CN108430494A - 用于治疗亨特综合征的方法和组合物 - Google Patents
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Abstract
本发明尤其提供了用于有效治疗亨特综合征的用于CNS递送艾杜硫酸酯酶‑β(人重组艾杜糖醛酸‑2‑硫酸酯酶蛋白)的组合物和方法。本发明提供的组合物和方法不仅在脑和脊髓中而且在外周组织(包括心脏、肝、脾、肺和肾)中有效地减轻症状。
Description
技术领域
本发明涉及用于治疗亨特综合征(hunter syndrome)的改进的方法和组合物。
背景技术
黏多糖贮积症II型(mucopolysaccharidosis,MPS II,亨特综合征)是由缺乏发挥降解黏多糖之功能的艾杜糖醛酸-2-硫酸酯酶(iduronate-2-sulfatase)引起的X连锁隐性遗传性溶酶体贮积症[1]。缺乏艾杜糖醛酸-2-硫酸酯酶导致未降解的糖胺聚糖(glycosaminoglycan,GAG)在细胞中累积并导致进行性多器官损伤[2]。在多种类型的GAG中,硫酸皮肤素(dermatan sulfate,DS)和硫酸乙酰肝素(heparan sulfate,HS)是MPS II中主要的累积GAG[2]。
MPS II的临床表型分为减弱形式和严重形式。具有减弱形式的患者显示出躯体表现,包括粗糙的面部、肝脾肿大、多发性骨发育不良和关节僵硬而无神经受累,而具有严重形式的患者除躯体症状之外还具有神经损伤和进行性神经变性。内源性IDS水平不足导致硫酸乙酰肝素和硫酸皮肤素在例如心脏、肝、中枢神经系统(central nervous system,CNS)等中的病理积聚。包括神经变性和智力低下(mental retardation)的症状在童年期间出现;并且早逝(early death)可由于脑中的器官损伤而发生。
酶替代疗法(enzyme replacement therapy,ERT)涉及向对象全身性施用天然或重组来源的蛋白质和/或酶。经批准的疗法通常静脉内施用于对象并且通常在治疗潜在酶缺乏的躯体症状中有效。
由于静脉内施用的蛋白质和/或酶有限地分布到中枢神经系统(CNS)的细胞和组织中,因此具有CNS病因学的疾病的治疗尤其具有挑战性,因为静脉内施用的蛋白质和/或酶无法充分穿过血脑屏障(blood-brain barrier,BBB)。
血脑屏障(BBB)是由内皮细胞构成的结构系统,其通过限制血流中的有害物质(例如细菌、大分子(例如,蛋白质)和其他亲水性分子)穿过BBB并进入下面的脑脊液(CSF)和CNS中的扩散来发挥保护中枢神经系统(CNS)免受此类物质影响的作用。
许多人认为,在脑表面扩散的屏障以及缺乏有效且方便的递送方法对任何疾病来说对于在脑中实现足够的治疗效果而言是太大的障碍。
亨特综合征影响神经系统并因此在用传统疗法治疗这些疾病中显示出独特的挑战。在受影响的个体的神经元和脑脊膜中常存在大量的糖胺聚糖(GAG)积聚,导致多种形式的CNS症状。
因此,仍然非常需要将治疗剂有效地递送至脑。更特别地,非常需要将活性剂更有效地递送至中枢神经系统以治疗溶酶体贮积症(例如亨特综合征)。
为了克服BBB,通过鞘内或脑室内注射重组酶的直接药物递送已在数种类型的MPS动物模型中显示出有前景的结果[3-7]。此外,I/II期临床试验报道了鞘内(intrathecal,IT)注射艾杜硫酸酯酶(idursulfase,IDS)在患有严重形式的MPS II的儿童中使脑脊液(cerebrospinal fluid,CSF)中的GAG浓度降低约8090%。但在临床试验中已报道大量不良事件,大部分不良事件与IT药物递送装置的故障相关[8]。
尽管严重形式的MPS II中的神经变性的细胞机制尚未被完全了解,但数个最近的研究已表明了大MPS患者群组中HS来源的二糖与智力低下之间的相关性[9,10]。此外,动物研究已表明,HS可能通过激活星形胶质细胞或神经干细胞中基于整合素的黏着斑而导致与MPS III小鼠模型相关的神经疾病[11,12]。Akiyama等[13]报道,通过Sensi-Pro非还原端HS测定[14]测量的“病理性GAG”比MPS II小鼠脑组织中的总GAG具有更高的灵敏度和特异性[13]。基于这些数据,与总GAG量相比,累积的HS的量可以是用于表示MPS II的脑病理状况和神经功能的更敏感的生物标志物。然而,在临床环境中测量脑组织HS是不可能的。因此,需要发现表示脑组织HS的可用的临床生物标志物。如果CSF中的HS浓度与脑组织GAG(尤其是HS)的量相关,我们假设其可以是临床生物标志物之一。
根据本发明的IDS-β的单次ICV(脑室内(intracerebroventricular))注射耐受良好,并且其导致脑和其他躯体组织中HS和GAG的显著降低。我们还发现,脑HS与脑GAG之间CSF中HS含量的显著正相关表明CSF HS浓度可以是用于表示CNS受累MPS患者中脑病理状况的可用生物标志物。
本发明提供了用于将治疗剂直接递送至中枢神经系统(CNS)的有效方法。本发明基于如下发现:艾杜硫酸酯酶-β(IDS-β)(作为用于亨特综合症的有效替代酶开发的人重组艾杜糖醛酸-2-硫酸酯酶蛋白)可通过脑室内(ICV)施用被直接引入到对象的脑室(ventricle)中,使得该酶有效且广泛地穿过多种表面扩散并渗透整个脑的多个区域(包括深部脑区域)。本发明人已示出,这样的蛋白质递送可使用简单的基于盐水的制剂来实现并且不在对象中引起显著的不良作用(例如严重的免疫应答)。因此,本发明提供了用于治疗亨特综合征的直接CNS递送的高度高效、临床上期望且患者友好的方法。
发明内容
技术问题
为了治疗亨特综合征,仍然非常需要将治疗剂有效地递送至脑。近来已经尝试鞘内(IT)注射或向脑脊液(CSF)施用治疗性蛋白质来治疗亨特综合征患者,但在临床试验中已报道了大量不良事件[8]。尽管大多数不良事件与IT药物递送装置的故障相关,但是将需要其他方法(例如脑室内(ICV))施用来治疗亨特综合征患者。ICV施用将是用于将治疗剂直接递送至患者脑室的有效方法,目前还没有用于通过ICV施用来治疗亨特综合征的经批准产品和/或正在开发的产品。
技术方案
1.治疗亨特综合征的方法,其包括向需要治疗的对象脑室内施用(ICV施用)治疗有效剂量的ICV制剂的步骤,所述ICV制剂包含浓度为约0.1mg/ml至约60mg/ml的艾杜硫酸酯酶-β(IDS-β)蛋白、浓度为约150mM的氯化钠、浓度为约0.05mg/ml的聚山梨酯20,并且pH为约6。
2.所述技术方案1所述的方法,其中所述ICV制剂包含浓度为约15mg/ml的艾杜硫酸酯酶-β(IDS-β)蛋白、浓度为约150mM的氯化钠、浓度为约0.05mg/ml的聚山梨酯20,并且pH为约6。
3.所述技术方案1所述的方法,其中所述治疗有效剂量为约1mg至约30mg。
4.所述技术方案1所述的方法,其中所述治疗有效剂量为约10mg。
5.所述技术方案1所述的方法,其中所述ICV施用每三周进行一次。
6.所述技术方案1所述的方法,其中所述ICV施用每月进行一次。
7.所述技术方案1所述的方法,其中所述ICV施用通过包含储存器和与所述储存器相连接的导管的脑室内导管系统进行。
8.所述技术方案7所述的方法,其还包括以下步骤:外科手术植入所述脑室内导管系统,其中将所述储存器放置在所述需要治疗的对象的头皮与脑之间,并且将所述导管的末端放置在所述对象的脑室内,使得所述储存器的内部空间通过所述导管的内部空间与所述脑室的内部空间相连接,使得脑脊液从所述脑室流入到所述储存器中以填充所述储存器;以0.1至60ml/分钟的流量从所述储存器中取出0.1至5ml的脑脊液;以0.1至60ml/分钟的流量将0.1至5ml的所述ICV制剂注入到所述储存器中;以及使所述ICV制剂从所述储存器流经所述导管进入到所述脑室中。
9.所述技术方案1所述的方法,其中所述ICV施用与至少一种用于亨特综合征的另外形式的酶替代疗法治疗组合进行。
10.所述技术方案9所述的方法,其中所述用于亨特综合征的另外形式的酶替代疗法治疗选自静脉内施用和皮下施用。
11.所述技术方案10所述的方法,其中所述ICV施用每月进行一次,并且所述静脉内施用每周进行一次。
12.所述技术方案10所述的方法,其中所述ICV施用每三周进行一次,并且所述静脉内施用每周进行一次。
13.所述技术方案10所述的方法,其中所述ICV施用每月进行一次,并且所述皮下施用每周进行一次。
14.所述技术方案10所述的方法,其中所述ICV施用每三周进行一次,并且所述皮下施用每周进行一次。
15.所述技术方案10所述的方法,其中所述ICV施用每月进行一次,并且所述皮下施用每周进行两次。
16.所述技术方案10所述的方法,其中所述ICV施用每三周进行一次,并且所述皮下施用每周进行两次。
17.所述技术方案10所述的方法,其中所述ICV施用每月进行一次,并且所述静脉内施用和所述皮下施用以一周的间隔交替进行。
18.所述技术方案10所述的方法,其中所述ICV施用每三周进行一次,并且所述静脉内施用和所述皮下施用以一周的间隔交替进行。
19.用于治疗亨特综合征的用于脑室内施用的制剂,其包含浓度为约0.1mg/ml至约60mg/ml的艾杜硫酸酯酶-β(IDS-β)蛋白、浓度为约150mM的氯化钠、浓度为约0.05mg/ml的聚山梨酯20,并且pH为约6。
有益效果
根据本发明的脑室内施用的IDS-β降低MPS II小鼠中脑和脑脊液(CSF)中的硫酸乙酰肝素(HS)和糖胺聚糖(GAG)水平。
根据本发明的脑室内施用的IDS-β降低MPS II小鼠中的躯体(外周)组织(包括心脏、肺、肝、脾和肾)中的硫酸乙酰肝素(HS)和糖胺聚糖(GAG)水平。
根据本发明,脑中的GAG浓度的趋势可由CSF中的硫酸乙酰肝素水平预测,这可允许更安全且更容易地诊断脑GAG累积的严重程度。
附图说明
图1示出了在单次ICV注射IDS-β之后IDS KO小鼠的脑组织中的GAG水平。
图2示出了在单次ICV注射IDS-β之后IDS KO小鼠的CSF和脑组织中的HS水平。
图3示出了在单次ICV注射IDS-β之后IDS KO小鼠的CSF中HS水平与脑组织中HS水平之间的相关性。
图4示出了在单次ICV注射IDS-β之后IDS KO小鼠的躯体组织中的GAG水平。
图5示出了在注射之后的不同时间点处收获并用台盼蓝(trypan blue)可视化的脑组织。
图6示出了在单次ICV注射IDS-β之后IDS KO小鼠的心脏组织中的GAG水平。
图7示出了在单次ICV注射IDS-β之后IDS KO小鼠的肺组织中的GAG水平。
图8示出了在单次ICV注射IDS-β之后IDS KO小鼠的肝组织中的GAG水平。
图9示出了在单次ICV注射IDS-β之后IDS KO小鼠的脾组织中的GAG水平。
图10示出了在单次ICV注射IDS-β之后IDS KO小鼠的肾组织中的GAG水平。
具体实施方式
如下面详细描述的,本发明人已成功地开发了用于有效地脑室内(ICV)施用艾杜硫酸酯酶-β(IDS-β)蛋白的稳定制剂。
在多个实施方案中,本发明包括用于直接脑室内(ICV)施用的稳定制剂,其包含艾杜硫酸酯酶-β(IDS-β)蛋白、盐和聚山梨酯表面活性剂。在一些实施方案中,IDS-β蛋白以约0.1至60mg/ml(例如,0.1至60mg/ml、0.1至30mg/ml、0.3至30mg/ml、0.2至20mg/ml、0.2至6mg/ml、0.6至6mg/ml、5至60mg/ml或10至60mg/ml)的浓度存在于ICV制剂中。在一些实施方案中,IDS-β蛋白以选自0.1mg/ml、0.2mg/ml、0.5mg/ml、0.6mg/ml、1mg/ml、2mg/ml、5mg/ml、6mg/ml、10mg/ml、15mg/ml、20mg/ml、30mg/ml、40mg/ml、50mg/ml、55mg/ml或60mg/ml的浓度或高至这样的浓度存在于ICV制剂中。
在多个实施方案中,本发明包括本文中描述的任何实施方案的稳定制剂。在一些实施方案中,IDS-β包含具有SEQ ID NO:1的氨基酸序列的蛋白质。在一些实施方案中,IDS-β还包含具有SEQ ID NO:2的氨基酸序列的蛋白质。SEQ ID NO:1是重组人艾杜糖醛酸-2-硫酸酯酶蛋白。SEQ ID NO:2是其第59位半胱氨酸被甲酰基-甘氨酸(G*)替代的重组人艾杜糖醛酸-2-硫酸酯酶蛋白。
在一些实施方案中,IDS-β包含约35%(mol百分比)或更少的具有SEQ ID NO:1的蛋白质和约65%(mol百分比)或更多的具有SEQ ID NO:2的蛋白质。在一些实施方案中,IDS-β包含约20至35%(mol百分比)的具有SEQ ID NO:1的蛋白质和约65至80%(mol百分比)的具有SEQ ID NO:2的蛋白质。
在一些实施方案中,IDS-β包含具有与SEQ ID NO:1具有至少60%、65%、70%、75%、80%、85%、90%、95%或98%同一性的氨基酸序列的蛋白质。在一些实施方案中,IDS-β包含具有与SEQ ID NO:2具有至少60%、65%、70%、75%、80%、85%、90%、95%或98%同一性的氨基酸序列的蛋白质。
在一些实施方案中,本文中描述的任何实施方案的稳定制剂包含盐。在一些实施方案中,盐是氯化钠(NaCl)。在一些实施方案中,NaCl以约0至300mM(例如,0至250mM、0至200mM、0至150mM、50至250mM或100至200mM)的浓度存在。在一些实施方案中,NaCl以约125至175mM的浓度存在。在一些实施方案中,NaCl以约150mM的浓度存在。
在多个实施方案中,本发明包括本文中描述的任何实施方案的稳定制剂,其中聚山梨酯表面活性剂选自聚山梨酯20、聚山梨酯40、聚山梨酯60、聚山梨酯80、及其组合。在一些实施方案中,聚山梨酯表面活性剂是聚山梨酯20(吐温20)。在一些实施方案中,聚山梨酯20以约0至0.02%(0至0.2mg/ml)的浓度存在。在一些实施方案中,聚山梨酯20以约0.005%(0.05mg/ml)的浓度存在。
在多个实施方案中,本发明包括本文中所述的任何实施方案的稳定制剂,其中所述制剂还包含缓冲剂。在一些实施方案中,缓冲剂选自磷酸盐、乙酸盐、组氨酸、琥珀酸盐、Tris、及其组合。在一些实施方案中,缓冲剂是磷酸盐。在一些实施方案中,磷酸盐以不大于50mM(例如,不大于45mM、40mM、35mM、30mM、25mM、20mM、15mM、10mM、5mM、0.25mM或0.12mM)的浓度存在。在一些实施方案中,磷酸盐以不大于20mM的浓度存在。在多个方面,本发明包括本文中描述的任何实施方案的稳定制剂,其中所述制剂的pH为约3至8(例如,约4至7.5、5至8、5至7.5、5至6.5、5至7.0、5.5至8.0、5.5至7.7、5.5至6.5、6至7.5或6至7.0)。在一些实施方案中,制剂的pH为约5.5至6.5(例如,5.5、6.0、6.1、6.2、6.3、6.4或6.5)。在一些实施方案中,所述制剂的pH为约6.0。
在多个实施方案中,本发明包括本文中描述的任何实施方案的稳定制剂,其中所述制剂是液体制剂。在多个实施方案中,本发明包括本文中描述的任何实施方案的稳定制剂,其中所述制剂配制成冻干干粉。
在一些实施方案中,本发明包括用于ICV施用的稳定制剂,其包含浓度为约0.1至60mg/ml的IDS-β蛋白、浓度为约150mM的NaCl、浓度为约0.005%(0.05mg/ml)的聚山梨酯20,并且pH为约6.0。在一些实施方案中,IDS-β蛋白的浓度为约0.1mg/ml、0.2mg/ml、0.5mg/ml、0.6mg/ml、1mg/ml、2mg/ml、5mg/ml、6mg/ml、10mg/ml、15mg/ml、20mg/ml、30mg/ml、40mg/ml、50mg/ml、55mg/ml或60mg/ml。
在多个方面,本发明包括本文中描述的多个实施方案中的包含单一剂量形式的稳定制剂的容器。在一些实施方案中,容器选自安瓿、小瓶、瓶、药筒(cartridge)、储存器、冻干注射器(lyo-ject)或预填充注射器。在一些实施方案中,容器是预填充注射器。在一些实施方案中,预填充注射器选自具有烘烤硅酮涂层(baked silicone coating)的硼硅酸盐玻璃注射器、具有喷涂硅酮(sprayed silicone)的硼硅酸盐玻璃注射器或不具有硅酮的塑料树脂注射器。在一些实施方案中,稳定制剂以小于约50mL(例如,小于约45ml、40ml、35ml、30ml、25ml、20ml、15ml、10ml、5ml、4ml、3ml、2.5ml、2.0ml、1.5ml、1.0ml或0.5ml)的体积存在。在一些实施方案中,稳定制剂以约6.0ml的体积存在。在一些实施方案中,稳定制剂以约3.0ml的体积存在。在一些实施方案中,2.0ml的稳定制剂存在于6.0ml小瓶中。在一些实施方案中,1.5ml的稳定制剂存在于5.0ml小瓶中。在一些实施方案中,1.0ml的稳定制剂存在于3.0ml小瓶中。
在多个方面,本发明包括治疗亨特综合征的方法,其包括向需要治疗的对象脑室内施用根据本文中描述的任何实施方案的制剂的步骤。
在一些实施方案中,本发明包括治疗亨特综合征的方法,其包括向需要治疗的对象脑室内施用制剂的步骤,所述制剂包含浓度为约0.1至60mg/ml的IDS-β蛋白、浓度为约150mM的氯化钠、浓度为约0.005%(0.05mg/ml)的聚山梨酯20,并且pH为约6。
在一些实施方案中,需要治疗的对象具有为了ICV施用而植入的脑室内导管系统,其具有储存器和导管,例如Ommaya储存器。在一些实施方案中,ICV施用通过以0.1至60ml/分钟的流量将上述ICV制剂注入到储存器中来进行。在一些实施方案中,在ICV施用制剂之前,将对象的脑脊液(CSF)以0.1至60ml/分钟的流量从储存器中取出,使得在ICV施用之后对象的CSF体积没有净提高,以防止脑中的压力提高。在一些实施方案中,通过轻轻按压并释放储存器使注入到储存器中的制剂通过导管行进到对象的脑室中。
在一些实施方案中,ICV施用在对象中不导致显著的不良作用(例如,严重的免疫应答)。在一些实施方案中,ICV施用在对象中不导致显著的适应性T细胞介导的免疫应答。
在一些实施方案中,制剂的ICV施用导致将IDS-β蛋白递送至脑、脊髓和外周器官中的多种靶组织。在一些实施方案中,制剂的ICV施用导致将IDS-β蛋白递送至脑靶组织。在一些实施方案中,脑靶组织包含灰质中的神经元和/或白质。在一些实施方案中,将IDS-β蛋白递送至神经元、胶质细胞、血管周细胞(perivascular cell)和/或脑脊膜细胞。在一些实施方案中,将IDS-β蛋白还递送至脊髓中的神经元。
在一些实施方案中,制剂的ICV施用还导致将IDS-β蛋白全身性递送至外周靶组织。在一些实施方案中,外周靶组织选自但不限于心脏、肝、脾、肺和/或肾。
在一些实施方案中,制剂的ICV施用导致脑靶组织、脊髓神经元和/或外周靶组织中的细胞溶酶体定位。在一些实施方案中,制剂的ICV施用导致脑靶组织、脊髓神经元和/或外周靶组织中GAG贮积的降低。在一些实施方案中,与阴性对照(例如,在治疗之前或在仅载剂施用之后对象中的GAG贮积)相比,GAG贮积降低至少10%、20%、30%、40%、50%、60%、70%、80%、90%、1倍、1.5倍或2倍。在一些实施方案中,制剂的ICV施用导致神经元中的降低的空泡形成(例如,与阴性对照相比,降低至少20%、40%、50%、60%、80%、90%、1倍、1.5倍或2倍)。在一些实施方案中,神经元包含浦肯野细胞(Purkinje cell)。
在一些实施方案中,制剂的ICV施用导致脑靶组织、脊髓神经元和/或外周靶组织中的IDS-β酶活性提高。在一些实施方案中,与阴性对照(例如,在治疗之前或在仅载剂施用之后对象中的内源酶活性)相比,IDS-β酶活性提高至少1倍、2倍、3倍、4倍、5倍、6倍、7倍、8倍、9倍或10倍。在一些实施方案中,提高的IDS-β酶活性为至少约10nmol/hr/mg、20nmol/hr/mg、40nmol/hr/mg、50nmol/hr/mg、60nmol/hr/mg、70nmol/hr/mg、80nmol/hr/mg、90nmol/hr/mg、100nmol/hr/mg、150nmol/hr/mg、200nmol/hr/mg、250nmol/hr/mg、300nmol/hr/mg、350nmol/hr/mg、400nmol/hr/mg、450nmol/hr/mg、500nmol/hr/mg、550nmol/hr/mg或600nmol/hr/mg。
在一些实施方案中,制剂的ICV施用导致亨特综合征的至少一种症状或特征的强度、严重程度或频率降低或发作延迟。在一些实施方案中,亨特综合征的至少一种症状或特征是认知损伤;白质病变;脑实质、神经节、胼胝体和/或脑干中的扩张的血管周隙;萎缩;和/或脑室扩大。
在一些实施方案中,ICV施用每两周发生一次。在一些实施方案中,ICV施用每三周发生一次。在一些实施方案中,ICV施用每月发生一次。在一些实施方案中,ICV施用每两个月发生一次。在一些实施方案中,施用是连续的,例如通过连续灌注泵。在一些实施方案中,ICV施用与静脉内(IV)施用联合使用。在一些实施方案中,IV施用每周发生一次。在一些实施方案中,IV施用每两周发生一次。在一些实施方案中,IV施用每月发生一次。在一些实施方案中,IV施用每两个月发生一次。
在一些实施方案中,IV和ICV施用在同一天进行。在一些实施方案中,IV和ICV施用不在彼此的一定时间量内(例如不在至少2天内、至少3天内、至少4天内、至少5天内、至少6天内、至少7天内或至少1周内)进行。在一些实施方案中,IV和ICV施用以交替的时间表进行,例如每周、每隔一周、每月两次或每月交替施用。在一些实施方案中,ICV施用在施用时间表中(例如在每周、每隔一周、每月两次或每月IV施用的时间表中)替代IV施用,该时间表中的每三或四或五次施用可用代替IV施用的ICV施用替代。
在一些实施方案中,IV和ICV施用依次进行,例如首先进行IV施用(例如,每周、每隔一周、每三周一次、每月两次或每月给药持续两周、一个月、两个月、三个月、四个月、五个月、六个月、一年或更长),随后是ICV施用(例如,每周、每隔一周、每三周一次、每月两次或每月给药持续多于两周、一个月、两个月、三个月、四个月、五个月、六个月、一年或更长)。在一些实施方案中,首先进行ICV施用(例如,每周、每隔一周、每三周一次、每月两次、每月、每两个月一次、每三个月一次给药持续两周、一个月、两个月、三个月、四个月、五个月、六个月、一年或更长),随后是IV施用(例如,每周、每隔一周、每三周一次、每月两次或每月给药持续多于两周、一个月、两个月、三个月、四个月、五个月、六个月、一年或更长)。
在一些实施方案中,在不存在IV施用的情况下使用ICV施用。
在一些实施方案中,在不存在并行免疫抑制疗法的情况下使用ICV施用。
实施例
在下文中,将参照实施例进一步详细描述本发明。对于本领域普通技术人员而言明显的是,这些实施例仅是举例说明性目的并且不应被解释为限制本发明的范围。
实施例1
1-1:概述
进行本研究以研究MPS II小鼠中单次脑室内(ICV)注射艾杜硫酸酯酶-β(IDS-β)的药理作用和剂量反应关系。此外,我们测量了CSF中的HS浓度并且研究了MPS II小鼠的CSF HS与脑组织HS和GAG之间的相关性。
进行三种剂量的ICV IDS-β注射(3μg、10μg和30μg),并在注射之后7、14和28天测量组织GAG(脑、心脏、肺、肝、脾和肾)。在小鼠的CSF和脑中通过使用LC/MS-MS测量HS。所有经IDS-β处理的组的脑和其他躯体组织中的总GAG显著降低。在30μg注射组中显著降低保持28天。我们还示出,在所有经IDS-β处理的组的CSF和脑组织二者中HS含量均降低。此外,我们示出CSF中的HS浓度与脑HS和脑组织GAG显著相关。
单次ICV注射根据本发明的IDS-β耐受良好,并且其产生脑和其他躯体组织中的HS和GAG的显著降低。我们还发现,脑HS与脑GAG之间CSF中HS含量的显著正相关表明CSF HS浓度可以是用于表示CNS受累MPS II患者中脑病理状况的可用生物标志物。
1-2:方法
动物
我们使用了先前报道的IDS敲除(KO)的小鼠。简言之,使Ids基因从外显子2至外显子3中缺失[15]。IDS KO小鼠从C57BL/6.129S背景品系繁殖并在Ids基因中具有无效突变(null mutation)。野生型(wild-type,WT)对照小鼠从C57BL/B6.129S品系繁殖。所有小鼠的基因型通过由剪尾(tail snip)获得的DNA的聚合酶链反应确认。本研究得到机构动物护理和使用委员会(Institutional Animal Care and Use Committee)的批准(批准No.20140925005)并且按照韩国首尔三星生物医学研究所(Samsung Biomedical ResearchInstitute)的动物福利政策进行。
研究设计
通过分层随机化将6周龄动物分配至五个组(每组中12只动物)。将IDS KO小鼠分配至四个组:具有载剂注射的IDS KO小鼠和用三种不同剂量(3μg、10μg和30μg)的IDS-β(Green Cross Corp.,Yongin,Korea)注射的IDS KO小鼠。ICV注射之后每7、14和28天处死每组中的四只动物。分析多种组织(脑、心脏、肺、肝、脾和肾)的GAG浓度,并在注射之后7、14和28天测量来自CSF和脑的HS浓度。
制备用于ICV注射的IDS-β
载剂溶液是150mM氯化钠0.05mg/mL吐温20溶液(Merck Millipore,Darmstadt,Germany)。用载剂稀释浓缩的IDS-β(50mg/mL)药物溶液以使浓度为0.6mg/mL、2mg/mL和6mg/mL。
ICV注射
在6周龄时进行小鼠的单次ICV注射。将各药物溶液或载剂以5μL的总体积ICV施用于小鼠。在给药当天,将小鼠用异氟烷(Hana Pharm.,韩国)吸入麻醉并放置在立体定向仪中。在做一个小切口之后,将颅骨暴露并清洗。ICV注射根据先前报道的经改进方法进行[16,17]。使用以下坐标(Benchmark,Neurolab),用31号针将IDS-β或载剂以通过注射泵(Harvard Apparatus,Holliston,MA,USA)控制的10mL/分钟的流量注射到右侧脑室中:前囟点尾侧0.58mm,矢状缝侧面1.25mm,且深度1.77mm。监测注射部位的破裂血管或面部肿胀。并随后在停止柱塞运动之后15秒移除针以防止回流。将切口用伤口夹(wound clip)闭合,并且将小鼠放置在37℃的等温垫上并在外科手术之后进行观察直至恢复。对于一只动物,整个方案花费10至15分钟。为了证明成功的ICV注射技术,ICV注射染料溶液。在注射之后的不同时间点处收集脑并使其可视化。脑室之一的适当注射允许注射之后约10至15分钟在脑的注射侧分布台盼蓝(0.05%)。注射之后约1小时,大脑半球中台盼蓝的广泛分布是可见的。不准确的注射可由在大脑半球中缺乏蓝色来区分(图5)。
CSF和组织收集
在注射之后7、14和28天,通过注射过量的阿法沙龙(Jurox/名称:Alfaxan)溶液(15mg/kg)使小鼠安乐死。通过硼硅酸盐玻璃(O.D.:10mm,I.D.:0.75mm)从大池(cisternamagna)收集CSF并冷冻用于HS浓度测量。用磷酸缓冲盐水(phosphate-buffered saline,PBS)通过经心脏灌注(transcardiac perfusion)清洁小鼠脑组织中的血液1520分钟。收集脑组织并在干冰上冷冻。然后,将样品匀浆并分成四份(一半用于GAG测量,且一半用于HS测量)。还收集其他躯体组织(心脏、肺、肝、脾和肾)并在PBS中匀浆。
测量组织中的总GAG浓度
将经匀浆组织样品在4℃下摇动过夜并以12,000×g离心15分钟,并随后收集上清液。使用sGAG测定试剂盒(Kamiya Biochemicals,Japan)测量总GAG水平。首先,将50μL经匀浆样品在室温(room temperature,RT)下用50μL 8mol/L胍-HCl孵育15分钟。然后,在RT下添加50μl STA溶液(0.3%H2SO4,0.75%Triton X-100)15分钟,并向该溶液中添加阿尔新蓝(alcian blue)溶液持续15分钟。然后将样品以12,000rpm离心15分钟并用DMSO溶液(40%DMSO,0.05mol/LMgCl2)润洗。最后,向沉淀物中添加500μL Gu-prop溶液(4mol/L胍-HCl,33%1-丙醇,0.25%TritonX-100),并使混合物完全溶解。或者,在600nm下在X-Mark(Bio-Rad,Hercules,CA)中读取吸光度。将GAG浓度归一化为蛋白质浓度,所述蛋白质浓度用BCA蛋白质测定试剂盒(ThermoFisher,Waltham,MA)测量。如通过GAG底物6-硫酸软骨素(chondroitin sulfate-6)的标准曲线计算的,将GAG浓度表示为gGAG/mg蛋白质。各样品的数据是重复测量的平均值。
测量CSF和脑组织中的HS
使用LC-MS/MS确定小鼠CSF和脑组织样品中的HS水平。通过将HS钠盐或DS溶解在水中来制备5mg/mL的各校准标准(STD)储备溶液。用适当体积的水稀释STD储备溶液以制备0.1、0.2、0.5、1.0、2.0、5.0、10和20μg/mL的STD和0.2、2和15μg/mL的质量控制(qualitycontrol,QC)样品。此外,5mg/mL的STD储备溶液是氘标记的以制备作为内标(internalstandard,IS)的HS-d6和DS-d6。将20μL STD溶液添加至玻璃试管并在氮气下蒸发。残余物通过与200μL甲醇-d4-乙酰氯(400∶64,v/v)混合并在65℃下加热90分钟来进行甲醇分解(methanolyze)。甲醇分解后,在氮气下蒸发溶剂。将残余物在1mL水中重构,用水-甲醇-甲酸(950∶50∶1,v/v/v:缓冲剂A)稀释,并将制备的溶液用作IS储备溶液。将小鼠CSF样品在4℃下以2100×g离心5分钟,并用等体积的PBS稀释上清液。将小鼠脑组织用0.01mol/L的氢氧化钠(脑重量的50或100倍体积)匀浆。将匀浆物在室温下孵育24小时并将20μL匀浆物添加至180μL水-氯仿(4∶5,v/v)中。混合之后,将样品在4℃下以10000×g离心5分钟,并将上清液用等体积的PBS稀释。将由CSF和脑制备的这些样品用作用于LC-MS/MS分析的受试样品。在氮气下蒸发试管中的4μL来自CSF(来自脑的20μL)、STD或QC的受试样品。向残余物中添加50μL 3M HCl-MeOH和5μL 2,2-二甲氧基丙烷,并进行超声处理3分钟,在65℃下加热90分钟并蒸发。将残余物用200μL IS储备溶液重构,超声处理3分钟并转移至离心过滤器,在4℃下以10000×g离心3分钟,并分析所得滤液。将5μL的各样品注入到配备有ACQUITY UPLC系统(Waters)的三重四极质谱仪API5000(AB/MDS Sciex)中。受试样品和IS用在40℃下加热的ACQUITY UPLC HSS T3柱(100A 1.8μm,2.1mm×100mm)分离。初始流动相由100∶0(v/v)缓冲剂A∶缓冲剂B[水-甲醇-甲酸(500∶500∶1,v/v/v)]组成,进行梯度洗脱,流量为0.4mL/分钟。洗脱是呈线性梯度的,其中缓冲剂B在0.5分钟和4分钟之间从0%提高至45%,然后在4.01分钟时提高至60%,在60%保持1分钟,然后在5.01分钟时降低至0%,然后在0%保持1分钟。质谱仪在选择电喷雾电离的电离方法和离子极性为正的设置下进行。使用氮气作为气帘气(Curtain gas)(40psi),并且使用空气作为喷雾器气体(50psi)和加热器气体(40psi)。离子监测条件被限定为4.5kV的离子喷雾电压和600℃的涡轮探针温度。去簇电位、入口电位和碰撞能量的这些设置分别为110V、8V和22eV。数据通过使用以下的多重反应监测(multiple reaction monitoring,MRM)获得:对于HS质荷比(m/z)384→162,对于DSm/z 426→236,对于HS-d6 m/z 390→162和对于DS-d6 m/z 432→162。用Analystver.1.5.1(AB Scix)计算峰面积、STD曲线和测量的浓度。
统计分析
统计分析通过GraphPad Prism 6进行。使用MannWhitney U检验来比较KO小鼠中各药物处理组和载剂处理组之间的差异。P值小于0.05的差异被认为是统计学上显著的。数据作为平均值和SEM表示。为了确定CSF HS与脑HS之间以及CSF HS与脑GAG之间的关系,我们评价了小鼠CSF和脑组织的73个样品,并且使用Spearman’s rho和线性回归分析数据。计算组内相关系数(Intraclass correlation coefficient,ICC)和95%置信区间。
1-3:结果
体重
在研究期间,所有实验组的体重均没有显著改变。与对照组(WT和未经处理的IDSKO小鼠)中的小鼠的体重相比,ICV ERT组中的小鼠的体重没有显著差异。在任何ERT组中在实验期间,我们也未发现任何异常的临床体征。
单次ICV注射IDS-β降低IDS KO小鼠脑组织中的GAG
与WT小鼠的脑组织中的总GAG相比,载剂注射组中的KO小鼠的脑组织中的总GAG显著更高(图1)。给药7天之后,与疾病对照小鼠的脑组织中的总GAG相比,所有IDS-β处理组的脑组织中的总GAG显著降低(图1)。然而,注射之后14天在3μg和10μg注射组中观察到GAG的再累积。在注射之后28天,在30μg注射组中保持显著的GAG降低,尽管总GAG水平与第7天和第14天相比略微再提高(图1)。
单次ICV注射IDS-β降低IDS KO小鼠的CSF和脑组织中的HS
与WT对照小鼠相比,在IDS KO小鼠的CSF和脑组织中HS水平显著提高(图2)。在ICV注射之后7天,在所有三个IDS-β处理组中,CSF和脑组织中的HS含量显著降低。在整个28天中保持脑组织中HS的显著降低(图2)。在ICV注射之后14和28天,CSF中的HS含量保持降低。然而,在ICV注射之后28天仅在30μg IDS-β处理组中发现统计学显著性(图2)。
CSF中的HS含量与脑组织HS和GAG呈正相关
在小鼠样品的CSF中的HS含量和脑组织中的HS浓度之间发现显著的正相关(r=0.785,P<0.0001)(图3A)。此外,CSF中的HS含量也与脑组织的GAG浓度呈显著正相关(r=0.703,P<0.0001)(图3B)。
单次ICV注射IDS-β降低IDS KO小鼠的躯体组织的GAG
我们在脑组织和其他躯体组织(心脏、肺、肝、脾和肾)二者中测量了单次ICV注射之后的总GAG浓度。与WT小鼠相比,在具有载剂注射的IDS KO小鼠的所有所分析组织中均发现了GAG的累积(图4)。在ICV注射之后28天,ICV施用30μg IDS-β保持所有经检查组织中总GAG的显著降低(图4)。图6-10中示出了在ICV注射之后7和14天躯体组织的GAG浓度。
1-4:讨论
MPS II是亚洲最常见的MPS类型,并且约70%的MPS II患者具有严重形式[18,19]。因此,纠正脑病理状况是MPS II患者的治疗中最重要且具有挑战性的问题之一。已经提出鞘内或脑室内注射重组酶作为将治疗药物递送到脑中的策略。在本研究中,我们在6周龄IDS KO小鼠中进行了三种不同剂量的IDS-β的单次ICV注射,以评价剂量反应关系和药理作用的时间过程。
所有IDS-β处理组的脑组织中总GAG显著降低,并且在30μg注射组中显著的GAG降低保持28天(图1)。在ICV注射之后28天,在30μg处理组中也始终观察到CSF HS浓度的显著降低(图2)。因此,我们提出每4周一次向侧脑室中注射30μg IDS-β可有效降低和保持MPSII小鼠中的累积的脑GAG。此外,这些结果可充当决定ICV注射重组酶的临床应用中的剂量和注射频率的基本依据,尽管应当考虑小鼠与人之间的脑的不同尺寸和代谢速率。然而,为了进一步阐明用于改善MPS II中CNS病理状况的ICV酶施用的效力,我们需要用重复注射来扩大研究并进行包括脑的行为测试和组织学分析的功能评估。
在多种类型的MPS中,CNS受累以MPS I(胡尔勒病(Hurler disease))的严重形式,MPS II、MPS III和MPS VII的严重形式存在。相比之下,MPS IV、MPS VI、减弱类型的MPS I(沙伊综合征(Scheie syndrome))和减弱类型的MPS II患者不具有认知损伤[2]。HS是MPSI、II、III和VII中主要累积的GAG之一[10]。一些报道已经表明,脑组织中的累积的HS是造成MPS的神经病学表现的原因[9-12]。此外,已经表明,HS浓度是MPS II小鼠脑组织中的更敏感且特异的生物标志物[13,20]。然而,直接测量脑组织中HS的量在临床环境中是不可能的。因此,我们分析了CSF中的HS浓度并试图找到CSF与脑组织中的HS水平之间的相关性。我们示出,与WT小鼠相比,在IDS KO小鼠的CSF和脑组织二者中HS含量均显著提高,并且在所有IDS-β处理组中均降低(图2)。此外,这是表明CSF中的HS浓度与脑组织HS和脑组织GAG显著相关的首个研究(图3)。因此,我们提出CSF中的HS含量可以是假设脑组织HS水平或GAG的潜在生物标志物之一。然而,为了示出CSF中的HS含量可真正表示CNS病理状况,我们需要包括脑组织病理学检查的另外的研究,因为MPS II的CNS病理状况不仅是由GAG积累的量,而且是由次级底物累积、炎症和CNS的退行性改变造成的[12,21,22]。如果相关性将被示出,则CSF HS含量可以是在CNS受累MPS II患者的可能的未来临床试验中用于评估CNS病理状况的可用参数。
此外,我们示出IDS-β的ICV施用还以剂量依赖性方式显著地降低躯体组织(肝、脾、肾、心脏和肺)以及脑组织的GAG累积,尽管效果在各组织中不同(图4和图6至10)。观察到GAG降低的程度是剂量依赖性的,并且我们注意到施用30μg IDS-β可显著降低并保持躯体组织中的累积的GAG达28天,这与脑组织中的相同。总体而言,这些数据表明在ICV施用之后治疗性蛋白质从CSF至全身器官的生理学转运,表明将治疗性酶递送至脑和全身器官二者的临床上可行的途径。此外,CSF可充当用于所注入酶的中间储存器,从该中间储存器一些量在ICV注射之后逐渐转移到体循环中。尽管从CSF至体循环的酶递送的机理尚不清楚,但已经提出,含有艾杜糖醛酸-2-硫酸酯酶的CSF可能通过蛛网膜下腔与全身静脉循环连通[6,23-25]。
总之,IDS-β的单次ICV注射耐受良好,并且其在IDS KO小鼠的脑组织中导致HS和GAG的显著降低以及躯体组织中的GAG的显著降低。此外,在ICV注射之后28天保持效果,尤其是以30μg剂量。此外,由于CSF HS浓度与脑组织HS和GAG呈正相关,因此CSF HS浓度可以是用于表示脑病理状况的可用生物标志物。
1-5:序列表
SEQ ID NO:1
长度:525
类型:PRT
SETQANSTTD ALNVLLIIVD DLRPSLGCYG DKLVRSPNID QLASHSLLFQ NAFAQQAVCA
PSRVSFLTGR RPDTTRLYDF NSYWRVHAGN FSTIPQYFKE NGYVTMSVGK VFHPGISSNH
TDDSPYSWSF PPYHPSSEKY ENTKTCRGPD GELHANLLCP VDVLDVPEGT LPDKQSTEQA
IQLLEKMKTS ASPFFLAVGY HKPHIPFRYP KEFQKLYPLE NITLAPDPEV PDGLPPVAYN
PWMDIRQRED VQALNISVPY GPIPVDFQRK IRQSYFASVS YLDTQVGRLL SALDDLQLAN
STIIAFTSDH GWALGEHGEW AKYSNFDVAT HVPLIFYVPG RTASLPEAGE KLFPYLDPFD
SASQLMEPGR QSMDLVELVS LFPTLAGLAG LQVPPRCPVP SFHVELCREG KNLLKHFRFR
DLEEDPYLPG NPRELIAYSQ YPRPSDIPQW NSDKPSLKDI KIMGYSIRTI DYRYTVWVGF
NPDEFLANFS DIHAGELYFV DSDPLQDHNM YNDSQGGDLF QLLMP
SEQ ID NO:2
长度:525
类型:PRT
SETQANSTTD ALNVLLIIVD DLRPSLGCYG DKLVRSPNID QLASHSLLFQ NAFAQQAVG*A
PSRVSFLTGR RPDTTRLYDF NSYWRVHAGN FSTIPQYFKE NGYVTMSVGK VFHPGISSNH
TDDSPYSWSF PPYHPSSEKY ENTKTCRGPD GELHANLLCP VDVLDVPEGT LPDKQSTEQA
IQLLEKMKTS ASPFFLAVGY HKPHIPFRYP KEFQKLYPLE NITLAPDPEV PDGLPPVAYN
PWMDIRQRED VQALNISVPY GPIPVDFQRK IRQSYFASVS YLDTQVGRLL SALDDLQLAN
STIIAFTSDH GWALGEHGEW AKYSNFDVAT HVPLIFYVPG RTASLPEAGE KLFPYLDPFD
SASQLMEPGR QSMDLVELVS LFPTLAGLAG LQVPPRCPVP SFHVELCREG KNLLKHFRFR
DLEEDPYLPG NPRELIAYSQ YPRPSDIPQW NSDKPSLKDI KIMGYSIRTI DYRYTVWVGF
NPDEFLANFS DIHAGELYFV DSDPLQDHNM YNDSQGGDLF QLLMP
(SEQ ID NO:2的第59位氨基酸“G*”代表甲酰基-甘氨酸。)
1-6:参考文献
[1]Bach G,Eisenberg F,Jr.,Cantz M,Neufeld EF:The defect in the Huntersyndrome:deficiency of sulfoiduronate sulfatase.Proc Natl Acad Sci U S A1973,70:2134-2138.
[2]Neufeld EF,Muenzer J.The mucopolysaccharidoses.In:Scriver CR,Beaudet AL,Sly WS,Valle D(eds).The Metabolic and Molecular Bases of InheritedDisease,vol.III.McGraw-Hill:New York,2001:34213452.
[3]Kakkis E,McEntee M,Vogler C,Le S,Levy B,Belichenko P,Mobley W,Dickson P,Hanson S,Passage M:Intrathecal enzyme replacement therapy reduceslysosomal storage in the brain and meninges of the canine model of MPS I.MolGenet Metab 2004,83:163-174.
[4] Auclair D,Finnie J,White J,Nielsen T,Fuller M,Kakkis E,Cheng A,O′Neill CA,HopwoodJJ:Repeated intrathccal injections of recombinant human 4-sulphatase remove dural storage in mature mucopolysaccharidosis VI catsprimed with a short-course tolerisation regimen.Mol Genet Metab 2010,99:132-141.
[5]Hemsley KM,Hopwood JJ:Delivery of recombinant proteins via thecere-brospinal fluid as a therapy option for neurodegenerative lysosomalstorage diseases.Int J Clin Pharmacol Ther 2009,47 Suppl 1:S118-123.
[6]Higuchi T,Shimizu H,Fukuda T,Kawagoe S,Matsumoto J,Shimada Y,Kobayashi H,Ida H,Ohashi T,Morimoto H et al:Enzyme replacement therapy(ERT)procedure for mucopoly saccharidosis type II(MPS II)by intraventricularadmin-istration(IVA)in murine MPS II.Mol Genet Metab 2012,107:122-128.
[7]Calias P,Papisov M,Pan J,Savioli N,Belov V,Huang Y,Lotterhand J,Alessandrini M,Liu N,Fischman AJ et al:CNS penetration of intrathecal-lumbaridursulfase in the monkey,dog and mouse:implications for neurologicaloutcomes of lysosomal storage disorder.PLoS One 2012,7:e30341.
[8]Muenzer J,Hendriksz CJ,Fan Z,Vijayaraghavan S,Perry V,Santra S,Solanki GA,Mascelli MA,Pan L,Wang N et al:A phase I/II study of intrathecalidursulfase-IT in children with severe mucopolysaccharidosis II.Genet Med2015.
[9]de Ruijter J,Ijlst L,Kulik W,van Lanthe H,Wagemans T,van Vlies N,Wijburg FA:Heparan sulfate derived disaccharides in plasma and total urinaryexcretion of gly-cosaminoglycans correlate with disease severity inSanfilippo disease.J Inherit Metab Dis 2013,36:271-279.
[10]Coppa GV,Gabrielli O,Zampini L,Maccari F,Mantovani V,Galeazzi T,Santoro L,Padella L,Marchesiello RL,Galeotti F et al:Mental retardation inmu-copolysaccharidoses correlates with high molecular weight urinary heparansulphate derived glucosamine.Metab Brain Dis 2015,30:1343-1348.
[11]Bruyere J,Roy E,Ausseil J,Lemonnier T,Teyre G,Bohl D,Etienne-Manneville S,Lortat-Jacob H,Heard JM,Vitry S:Heparan sulfate saccharidesmodify focal adhesions:implication in mucopolysaccharidosisneuropathophysiology.JMol Biol 2015,427:775-791.
[12]Wilkinson FL,Holley RJ,Langford-Smith KJ,Badrinath S,Liao A,Langford-Smith A,Cooper JD,Jones SA,Wraith JE,Wynn RF et al:Neuropathology inmouse models of mucopolysaccharidosis type I,IIIA and IIIB.PLoS One 2012,7:e35787.
[13]Akiyama K,Shimada Y,Higuchi T,Ohtsu M,Nakauchi H,Kobayashi H,Fukuda T,Ida H,Eto Y,Crawford BE et al:Enzyme augmentation therapy enhancesthe therapeutic efficacy of bone marrow transplantation inmucopolysaccharidosis type II mice.Mol Genet Metab 2014,111:139-146.
[14]Lawrence R,Brown JR,Al-Mafraji K,Lamanna WC,Beitel JR,Boons GJ,Esko JD,Crawford BE:Disease-specific non-reducing end carbohydrate biomarkersfor mucopolysaccharidoses.Nat Chem Biol 2012,8:197-204.
[15]Jung SC,Park ES,Choi EN,Kim CH,Kim SJ,Jin DK:Characterization ofa novel mucopolysaccharidosis type II mouse model and recombinant AAV2/8vector-mediated gene therapy.Mol Cells 2010,30:13-18.
[16]Lee WC,Tsoi YK,Troendle FJ,DeLucia MW,Ahmed Z,Dicky CA,DicksonDW,Eckman CB:Single-dose intracerebroventricular administration ofgalactocere-brosidase improves survival in a mouse model of globoid cellleukodystrophy.Faseb j 2007,21:2520-2527.
[17]Glascock JJ,Osman EY,Coady TH,Rose FF,Shababi M,Lorson CL:Delivery of therapeutic agents through intracerebroventricular(ICV)andintravenous(IV)injection in mice.J Vis Exp 2011.
[18]Lin HY,Lin SP,Chuang CK,Niu DM,Chen MR,Tsai FJ,Chao MC,Chiu PC,Lin SJ,Tsai LP et al:Incidence of the mucopolysaccharidoses in Taiwan,1984-2004.Am J Med Genet A 2009,149A:960-964.
[19]Sohn YB,Choi EW,Kim SJ,Park SW,Kim SH,Cho SY,Jeong SI,Huh J,KangIS,Lee HJ et al:Retrospective analysis of the clinical manifestations andsurvival of Korean patients with mucopolysaccharidosis type II:emphasis onthe car-diovascular complication and mortality cases.Am J Med Genet A 2012,158A:90-96.
[20]Shimada Y,Wakabayashi T,Akiyama K,Hoshina H,Higuchi T,KobayashiH,Eto Y,Ida H,Ohashi T:A method for measuring disease-specific iduronic acidfrom the non-reducing end of glycosaminoglycan in mucopolysaccharidosis typeII mice.Mol Genet Metab 2015.
[21]Hamano K,Hayashi M,Shioda K,Fukatsu R,Mizutani S:Mechanisms ofneu-rodegeneration in mucopolysaccharidoses II and IIIB:analysis of humanbrain tissue.Acta Neuropathol 2008.115:547-559.
[22]Archer LD,Langford-Smith KJ,Bigger BW,Fildes JE:Mucopolysaccharide diseases:a complex interplay between neuroinflammation,microglial activation and adaptive immunity.J Inherit Metab Dis 2014,37:1-12.
[23]Chen L,Elias G,Yostos MP,Stimec B,Fasel J,Murphy K:Pathways ofcere-brospinal fluid outflow:a deeper understanding ofresorption.Neuroradiology 2015,57:139-147.
[24]Hladky SB,Barrand MA:Mechanisms of fluid movement into,throughand out of the brain:evaluation of the evidence.Fluids Barriers CNS 2014,11:26.
[25]Glimcher SA,Holman DW,Lubow M,Grzybowski DM:Ex vivo model ofcerebrospinal fluid outflow across human arachnoid granulations.InvestOphthalmol Vis Sci 2008,49:4721-4728.
<110> 株式会社绿十字
株式会社医用基因生物
<120> 用于治疗亨特综合征的方法和组合物
<130> 16PCT12002P
<150> US 62/272,843
<151> 2015-12-30
<150> US 62/369,970
<151> 2016-08-02
<160> 2
<170> KoPatentIn 3.0
<210> 1
<211> 525
<212> PRT
<213> 未知
<220>
<223> IDS-β蛋白
<400> 1
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Ile Ile Val Asp Asp Leu Arg Pro Ser Leu Gly Cys Tyr Gly Asp Lys
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Leu Val Arg Ser Pro Asn Ile Asp Gln Leu Ala Ser His Ser Leu Leu
35 40 45
Phe Gln Asn Ala Phe Ala Gln Gln Ala Val Cys Ala Pro Ser Arg Val
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Ser Phe Leu Thr Gly Arg Arg Pro Asp Thr Thr Arg Leu Tyr Asp Phe
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Asn Ser Tyr Trp Arg Val His Ala Gly Asn Phe Ser Thr Ile Pro Gln
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His Pro Gly Ile Ser Ser Asn His Thr Asp Asp Ser Pro Tyr Ser Trp
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Thr Cys Arg Gly Pro Asp Gly Glu Leu His Ala Asn Leu Leu Cys Pro
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Val Asp Val Leu Asp Val Pro Glu Gly Thr Leu Pro Asp Lys Gln Ser
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Thr Glu Gln Ala Ile Gln Leu Leu Glu Lys Met Lys Thr Ser Ala Ser
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Pro Phe Phe Leu Ala Val Gly Tyr His Lys Pro His Ile Pro Phe Arg
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Tyr Pro Lys Glu Phe Gln Lys Leu Tyr Pro Leu Glu Asn Ile Thr Leu
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Ala Pro Asp Pro Glu Val Pro Asp Gly Leu Pro Pro Val Ala Tyr Asn
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Pro Trp Met Asp Ile Arg Gln Arg Glu Asp Val Gln Ala Leu Asn Ile
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Ser Val Pro Tyr Gly Pro Ile Pro Val Asp Phe Gln Arg Lys Ile Arg
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Gln Ser Tyr Phe Ala Ser Val Ser Tyr Leu Asp Thr Gln Val Gly Arg
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Ala Lys Tyr Ser Asn Phe Asp Val Ala Thr His Val Pro Leu Ile Phe
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Tyr Val Pro Gly Arg Thr Ala Ser Leu Pro Glu Ala Gly Glu Lys Leu
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<223> IDS-β蛋白(第59位的半胱氨酸翻译后修饰为甲酰基甘氨酸)
<220>
<221> MOD_RES
<222> (59)
<223> 甲酰化,(第59位是甲酰基甘氨酸)
<400> 2
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His Pro Gly Ile Ser Ser Asn His Thr Asp Asp Ser Pro Tyr Ser Trp
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Ser Phe Pro Pro Tyr His Pro Ser Ser Glu Lys Tyr Glu Asn Thr Lys
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Ala Phe Thr Ser Asp His Gly Trp Ala Leu Gly Glu His Gly Glu Trp
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Ala Lys Tyr Ser Asn Phe Asp Val Ala Thr His Val Pro Leu Ile Phe
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Tyr Val Pro Gly Arg Thr Ala Ser Leu Pro Glu Ala Gly Glu Lys Leu
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Phe Pro Tyr Leu Asp Pro Phe Asp Ser Ala Ser Gln Leu Met Glu Pro
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Gly Arg Gln Ser Met Asp Leu Val Glu Leu Val Ser Leu Phe Pro Thr
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Phe Arg Phe Arg Asp Leu Glu Glu Asp Pro Tyr Leu Pro Gly Asn Pro
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Arg Glu Leu Ile Ala Tyr Ser Gln Tyr Pro Arg Pro Ser Asp Ile Pro
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Gln Trp Asn Ser Asp Lys Pro Ser Leu Lys Asp Ile Lys Ile Met Gly
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Tyr Ser Ile Arg Thr Ile Asp Tyr Arg Tyr Thr Val Trp Val Gly Phe
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Asn Pro Asp Glu Phe Leu Ala Asn Phe Ser Asp Ile His Ala Gly Glu
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Claims (19)
1.治疗亨特综合征的方法,其包括向需要治疗的对象脑室内施用(ICV施用)治疗有效剂量的ICV制剂的步骤,所述ICV制剂包含浓度为约0.1mg/ml至约60mg/ml的艾杜硫酸酯酶-β(IDS-β)蛋白、浓度为约150mM的氯化钠、浓度为约0.05mg/ml的聚山梨酯20,并且pH为约6。
2.权利要求1所述的方法,其中所述ICV制剂包含浓度为约15mg/ml的艾杜硫酸酯酶-β(IDS-β)蛋白、浓度为约150mM的氯化钠、浓度为约0.05mg/ml的聚山梨酯20,并且pH为约6。
3.权利要求1所述的方法,其中所述治疗有效剂量为约1mg至约30mg。
4.权利要求1所述的方法,其中所述治疗有效剂量为约10mg。
5.权利要求1所述的方法,其中所述ICV施用每三周进行一次。
6.权利要求1所述的方法,其中所述ICV施用每月进行一次。
7.权利要求1所述的方法,其中所述ICV施用通过包含储存器和与所述储存器相连接的导管的脑室内导管系统进行。
8.权利要求7所述的方法,其还包括以下步骤:
外科手术植入所述脑室内导管系统,其中将所述储存器放置在所述需要治疗的对象的头皮与脑之间,并且将所述导管的末端放置在所述对象的脑室内,使得所述储存器的内部空间通过所述导管的内部空间与所述脑室的内部空间相连接,使得脑脊液从所述脑室流入到所述储存器中以填充所述储存器;
以0.1至60ml/分钟的流量从所述储存器中取出0.1至5ml的脑脊液;
以0.1至60ml/分钟的流量将0.1至5ml的所述ICV制剂注入到所述储存器中;以及
使所述ICV制剂从所述储存器流经所述导管进入到所述脑室中。
9.权利要求1所述的方法,其中所述ICV施用与至少一种用于亨特综合征的另外形式的酶替代疗法治疗组合进行。
10.权利要求9所述的方法,其中所述用于亨特综合征的另外形式的酶替代疗法治疗选自静脉内施用和皮下施用。
11.权利要求10所述的方法,其中所述ICV施用每月进行一次,并且所述静脉内施用每周进行一次。
12.权利要求10所述的方法,其中所述ICV施用每三周进行一次,并且所述静脉内施用每周进行一次。
13.权利要求10所述的方法,其中所述ICV施用每月进行一次,并且所述皮下施用每周进行一次。
14.权利要求10所述的方法,其中所述ICV施用每三周进行一次,并且所述皮下施用每周进行一次。
15.权利要求10所述的方法,其中所述ICV施用每月进行一次,并且所述皮下施用每周进行两次。
16.权利要求10所述的方法,其中所述ICV施用每三周进行一次,并且所述皮下施用每周进行两次。
17.权利要求10所述的方法,其中所述ICV施用每月进行一次,并且所述静脉内施用和所述皮下施用以一周的间隔交替进行。
18.权利要求10所述的方法,其中所述ICV施用每三周进行一次,并且所述静脉内施用和所述皮下施用以一周的间隔交替进行。
19.用于治疗亨特综合征的用于脑室内施用的制剂,其包含浓度为约0.1mg/ml至约60mg/ml的艾杜硫酸酯酶-β(IDS-β)蛋白、浓度为约150mM的氯化钠、浓度为约0.05mg/ml的聚山梨酯20,并且pH为约6。
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US201562272843P | 2015-12-30 | 2015-12-30 | |
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US62/369,970 | 2016-08-02 | ||
PCT/KR2016/015060 WO2017116066A1 (en) | 2015-12-30 | 2016-12-21 | Methods and compositions for treating hunter syndrome |
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103096918A (zh) * | 2010-06-25 | 2013-05-08 | 夏尔人类遗传性治疗公司 | 治疗试剂的cns 递送 |
CN103179980A (zh) * | 2010-06-25 | 2013-06-26 | 夏尔人类遗传性治疗公司 | 艾杜糖醛酸-2-硫酸酯酶的cns递送的方法和组合物 |
WO2013148277A1 (en) * | 2012-03-30 | 2013-10-03 | Shire Human Genetic Therapies, Inc. | Subcutaneous administration of iduronate- 2-sulfatase |
US20140271598A1 (en) * | 2010-06-25 | 2014-09-18 | Shire Human Genetic Therapies, Inc. | Methods and compositions for cns delivery of iduronate-2-sulfatase |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
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US5932211A (en) * | 1991-11-12 | 1999-08-03 | Women's And Children's Hospital | Glycosylation variants of iduronate 2-sulfatase |
US6534300B1 (en) * | 1999-09-14 | 2003-03-18 | Genzyme Glycobiology Research Institute, Inc. | Methods for producing highly phosphorylated lysosomal hydrolases |
JP2012062312A (ja) | 2010-08-19 | 2012-03-29 | Yoshikatsu Eto | ハンター症候群の治療剤 |
EP2672985B1 (en) | 2011-02-11 | 2016-04-27 | Swedish Orphan Biovitrum AB (Publ) | Citrate free pharmaceutical compositions comprising anakinra |
KR101158673B1 (ko) | 2011-06-24 | 2012-07-03 | 주식회사 지씨바이오 | 재조합 인간 이듀로네이트-2-설파타아제를 포함하는 조성물, 제제 및 이의 제조방법 |
AU2012358223B2 (en) | 2011-12-23 | 2018-01-18 | Takeda Pharmaceutical Company Limited | Treatment of cognitive impairment of Hunter syndrome by intrathecal delivery of iduronate-2-sulfatase |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103096918A (zh) * | 2010-06-25 | 2013-05-08 | 夏尔人类遗传性治疗公司 | 治疗试剂的cns 递送 |
CN103179980A (zh) * | 2010-06-25 | 2013-06-26 | 夏尔人类遗传性治疗公司 | 艾杜糖醛酸-2-硫酸酯酶的cns递送的方法和组合物 |
US20140271598A1 (en) * | 2010-06-25 | 2014-09-18 | Shire Human Genetic Therapies, Inc. | Methods and compositions for cns delivery of iduronate-2-sulfatase |
WO2013148277A1 (en) * | 2012-03-30 | 2013-10-03 | Shire Human Genetic Therapies, Inc. | Subcutaneous administration of iduronate- 2-sulfatase |
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PH12018550102A1 (en) | 2019-02-11 |
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