CN106362155A - Gsk3抑制剂在制备治疗尼曼匹克病c型疾病中的应用 - Google Patents
Gsk3抑制剂在制备治疗尼曼匹克病c型疾病中的应用 Download PDFInfo
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Abstract
本发明属于医药领域,涉及GSK3抑制剂在制备治疗尼曼匹克病C型疾病中的应用,通过细胞和动物NPC1基因表达敲低或敲除模型,发现尼曼匹克病C型疾病发病机制与GSK3活性异常升高有关,证明了GSK3特异抑制剂具有治疗尼曼匹克病C型疾病作用,有望用于制备治疗尼曼匹克病C型疾病的药物。
Description
技术领域
本发明属于医药领域,涉及GSK3抑制剂在制备治疗尼曼匹克病C型(Nieman-Pickdisease type C,NPD-C,NP-C)疾病中的应用。
背景技术
尼曼匹克病C型是一种常染色体隐性遗传病,欧洲的发病率估计为1.12∶100000,我国的发病率还不清楚,随着诊断技术的提高,新发现的病例增加,实际发病率在上升。自婴幼儿至成人均可发病,儿童期多见。因发病年龄不同,首发的神经系统症状不一致,临床表现不一。一般发病年龄越早,病情越重。严重的在新生儿期发病,短期内即可引起死亡,成人发病可以表现为慢性神经系统变性病。典型病例常首先表现为全身脏器受累,如新生儿期出现的胆汁淤积性黄疸,婴儿期或儿童期出现的肝脾肿大或单纯的脾脏肿大,然后影响到神经系统,出现小脑、脑干、基底节和大脑皮层等部位受累的症状,神经系统表现主要包括:快速眼动异常、共济失调、辨距不良、构音障碍、吞咽困难和进行性痴呆,痴笑猝倒发作、癫癎发作、听力损害和肌张力障碍也比较常见,最具特征性的表现是垂直性核上性眼肌麻痹(vertical supranuclear gaze palsy,VGSP),痴笑猝倒发作是因突然的肌张力丧失,不能维持立位姿势而跌倒,不伴有意识障碍,也是NP-C特异性症状之一。
正常情况下,NPC1和NPC2通过协同作用,维持细胞内游离胆固醇的流动,从而维持胆固醇代谢的平衡。低密度脂蛋白(LDL)通过泡饮作用进入细胞内,在晚期胞内体(lateendosome)和溶酶体(lysosome)中被溶酶体酸性脂肪酶水解而释放出游离胆固醇,再经NPC2和NPC1蛋白协同作用,转运到细胞器的脂膜。NPC1或者NPC2基因突变导致细胞游离胆固醇转运功能障碍,是NP-C发病的始动环节。NPC1和NPC2基因分析发现致病性突变是NP-C疾病诊断的金标准。基因检查也可用于产前诊断。随着基因检查技术的应用,报道的NP-C病例不断增加。NP-C病例95%由NPC1突变引起,5%由NPC2突变所致。
NP-C目前尚无有效的治疗方法,以对症治疗为主,采用综合治疗方法,改善病人的神经功能和生存质量。美格鲁特是目前唯一在欧洲、澳大利亚和日本等国家批准用于治疗NP-C的特效药物,经长期随访观察和队列研究证实,美格鲁特可以稳定并改善NP-C病人的神经系统症状,延长预期寿命。为避免神经系统损害继续加重,NP-C病人应在确诊后尽早给予美格鲁特治疗。该药主要的不良反应为胃肠不适、腹泻和体重下降,坚持用药一段时间后可逐渐减轻。但是,美格鲁特价格高,大部分病人无法承担。因此,现有技术条件下,还缺乏真正有效的用于治疗NP-C的药物。
发明内容
本发明针对现有技术在治疗尼曼匹克病C型疾病药物方面的瓶颈,阐明了GSK3抑制剂(LiCl,CHIR99021)显著改善NPC1KD或者NPC1KO造血、神经干细胞的自我更新和分化能力。以LiCl处理NPC1KD造血干细胞为例,10mM LiCl能够使造血干细胞增殖能力增加50%以上,聚落形成能力增加30%以上。提供了GSK3抑制剂在制备治疗尼曼匹克病C型疾病药物中的应用。
本发明采用NPC1KO小鼠模型,从第1周起,NPC1KO小鼠腹腔注射LiCl(85mg/kg)或者CHIR99021(20mg/kg)或者同剂量经口灌胃给药,小鼠造血功能明显改善和神经系统退行性改变症状也明显好转,其中CHIR99021的作用更明显。更重要的是,两种GSK3抑制剂延长NPC1KD小鼠寿命3-6周。明确了GSK3抑制剂组合物的有效性,并为注射给药和口服给药提供了依据。
本发明提供了用于制备治疗尼曼匹克病C型疾病药物的GSK3抑制剂,包括锂盐,CHIR99021,6-BIO,TDZD-8,SB-216763。
本发明所述的药物组合物,包括口服制剂或非口服制剂。口服制剂包括:片剂、胶囊、颗粒、糖浆、溶液,非口服制剂包括注射液、冻干制剂等。
本发明所述的GSK3抑制剂,在临床上剂量可以根据病人的病情和年龄等因素进行调整。
本发明所述的药物组合物,所用的载体辅料可以是制剂上常用的各种辅料。
附图说明
图1 NPC1基因敲低细胞GSK3磷酸化降低,β-catenin表达下调。NPC1shRNA转染293T细胞,NPC1表达下调约75%,GSK3磷酸化率下调约43%,β-catenin的表达下调72%。图A:western blotting一次结果,图B:3次western blotting结果灰度值统计结果。
图2 NPC1KO小鼠细胞造血干细胞减少,神经元减少。NPC1KO小鼠造血干细胞(LSK,lineage-Sca-1+c-kit+)NPC1表达完全抑制,pGSK3磷酸化降低,wnt信号通路效应分子β-catenin表达降低,wnt信号通路靶基因c-myc表达降低(A);小鼠骨髓LSK细胞明显降低(B);小鼠神经元(lamina VII阳性细胞)明显减少(C和D)。
图3 GSK3抑制剂延长NPC1KO小鼠寿命。NPC1KO小鼠分3组(对照组,LiCl治疗组和CHIR99021治疗组),每组5只,小鼠出生后第1周开始,LiCl治疗组和CHIR99021治疗组每天腹腔分别注射LiC1(85mg/kg)和CHIR99021(20mg/kg),对照组腹腔注射生理盐水,连续观察小鼠的存活率。
具体实施方式
实施例一、NPC细胞模型的制备和疾病机制的发现
1.方法
细胞准备:
1)NP-C病人的成纤维细胞:取NP-C患者皮肤成纤维细胞。
2)NPC1基因表达敲低(knock-down,KD)人和小鼠细胞:制备表达人和小鼠NPC1shRNA的慢病毒,慢病毒感染人胚胎肾293T和小鼠胚胎纤维细胞MEF,嘌呤霉素筛选阳性感染细胞,qPCR和western blotting验证NPC1基因表达敲低的效果,获得NPC1KD细胞模型。
检测指标:NPC1,GSK3,β-catenin
2.结果
1)与正常人相比,NP-C患者成纤维细胞NPC1表达显著减低。
2)与正常细胞相比,NPC1基因敲低细胞NPC1的表达下调超过70%。
3)NP-C患者成纤维细胞和NPC1KD细胞,GSK-3β活性增加,β-catenin稳定性减低,表达减少。
结果表明,NPC1KD或者NPC1KO细胞β-catenin表达降低,wnt信号通路转导障碍,细胞生长、分化异常。表明NPC1KD或者NPC1KO细胞是筛选药物的可靠模型,作用于wnt信号通路的药物具有治疗NPC的用途。
实施例二、NPC小鼠模型的制备和发病机制验证
1.方法
NPC1基因knock-out(KO)小鼠制备方法:利用CRISPY-Cas9敲除NPC1基因,获得NPC1-/-小鼠。
测定指标:造血系统、神经系统干细胞的功能、表型,症状体征
2.结果
1)NPC1KO小鼠模型造血系统及神经系统表型和NP-C患者很相似,表现为造血功能障碍及神经系统退行性改变。在没有有效干预措施的条件下,小鼠的寿命不超过14周。与临床患者具有较大的相似性。
2)NPC1KO小鼠的神经干细胞、造血干细胞和肝脏实质细胞β-catenin表达明显降低,wnt信号通路靶基因表达下调。
结果表明,利用动物模型验证了wnt信号通路转导障碍是NPC1KO小鼠相应器官、系统发育障碍的重要原因,表现与临床具有较大的相似性,具有筛选药物的可靠性,进一步表明作用于wnt信号通路的药物具有治疗NP-C的用途。
实施例三、GSK3抑制剂改善NP-C细胞模型的作用
1.方法
参照实施例一的方法,制备NPC模型细胞,分离NPC1KO小鼠造血干细胞和神经干细胞
实验步骤和测定指标:GSK3特异抑制剂LiCl,CHIR99021处理NPC1KD和NPC1KO细胞,观察细胞增殖、干细胞自我更新和分化的变化。
2.结果
LiCl(浓度为10MM)和CHIR99021(浓度为3uM)显著改善NPC1KD或者NPC1KO造血、神经干细胞的自我更新和分化能力。以LiCl处理NPC1KD造血干细胞为例,能够使造血干细胞增殖能力增加50%以上,聚落形成能力增加30%以上。
结果表明,GSK3抑制剂显著增强NP-C细胞的自我更新和分化能力,可以用于治疗NPC。
实施例四 GSK3抑制剂改善NPC模型小鼠的作用
1.方法
参照实施例二的方法制备NPC小鼠模型,第1周起每天连续腹腔注射LiCl(剂量85mg/kg)或者CHIR99021(剂量20mg/kg)。
检测指标:血液系统、神经系统表型,症状和体征。
2.结果
1)小鼠造血功能明显改善和神经系统退行性改变症状也明显好转,其中CHIR99021的作用更明显。
2)两种GSK3抑制剂延长NPC1KD小鼠寿命3-6周。
结果表明,GSK3抑制剂具有改善NPC1KO小鼠的症状,延长生命,表明具有明显的治疗NPC的作用。
Claims (5)
1.GSK3抑制剂在制备治疗尼曼匹克病C型疾病药物中的应用。
2.权利要求1所述的GSK3抑制剂为有效成份与药学上可接受的辅料组成组合物在制备治疗尼曼匹克病C型疾病药物中的应用。
3.权利要求1和2所述的GSK3抑制剂,其特征是锂盐,CHIR99021,6-BIO,TDZD-8,SB-216763。
4.权利要求1和2所述的组合物,其特征是口服制剂或非口服制剂,口服制剂包括:片剂、胶囊、颗粒、糖浆、溶液,非口服制剂包括注射液、冻干制剂等。
5.权利要求1和2所述的应用,在临床上GSK3抑制剂的剂量可以根据病人的病情和年龄等因素进行调整。
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CN201610883764.9A CN106362155A (zh) | 2016-10-08 | 2016-10-08 | Gsk3抑制剂在制备治疗尼曼匹克病c型疾病中的应用 |
EP17857803.5A EP3505185A4 (en) | 2016-10-08 | 2017-09-05 | APPLICATION OF A GSK3 INHIBITOR IN THE PREPARATION OF A MEDICAMENT FOR THE TREATMENT OF NIEMANN-PICK TYPE C DISEASE |
US16/339,746 US20200046763A1 (en) | 2016-10-08 | 2017-09-05 | Application of gsk3 inhibitor in preparing a drug to treat niemann-pick disease type c |
PCT/CN2017/100469 WO2018064922A1 (zh) | 2016-10-08 | 2017-09-05 | Gsk3抑制剂在制备治疗尼曼匹克病c型疾病药物中的应用 |
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US20200046763A1 (en) | 2020-02-13 |
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