制剂2:Selleck公司产品PF-06446846,化学式:C22H20ClN7O,分子量:434.04,结构式:PCSK9小分子化合物抑制剂3:Selleck公司产品SBC-115076,化学式:C31H33N3O5,分子量:527.61,结构式:PCSK9小分子化合物抑制剂4:Selleck公司产品SBC-110736,化学式:C26H27N3O2,分子量:413.51,结构式:
(3)PCSK9单克隆抗体1:购于Abcam公司(ab84041);PCSK9单克隆抗体2:evolocumab(依洛尤单抗);PCSK9单克隆抗体3:alirocumab(阿利西尤单抗)。
(4)PCSK9多肽:Abcam公司的ab32727。
(5)阳性治疗药:糠酸莫米松乳膏(商品名:艾洛松,先灵葆雅中国有限公司生产)(6)实验动物:SPF级黑色豚鼠,体质量(252±18)g,雌雄各半。
(7)治疗乳膏制备方法:赋形剂基质组成成分包括甲基硅油(15%)、硬脂酸(6%)、白凡士林(5%)、液体石蜡(5%)、十八醇(5%)、甘油(20%)、烷基芳基聚乙醇醚(1%)、脂肪醇聚氧乙烯醚(1%)、吐温-807(1%)、尼泊金乙酯(0.1%)、蒸馏水(约31-55%),分别与适量以上PCSK9抑制剂混匀形成混合乳剂。本实施例所用的乳膏基质是指乳膏除去活性成分的基质成分。
1.2实验动物分组与造模:SPF级雄性大鼠,体重(210±28)g,来源于南医大动物中心。大鼠按体重编号,采用随机排列表法分为化合物组1(皮肤涂抹0.5%R-IMPP乳膏)、化合物组2(皮肤涂抹0.5%PF-06446846乳膏)、化合物组3(皮肤涂抹0.5%SBC-115076乳膏)、化合物组4(皮肤涂抹0.5%SBC-110736乳膏)、单抗1组(皮下注射PCSK9单克隆抗体ab81041,3mg/kg.d)、单抗2组(皮下注射evolocumab,3mg/kg.d)、单抗3组(皮下注射alirocumab,3mg/kg.d)、PCSK9干扰RNA组-1(皮肤涂抹0.5%PCSK9小干扰RNA-1乳膏)、PCSK9干扰RNA组-2(皮肤涂抹0.5%PCSK9小干扰RNA-2乳膏)、PCSK9干扰RNA组-3(皮肤涂抹0.5%PCSK9小干扰RNA-3乳膏)、多肽组(皮下注射Abcam公司ab32727,3mg/kg.d)、阳性治疗组(皮肤涂抹艾洛松)、空白对照组(皮肤涂抹乳膏基质)、模型组(尾静脉注射生理盐水,皮肤涂抹乳膏基质),每组各6只。各组大鼠用2%戊巴比妥钠(120mg/kg)腹腔注射麻醉后固定于手术台上,然后在其背部中左侧选择一块4×5cm的完整皮肤,8%硫化钠脱毛,用组织剪在脱毛处各剪成一直径为2.4cm圆形深达肌筋膜的伤口,破坏部分肌肉表面筋膜。动物分笼饲养防止大鼠撕咬、舔蹭。创面每日涂2%碘酊常规消毒,观察大鼠创面愈合情况。
2.实验结果
2.1大鼠创面观测结果
创面每天常规消毒,第1d、3d、5d、7d、12d、20d观察大鼠创面。自第5天开始小分子化合物治疗组、PCSK9小干扰RNA治疗组、PCSK9单抗治疗组和阳性治疗组伤口恢复速度明显比模型组快,创面面积逐渐变小。PCSK9多肽抑制剂治疗组自第7天开始伤口恢复速度好于模型组和空白对照组。第12天,小分子化合物治疗组、PCSK9小干扰RNA治疗组、PCSK9单抗创面已经基本恢复,而模型组和空白对照组分别仍有约0.4cm2和0.36cm2大小的创面,多肽抑制剂治疗组仍有0.2cm2左右大小创面。到第20天时,各组创面均已经恢复,模型对照组和空白对照组留下明显疤痕,而其他组只留下数量不等的色素沉着。
3.实验结论
各PCSK9抑制剂均能明显促进皮肤创面愈合,减少疤痕(瘢痕)形成。
序列表
<110> 陈敏
<120> PCSK9抑制剂在制备预防和治疗疤痕产品中的应用
<150> 2021103213902
<151> 2021-03-25
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Claims (11)
1.PCSK9抑制剂在制备预防和治疗疤痕产品中的应用,其特征在于所述PCSK9是前蛋白转化酶枯草杆菌转化酶/kexin9型,属前蛋白转换酶家族。
2.根据权利要求1所述的应用,其特征在于所述疤痕包括但不限于增殖性疤痕、疤痕疙瘩、浅表性疤痕、萎缩性疤痕、挛缩性疤痕和凹陷性疤痕。
3.根据权利要求1和2所述的应用,其特征在于,所述PCSK9抑制剂包括但不限于PCSK9小分子化合物抑制剂、PCSK9干扰RNAi抑制剂、PCSK9单克隆抗体抑制剂、PCSK9模拟肽抑制剂、PCSK9模拟抗体蛋白抑制剂、PCSK9反义寡核苷酸抑制剂或PCSK9疫苗抑制剂。
4.根据权利要求1和2所述的应用,其特征在于,所述PCSK9抑制剂为PCSK9小分子化合物抑制剂、PCSK9干扰RNAi抑制剂、PCSK9单克隆抗体抑制剂。
6.式Ⅰ 式Ⅱ 式Ⅲ 式Ⅳ
根据权利要求1和2所述的应用,其特征在于,所述PCSK9单克隆抗体抑制剂包括但不限于Abcam公司的抗体ab84041,或依洛尤单抗,或阿利西尤单抗,或重组人源化抗PCSK9单克隆抗体JS002,或重组全人源抗PCSK9单克隆抗体,或PCSK9单克隆抗体LY3015014。
7.根据权利要求1和2所述的应用,其特征在于,所述的PCSK9干扰RNAi抑制剂包括但不限于Inclisran注射剂、ALN-PCS注射剂或ALN-PCSsc注射剂。
8.根据权利要求1和2所述的应用,其特征在于,所述的PCSK9模拟肽抑制剂和PCSK9模拟抗体蛋白抑制剂包括但不限于Abcam公司的多肽ab32727,或模拟抗体蛋白DS9001,或PCSK9人抗体-抗原结合片段1G08。
9.根据权利要求1和2所述的应用,其特征在于,所述PCSK9反义寡核苷酸抑制剂包括但不限于Santaris Pharma公司的SPC5001;所述PCSK9疫苗抑制剂包括但不限于PCSK9疫苗AT04A或PCSK9疫苗AT06A。
10.根据权利要求1和2所述的应用,其特征在于PCSK9抑制剂可单独使用,也可以联合其他治疗方法或药物预防和治疗疤痕性疾病。
11.根据权利要求10所述的产品,其特征在于,所述PCSK9抑制剂选自PCSK9小分子化合物抑制剂、PCSK9干扰RNAi抑制剂、PCSK9单克隆抗体抑制剂、PCSK9模拟肽抑制剂、PCSK9模拟抗体蛋白抑制剂、PCSK9反义寡核苷酸抑制剂或PCSK9疫苗抑制剂。
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