CN101541172A - 溶酶体酶编码基因突变相关的cns紊乱的治疗 - Google Patents
溶酶体酶编码基因突变相关的cns紊乱的治疗 Download PDFInfo
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Abstract
本发明描述的是用于治疗患有神经病学紊乱个体的方法,该神经病学紊乱与溶酶体酶编码基因的突变有关。具体地,对个体施用溶酶体酶的特异性药理伴侣,其增加神经细胞中蛋白质从ER到溶酶体的运输,有或者没有伴随地增加神经细胞中的酶活性。运输的修复减轻细胞应激反应及其他与突变蛋白质累积有关的毒性。酶活性的修复减轻底物累积及与脂质累积有关的病状。在一个具体实施方案中,神经病学紊乱是与葡糖脑苷脂酶突变有关的帕金森氏病或者帕金森综合征。
Description
本申请要求2005年6月8日提交的美国临时申请系列号60/689,120的优先权,将其全文引入本文作为参考。
发明领域
本发明涉及治疗患有与溶酶体酶例如酸性β-葡糖苷酶突变相关的神经病学危险因素、状况或疾病个体的方法。具体地,对个体施用溶酶体酶的特异性药理伴侣(pharmacological chaperone),其增加神经细胞中从内质网(ER)到溶酶体的蛋白质运输,和/或伴随增加神经细胞中的酶活性。
发明背景
溶酶体贮积病(Lysosomal storage disorders,LSD)是一类由于缺陷型水解酶导致细胞中糖鞘脂、糖原或粘多糖累积所引起的常染色体隐性疾病。LSD的实例包括但不限于戈谢病(Gaucher disease)(Beutler等人,TheMetabolic and Molecular Bases of Inherited Disease,第8版,2001 Scriver等人编辑,3635-3668页,McGraw-Hill,纽约)、GM1-神经节苷脂贮积病(同上,3775-3810页)、岩藻糖苷贮积病(The Metabolic and Molecular Bases ofInherited Disease 1995.Scriver,C.R.,Beaudet,A.L.,Sly,W.S.和Valle,D.编辑,2529-2561页,McGraw-Hill,纽约)、粘多糖贮积病(同上,3421-3452页)、庞倍氏症(同上,3389-3420页)、胡尔勒-沙伊病(Hurler-Scheiedisease)(Weismann等人,Science.1970;169,72-74)、A型和B型尼曼-皮克病(The Metabolic and Molecular Bases of Inherited Disease,第8版,2001.Scriver等人编辑,3589-3610页,McGraw-Hill,纽约)和法布里病(同上,3733-3774页)。其他包括异染性脑白质营养不良、库夫斯病(成人型神经元脂质脂褐质沉积病)和肾上腺脑白质营养不良。每种LSD与特定的由一个或多个突变所引起的缺陷型水解酶有关,所述的一个或多个突变导致该酶合成后在内质网(ER)中构象不稳定,因此,成为降解的靶标而不是通过高尔基体运输到溶酶体中的天然场所。
几种LSD具有显著的神经病学受累情况。例如,戈谢病是最常见的LSD,其与患者细胞、尤其是单核细胞和巨噬细胞中的糖鞘脂(GSL)累积有关。这种异常的GSL增加产生于溶酶体酶酸性β-葡糖苷酶(Gba;葡糖脑苷脂酶)的遗传缺陷(突变),酸性β-葡糖苷酶是一种可以分解GSL葡萄糖神经酰胺(GluCer)的溶酶体水解酶。根据神经病学受累情况和罹病度,该疾病分为三种临床类型(Cox等人,Q J Med.2001;94:399-402)。2型戈谢病是最罕见且最严重的类型,它与急性神经源性疾病的早期发病有关。神经元型戈谢病的典型特征是水平凝视异常。患者发展为进行性脑病和锥体外系症状,例如强直和帕金森样运动(帕金森综合征)。大多数2型戈谢病患者在童年早期死于神经退化导致的呼吸暂停或误吸。
3型戈谢病也具有神经病学受累情况,不过比2型的程度要轻。3型患者具有中枢神经***症状,包括运动失调(共济失调)、发作、眼肌瘫痪、癫痫和痴呆。3型的一个亚类3c型,伴有肝脾肿大、角膜浑浊、进行性共济失调和痴呆以及心瓣膜和主动脉根钙化。
其他有神经病学受累情况的溶酶体贮积病包括与β-半乳糖苷酶突变有关并导致神经元脂沉积的GM1神经节苷脂贮积病;与己糖胺酶A突变有关并导致神经元脂沉积的GM2神经节苷脂贮积病(泰-萨病);与鞘磷脂酶突变有关并导致神经元脂沉积的尼曼-皮克病;(克拉贝病)半乳糖脑苷脂酶脑白质营养不良;和与溶酶体蛋白酶突变有关并导致神经元脂沉积的神经元蜡样质脂褐质沉积病。异染性脑白质营养不良是芳基硫酸酯酶A酶缺陷,且患者的症状包括进行性运动障碍、发作、认知障碍,除胃肠紊乱外,还有精神***症和精神病问题。库夫斯病(成人型神经元脂质脂褐质沉积病)表现为精神病症状和发作。肾上腺脑白质营养不良是一种特征为中枢神经***进行性白质脱髓鞘病和肾上腺皮质功能不全的紊乱。
特异性药理伴侣
近期,特异性药理伴侣策略已经发展到挽救不稳定的突变蛋白质,使之免于推测的内质网(ER)或其他细胞蛋白质降解/处理***的降解。在特别的实施方案中,该范例的变化策略使用特异性地结合与特定溶酶体紊乱有关的缺陷型溶酶体酶的小分子可逆性抑制剂,所述抑制剂在ER内稳定突变酶并“陪伴”该突变酶以使其退出ER。出人意料地发现所述抑制剂可在内质网中在酶合成和折叠期间特异性结合该酶,但在其天然场所与该酶解离,从而修复其活性。缺少伴侣时,突变的酶蛋白质在ER中不恰当折叠(Ishii等人,Biochem.Biophys.Res.Comm.1996;220:812-815),妨碍其成熟为终产品,并且随后在ER中降解。这些特异***称为特异性药理伴侣(或活性位点特异***,其中所述伴侣是酶的竞争性抑制剂)。
术语“活性位点特异***”是从最初的利用野生型和突变的溶酶体酶研究发展来的。酶的催化部分,即酶与其底物结合和相互作用的部分,通常称为“活性位点”。利用酶的可逆竞争性抑制剂(即与底物竞争结合催化中心的酶抑制剂)来诱导错误折叠的溶酶体酶采取稳定分子构象的反直觉策略,最初是根据一些竞争性抑制剂在生物合成期间结合催化中心并稳定酶的能力而假定的。因此,在体内ER中新生酶的折叠期间可实现任何稳定作用,尤其对具有折叠缺陷的突变酶,这将是有利的,因为这将阻止内源ER“伴侣”结合错误折叠的多肽并将其作为降解靶。而且,竞争性抑制剂是“可逆的”,因为一旦酶到达溶酶体它就与酶解离,在这里抑制剂竞争不过天然底物。
参与LSD的约15种酶的特异***策略已经在授予Fan等人的美国专利号6,274,597、6,583,158、6,589,964和6,599,919中描述和例证,它们全文引入本文作为参考。例如,半乳糖的小分子衍生物1-脱氧半乳糖野尻霉素(DGJ),是突变的法布里酶α-半乳糖苷酶A(α-Gal A)有效的竞争性抑制剂,有效地增加人突变α-Gal A(R301Q)在中性pH下的体外稳定性,并增强从R301Q或Q279E突变的法布里患者建立的淋巴母细胞中突变酶的活性。而且,对过表达突变(R301Q)α-Gal A的转基因小鼠口服给予DGJ大大升高了主要器官中的酶活性(Fan等人,Nat.Med.1999;5:112-115)。已描述了利用另外的亚氨基糖,异法戈明(isofagomine)(IFG)及其衍生物从戈谢患者细胞中Gba的相似挽救,描述于授予Fan等人的美国专利6,916,829,和利用其他特异于Gba的化合物(描述于未决的美国专利申请系列号10/988,428和10/988,427,两者均于2004年11月12日提交)。
溶酶体贮积病酶突变和神经病学紊乱
Gba和帕金森氏病最近已经发现溶酶体酶突变除LSD外还和神经病学紊乱之间有联系。作为一个实例,Gba基因突变和帕金森氏病之间存在充分确立的联系。在一项研究中发现,一组患有罕有的、早期发病的、对治疗有抵抗性的帕金森综合征的17名患者的至少一个等位基因具有Gba错义突变,包括N370S的纯合和杂合个体,N370S是通常与1型非神经元型疾病相关的突变(Tayebi等人,Mol.Genet.Metab.2003;79;104-109)。在另一项研究中,评价了99名患有特发性帕金森氏病的德系犹太人群的6个Gba突变(N370S、L444P、84GG、V394L和R496H)。31名帕金森患者有1或2个突变的Gba等位基因:其中23人是N370S杂合型;3人是N370S纯合型;4人是84GG杂合型;1人是R496H杂合型(Aharon-Peretz等人,New Eng.J.Med.2004;351:1972-77)。突变N370S等位基因的发生频率是1573名正常受试者发生频率的5倍,而84GG的发生频率是正常受试者发生频率的21倍。在帕金森氏病患者中,携带Gba突变的患者也比非携带患者年龄小。这项研究表明,Gba突变的杂合性可能使德系犹太人易患帕金森氏病。
帕金森氏病和戈谢病也共享一些病理学特征,包括神经元损失、星形胶质增生和在海马神经元出现细胞毒性雷维小体样α-突触核蛋白包涵体(CA2-4区)。新近出版物描述了所有三种类型戈谢病的神经病学症状(Wong等人,Mol.Genet.Metabol.2004;38:192-207)。发现所有三种类型戈谢病患者的大脑皮层3和5、海马CA2-4区和4b层异常。神经元损失仅仅在2和3型患者中是明显的,而1型患者出现星形胶质增生(Wong等人,上述)。患1型戈谢病和帕金森综合征/痴呆的两个患者海马CA2-4神经元显示α-突触核蛋白阳性的包涵体,一个患者具有脑干型和皮层型雷维小体,一个具有显著的黑质神经元的神经元损失(Wong等人,上述)。总之,全部4个帕金森综合征和痴呆患者具有海马CA2-4神经胶质增生和神经元耗竭、神经胶质增生和黑质中的脑干型雷维小体。
几个鼠模型也表明Gba和帕金森氏病之间的这种联系。Gba的体外最佳水解酶活力需要鞘脂激活蛋白(saposin)C,一种衍生自鞘脂激活蛋白原(prosaposin)的激活蛋白。表达低水平(野生型的4-45%)鞘脂激活蛋白原和鞘脂激活蛋白(PS-NA)转基因小鼠,与具有特定Gba点突变(V394L/V394L或D409H/D409H)的小鼠回交后,具有几个类似于PD表型的CNS表型,包括:步态共济失调、震颤、跌倒程度的震颤、和神经源性膀胱(Sun等人,J Lipid Res.2005.46(10):2102-13)。
上面描述的特异性药理伴侣工作建立了修复突变酶(构象突变)的功能,足以减少乃至消除LSD中毒性量脂质底物增加的能力。然而,并不清楚该方法可影响杂合个体,或根据当前标准没有诊断患有LSD但由于突变的影响而具有罹患神经病学状况或紊乱风险的纯合突变个体,或诊断有溶酶体贮积病但具有除了或不同于构象突变的使蛋白质无功能突变的个体。由于毒性功能获得、病理性功能损失、或者其组合,所有的这些群体都有罹患神经病学紊乱的风险。因此,本领域依然需要能够鉴定致病因素并解决这些患者群体中此类突变的后果。
发明概述
本发明提供一种用于治疗个体神经紊乱的方法,其中该神经病学紊乱与溶酶体酶编码基因的突变有关,通过施用有效量的特异性药理伴侣以治疗所述神经病学紊乱。
在一个实施方案中,个体是突变纯合型的。在另一个实施方案中,个体是突变半合子型的、杂合型的或者复合杂合型的。
在一个实施方案中,突变导致酶成为构象突变体。
在具体的实施方案中,其中伴侣增加突变酶从内质网的运输,且有或者没有伴随地修复酶活性。
在另一个实施方案中,突变导致另外的细胞物质(例如脂质)或另外的蛋白质或蛋白质片段(例如α-突触核蛋白)的量增加或聚集。
在本发明的具体实施方案中,溶酶体酶是葡糖脑苷脂酶,并且神经紊乱是帕金森氏病或帕金森综合征。
在另一个具体实施方案中,帕金森氏病是早期发病的帕金森氏病。
在本发明的一些实施方案中,特异性药理伴侣是溶酶体酶的抑制剂,且所述抑制剂是可逆性或竞争性抑制剂或两者兼是。
在具体的实施方案中,葡糖脑苷脂酶的药理伴侣是异法戈明或者(5R,6R,7S,8S)-5-羟甲基-2-辛烷基-5,6,7,8-四氢咪唑并[1,2-a]吡啶-6,7,8-三醇。
本发明也提供一种用于诊断与溶酶体酶突变有关的神经紊乱的方法,通过筛选显示出一个或多个溶酶体酶突变的神经病学症状的个体。
在一个实施方案中,突变导致酶成为构象突变体。
在另一个实施方案中,通过与健康个体生物样品相比确定个体生物样品中降低的酶活性进行筛选。
在具体的实施方案中,神经紊乱诊断为帕金森综合征或帕金森氏病。
附图简述
图1.图1显示用特异性药理伴侣异法戈明处理的L444P转基因小鼠脑中的Gba活性水平(1A)。也显示在洗脱和再处理周期之后脑中的Gba活性水平(1B)。
图2A-N.图2显示利用红对戈谢病成纤维细胞(2A)和正常成纤维细胞(2B)中的溶酶体荧光染色。也对正常成纤维细胞(2C)和戈谢病成纤维细胞(2D)进行了溶酶体蛋白质LAMP-1染色。图2E-F显示戈谢病成纤维细胞中双重Gba和LAMP-1染色的叠加。也显示用特异性药理伴侣异法戈明(2G-H)和特异性药理伴侣C-苯甲基-异法戈明(2I-J)处理的戈谢病细胞双重叠加(LAMP-1和Gba)。最后,图2K-N显示仅Gba染色的戈谢病细胞。对照戈谢病细胞仅用第二抗体染色(2K),或者未处理(2L),或者用异法戈明(2M)或C-苯甲基-异法戈明(2N)处理。
图3A-I.图3显示戈谢病细胞(3D-I)和正常成纤维细胞(3A-C)的荧光染色,用于表明多聚泛素化蛋白质(PUP)(3A,3D,3G)和Gba(3B,3E,3H)的存在及两者的叠加(3C,3F,3I)。
图4.图4显示人酸性β-葡糖苷酶、也称为葡糖脑苷脂酶或Gba的编码基因(GenBank登录号J03059;SEQ ID NO:1)。
图5.图5显示野生型的人Gba蛋白质。Gba蛋白质由536个氨基酸组成,GenBank登录号J03059(SEQ ID NO:2)。
图6.图6显示位于Gba基因下游约16kb的Gba同源假基因(GenBank登录号Ml 6328;SEQ ID NO:3)。
图7.图7显示Gba同源假基因编码的多肽(SEQ ID NO:4)。
详述
本发明基于发现存在于个体但没有诊断为溶酶体贮积病的神经病学紊乱可能与溶酶体酶的突变有联系。因此,本发明特异性药理伴侣例如ASSC,可改善关联神经病学危险因素、状况或紊乱的与溶酶体酶突变有关的功能获得和功能损失病状。伴侣可以以充分的水平诱导突变蛋白质适当的运输,以抑制甚至达到预防与由错误折叠的突变蛋白质增加(即功能获得)有关的毒性累积,进而能够影响神经功能。有些情况下突变仅仅削弱蛋白质的折叠和到天然细胞场所的运输,而不是,例如削弱蛋白质催化或其他活性的突变体,或是无义突变,伴侣也可修复突变蛋白质的活性,从而解决与蛋白质功能损失(例如底物累积乃至由于底物累积导致的其他毒性蛋白质或片段的聚集)有关的病状。
定义
用于本说明书的术语在使用各术语的本发明上下文和具体上下文中通常具有本领域的常规含义。下文或说明书别处论述了某些术语,以对专业人员在描述本发明组合物和方法及如何制备和使用方面提供补充指导。
术语“戈谢病”包括基于表型表现的1型、2型和3型及其中间类型和亚群。
“神经紊乱”表示任何与神经元或胶质细胞缺陷有关的中枢神经***(CNS)或周围神经***(PNS)疾病,包括但不限于神经元损失、神经元退化、神经元脱髓鞘、神经胶质增生(即星形胶质增生)、或者异常蛋白质或者毒素(例如β-淀粉样蛋白或α-突触核蛋白)的神经元或神经元外累积。神经病学紊乱可是慢性的或急性的。典型的神经病学紊乱包括但不限于戈谢病及其他LSD:包括法布里病、泰-萨病、庞倍氏症和粘多糖贮积病;帕金森氏病;阿尔茨海默氏病;肌萎缩性侧索硬化(ALS);多发性硬化症(MS);亨廷顿病;Fredrich共济失调;轻度认知损伤;和运动障碍(包括共济失调、大脑性麻痹、舞蹈手足徐动症、肌张力障碍、图雷特综合症、核黄疸);震颤紊乱、脑白质营养不良(包括肾上腺脑白质营养不良、异染性脑白质营养不良、卡纳万病、亚历山大病、家族性中叶性硬化);神经元蜡样脂褐质沉积病;毛细管扩张性共济失调;和雷特综合症。该术语也包括脑血管事件例如中风和缺血性疾病发作。
如本文使用的,术语“神经紊乱”也包括处于罹患神经紊乱、疾病或状况风险的人和已诊断为神经紊乱、疾病或状况的人。
“与溶酶体酶突变有关的神经紊乱”表示任何与不患有或不处于罹患神经紊乱风险的个体(即健康个体)相比,当在患神经紊乱个体中评估时也存在所述酶编码基因突变的神经紊乱。在具体实施方案中,与Gba(戈谢病)突变体有关的神经紊乱是帕金森病或帕金森综合征。
术语“人Gba基因”表示酸性β-葡糖苷酶、也称为葡糖脑苷脂酶或Gba的编码基因。Gba基因位于1号染色体的q21,并含有11个外显子(GenBank登录号J03059;SEQ ID NO:1)。还有位于Gba基因下游约16kb的Gba同源假基因(GenBank登录号M16328;SEQ ID NO:3)。
“人Gba”蛋白质表示野生型人Gba蛋白质。Gba蛋白质由536个氨基酸组成,GenBank登录号J03059(SEQ ID NO:2)。上述假基因编码的多肽如SEQ ID NO:4所示。
如本文使用的,术语“药理伴侣”或有时称作“特异性药理伴侣”(“SPC”)表示与蛋白质例如溶酶体酶(例如Gba)特异性结合的分子,并具有一个或多个以下作用:(i)增强蛋白质稳定分子构象的形成;(ii)诱导从内质网到另外细胞场所的蛋白质运输,优选天然细胞场所,即阻止蛋白质的内质网相关的降解;(iii)阻止错误折叠蛋白质的聚集;(iv)修复或增强蛋白质至少部分野生型功能、稳定性和/或活性;和/或改善含蛋白质细胞的表型或功能。因此,蛋白质的药理伴侣是这样的分子,其与蛋白质结合导致该蛋白质的恰当折叠、运输、无聚集和活性。如本文使用的,该术语不表示内源伴侣诸如BiP,或者对多种蛋白质具有非特异伴侣活性的非特异性物质,如往往称为“化学伴侣”的甘油、二甲亚砜或重水(参见Sato等人,Biochem Biophys Acta.1988;126(2):756-62;Welch等人,Cell Stress andChaperones 1996;l(2):109-115;Welch等人,Journal of Bioenergetics andBiomembranes 1997;29(5):491-502;美国专利5,900,360;美国专利6,270,954和美国专利6,541,195)。
如本文使用的,术语“特异性结合”表示药理伴侣和特定蛋白质的相互作用,具体地,与直接参与接触药理伴侣的蛋白质氨基酸残基相互作用。与靶蛋白例如Gba特异性结合的化合物,意指与Gba结合并对Gba发挥药理伴侣效果,而不是针对一类相关或不相关蛋白质。与任何给定的药理伴侣相互作用的蛋白质氨基酸残基可在或不在该蛋白质的“活性位点”内。特异性结合可通过常规结合试验或通过结构研究鉴定,例如共结晶、核磁共振(NMR)等等。
术语“野生型蛋白质”表示编码功能性蛋白质的核苷酸序列,和上述核苷酸序列编码的多肽序列,以及其他编码功能性多肽(具有如上述的多肽序列同样的功能特性和结合亲和性)的核苷酸序列,例如正常个体中的等位变体,能够实现ER中的功能性构象,实现细胞内的适当定位,并显示野生型活性(例如GluCer水解)。
如本文使用的,术语“突变蛋白质”表示含遗传突变的基因翻译的多肽,该遗传突变导致改变的氨基酸序列。在一个实施方案中,当与野生型蛋白质相比时,突变体导致蛋白质在正常地存在于ER的条件下不能形成天然构象,或显示出与野生型蛋白质相比降低的稳定性或活性。本文述及的这种突变类型为“构象突变”,并且带有这种突变的蛋白质为“构象突变体”。无法达到该构象导致蛋白质被降解或聚集,而不是通过蛋白质转运***中的正常途径转运到细胞中的天然场所或转运至胞外环境。
在另一个实施方案中,蛋白质具有除了或不同于构象变体外的其他突变,其能够翻译,由此所有或部分蛋白质能够ER累积(蛋白质可或不保持野生型活性)。
在一些实施方案中,突变可发生在蛋白质编码基因的非编码部分以致引起蛋白质的低效率表达,例如影响转录效率、剪接效率、mRNA稳定性等等的突变。通过增强蛋白质野生型和构象突变变体的表达水平,施用药理伴侣可改善由这种低效蛋白质表达产生的缺陷。
其他突变可导致降低的酶活性或更迅速的转换。
与神经元病相关的Gba突变的具体实施方案包括但不限于:N370S、L444P、K198T、D409H、R496H、V394L、84GG和R329C。
杂合的Gba突变表示基因型中有一个是野生型等位基因并且一个是突变型等位基因,例如N370S/wt。杂合的Gba突变也表示基因型中有两个突变的等位基因,分别具有不同的突变,例如N370S/L444P。该术语也包括突变/无效基因型,即N370S/无效。当表示其他溶酶体酶中的杂合突变时该定义也是适用的。
纯合的Gba突变表示基因型中有两个突变Gba等位基因,其中突变是相同的,例如N370S/N370S。当表示其他溶酶体酶中的纯合突变时该定义也是适用的。
术语“使恰当的构象稳定”表示药理伴侣诱导或使突变蛋白质构象稳定的能力,所述构象与野生型对应物的构象在功能上相同。术语“功能上相同”意指虽然可能在构象上有微小的变化(几乎所有的蛋白质在它们的生理状态下都显示出一些构象上的灵活性),但构象灵活性不会导致(1)蛋白质聚集,(2)通过内质网相关的降解途径消除,(3)削弱蛋白质功能,例如Gba活性,和/或(4)细胞内不恰当的转运,例如定位到溶酶体,程度与野生型蛋白质相比更大或更小。
术语“稳定的分子构象”表示蛋白质即Gba的构象,通过特异性药理伴侣诱导,以致在细胞中提供至少部分的野生型功能。例如,突变蛋白质稳定的分子构象使蛋白质从ER释放并运输到天然细胞场所,如野生型Gba一样(例如溶酶体),而不是错误折叠然后被降解。另外,突变蛋白质的稳定的分子构象可能也具有完全的或部分活性,例如GluCer水解。然而,稳定的分子构象无需具有野生型蛋白质的所有功能性特征。
术语“野生型活性”表示细胞中蛋白质如Gba的正常生理功能。例如Gba活性包括折叠并从ER运输到溶酶体,有或者没有伴随的水解底物(如GluCer或4-甲基伞形酮(4-MU))的能力。这种功能性可通过任何已知确定这类蛋白质功能性的手段来检验。
某些检验可评价蛋白质的属性,其可能或不能相当于它的实际体内功能,然而是蛋白质功能性的总替代,并且在该检验中的野生型行为是本发明蛋白质折叠挽救或增强技术的可接受结果。根据本发明,一种这样的活性是突变蛋白质的适当转运,例如Gba从内质网到天然细胞场所例如溶酶体或到胞外环境的转运。
术语“内源表达”表示个体细胞中蛋白质的正常生理表达,所述个体不患有或怀疑患有CNS疾病或与蛋白质的缺失、过表达或其他缺陷相关的紊乱,例如核酸或多肽序列中抑制其表达、活性或稳定性的缺陷。该术语也表示蛋白质在正常表达该蛋白质的细胞类型中表达,而不包括其中蛋白质不在健康个体中表达的细胞或细胞类型如肿瘤中的表达。
如本文使用的,术语“增强表达”或“提高表达”表示相对于细胞中(优选相同的细胞类型或同样的细胞,例如早期的细胞)不与蛋白质特异性药理伴侣接触的表达,增加细胞中与蛋白质特异性药理伴侣接触的采取功能性构象多肽的量。上述术语的另外意思指相对于细胞中不与蛋白质特异性药理伴侣接触的野生型对应物的转运效率(优选同样的细胞,例如早期细胞,或相同的细胞类型),增加细胞中与蛋白质特异性药理伴侣接触的来自ER的多肽的转运效率。
如本文使用的,术语“转运效率”表示从内质网转运突变蛋白质到其细胞内天然场所、到细胞内另外的场所、到细胞膜或到胞外环境的能力。
酶的“竞争性抑制剂”表示结构上类似酶底物的化学结构和分子几何学的化合物,其以与底物在大致相同的位置结合酶。因此,抑制剂与底物分子竞争相同的活性位点,因此增加Km。如果底物分子充足可置换抑制剂时,竞争性抑制通常是可逆的,即竞争性抑制剂能够可逆结合。因此,酶抑制的量取决于抑制剂浓度、底物浓度和抑制剂与底物对活性位点的相对亲和性。
当抑制剂远离活性位点之处结合时发生非经典的竞争性抑制,引起酶的构象变化以致底物不能再与其结合。在非经典的竞争性抑制中,底物在活性位点的结合阻止抑制剂在不同位点的结合,反之亦然。这包括变构抑制。
酶的“线性混合型抑制剂”是一种允许底物结合但降低其亲和性的竞争性抑制剂,因此Km增加,而Vmax降低。
“非竞争性抑制剂”表示与酶形成强的键,并且不能通过加入过量底物置换的化合物,即非竞争性抑制剂是不可逆的。非竞争性抑制剂可在酶或蛋白质活性位点处、附近或远处结合,并且就酶而言,对Km没有影响但降低Vmax。反竞争性抑制表示抑制剂仅结合酶-底物(ES)复合物的情况。当抑制剂结合时酶变得无活性。这不同于可在无底物时结合酶的非经典竞争性抑制剂。
术语“Vmax”表示酶催化反应的最大起始速度,即在饱和底物水平。术语“Km”是达到1/2 Vmax所需的底物浓度。
“应答者”是诊断患有与溶酶体酶突变有关的神经紊乱并且根据本文要求保护的方法治疗显示出改善、缓解或预防一种或多种临床症状,或者改善或逆转一个或多个替代的临床标记物的个体。作为一个实例,患有帕金森氏病(具有伴行的Gba突变)的个体“应答者”是显示出改善、缓解或预防一种或多种临床症状,或者改善或逆转一个或多个替代的临床标记物的人,包括但不限于:神经元损失、星形胶质增生、和在CA2-3神经元出现神经元内雷维小体样α-突触核蛋白包涵体。
术语“治疗有效剂量”和“有效量”表示足以导致治疗反应的特异性药理伴侣的量。治疗反应可以是使用者(例如临床医师)认为对疗法有有效反应的任何反应,例如通过症状和替代的临床标记物评定。因此,治疗反应通常是疾病或紊乱(例如神经紊乱)一个或多个症状的改善。
短语“可药用的”表示当施用于人时是生理上可耐受的并且通常不会产生不利反应的分子实体和组合物。优选,如本文使用的,术语“可药用的”指经联邦或州政府管理机构批准的或在美国药典或其他普遍认可的药典列出用于动物,更特别是人。术语“载体”表示与化合物一起给药的稀释剂、佐剂、赋形剂或运载体。这类药物载体可以是无菌的液体,如水或油。优选使用水或水性溶液、盐溶液和葡萄糖水性溶液和甘油溶液作为载体,尤其是可注射溶液。E.W.Martin在“Remington′s PharmaceuticalSciences”第18版或其他版本中描述了适合的药用载体。
术语“约”和“大约”通常应当指鉴于测量性质或精确度所测量的量的可接受的误差程度。通常,示例性误差程度在给定数值或数值范围的20%以内,优选10%以内,更优选5%以内。可选的,并且尤其在生物学***中,术语“约”和“大约”可指在给定数值的数量级内的数值,优选5倍以内,更优选2倍以内。除非另有说明,本文所给的数字量均是近似值,这意味着当没有明确说明时可推断具有术语“约”或“大约”的含义。
分子生物学定义
根据本发明,可以采用本领域常规的分子生物学、微生物学和重组DNA技术。这类技术在文献中有详尽解释。参见例如Sambrook,Fritsch &Maniatis,Molecular Cloning:A Laboratory Manual,第2版(1989)Cold SpringHarbor Laboratory Press,Cold Spring Harbor,纽约(本文称为“Sambrook等人,1989”);DNA Cloning:A Practical Approach,第I和II卷(D.N.Glover编辑,1985);Oligonucleotide Synthesis(M.J.Gait编辑,1984);Nucleic Acid Hybridization[B.D.Hames & S.J.Higgins编辑(1985)];Transcription And Translation[B.D.Hames &S.J.Higgins编辑,1984];Animal Cell Culture[R.I.Freshney编辑,(1986)];Immobilized Cells And Enzymes;[IRL Press,(1986)];B.Perbal,A Practical GuideTo Molecular Cloning(1984);F.M.Ausubel等(编辑),Current Protocols inMolecular Biology,John Wiley & Sons,Inc.(1994)。
如本文使用的,术语“分离的”意味着所提到的材料是从其正常发现的环境中移出的。因而,分离的生物材料能够不含细胞组分,即发现或生产该材料的细胞的组分。在核酸分子的情况下,分离的核酸包括PCR产物、分离的mRNA、cDNA或限制片段。在另一个实施方案中,分离的核酸优选从在可发现核酸的染色体中切下,更优选其不再与非调节性、非编码区或与其他基因连接,所述非调节性、非编码区或与其他基因位于在见于染色体中时分离的核酸分子所含有的基因的上游或下游。在又一个实施方案中,分离的核酸缺少一个或多个内含子。分离的核酸分子包括***质粒、粘粒、人工染色体等中的序列。因此,在一个具体实施方案中,重组核酸是一种分离的核酸。分离的蛋白质可以与其他细胞中与之结合的蛋白质或核酸或此二者结合,或者如果它是一种膜结合蛋白质时与细胞膜结合。分离的细胞器、细胞或组织在其发现的生物体中自其解剖位点移出。分离的材料可是但无须是纯化的。
本文使用的术语“纯化的”表示已经在减少或消除无关材料即杂质的条件下分离的材料,如Gba核酸或多肽。例如,纯化的蛋白质优选基本上不含有其他在细胞中与之结合的蛋白质或核酸。如本文使用的,术语“基本上不含”可操作地用在材料的分析性检测环境中。优选地,基本上不含杂质的纯化材料的纯度是至少50%,更优选至少90%,进而更优选至少99%。可以通过色谱法、凝胶电泳、免疫测定、组成分析、生物测定和本领域已知的其他方法对纯度进行评估。
术语“宿主细胞”意指以任何方式选择、修饰、转化、生长、使用或操作的任何生物的任何细胞,用于通过该细胞产生物质,例如由该细胞表达基因、DNA或RNA序列、蛋白质或酶。根据本发明,修饰宿主细胞以表达突变型或野生型溶酶体酶核酸和多肽。宿主细胞可进一步用于筛选或其他测定。“重组DNA分子”是进行了分子生物学操作的DNA分子。用于本发明的宿主细胞的实例是HEK293细胞、COS细胞和CHO细胞。
本文的多核苷酸可在两侧有天然调控(表达控制)序列,或可与异源序列相连,包括启动子、内部核糖体进入位点(IRES)及其他核糖体结合位点序列、增强子、应答元件、抑制子、信号序列、聚腺苷酸序列、内含子、5’-和3’-非编码区等等。也可通过本领域已知的多种方式修饰核酸。这样修饰的非穷举的实例包括甲基化、“加帽”、利用类似物取代一个或多个自然存在的核苷酸、和诸如核苷酸内修饰,例如,不带电荷的连接(如甲基膦酸酯、磷酸三酯、氨基磷酸酯、氨基甲酸酯等)和带电荷的连接(如硫代磷酸酯、二硫代磷酸酯等)。多核苷酸可包含一个或多个附加的共价连接的部分,例如,蛋白质(如核酸酶、毒素、抗体、信号肽、聚-L-赖氨酸等)、嵌入剂(如吖啶、补骨脂素等)、螯合剂(如金属、放射性金属、铁、氧化的金属等)和烷化剂。多核苷酸可由形成甲基或乙基磷酸三酯或者烷基氨基磷酸酯连接衍生而来。而且,本文的多核苷酸也可直接或间接由能够提供可检测信号的标记修饰。标记的实例包括放射性同位素、荧光分子、生物素等。
“编码序列”或“编码”表达产物如RNA或多肽的序列,是当表达时导致RNA或多肽产生的核苷酸序列,例如Gba核苷酸序列编码Gba多肽(蛋白质)的氨基酸序列。蛋白质的编码序列可包括起始密码子(通常是ATG)和终止密码子。
术语“基因”,也称为“结构基因”指编码或相应于包含构成全部或部分一个或多个溶酶体蛋白质的特定氨基酸序列的DNA序列,并且可能或可能不包括调控DNA序列,例如决定如在何种条件下表达基因的启动子序列。
当用于从核酸序列生产氨基酸序列的情况时,术语“表达”指允许或导致基因或DNA序列中的信息显现出来,例如通过激活参与相应Gba基因或DNA序列转录和翻译的细胞功能来生产Gba蛋白质。在细胞中或由细胞表达的DNA序列形成“表达产物”例如Gba蛋白质。表达产物本身,例如所得的蛋白质,也可表述为是由细胞“表达”的。表达产物可表征为胞内的、胞外的或分泌的。根据本发明,蛋白质在神经元中细胞内表达。
术语“胞内的”指细胞内的东西。术语“胞外的”指细胞外的东西。如果在细胞外表现出显著量,则物质是通过细胞从细胞上或细胞内某处“分泌的”。
术语“异源的”表示非天然组合出现的元件组合。例如,异源的DNA表示非天然位于细胞或细胞染色***点的DNA。优选,异源DNA包括细胞的外源基因。异源表达调控元件是与不同于天然有效连接的基因有效连接的元件。在本发明的上下文中,编码目的蛋白质的基因对于其用于克隆或表达而***的载体DNA是异源的,并且对于包含上述载体的表达该基因的宿主细胞是异源的,例如大肠杆菌细胞。
术语“转化”表示从周围介质中将DNA即编码溶酶体酶多肽的核酸引入宿主细胞的过程。
术语“转导”表示将DNA即编码Gba多肽的核酸引入到原核宿主细胞中,例如通过细菌病毒或噬菌体引入原核宿主细胞。接受并表达所引入的DNA或RNA的原核或真核宿主细胞已经被“转化”或“转导”,并且是“转化体”或“克隆”。引入宿主细胞的DNA或RNA可来自任何来源,包括与宿主细胞相同属或种的细胞、或不同属或种的细胞、或合成序列。
术语“工程重组细胞”表示经操作以表达或过表达目的核酸即Gba多肽编码核酸的任何原核或真核细胞,通过任何适当的方法实现,包括转染、转化或转导。该术语也包括细胞中核酸的内源活化,该细胞通常不表达或以次佳水平表达所述基因产物。
术语“转染”指向细胞中引入“外来”(即外部的或胞外的)核酸。“外来”核酸包括引入宿主细胞的基因、DNA或RNA序列,以便使宿主细胞复制该DNA,并表达所引入的基因或序列,从而产生期望的物质,通常是所引入基因或序列编码的蛋白质或酶。所引入的基因即编码Gba多肽的核酸或序列,也可称为“克隆的”基因或序列,可以包括调节或控制序列,诸如起始序列、终止序列、启动子序列、信号序列、分泌序列或细胞遗传机器所使用的其他序列。基因或序列可以包括非功能序列或者无已知功能的序列。所引入的DNA或者作为染色体外元件,或通过染色体整合入接受并表达所引入的DNA或RNA的宿主细胞中。
取决于所使用的宿主细胞,使用适合于此类细胞的标准技术进行转化/转染。如上述Sambrook等人1989中第1.82节描述的,使用氯化钙的钙处理通常用于含实体细胞壁屏障的细菌细胞。用于转化的另一个方法如Chung和Miller(Nucleic Acids Res.1988,16:3580)描述的使用聚乙二醇/DMSO。又一个方法是使用称为电穿孔的技术。另外,对于使用病毒载体的情况,宿主细胞可通过包含目的基因的病毒感染。
术语“载体”、“克隆载体”和“表达载体”指DNA或RNA序列(例如Gba基因)可以通过其被引入到宿主细胞中以转化宿主并促进所引入序列的表达(例如转录和翻译)的运载体。载体包括质粒、噬菌体、病毒等;这些在下文更详细讨论。
载体通常包含可传递因子的DNA,外源DNA***其中。将DNA区段***另一DNA区段的常规方法包括利用称为限制性内切酶的酶在称为限制性位点的特异位点(特异的核苷酸组)切割DNA。“表达盒”表示编码表达产物的DNA编码序列或DNA区段,可在规定的限制性位点***载体。设计表达盒限制性位点,以确保以正确的阅读框***表达盒。通常,在载体DNA的一个或多个限制性位点***外来DNA,然后通过载体与可传递的载体DNA一起携带入宿主细胞。具有***或附加DNA的DNA区段或序列如表达载体也称为“DNA构建体”。载体的常见类型是“质粒”,其通常是双链DNA的自容式分子,通常为细菌来源,其可容易地接受附加的(外来的)DNA并可容易地引入适当的宿主细胞。质粒载体往往包含编码DNA和启动子DNA,并具有一个或多个适于***外来DNA的限制性位点。编码DNA是编码特定蛋白质或酶的特定氨基酸序列的DNA序列。启动子DNA是起始、调节或以其他方式介导或控制编码DNA表达的DNA序列。启动子DNA和编码DNA可来自相同或不同的基因,并且可来自相同或不同的生物。
许多载体,包括质粒和真菌载体,已被描述用于多种真核和原核宿主中的复制和/或表达。非穷举的实例包括pKK质粒(Clonetech)、pUC质粒、pET质粒(Novagen,Inc.,Madison,WI)、pRSET或pREP质粒(Invitrogen,San Diego,CA)、或pMAL质粒(New England Biolabs,Beverly,MA)、pCXN和很多合适的宿主细胞,使用本文公开或引用或相关领域技术人员已知的其他方法。重组克隆载体往往包括一个或多个用于克隆或表达的复制***、一个或多个用于宿主中选择的标记例如抗生素抗性、和一个或多个表达盒。
很多宿主/表达载体组合(即表达***)可应用于目的蛋白质的表达。有用的表达载体,例如,可由染色体区段、非染色体和合成DNA序列组成。合适的载体包括已知的细菌质粒,例如大肠杆菌质粒col El、pCR1、pBR322、pMal-C2、pET、pGEX(Smith等人,Gene 67:31-40,1988)、pMB9和它们的衍生物,质粒如RP4;噬菌体DNA,例如噬菌体1的众多衍生物例如NM989,及其他噬菌体DNA,例如M 13和丝状单链噬菌体DNA;酵母质粒如2m质粒或其衍生物;来源于质粒和噬菌体DNA组合的载体,如已被修饰使用噬菌体DNA或其他表达控制序列的质粒;等等。另外的通用表达***使用昆虫宿主细胞和杆状病毒载体。
可商购的用于哺乳动物细胞的典型表达载体包括pMEP4、pCEP4、pLXSN、PXT1、pcDNA3系列、pcDNA4系列、pCMV-Script、pCMV-标签及其他基于CMV的载体、pVP22、pVAX1、pUB6。为进行哺乳动物细胞的转染,病毒载体包括腺相关病毒载体、痘病毒和逆转录病毒。哺乳动物表达载体是本领域常规和公知的。
宿主细胞也可固有地含有目的多肽如Gba。对于异源多肽如Gba,将异源核酸(例如cDNA)相配地***可复制的载体,在适当的启动子调控下在培养基中表达。正如上述所指出的,许多载体都可用于该目的,并且合适载体的选择主要取决于***载体的核酸大小和转化该载体的特定宿主细胞。每个载体取决于其功能(DNA扩增或DNA表达)和与其相容的特定宿主细胞而包含不同的组件。用于细菌转化的载体组件通常包括但不限于下列的一个或多个:信号序列、复制起点、一个或多个标记基因和启动子。
编码Gba多肽的DNA不仅可直接表达,而且也可与另外的多肽融合表达,优选信号序列或其他在成熟多肽N-末端具有特异性切割位点的多肽。通常,信号序列可以是载体的一个组件,或可以是***载体的多肽DNA的一部分。选择的异源信号序列应当可被宿主细胞识别和加工(即通过信号肽酶切割)。对于细菌宿主细胞不识别和加工的天然多肽信号序列,该信号序列由选择的细菌信号序列代替,例如选自碱性磷酸酶、青霉素酶、lpp或热稳定的肠毒素II前导肽。
表达和克隆载体都包含使载体在一种或多种选择的宿主细胞中复制的核酸序列。通常,在克隆载体中,该序列是使载体独立于宿主染色体DNA复制并且包含复制起点或自主复制序列的序列。对于多种细菌这样的序列为大家所熟知。质粒pBR322的复制起点适于大多数革兰氏阴性细菌。
通常表达和克隆载体也包含选择基因,也称为可选择标记。该基因编码在选择性培养基中培养的转化宿主细胞存活或生长所必需的蛋白质。没有转化含选择基因载体的宿主细胞不会在该培养基上存活。通常选择基因编码如下的蛋白质:(a)赋予对抗生素或其他毒素的抗性,例如氨苄青霉素、新霉素、氨甲喋呤或四环素;(b)补偿营养缺陷;或(c)提供从复合培养基中不能获得的关键养分。选择方案的一个实例利用药物阻止宿主细胞的生长。那些成功转化异源基因的细胞产生赋予抗药性的蛋白质,因此幸免于选择方案。
生产异源多肽的表达载体也包含宿主生物识别的诱导型启动子并与编码目的多肽的核酸有效连接。
“启动子序列”是能够在细胞中结合RNA聚合酶的DNA调控区,并且起始下游(3’方向)编码序列的转录。为了定义本发明,启动子序列在其3’末端以转录起始位点为界,并且上游(5’方向)延伸至包括以高于背景的可检测水平起始转录所必需的最小数目的碱基或元件。在启动子序列内会发现转录起始位点和负责结合RNA聚合酶的蛋白质结合结构域(共有序列)。
编码序列“处于”细胞中转录和翻译控制序列的“控制下”或与之“有效连接”,此时RNA聚合酶转录编码序列为mRNA,然后mRNA经RNA剪接(如果包含内含子)并且被翻译为编码序列编码的蛋白质。
包含一个或多个上述所列组件的适当载体的构建使用标准连接技术。切割、加尾和再连接分离的质粒或DNA片段,以期望的形式产生所需质粒。
为了分析以确认所构建质粒的正确序列,用连接混合物转化细菌菌株,并在适用的情况下,通过氨苄青霉素或四环素抗性筛选成功的转化体。制备从转化体获得的质粒,通过限制性内切酶消化分析,和/或通过Sanger等人,Proc.Natl.Acad.ScL USA.1977,74:5463-5467或Messing等人,NucleicAcidsRes.1981,9:309的方法测序,或通过Maxam等人的方法(Methods in Enzymology1980,65:499)。利用以上描述的表达载体转化宿主细胞,并在为所用启动子酌情改变的常规培养基中培养。
化学定义
术语“烷基”表示直链或支链的C1-C20烃基,其仅由碳和氢原子组成,不含不饱和度,通过单键与分子其余部分连接,例如甲基、乙基、正丙基、1-甲基乙基(异丙基)、正丁基、正戊基、1,1-二甲基乙基(叔丁基)。本文所使用的烷基优选C1-C8烷基。
术语“烯基”表示含有至少一个碳-碳双键的C2-C20脂族烃基,并且其可以是直链或支链的,例如乙烯基、1-丙烯基、2-丙烯基(烯丙基)、异丙烯基、2-甲基-1-丙烯基、1-丁烯基、2-丁烯基。
术语“环烷基”表示不饱和的非芳族单环或多环的烃环系,例如环丙基、环丁基、环戊基、环己基。多环环烷基的实例包括全氢萘基、金刚烷基和降冰片基(norbornyl)桥连的环状基团或螺二环基团,例如螺(4,4)壬-2-基。
术语“环烷基烷基”表示直接与如上所定义的烷基连接的如上所定义的环烷基,这导致稳定结构的产生,例如环丙基甲基、环丁基乙基、环戊基乙基。
术语“烷基醚”表示具有至少一个掺入烷基链的氧的如上所定义的烷基或环烷基基团,例如甲***、二***、四氢呋喃。
术语“烷基胺”表示具有至少一个氮原子的如上所定义的烷基或环烷基基团,例如正丁胺和四氢噁嗪。
术语“芳基”表示具有约6至约14个碳原子的芳族原子团,例如苯基、萘基、四氢萘基、茚满基、联苯基。
术语“芳基烷基”表示如上所定义的芳基直接键合到如上所定义的烷基,例如-CH2C6H5和-C2H4C6H5。
术语“杂环”表示稳定的由碳原子和一至五个选自氮、磷、氧和硫的杂原子组成的3-至15-元环原子团。对于本发明的目的,杂环原子团可以是单环、二环或三环环系,其可以包括稠合、桥连或螺环系,杂环中的氮、磷、碳、氧或硫原子可以任选地被氧化为各种氧化态。另外,氮原子可以任选地被季铵化;环原子团可以是部分或完全饱和的(即,杂芳族的或杂芳基芳族的)。这类杂环原子团的实例包括但不限于氮杂环丁烷基、吖啶基、苯并间二氧杂环戊烯基、苯并二噁烷基、苯并呋喃基、咔唑基、噌啉基、二氧戊环基、吲嗪基、萘啶基、全氢氮杂基、吩嗪基、吩噻嗪基、吩噁嗪基、酞嗪基、吡啶基、蝶啶基、嘌呤基、喹唑啉基、喹喔啉基、喹啉基、异喹啉基、四唑基、咪唑基、四氢异喹啉基(tetrahydroisouinolyl)、哌啶基、哌嗪基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、2-氧代氮杂基、氮杂基、吡咯基、4-哌啶酮基、吡咯烷基、吡嗪基、嘧啶基、哒嗪基、噁唑基、噁唑啉基、噁唑烷基、***基、茚满基、异噁唑基、异噁唑烷基、吗啉基、噻唑基、噻唑啉基、噻唑烷基、异噻唑基、奎宁环基、异噻唑烷基、吲哚基、异吲哚基、吲哚基、异吲哚基、八氢吲哚基、八氢异吲哚基、喹啉基、异喹啉基、十氢异喹啉基、苯并咪唑基、噻二唑基、苯并吡喃基、苯并噻唑基、苯并噁唑基、呋喃基、四氢呋喃基、四氢吡喃基、噻吩基、苯并噻吩基、硫吗啉基、硫吗啉基亚砜、硫吗啉基砜、二氧磷杂环戊烷基、噁二唑基、苯并二氢吡喃基、异苯并二氢吡喃基。
杂环原子团可以在任何导致稳定结构产生的杂原子或碳原子上与主结构连接。
术语“杂芳基”表示杂环中的环是芳族的。
术语“杂芳基烷基”表示直接与烷基键合的如上所定义的杂芳基环原子团。杂芳基烷基原子团可以在任何导致稳定结构产生的烷基碳原子上与主结构连接。
术语“杂环基烷基”表示如上所定义的杂环原子团。杂环基烷基环原子团可以在任何导致稳定结构产生的杂原子或碳原子上与主结构连接。
术语“杂环基烷基”表示直接与烷基键合的如上所定义的杂环原子团。杂环基烷基原子团可以在任何导致稳定结构产生的烷基碳原子上与主结构连接。
“取代的烷基”、“取代的烯基”、“取代的炔基”、“取代的环烷基”、“取代的环烷基烷基”、“取代的环烯基”、“取代的芳基烷基”、“取代的芳基”、“取代的杂环”、“取代的杂芳基环”、“取代的杂芳基烷基”或“取代的杂环基烷基环”中的取代基可以是相同或不同的,有一个或多个选自下组的基团:氢、羟基、卤素、羧基、氰基、氨基、硝基、氧代基(=O)、硫代基(=S)或任选地被取代的选自以下的基团:烷基、烷氧基、烯基、炔基、芳基、芳基烷基、环烷基、芳基、杂芳基、杂芳基烷基、杂环、-COORx、-C(O)Rx、-C(S)Rx、-C(O)NRxRy、-C(O)ONRxRy、-NRxCONRyRz、-N(Rx)SORy、-N(Rx)SO2Ry、-(=N-N(Rx)Ry)、-NRxC(O)ORy、-NRxRy、-NRxC(O)Ry、-NRxC(S)Ry、-NRxC(S)NRyRz、-SONRxRy、-SO2NRxRy、-ORx、-ORxC(O)NRyRz、-ORxC(O)ORy、-OC(O)Rx、-OC(O)NRxRy、-RxNRyRz、-RxRyRz、-RxCF3、-RxNRyC(O)Rz、-RxORy、-RxC(O)ORy、-RxC(O)NRyRz、-RxC(O)Rx、-RxOC(O)Ry、-SRx、-SORx、-SO2Rx、-ONO2,其中以上各基团中的Rx、Ry和Rz可以是氢原子、取代或未取代的烷基、卤代烷基、取代或未取代的芳基烷基、取代或未取代的芳基、取代或未取代的环烷基、取代或未取代的环烷基烷基、取代或未取代的杂环、取代或未取代的杂环基烷基、取代或未取代的杂芳基或者取代或未取代的杂芳基烷基。
术语“卤素”表示氟、氯、溴和碘的原子团。
毒性功能获得
在一个特别的实施方案中,本发明涉及利用溶酶体酶特异性药理伴侣以提高恰当的蛋白质运输水平并降低突变酶的累积水平。其依次可用于治疗与酶突变有关的神经病学状况,包括种种形式的溶酶体贮积病,其中一个或两个等位基因上的突变产生构象突变酶,但也具有功能性结构域突变,废除了酶活性。本文的实施方案通过特异性药理伴侣对突变Gba的作用举例说明,该Gba突变发现于无功能性Gba存在的戈谢病的神经病学形式。该伴侣增加从内质网运输Gba蛋白质的水平,并恢复突变蛋白质的正确泛素化。该作用不能从现有的对蛋白质功能ASSC拯救的工作中预见到。
CNS中蛋白质聚集如突变Gba累积是特别可怕的,因为神经元不能在由于与毒性累积有关的神经元应激形成的神经退化或细胞凋亡后再生。因此,纯合或杂合型突变的存在足以引起神经元中突变蛋白质聚集或累积和细胞应激,最终导致细胞死亡。众多报道已公开CNS中的蛋白质聚集与病状相关联。
因此,在一个实施方案中,本发明基于这样的概念,即溶酶体贮积病中CNS病状及其他与溶酶体酶突变有关的神经紊乱,可部分地通过神经元中突变的错误折叠酶的毒性累积进行解释,而特异性药理伴侣方法可逆转这种效应。毒性效应也依赖于蛋白质的功能,突变对蛋白质的功能和稳定性的影响,以及蛋白质功能的损失或降低的害处是否甚于或不及蛋白质累积和/或聚集的毒性影响。因此,使用特异性药理伴侣增加来自ER蛋白质的运输可通过降低该蛋白质累积/聚集的毒性作用而减轻疾病病状,甚至无需恢复蛋白质功能。
由此可见特异性药理伴侣可潜在地用来治疗任何蛋白质毒性累积和/或蛋白质聚集为疾病病理重要病因的疾病,包括与神经退化疾病相关,特别是有神经病学受累情况的溶酶体贮积病如戈谢病,及其他神经病学危险因素、紊乱或与溶酶体酶突变有关的状况,如帕金森氏病。如上文所指出的那样,可能与功能障碍的溶酶体酶有关并可通过药理伴侣治疗的其他神经疾病类型为阿尔茨海默病、肌萎缩性侧索硬化、卡纳万病、克罗伊茨费尔特-雅各布病、亨廷顿病、多发性硬化症、皮克病和脊髓小脑萎缩症。
因此,增加从ER运输的突变酶,和/或提高酶活性的治疗方法有益于减轻与溶酶体贮积病有关的神经元致病作用或与溶酶体酶突变相关的其他神经疾病。甚至在没有提高酶活性(即恢复功能损失)和降低底物累积的情况下,突变酶的适当的运输对神经元也具有有利的影响,例如(i)减轻对正常蛋白质泛素/蛋白酶体降解途径的细胞应激;或(ii)降低由ER应激所引起的解折叠蛋白质反应,因而改善病状例如具有Gba突变的帕金森氏患者的α-突触核蛋白聚集。以下直接提供这些作用的证据。
细胞应激已明确确定细胞中大量错误折叠的蛋白质累积或聚集导致细胞应激。该应激往往与细胞“应激”蛋白质——多聚泛素的量增加有关系。泛素-蛋白质缀合物已揭示泛素是许多神经退化疾病所特有的丝状包涵体的组件,表明这类疾病过程中的激活或常见的神经元反应(Lowe等人,Neuropathol Appl Neurobiol.1990;16:281-91)。例如,遗传研究,包括与家族性帕金森氏病(包括α-突触核蛋白)有关的基因中突变的鉴别,和在帕金森氏病散发病例的少量多巴胺能黑质神经元中蛋白质原性胞浆包涵体的存在,已表明泛素-蛋白酶体***和异常蛋白质降解的重要功用(Betarbet等人,Exp Neurol.2005;191 Suppl l:S17-27)。
另外,体内和体外研究已将聚集的α-突触核蛋白和氧化应激与受损的泛素-蛋白酶体***和帕金森氏病发病机理关联在一起。而且,已在散发性帕金森氏病患者的黑质部分致密层中鉴别出伴有潜在的细胞毒性异常蛋白质累积和聚集的26/20S蛋白酶体的结构和功能缺陷(McKnaught等人,AnnNeurol.2003;53 Suppl 3:S73-84)。具体地,引起蛋白质错误折叠和抵抗蛋白酶体降解的α-突触核蛋白的突变导致家族性帕金森氏病。因而,蛋白质处理方面的缺陷似乎是散发性和不同家族性PD的共同因素。从添加蛋白酶体抑制剂与诱导蛋白质错误折叠物质组合到多巴胺能神经元培养物的试验中得到相同的结论(Mytilineou等人,J Neural Transm.2004;111(10-11):1237-51)。当两者组合时,占优势的多巴胺神经元丢失和细胞死亡明显增加。
更进一步地,已报道在一些溶酶体贮积病包括戈谢病患者细胞中发现泛素化蛋白质的聚集体(Asmarina等人,Eur.J.Biochem.2003;增刊1;摘要编号P3.7-08)。这些细胞与泛素/蛋白酶体途径相关的基因也显示出改变的基因表达模式。
对于伴有CNS受累情况的LSD神经元稳态混乱的另一个学说是归因于累积的酶抑制泛素/蛋白酶体途径(Rocca等人,Molecular Biology of theCell.2001;12:1293-1301)。例如,已发现与α-突触核蛋白聚集有关的毒性机制之一是发生在许多神经退化过程中的蛋白酶体抑制作用。具体地,表明聚集的α-突触核蛋白通过与蛋白酶体的亚基S6’相互作用来抑制蛋白酶体功能(Snyder等人,J Mol Neurosci.2004;24(3):425-42)。在帕金森氏病受试者的脑中以及在没有E3泛素连接酶二乙嗪(parkin)和部分泛素蛋白酶体***的个体和动物脑中蛋白酶体功能降低。蛋白质聚集和相关的蛋白酶体抑制也已与炎症相联系(Li等人,Int.J.Biochem.Cell Biol.2003;35:547-552)。已提出分子伴侣和损坏的/变性的/错误折叠的蛋白质间的不平衡导致后者的累积,取决于不平衡的严重程度可导致衰老、蛋白酶体的抑制(导致细胞凋亡)或坏死(Soti等人,Aging Cell.2003;2:39-45)。这些假说称为“毒性蛋白质积累假说”。因为认为α-突触核蛋白单体通过蛋白酶体降解并且寡聚物的形成是浓度依赖性的,这可导致α-突触核蛋白的累积和寡聚作用。突变Gba和α-突触核蛋白两者的累积(后者由于Gba活性损失所致)都将加重对蛋白酶体的影响,并且缺陷型Gba也可削弱溶酶体自体吞噬反应的任何增加,自体吞噬反应是为了补偿蛋白酶体降解途径的缺陷而发生的。
内质网应激除了以上引证的讨论,ER腔中错误折叠蛋白质的持续累积引起ER应激反应,其依次引起“解折叠蛋白质反应”(UPR)。UPR是由蛋白质合成抑制作用引起的细胞应激反应的质量控制,例如通过氧化应激、或ER中不能折叠的突变蛋白质的滞留。若没有该反应,ER将会变得充满可通过细胞凋亡导致细胞死亡的错误折叠的不稳定蛋白质(Gow等人,Neuro Molecular Med.2003;4:73-94)。
也已表明ER中Gba与兰尼碱(Rhyanodine)受体相互作用干扰Ca2+动态平衡,由于胞液中Ca2+的增加而导致削弱蛋白质折叠和UPR、ER应激诱发的细胞凋亡和线粒体指导的细胞死亡(Korkotian等人,J Biol Chem.1999.274(31):21673-8;Lloyd-Evans等人,J Biol Chem.2003.278(26):23594-9;Pelled等人,Neurobiol Dis.2005.18(1):83-8)。
自体吞噬除了降解脂质,溶酶体也负责降解聚集的蛋白质(下面进一步论述)。该过程称为自体吞噬,通过此胞内整体降解过程,部分细胞质被递送到溶酶体以被溶酶体酶降解。这样的酶包括切割肽键的蛋白酶(组织蛋白酶)、除去共价结合磷酸的磷酸酶、切割DNA/RNA的核酸酶、切割脂质分子的脂肪酶及糖类切割酶。聚集的蛋白质包括突变的溶酶体酶,可引起导致神经元中持久的退行性病变的显著自体吞噬反应的活化。许多CNS紊乱包括肌萎缩性侧索硬化(ALS)的神经元显示不规则的囊泡运输和自体吞噬反应。
过度的自体吞噬-溶酶体空泡形成有可能可引起神经元死亡。自体吞噬反应的过度激活,特别是组合累积的突变蛋白质对作为补偿机制的蛋白酶体途径的抑制作用,是有关累积的突变体溶酶体酶和神经退行性变特别是阿尔茨海默氏病之间联系的一个假说。
病理性功能损失
除了修复溶酶体酶的恰当运输,特异性药理伴侣对突变体酶活性的修复对持有一个或两个等位基因不稳定突变的患者是有利的,由于不充足的折叠合运输所述突变降低天然场所(如溶酶体)中功能性酶(例如Gba)的量。甚至小量的功能损失即可导致病状诸如底物累积或聚集,其可导致其他病理性聚集体的产生。
因此,在一个实施方案中,本发明提供了用于改善与突变溶酶体酶蛋白质有关的神经紊乱的方法,该方法通过提高酶的降低活性实现,其依次将(i)提高底物、聚集的蛋白质或片段的溶酶体降解;(ii)降低神经元细胞凋亡或坏死;和(iii)阻止细胞膜中磷脂“平衡”的改变(直接在下面论述)。
假定对戈谢病中神经元损失或神经病的可能性说明可通过与突变有关的Gba活性损失来解释。活性损失引起缺陷Gba的细胞中诸如GluCer的神经酰胺累积。这些已显示由于胞内钙的增加和钙-介导的细胞死亡的灵敏度增加在培养的海马CA2-4神经元细胞中引起细胞凋亡。多巴胺能神经元也已显示在神经酰胺-诱导损伤后遭受细胞凋亡。
第二,已在致死的无效等位基因戈谢病小鼠的器官中发现高水平的毒性化合物葡糖鞘氨醇,其也是Gba的底物。葡糖鞘氨醇也在所有三种戈谢病类型患者的组织中升高。不过,使用目前的检测方法只在伴有神经元受累情况的患者脑中水平提高(Sidransky,Mol.Gen.Metabol.2004;83:6-15),使用目前的方法不能检测出的小量累积仍可影响蛋白质折叠以及通过影响脂筏成分削弱蛋白质运输(下文论述)。
第三,膜磷脂内容物影响细胞中Gba的活性。也就是说,带负电荷的磷脂提高Gba活性,而带正电荷的磷脂诸如磷脂酰胆碱(PC)却不能。因此,在戈谢病中降低Gba的机制激活参与PC合成的酶,从而提高PC,可引起Gba进一步的减少(Wong等人,上述)。另外,升高的神经酰胺可阻碍α-突触核蛋白的轴突运输,有利于聚集和雷维小体形成。推测神经元发挥功能需要α-突触核蛋白。由于α-突触核蛋白结合PC不足,主要由PC组成的轴突运输囊泡不能与由酸性磷脂组成的囊泡一样有效(Wong等人,上述)。
另外,正如以上讨论的,溶酶体通过自体吞噬参与清除涉及众多CNS紊乱的聚集体。自体吞噬在神经元中有特别重大的意义,因为甚至在没有任何疾病-相关的突变蛋白质的情况下自体吞噬的损失导致神经退行性变(Hara等人,Nature.2006年4月19日在线公开)。在氧化应激期间发生溶酶体自体吞噬***的诱导,以致力于保护性地消除胞内组分的改变(Kiffm等人,Antioxid Redox Signal.2006;8(l-2):152-62)。
α-突触核蛋白寡聚体作为一个实例。一个研究小组报道了人脑匀浆的溶酶体中含葡糖苷酰鞘氨醇的神经节苷脂和α-突触核蛋白之间的相互作用(Schlossmacher等人,New Eng J Med.2005;352:730)。在患有帕金森氏病的戈谢病患者中,Gba与α-突触核蛋白共定位于雷维小体(Wong等人,Mol.Genet.Metabol.2004;38:192-207)。这些结果支持发生在溶酶体内的α-突触核蛋白的加工,并且提供帕金森氏病中降低的Gba活性和突触核蛋白病变(synucleinopathy)之间的生化联系。
另外,自体吞噬对消除来自胞质区室的聚集形式的突变亨廷顿蛋白(huntingtin)和共计失调I型蛋白(ataxin-1)是必不可少的(Iwata等人,ProcNatlAcadSci U S A.2005;102(37):13135-40)。自体吞噬在清除来自肌萎缩性侧索硬化、阿尔茨海默氏病、帕金森氏病、亨廷顿病及其他多聚谷氨酸扩展紊乱细胞中的蛋白质聚集体方面也起到重要的作用(Meriin等人,IntJ Hyperthermia.2005;21(5):403-19)。因而,溶酶体水解酶的缺陷将对蛋白质毒性累积(包括累积的溶酶体蛋白质本身)的自体吞噬反应产生不利的影响。
底物累积和胞吞运输缺陷细胞底物的累积,如溶酶体疾病中的神经鞘脂类和胆固醇,特别是那些涉及CNS的神经鞘脂类和胆固醇,与蛋白质和脂质的胞吞运输混乱有关。这可由于rab(脑中的ras)蛋白质的混乱发生,rab蛋白质定位于分离的亚细胞区室并与蛋白质运输有关的膜结合蛋白质。rab混乱通过膜结合蛋白质进入“脂筏”导致隔绝。脂筏是富含神经鞘脂类(鞘磷脂和磷脂酰胆碱)和胆固醇的膜微域。它们已表明为多种细胞事件,包括信号传导和膜运输中提供平台。特别地,脂筏稳定ER膜内GPI-锚定蛋白质的结合,直接参与蛋白质构象以及指导脂质或脂质相关蛋白质通过吞饮泡进入细胞的合适区室。因此,由于脂质水解酶活性的降低在例如溶酶体贮积病中吞饮泡和溶酶体膜内的脂筏累积可改变胞内糖鞘脂(已是累积的)和进入细胞的脂质相关蛋白质的分选(Pagano等人,Philos TransR Soc Lond B Biol Sci.2003;358:885-91)。
近来有关粘多糖(MPS)的发现支持该错误-分选假说,其中证实两种不同累积的底物即GM2和GM3神经节苷脂在相同神经元中累积,却一向位于不同的细胞质囊泡群中(McGlynn等人,Comp Neurol.2004;480:415-26)。这些作者假定个体神经元间的共隔绝表明在组成、运输和/或脂筏组分再循环方面缺陷的存在导致在MPS紊乱中阐明神经元机能障碍的新机制产生。
对戈谢病小鼠模型的研究也表明降低的Gba活性通常干扰糖鞘脂分解代谢,导致更复杂类型(神经节苷脂)的累积。神经节苷脂的累积可导致人的肌张力障碍和帕金森综合征(Roze等人,Movement Disorders.2005;20(10):1366-1369)。累积GM2神经节苷脂的小鼠模型也累积α-突触核蛋白(Suzuki等人,Neuroreport.2003;14(4):551-4)。这种神经节苷脂的累积也可导致α-突触核蛋白累积和通过UPR途径导致神经元死亡(Lee等人,JBiol Chem.2002.277(1):671-8)。此外,如上所述,表明神经鞘脂类可对α-突触核蛋白聚集体的形成起种子作用。
这些神经毒性的机制是脂质累积的结果,可部分阐明戈谢病的神经病理学,因为在Gba活性和戈谢病严重程度之间有弱的相关性。该相关性区分三种主要疾病类型(I-III),虽然在个体类型中存在重叠,且相关性微弱。杂合的正常Gba患者不经历显著的脂质累积,因为通过正常的等位基因产生一些量的活性Gba。然而,甚至少量的GluCer累积可干扰ER钙的动态平衡并削弱蛋白质折叠(如上所述),或甚至可能通过一些机制使α-突触核蛋白聚集。
考虑到上述,根据本发明特异性药理伴侣的用途对于酶替代疗法(ERT)和底物降低疗法(SRT)是有利的,因为前者必须通过导管直接施用入脑,并且因为两者都不解决突变体溶酶体酶本身即突变Gba的毒性累积问题。因此,相比可降低突变蛋白质累积、或者提高和/或修复蛋白质功能(从而降低底物累积)或两者兼而有之的疗法,这些疗法是低效的。
突变体溶酶体酶类和特异性药理伴侣下面是列出溶酶体酶和特异性药理伴侣的表格,对于那些可用于治疗具有酶突变个体的溶酶体酶,所述个体具有作为结果发生的神经病学状况或紊乱,或处于发展为神经病学状况或紊乱的风险中。
溶酶体酶 | 特异性药理伴侣 |
α-葡糖苷酶GenBank登录号Y00839 | 1-脱氧野尻霉素(DNJ)α-homonojirimycin栗精胺(castanospermine) |
酸性β-葡糖苷酶(葡糖脑苷酯酶)GenBank登录号J03059 | 异法戈明(isofagomine)C-苯甲基异法戈明及衍生物N-烷基(C9-12)-DNJ葡糖咪唑(及衍生物)C-烷基-IFG(及衍生物)N-烷基-β-井冈霉烯胺氟奋乃静(Fluphenozine)Calystegine A3、B1、B2和C1 |
α-半乳糖苷酶AGenBank登录号NM000169 | 1-脱氧半乳糖野尻霉素(DGJ)α-allo-homonojirimycinα-galacto-homonojirimycinβ-1-C-丁基-脱氧野尻霉素Calystegine A2和B2N-methyl Calystegine A2和B2 |
酸性β-半乳糖苷酶GenBank登录号M34423 | = |
半乳糖脑苷脂酶(酸性β-半乳糖苷酶)GenBank登录号D25283 | 4-epi-异法戈明1-脱氧半乳糖野尻霉素 |
酸性α-甘露糖苷酶GenBank登录号U68567 | 1-脱氧甘露糖野尻霉素苦马豆素(swainsonine)Mannostatin A |
酸性β-甘露糖苷酶GenBank登录号U60337 | 2-羟基-异法戈明 |
酸性α-岩藻糖苷酶GenBank登录号NM_000147 | 1-脱氧岩藻糖野尻霉素β-homofuconojirimycin2,5-亚氨基-1,2,5-三脱氧-L-葡萄糖醇2,5-脱氧-2,5-亚氨基-D-果糖醇2,5-亚氨基-1,2,5-三脱氧-D-阿卓糖醇 |
α-N-乙酰氨基葡糖苷酶GenBank登录号U40846 | 1,2-双脱氧-2-N-乙酰胺基-野尻霉素 |
α-N-乙酰氨基半乳糖苷酶GenBank登录号M62783 | 1,2-双脱氧-2-N-乙酰胺基-半乳糖野尻霉素 |
β-氨基己糖苷酶AGenBank登录号NM_000520 | 2-N-乙酰氨基-异法戈明1,2-乙酰胺基-野尻霉素nagstain |
β-氨基己糖苷酶BGenBank登录号NM_000521 | 2-N-乙酰胺基-异法戈明1,2-双脱氧-2-乙酰胺基-野尻霉素nagstain |
α-L-艾杜糖醛酸酶GenBank登录号NM_000203 | 1-脱氧艾杜糖野尻霉素2-羧基-3,4,5-三脱氧哌啶 |
β-葡萄糖醛酸酶GenBank登录号NM_000181 | 4-羧基-异法戈明2-羧基-3,4,5-三脱氧哌啶 |
唾液酸酶GenBank登录号U84246 | 2,6-双脱氧-2,6,亚氨基-唾液酸制唾液酸酶素 |
艾杜糖醛酸硫酸酯酶GenBank登录号AF_011889 | 2,5-脱水甘露醇-6-硫酸盐 |
酸性神经磷脂酶GenBank登录号M59916 | 脱甲丙咪嗪,磷脂酰肌醇-4,5-二磷酸 |
在一个具体实施方案中,下面是本发明预期的一些特异性药理伴侣,可用于治疗Gba突变的神经病学危险因素、状况或紊乱。也举例说明了Gba突变,预期通过伴侣“拯救”。
Gba突变 在至少一个等位基因上(杂合子)的Gba点突变N370S的存在几乎普遍与1型戈谢病有关(Cox,上述)。N370S纯合型比Gba无效/N370S杂合型(N370S/无效)有较轻的表型,可能由于纯合子的残留Gba活性。事实上,一些N370S/N370S患者在其整个生命的大部分时间都是无症状的,然而却可能处于发展为神经紊乱如帕金森氏病的危险之中。在这种情况下,Gba突变将是帕金森氏病的危险因素。与1型戈谢病有关的其他点突变包括84GG、R496H、Q350X和H162P(Orvisky等人,Human Mutation.2002;495,19(4):458-9)。另外,剪接位点突变IVS10+2T→G和IVS10+2T→A也与I型戈谢病有关(Orvisky,上述)。
神经元病2型戈谢病与主要产生两个氨基酸取代L444P和A456P的突变有关。L444P纯合型也通常与3型戈谢病有关,虽然该突变已经在所有三种疾病类型的患者中鉴别。其他与2型和3型神经元病戈谢病有关的点突变包括D409H(纯合子)和V349L和D409V(杂合子)。D409H纯合型的患者显示出除神经病学受累情况外的独特表型包括脑积水及心瓣膜和主动脉钙化。后两种点突变V349L和D409V导致催化缺陷型的Gba。其他在2型或3型疾病中鉴别的突变是K198E、K198T、Y205C、F251L、1402F和剪接位点突变IVS10+2T→A(Orvisky等人,上述;和Lewin等人,Mol Genet Metab.2004;81(1):70-3)。缺乏任何Gba活性的患者和敲除小鼠由于脱水在出生后不久死亡,因为神经酰胺对皮肤皮的完整性是必不可少的(Liu等人,Proc.Natl.Acad.ScL USA.1998;95:2503-08)。
Gba的伴侣异法戈明(IFG;(3R,4R,5R)-5-(羟甲基)-3,4-哌啶二醇)表示具有如下结构的化合物:
IFG具有C6H13NO3的分子式和147.17的分子量。授予Sierks等人的美国专利5,844,102和授予Lundgren等人的美国专利5,863,903进一步描述了该化合物。
C-苯甲基-IFG表示具有如下结构的化合物:
其他Gba的伴侣包括均在2004年11月12日提交的未决美国公开申请2005/0130972和2005/0137223及对应的PCT公告号WO 2005/046611和WO2005/046612中描述的葡糖咪唑、多聚环己烷基(polycyclohexanyl)和羟基哌啶衍生物,并且本文引用作为参考。葡糖咪唑和衍生物以如下的化学结构为代表:
其中B选自氢、羟基、乙酰氨基和卤素;
任选存在的R1和R2是短的柔性连接基团,其线性长度(linear length)为约至约优选约R1和R2也可以独立地选自C2-C6取代或未取代的烷基,其任选地被一个或多个选自NH、NHCOO、NHCONH、NHCSO、NHCSNH、CONH、NHCO、NR3、O、S、S(O)m和-S(O)mNR3的部分所间断;C2-C6取代或未取代的烯基,其任选地被一个或多个选自NH、NHCOO、NHCONH、NHCSO、NHCSNH、CONH、NHCO、NR3、O、S、S(O)m和-S(O)mNR3的部分所间断;C2-C6取代或未取代的炔基,其任选地被一个或多个选自NH、NHCOO、NHCONH、NHCSO、NHCSNH、CONH、NHCO、NR3、O、S、S(O)m和-S(O)mNR3的部分所间断,其中m是1或2,且R3每次出现时独立地选自氢、取代或未取代的烷基;取代或未取代的烯基;取代或未取代的炔基;取代或未取代的环烷基;取代或未取代的环烯基;取代或未取代的芳基;取代或未取代的芳基烷基;取代或未取代的杂芳基;取代或未取代的杂环基;取代或未取代的杂环基烷基;取代或未取代的杂芳基烷基;及其可药用的盐和前体药物。
此外,如果R2-L2或R1-L1各自不是氢,则R1-L1或R2-L2可以是氢。
R5表示氢、羟基或羟甲基;
L1和L2是亲脂基团,选自C3-C12取代或未取代的烷基、取代或未取代的烯基、取代或未取代的炔基;取代或未取代的环烷基、取代或未取代的环烯基;取代或未取代的芳基;取代或未取代的芳基烷基;取代或未取代的杂芳基;取代或未取代的杂环基;取代或未取代的杂环烷基;取代或未取代的杂芳基烷基。
在具体实施方案中,GIZ化合物包括(5R,6R,7S,8S)-5-羟甲基-2-辛基-5,6,7,8-四氢咪唑并[1,2-a]吡啶-6,7,8-三醇和(5R,6R,7S,8S)-5-羟甲基-2-(3,3-二甲基丁基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-6,7,8-三醇。
考虑用于本发明的聚羟基环烷基(polyhydroxylcycloalkyl)(PHCA)衍生物包括如下化学结构式所代表的化合物:
其中B选自氢、羟基、N-乙酰氨基或卤素。
R1每次出现时独立地选自氢;取代或未取代的烷基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的环烷基、取代或未取代的环烯基、取代或未取代的芳基、取代或未取代的芳基烷基、取代或未取代的杂芳基、取代或未取代的杂环基、取代或未取代的杂环基烷基、取代或未取代的杂芳基烷基、-C(O)R3和-S(O)mR3,其中m是1或2,且R3每次出现时独立地选自氢、取代或未取代的烷基、取代或未取代的烯基、取代或未取代的炔基;取代或未取代的环烷基、取代或未取代的环烯基;取代或未取代的芳基;取代或未取代的芳基烷基;取代或未取代的杂芳基;取代或未取代的杂环基;取代或未取代的杂环基烷基;取代或未取代的杂芳基烷基,并且-C(O)连接于C1-C6取代或未取代的烷基。
任选存在的R2是短的柔性连接基团,其线性长度为约至约优选约R2也可以选自C2-C6取代或未取代的烷基,其任选地被一个或多个选自NH、NHCOO、NHCONH、NHCSO、NHCSNH、CONH、NHCO、NR3、O、S、S(O)m和-S(O)mNR3的部分所间断;C2-C6取代或未取代的烯基,其任选地被一个或多个选自NH、NHCOO、NHCONH、NHCSO、NHCSNH、CONH、NHCO、NR3、O、S、S(O)m和-S(O)mNR3的部分所间断;C2-C6取代或未取代的炔基,其任选地被一个或多个选自NH、NHCOO、NHCONH、NHCSO、NHCSNH、CONH、NHCO、NR3、O、S、S(O)m和-S(O)mNR3的部分所间断,其中m是1或2,且R3每次出现时独立地选自氢、取代或未取代的烷基、取代或未取代的烯基、取代或未取代的炔基;取代或未取代的环烷基、取代或未取代的环烯基;取代或未取代的芳基;取代或未取代的芳基烷基;取代或未取代的杂芳基;取代或未取代的杂环基;取代或未取代的杂环基烷基;取代或未取代的杂芳基烷基,并且-C(O)连接于C1-C6取代或未取代的烷基;及其可药用的盐和前体药物。
L是亲脂基团,选自C3-C12取代或未取代的烷基、取代或未取代的烯基、取代或未取代的炔基;取代或未取代的环烷基、取代或未取代的环烯基;取代或未取代的芳基;取代或未取代的芳基烷基;取代或未取代的杂芳基;取代或未取代的杂环基;取代或未取代的杂环烷基;取代或未取代的杂芳基烷基。
考虑用于本发明的Gba突变的羟基哌啶衍生物以如下的化学结构为代表:
其中A代表碳或氮;
B是氢、羟基、N-乙酰胺或卤素;
R1是氢;取代或未取代的:烷基、烯基、炔基、环烷基、环烯基、芳基、芳基烷基、杂芳基、杂环基、杂环基烷基或杂芳基烷基;-C(O)R3或-S(O)mR3。优选地,R1包括H或具有1-12个碳原子的有机部分;
R2是任选的短的柔性连接基团,其线性长度为约至约或者,R2是C1-C6的取代或未取代的:烷基、烯基或炔基,其任选地被一个或多个选自下组的部分所间断:NH、NHCOO、NHCONH、NHCSO、NHCSNH、CONH、NHCO、NR3、O、S、S(O)m和-S(O)mNR3;
R3是氢,或者取代或未取代的:烷基、烯基;炔基;环烷基、环烯基;芳基;芳基烷基;杂芳基;杂环基;杂环基烷基;或杂芳基烷基。优选地,R3包括H或者具有1-12个碳原子或者更优选地1-6个碳原子的有机部分。
m是1或2,和
R5是氢、羟基或羟甲基。
L是具有1-12个碳原子的亲脂基团,其包括取代或未取代的:烷基、烯基、炔基;环烷基、环烯基;芳基;芳基烷基;杂芳基;杂环基;杂环烷基;或杂芳基烷基。
在具体实施方案,考虑用于本发明的羟基哌啶化合物包括但不限于如下:(3R,4R,5R,6S/6R)-5-(羟甲基)-6-正丁基-3,4-二羟基哌啶;(3R,4R,5R,6S/6R)-5-(羟甲基)-6-正己基-3,4-二羟基哌啶;(3R,4R,5R,6S/6R)-5-(羟甲基)-6-正庚基-3,4-二羟基哌啶;(3R,4R,5R,6S/6R)-5-(羟甲基)-6-正辛基-3,4-二羟基哌啶;(3R,4R,5R,6S/6R)-5-(羟甲基)-6-正壬基-3,4-二羟基哌啶;(3R,4R,5R,6S/6R)-5-(羟甲基)-6-苄基-3,4-二羟基哌啶。
授予Fan等人的美国专利6,599,919描述了Gba的其他伴侣,包括calystegine A3、calytegine A5、calystegine B1、calytegine B2、calystegine B3、calystegine B4、calystegine C1、N-methyl-calystegine B2、DMDP、DAB、栗精胺、1-脱氧野尻霉素、N-丁基-1-脱氧野尻霉素、1-脱氧野尻霉素亚硫酸氢盐、N-丁基-异法戈明、N-(3-环己基丙基)-异法戈明、N-(3-苯丙基)-异法戈明和N-[(2E,6Z,10Z)-3,7,11-三甲基十二碳三烯基]-异法戈明.K。
在下述另一个具体实施方案中是特异性药理伴侣包括1-脱氧野尻霉素(DNJ;1,5-亚氨基-l,5-双脱氧-D-葡萄糖醇-CAS No.19130-96-2)及衍生物,它们可用来治疗溶酶体酶α-葡糖苷酶(Gaa)突变的神经病学危险因素、状况或紊乱。
典型的Gaa突变包括如下:D645E(Lin等人,Zhonghua Min Guo XiaoErKe YitXue Hui Za Zhi.1996;37(2):115-21);D645H(Lin等人,Biochem BiophysRes Commun.199517;208(2):886-93);R224W、S619R和R660H(New等人,Pediatr Neurol.2003;29(4):284-7);T1064C和C2104T(Montalvo等人,Mol GenetMetab.2004;81(3):203-8);D645N和L901Q(Kroos等人,Neuromuscul Disord.2004;14(6):371-4);G219R、E262K、M408V(Fernandez-Hojas等人,Neuromuscul Disord.2002;12(2):159-66);G309R(Kroos等人,Clin Genet.1998;53(5):379-82);D645N、G448S、R672W和R672Q(Huie等人,BiochemBiophys Res Commun.1998;27;244(3):921-7);P545L(Hermans等人,Hum MolGenet.1994;3(12):2213-8);C647W(Huie等人,Huie等人,Hum Mol Genet.1994;3(7):1081-7);G643R(Hermans等人,Hum Mutat.1993;2(4):268-73);M318T(Zhong等人,Am J Hum Genet.1991;49(3):635-45);E521K(Hermans等人,Biochem Biophys Res Commun.1991;179(2):919-26);W481R(Raben等人,Hum Mutat.1999;13(l):83-4);及L552P和G549R(未公开数据)。
剪接突变体包括IVSlAS、T>G、-13和IVS8+1G>A)。
典型的α-葡糖苷酶伴侣以如下的化学结构为代表:
其中:
R1是H或者含1-12个碳原子的直链或支链的烷基、环烷基、烯基、烷基醚或烷基胺,含5-12个环原子的芳基、烷基芳基、杂芳基、或杂芳基烷基,其中R1任选地由一个或多个OH、-COOH、-Cl、-F、-CF3、-OCF3、-O-C(=O)N-N-(烷基)2取代;和
R2是H;含1-9个碳原子的直链或支链的烷基、环烷基、烯基或烷基醚,或含5-12个碳原子的芳基,其中R2任选地由-OH、-COOH、-CF3、-OCF3或杂环取代;
其中R1和R2中至少一个不是H,或其可药用的盐。
特别的,酸性α-葡糖苷酶的伴侣包括但不限于N-甲基-DNJ,、N-乙基-DNJ、N-丙基-DNJ、N-丁基-DNJ、N-戊基-DNJ、N-己基-DNJ、N-庚基-DNJ、N-辛基-DNJ、N-壬基-DNJ、N-甲基环丙基-DNJ和N-甲基环戊基-DNJ。
除了氮取代的DNJ衍生物,其他作为Gaa有用伴侣的DNJ衍生物,包括N-苯甲基取代的DNJ衍生物和具有连接到邻近于环氮原子的C-1碳的取代基的衍生物也是本发明优选的化合物。这样的化合物描述于2006年5月17日提交的共同拥有的未决申请序号11/---,---。
在又一个实施方案中,优选的用于治疗与另一溶酶体酶α-半乳糖苷酶(α-Gal A)中杂合突变有关的神经紊乱的伴侣以如下的化学结构为代表:
其中R1和R1’表示H、OH、或1-12碳的烷基、羟基烷基或烷氧基基团;
R2和R2′独立地表示H、LH、或N-乙酰胺基基团,或1-12碳的烷基;
R4和R4′独立地表示H、OH;
R6和R6′独立地表示H、CH2OH、CH3或COOH;
R7表示H或OH;
R0表示H、甲基、或者含9-12个碳原子的直链或支链饱和或不饱和的碳链,任选地由苯基、羟基或环己基基团取代。
在一个具体的实施方案中,伴侣是1-脱氧野尻霉素。
与法布里病有关的α-Gal A突变的实例包括R301Q、L166V、A156V、G272S和M296I。
测定
累积蛋白质的检测和运输可以检测和/或观察ER中的蛋白质累积,并表示为与ER定居蛋白质如BiP共定位的管泡中核周定位的分布图。这些蛋白质也在它们的天然场所细胞内如细胞表面或者在另外的细胞区室如溶酶体中降低或不存在。可利用与胞质蛋白质相似的共定位方法检测细胞质中蛋白质的累积。
本领域技术人员熟知检测受损的溶酶体酶运输的方法。例如,对于高尔基体中N-和O-糖基化的蛋白质,利用放射性标记蛋白质的代谢性标记脉冲追踪,结合糖苷酶处理和免疫沉淀反应,可用于检测所述蛋白质是否在高尔基体中进行完全的糖基化作用,或者它们是否保持在ER中而不是为了进一步糖基化作用运输到高尔基体。
直观检测蛋白质细胞定位的灵敏方法也包括利用荧光蛋白质或荧光抗体的荧光显微镜检。为了评价细胞样品,可利用荧光抗体检测蛋白质。为了在操作的或工程化的细胞中进行检测,目的蛋白质可在转染前标记有诸如绿色荧光蛋白质(GFP)、青色荧光蛋白质、黄色荧光蛋白质(YFP)和红色荧光蛋白质,继以多色和延时显微镜检及电子显微镜检,以研究固定细胞和活细胞中所述蛋白质的命运。对于在蛋白质运输中利用荧光成像的综述,参见Watson等人,Adv DrugDeliv Rev.2005;57(1):43-61)。对于胞内蛋白质共定位的利用共焦显微镜检的描述,参见Miyashita等人,Methods Mol Biol.2004;261:399-410。
另外,利用抗体的双重标记试验,例如LAMP-1或Lyso对溶酶体(红色)(或特异于溶酶体的其他染色或标记,如荧光量子点,级联蓝色葡聚糖(Cascade blue dextran)),以及溶酶体酶(绿色),绿色/红色重叠比率(共定位)可用于测量溶酶体酶的改变,例如运输到溶酶体的酶(提高的绿色/红色比率意指更多的酶运输到溶酶体)。具有正常胞吞途径的正常健康细胞将产生更多的荧光。也参见实施例2,下文。
荧光相关光谱学(FCS)是能够进行单分子和实时分辨的超灵敏和非侵入性的检测方法(Vukojevic等人,Cell Mol Life Sci.2005;62(5):535-50)。SPFI(单粒子荧光成像)利用高灵敏度的荧光以显现那些已选择性地标记有小荧光粒子的个体分子(Cherry等人,Biochem Soc Trans.2003;31(Pt 5):1028-31)。对于脂筏内蛋白质的定位,参见Latif等人,Endocrinology.2003;144(11):4725-8)。对于活细胞成像的综述,参见Hariguchi,Cell Struct Funct.2002;27(5):333-4)。
荧光共振能量传递(FRET)显微镜检也用来研究生理条件下蛋白质的结构和定位(Periasamy,J Biomed Opt.2001;6(3):287-91)。
在优选的实施方案中,个体中带Gba突变的α-突触核蛋白的检测可利用ELISA或western印记分析进行。LCMS/MS方法和/或TLC可用来监测GluCer水平(底物累积)。
响应于用抑制剂和/或伴侣对动物的处理,α-突触核蛋白水平和寡聚体/单体比率的先体外后体内(ex vivo)监测,可利用脑切片测定来评定。
泛素化测定另外,确定泛素-溶酶体酶缀合物存在和定位的测定可用来评估突变以及响应伴侣处理的毒性功能获得。利用免疫组织化学或免疫荧光来定位这些缀合物的形态学研究是灵敏的检测方法。参见实施例3,下文。如上所指出的那样,与非应激细胞相比低水平泛素化蛋白质的存在可指示明蛋白酶体功能的抑制。
作为另一个实例,称为AlphaScreenTM(Perkin-Elmer)的方法可用于检测泛素化蛋白质。在该模型中,GST-UbcH5a融合蛋白质的GST部分是利用生物素-泛素(bio-Ub)进行泛素化的。在通过E1使泛素激活之后,在有ATP参与的情况下,转移bio-Ub到UbcH5a。在该反应中,UbcH5a作为载体以转移bio-Ub至其标记的GST部分。随后通过抗-GST受体和链霉亲和素捕获成为生物素化和泛素化的蛋白质。供体珠导致信号生成。在没有泛素化的情况下没有信号生成。
另外,用于多种E3泛素连接酶和E2缀合酶活性测量的高通量测定可用于确定蛋白质泛素化的增减(Meso Scale Discovery,Gaithersburg,MD)。
UPR反应ER应激可通过测定参与UPR的基因和基因编码的蛋白质的表达水平来鉴定。这样的基因和蛋白质包括上述的那些,在UPR早期阶段上调的Grp78/BiP、Grp94和orpl50。参与ER应激的其他蛋白质包括在经受持续ER应激的细胞中上调的IRE1、PERK、ATF6和XBP1。此外,延长的细胞应激导致细胞凋亡,并从而上调jun激酶(JNK)及胱天蛋白酶(caspase)3、9和12。
本发明考虑毒性蛋白质或者底物累积或聚集患者与健康个体间上述指示基因和/或蛋白质表达水平的比较。
在另一个实施方案中,本发明也考虑评价特异性药理伴侣在应激细胞中的效果,以确定用于减轻由毒性功能获得聚集体所引起细胞应激反应。作为阳性对照,ER应激诱导剂诸如衣霉素、二硫苏糖醇(DTT)、乳胞素(lacatcystin)和过氧化物可用于引起ER中解折叠蛋白质的累积。衣霉素抑制N-连接的糖基化,而二硫苏糖醇阻止二硫键形成。乳胞素是蛋白酶体抑制剂。应激舒缓剂如蛋白质合成抑制剂环己酰亚胺(cyclohexamide),可在应激细胞中评价伴侣化合物时用作为阳性对照。
通过微阵列分析测定包括基因表达的表达水平。这可利用例如包含这类基因的Affymetrix Ul33基因芯片集(人类基因组)(Affymetrix,SantaClara,CA)完成。另外,他人已使用该技术。例如,在6-羟基多巴胺(6-OHDA)处理后多时点收集RNA,进行微阵列分析,与数据筛选和聚类技术结合,以确定细胞应激基因的不同的功能性亚群(Holtz等人,Antioxidants &Redox Signaling.2005;7:639-648)。6-OHDA是已显示引起与细胞应激和UPR有关的翻译改变的帕金森氏病模拟物。
细胞凋亡另外,如上所述,通过UPR不能消除的延长的持久内质网应激还可以导致神经元细胞中的细胞程序性死亡,例如细胞凋亡。对于体外评价,神经元细胞系如hNT2(ATCC保藏号#CRL-10742)、Hs68(#CRL-1636)、HCN-1A(#CRL-10442)、SK-N-FI(#CRL-2142)、SK-N-DZ(#CRL-2149)、SK-N-SH(#HTB-1l)或NT2/D1(#CRL-1973),或者已在体外分化为神经元的胚胎干细胞或神经干细胞(参见,例如Laeng等人的US2003/0013192;及Yan等人,Stem Cells.2005;23:781-90),可利用突变Gba转染并用于细胞凋亡评价。
因此,凋亡细胞的数目可利用例如凋亡早期指示物胱天蛋白酶3的荧光底物类似物测量。可利用本领域的众多方法检测细胞凋亡,包括荧光激活细胞分选(FACS),和/或利用荧光板读出器(例如高通量的96孔板)。对于后者,可确定细胞凋亡或细胞死亡阳性的细胞百分比,或者相对于蛋白质浓度可测量荧光强度。
细胞/细胞器形态学神经元的形态学异常可由突变蛋白质累积引起,并可利用形态测量分析评价。例如,转染了tau-GFP的神经元中神经元形态学改变包括非对称现象、前和后投射区轴突数目的减少、异常的轴突束、轴突气泡及降低的末端分支。细胞形态学的其他改变包括聚集、细胞大小(细胞面积或细胞密度)、polymegathism(细胞大小的变化如平均细胞面积变异系数)、多形性(细胞形状的变化如六角形细胞的百分比或细胞形状变异系数)、细胞周长、平均细胞边长、细胞形状等等。可利用根据Ventimiglia等人,J Neurosci Methods.1995;57:63-6;和Wu等人,CerebralCortex.2004;14:543-54(高通量分析)描述的方法进行定量的形态测量分析,和利用图像分析软件如Image Pro-Plus软件来评价形态学。
还可以通过评价细胞器形态检测细胞/ER应激。例如,与野生型CY000生产的酿酒酵母细胞中ER形态和膜增殖相比,CY028-表达的酿酒酵母中UPR显示为内质网(ER)的异常形态并且为广泛的膜增殖(Sagt等人,Appliedand Environmental Microbiology.2002;68:2155-2160)。
而且,特异的形态学指示物可与个体的聚集疾病有关。例如,在戈谢病中,巨噬细胞溶酶体中脂质的累积导致活化的巨噬细胞不同的形态表征。
内质网钙存储ER应激也可通过测量内质网腔和胞液中钙的水平探测,也可通过测定钙调控蛋白质如SERCA2b的水平检测,SERCA2b是遍在的调节胞内钙存储的钙-ATPase。作为对照,内质网应激可通过钙耗竭诱导,使用例如毒胡萝卜素。
蛋白酶体功能蛋白酶体功能是对蛋白质或底物累积的一种细胞反应,可根据Glas等人(Nature.1998;392:618-622)的方法测量。在活动物体内通过成像对26S蛋白酶体功能的评价已利用生物发光成像泛素-荧光素酶报告基因实现(luker等人,Nature Medicine.2003.9,969-973)。蛋白酶体的分离和测定描述于Craiu等人,JBC。用于蛋白酶体分离的试剂盒是市场上可买到的,例如来自Calbiochem(Cat.No.539176)。该试剂盒可用于从细胞提取物中分离蛋白酶体亚基,以研究它们的功能和与其他蛋白质的相互作用。蛋白酶体亚基可通过将珠子直接上样于SDS-PAGE凝胶上并利用亚基特异性抗体的免疫印迹法鉴定。可选地,与珠子结合的蛋白酶体可用于利用蛋白酶体底物的蛋白水解测定。
细胞生长和运输的pH测定细胞中蛋白质的运输沿pH梯度发生(即,ER pH约7.0、高尔基体pH约6.2-7.0、高尔基体外侧网络pH约6.0、早和晚吞饮泡pH约6.5、溶酶体pH约4.5)。在一些溶酶体贮积病中,运输、溶酶体/吞饮泡形态和管腔(luminal)pH也遭到破坏(Ivleva等人,Biomed Sci.1991;2:398-402;Futerman和van Meer,Nat Rev Mol Cell Biol.2004;5:554-65),并且吞饮泡中升高的pH已表明促进从吞饮泡到高尔基体囊泡运输的逆转(van Wert等人,1995,上述)。
可测量接触pH范围条件的细胞(例如野生型、未经处理的患者细胞和伴侣处理的患者细胞)的生长速率,并利用荧光板读出器比较。细胞凋亡和细胞死亡测定(如上所述)还可以用来测定细胞存活力的pH敏感性。
可选地,溶酶体pH和pH对运输的影响可利用共焦显微镜评价。通过细胞胞饮的pH敏感的荧光探针可用于测量溶酶体和吞饮泡中的pH范围(即在pH 5.0时荧光素是红色,而在pH 5.5到6.5时是蓝色到绿色)。可比较野生型和经伴侣处理及未经处理的患者细胞中的溶酶体形态和pH。该测定可与平板读出器测定并行运行,以测定pH敏感性。另外,到溶酶体的酶运输可利用如上所述的双重标记实验在不同pH的细胞中评价。
接触多种pH条件的细胞(野生型、经伴侣处理的和未经处理的患者细胞)的内吞作用速率可利用量子点(Quantum dots)或蓝色葡聚糖(DextranBlue)测量。另外,描述利用荧光脂质类似物的测定(BODIP Y-LacCer、-GM1神经节苷脂等等)描述于Pagano,Phil Trans R Soc Lond B.2003;358-885-91。
酶活性利用如上所述的蛋白质定位测定,除了鉴定伴侣对聚集和/或运输的效果外,还可以利用生物化学测定来测定是否蛋白质是功能性的,并且一旦它们已与伴侣一起离开ER进入例如溶酶体中,可用来评估修复功能的效果。活性测定通常设计成能测量在测试物质存在或不存在时靶蛋白的活性。这类测定将取决于特定的蛋白质。例如,蛋白质是酶时,利用底物的胞内酶活性测定是本领域常规的可用来评估酶活性。
酶活性的先体外后体内和体内评价可利用正常动物和疾病状态诸如下文描述的动物模型执行。
诊断方法
本发明提供一种用于诊断与溶酶体酶突变有关的危险因素、状况或神经紊乱的方法。因为发生在LSD患者中的神经病学效应可存在于其他神经紊乱中,有溶酶体酶突变却没有诊断为LSD的人可能未得到有效治疗。一个实例是有Gba基因杂合突变的个体,该个体处于发展的风险中或已经发展为帕金森综合征或帕金森氏病。其他可能与突变溶酶体酶有关的典型神经病学症状包括神经退行性变、神经病学退行、发作、失明、眼球运动紊乱、强直(spacisticity)、痴呆;发育延迟;神经肌肉症状、周围神经病(神经性疼痛)、肢端感觉异常、长时记忆损伤、脑血管事件如脑血管的事件(中风、暂时性缺血性发作)及吞咽困难。
本领域熟知鉴定溶酶体酶突变的方法,并且包括比较来自生物样品的溶酶体酶的酶活性,所述生物样品来自显示神经病学症状的个体或处于发展为神经病学症状风险的个体(如LSD携带者或LSD个体的亲人)。在分子水平(即核苷酸或氨基酸改变)鉴定突变的方法也是本领域技术人员已知的,如PCR扩增继之以测序、单链构象多形性(SSCP)或对于大样本利用DNA微阵列(Tennis等人,Cancer Epidemiology Biomarkers & Preventio.2006;15:80-85)。
特异性药理伴侣的剂型、剂量和给药
本发明提供的特异性药理伴侣可以以允许***给药的剂型施用,因为所述化合物需要穿过血脑屏障以发挥对神经元细胞的作用。在一个实施方案中,特异性药理伴侣是作为单一疗法施用的,虽然考虑其他剂型,但优选口服剂型(下文进一步描述)。在一个实施方案中,考虑剂量给药方案应该是可在治疗个体血浆中提供化合物的周期性峰值水平。其他实施方案可在血浆中要求化合物的恒定稳定水平。这可通过分开剂量的日常给药或控制-释放剂型或通过持续-释放剂型的低频率给药获得。下面详细介绍特异性药理伴侣的剂型、剂量和给药。
剂型
特异性药理伴侣可以以适于任何给药途径的形式来施用,包括例如以片剂或胶囊或液体形式口服,或者以无菌水溶液形式注射。当特异性药理伴侣配制为口服剂型施用时,可通过常规方法采用可药用的赋形剂来制备片剂或者胶囊,所述赋形剂诸如粘合剂(例如预胶化玉米淀粉、聚乙烯吡咯烷酮或羟丙基甲基纤维素);填充剂(例如乳糖、微晶纤维素或磷酸氢钙);润滑剂(例如硬脂酸镁、滑石或硅质);崩解剂(例如马铃薯淀粉或羟基乙酸淀粉钠);或者润湿剂(例如月桂基硫酸钠)。片剂可采用本领域公知的方法进行包衣。用于口服给药的液体制品可采取例如溶液、糖浆剂或混悬剂的形式,或者它们以使用前用水或其他适当的运载体构造的干燥产品存在。这样的液体制品可通过常规方法采用可药用的添加剂来制备,诸如助悬剂(例如山梨糖醇糖浆、纤维素衍生物或可食用的氢化脂肪);乳化剂(例如卵磷脂或***胶);非水性运载体(例如杏仁油、油性酯、乙醇或分馏植物油);以及防腐剂(例如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯或山梨酸)。制品也可酌情包含缓冲盐、调味剂、着色剂和甜味剂。口服给药制品可适宜地配制成控释或缓释特异性药理伴侣。
特异性药理伴侣适于非经肠/可注射使用的药用剂型通常包括无菌的水性溶液(水溶性情况下)或分散剂和临时制备无菌可注射溶液或分散剂的无菌散剂。在所有情况下,剂型必须是无菌的,并且必须是达到容易注射程度的流体。在生产和贮存条件下必须是稳定的,并且必须在不受微生物例如细菌和真菌的污染作用下保存。载体可以是溶剂或分散介质,包含例如水、乙醇、多元醇(例如甘油、丙二醇和聚乙二醇等等),其适宜的混合物和植物油。可以例如通过使用包衣如卵磷脂,在分散剂情况下通过维持所需的粒径和通过使用表面活性剂来维持适当的流动性。可以通过多种抗细菌剂和抗真菌剂来实现防止微生物的作用,例如对羟基苯甲酸酯、氯丁醇、苯酚、苯甲醇、山梨酸等等。在很多情况下,可合理的包含等渗剂,例如糖或氯化钠。可以通过在组合物中使用延迟吸收剂例如单硬脂酸铝和明胶来实现可注射组合物的延长吸收。
无菌的可注射溶液是这样制备的,将所需量的特异性药理伴侣加入所需的上文列举的多种其他成分的合适溶剂中,然后过滤或最终灭菌。通常,分散剂是这样制备的,将多种灭菌的活性成分加入无菌的运载体中,所述无菌运载体包含基本分散介质和所需的来自上文列举的其他成分。在用于制备无菌可注射溶液的无菌散剂的情况下,优选的制备方法是真空干燥和冷冻干燥技术,该技术从前面无菌滤过的溶液产生活性成分加任何额外期望成分的散剂。
剂型可以包含赋形剂。可以包含在剂型中的可药用赋形剂有缓冲剂,例如柠檬酸盐缓冲剂、磷酸盐缓冲液、乙酸盐缓冲剂和碳酸氢盐缓冲剂;氨基酸;脲;醇;抗坏血酸;磷脂;蛋白质,如血清白蛋白、胶原和明胶;盐,例如EDTA或EGTA和氯化钠;脂质体;聚乙烯吡咯烷酮;糖,例如葡聚糖、甘露醇、山梨醇和甘油;丙二醇和聚乙二醇(例如PEG-4000PEG-6000);甘油;甘氨酸或其他氨基酸;和脂质。用于剂型的缓冲***包含柠檬酸盐、乙酸盐、碳酸氢盐和磷酸盐缓冲液。磷酸盐缓冲液是优选的实施方案。
剂型还可以包含非离子型洗涤剂。优选非离子型洗涤剂包括聚山梨酸酯20、聚山梨酸酯80、Triton X-100、Triton X-114、Nonidet P-40、辛烷基α-葡糖苷、辛烷基β-葡糖苷、Brij 35、Pluronic和吐温20。
给药
特异性药理伴侣的给药途径可是口服的(优选)或胃肠外的,包括静脉内、皮下、动脉内、腹膜内、眼用、肌内、经口、直肠、***、眶内、脑内、皮内、颅内、脊柱内、心室内、鞘内、脑池内、囊内、肺内、鼻内、经粘膜、透皮或通过吸入给药。
上述特异性药理伴侣胃肠外剂型的给药可以是周期性浓注,或者通过静脉内或腹膜内从贮库施用,所述贮库是外部(例如静脉注射袋)或者内部(例如生物可消化的植入物)。参见例如美国专利号4,407,957和5,798,113,各文献都引入本文作为参考。肺内递药方法和装置描述于例如美国专利号5,654,007、5,780,014和5,814,607,各文献都引入本文作为参考。其他有用的胃肠外的递药***包括乙烯-醋酸乙烯酯共聚物微粒、渗透泵、可植入输注***、泵递药、形成胶囊的细胞递药(encapsulated cell delivery)、脂质体递药、针头递药注射、无针注射、喷雾器、雾化器、电穿孔和透皮贴剂。美国专利号5,879,327、5,520,639、5,846,233和5,704,911描述了无针注射器装置,以上文献的说明书引入本文作为参考。如上所述的任何剂型可采用这些方法来施用。
皮下注射有允许自我给药的优点,同时与静脉给药相比也会导致延长的血浆半衰期。而且,为患者方便而设计了多种装置,例如可重填充的注射笔和无针喷射装置,可用于本文所述的本发明的剂型。
剂量
本领域技术人员可根据个案为基础确定拯救内源突变Gba的特异性药理伴侣的有效量。可以用本领域已知的普通方法获得替代蛋白质和特异性药理伴侣的药代动力学和药效学数据,例如半衰期(t1/2)、峰值血浆浓度(Cmax)、达到峰值血浆浓度的时间(tmax)、按曲线下面积(AUC)测量的暴露量和组织分布,以及特异性药理伴侣/Gba结合的数据(亲合常数、结合及解离常数和化合价),以确定使替代蛋白质稳定但不抑制其活性,从而产生治疗作用所需的相容量。
从细胞培养物测定或者动物研究中获得的数据可用来配制供人和非人动物使用的治疗剂量范围。用于本发明治疗方法的化合物剂量优选位于包括ED50浓度(测试群体的50%有效)的循环浓度范围内,但几乎没有或没有毒性。用于任何治疗的特定剂量可在一定范围内改变,取决于因素例如所使用的特定剂型、使用的给药途径、个体(例如患者)的状况等等。
治疗有效量可以最初从细胞培养物测定中估算,并在动物模型中公式化以达到包括IC50的循环浓度范围。化合物的IC50浓度是达到症状的半数最大抑制的浓度(例如从细胞培养物测定中确定)。然后使用这些信息可以更准确地确定用在特定个体,例如人类患者中的合适剂量。
可以通过诸如高效液相色谱法(HPLC)或气相色谱法等技术在个体例如患者中按照常规方法测定血浆中的化合物。
组合物的毒性和治疗功效可通过规范化的药学方法确定,例如在细胞培养物测定或者使用试验动物以确定LD50和ED50。参数LD50和ED50是本领域熟知的,分别表示对群体的50%致死和对群体的50%治疗有效的化合物剂量。毒性和治疗作用之间的剂量比称为治疗指数,并且可表示为LD50/ED50之比。优选显示出大治疗指数的特异性药理伴侣。
特异性药理伴侣的最佳浓度根据使重组蛋白质例如Gba在体内、在组织或者循环中稳定并诱导适当构象而所需的量确定,不会持续阻止其活性或特异性药理伴侣在组织或者循环中的生物利用度及特异性药理伴侣在组织或者循环中的代谢。例如,若特异性药理伴侣是酶抑制剂,则该抑制剂的浓度可通过计算酶特异***的IC50值确定。考虑化合物的生物利用度和代谢,然后以酶活性的作用为根据计算约为IC50值或者略高于IC50值的浓度,例如提高所施用酶的酶活性的量或者延长酶活性所需的抑制剂的量。例如,用于Gba酶的化合物异法戈明的IC50值是0.04μM,表明它是一种有效的抑制剂。
组合药物治疗
用于治疗患有与溶酶体酶突变有关的CNS紊乱患者的特异性药理伴侣可组合使用治疗CNS紊乱使用的其他药物。
例如,对于患有帕金森氏病的患者,诸如多巴胺受体激动剂、抗胆碱能药、COMT抑制剂、单胺氧化酶B抑制剂。典型的物质包括但不限于左旋多巴(Merck)、(溴麦角环肽甲磺酸盐;Novartis);(甲磺酸培高利特;Eli Lilly);(盐酸罗匹尼罗(ropiniroleHCl)、(盐酸普拉克索(pramipexole dihydrochloride));(甲磺酸苯扎托品);(盐酸苯海索(trihexyphenidyl HCl));美国Cyanamid);金刚烷(盐酸金刚烷胺;Du Pont Merck);和(Somerset Pharmaceuticals)。
基因疗法的组合治疗
尽管基因疗法在美国治疗法中尚末获得批准,但很多遗传性紊乱的基因疗法(先体外后体内和直接转移法)正在研究之中。本发明也考虑使用特异性药理伴侣组合基因疗法以置换神经***疾病中有缺陷的Gba基因。这样的组合通过提高体内治疗性Gba的表达水平将提高基因疗法的效力,因为除了提高突变酶的折叠和加工外,特异性药理伴侣已表明提高野生型或者构象型稳定对应物的折叠和加工(参见,例如授予Fan等人的美国专利6,274,597,实施例3)。
Bankiewicz在美国专利6,309,634中描述了用于治疗帕金森氏病的基因治疗方法。根据该方法,在体外生产重组腺相关病毒(rAAV)病毒粒子,其包含编码芳香族氨基酸脱羧酸(AADC)的核酸序列。另一研究小组最近在帕金森氏病的猴模型中,也通过重组腺相关病毒载体***胶质细胞系来源的神经营养因子(GDNF)的基因(Eslamboli等人,J Neurosci.2005;25(4):769-77)。
本领域可获得的任何基因治疗的方法都可用于递送治疗的基因。典型的方法描述如下。对于基因治疗方法的一般综述,参见goldspiel等人,clinical Pharmacy 1993,12:488-505;Wu和Wu,Biotherapy 1991,3:87-95;Tolstoshev,Ann.Rev.Pharmacol.Toxicol.1993,32:573-596;Mulligan,Science.1993,260:926-932;及Morgan和Anderson,Ann.Rev.Biochem.1993,62:191-217;May,TIBTECH 1993,n:155-215。可使用的本领域通常已知的重组DNA技术的方法描述在Ausubel等人(编辑),1993,Current Protocols inMolecular Biology,John Wiley & Sons,NY;Kriegler,1990,Gene Transfer andExpression,A Laboratory Manual,Stockton Press,NY;及第12和13章,Dracopoli等人(编辑),1994,Current Protocols in Human Genetics,JohnWiley & Sons,NY;及Colosimo等人,Biotechniques 2000,29(2):314-8,320-2,324。
本发明方法施用的基因可利用本领域已知的普通分子生物学、微生物学和重组DNA技术分离和纯化。例如,编码靶蛋白的核酸可利用文献中描述的重组DNA表达分离。参见,例如Sambrook,Fritsch & Maniatis,Molecular Cloning:A Laboratory Manual,第二版(1989)Cold SpringHarbor Laboratory Press,Cold Spring Harbor,纽约;DNA Cloning:APractical Approach,I和II卷(D.N.Glover编辑1985);OligonucleotideSynthesis(MJ.Gait编辑1984);Nucleic Acid Hybridization[B.D.Hames &S.J.E Higgins编辑(1985)];Transcription And Translation[B.D.Hames & SJ.Higgins编辑(1984)];Animal Cell Culture[R.I.Freshney编辑(1986)];Immobilized Cells And Enzymes[IRL Press,(1986)];B.E Perbal,A PracticalGuide To Molecular Cloning(1984)。只要基因编码生物活性的蛋白质,编码蛋白质的核酸可是全长的或截断的。
然后,鉴定和分离的Gba基因可***合适的克隆载体。适于基因治疗的载体包括病毒、噬菌体、粘粒、质粒、真菌载体及其他本领域常用的重组载体,这些已描述的载体用于多种真核和原核宿主的表达,并且可用于基因治疗和简单的蛋白质表达。
在具体实施方案中,载体是病毒载体。病毒载体,特别是腺病毒载体可与阳离子亲水脂分子络合,如提供增加对靶细胞病毒感染效率的阳离子脂质、聚L-赖氨酸(PLL)和二乙氨基乙基葡聚糖(DELAE-葡聚糖)(参见,例如1997年11月20日提交的PCT/US97/21496,此处引用作为参考)。用于本发明的病毒载体包括来源于牛痘、疱疹病毒、AAV和逆转录病毒的载体。特别地,疱疹病毒,尤其是单纯疱疹病毒(HSV),诸如在美国专利号5,672,344中公开的那些(其公开内容引入本文作为参考),尤其可用于将转基因递送至神经元细胞。AAV载体,诸如在美国专利号5,139,941、5,252,479和5,753,500及PCT公开WO 97/09441中公开的那些(其公开内容引入本文作为参考)也是有用的,因为这些载体整合入宿主染色体,具有载体重复给药的最低需要。对于基因治疗中病毒载体的综述,参见McConnell等人,Hum Gene Ther.2004;15(11):1022-33;Mccarty等人,Annu Rev Genet.2004;38:819-45;Mali等人,Clin.Pharmacokinet.2002;41(12):901-ll;Scott等人,Neuromuscul Disord.2002;12Suppl 1:S23-9。另外,参见美国专利号5,670,488。
递送的基因的编码序列有效连接于表达调控序列,例如指导基因表达的启动子。如本文使用的,短语“有效连接”表示多核苷酸/基因与核苷酸的调控和效应序列如启动子、增强子、转录和翻译终止位点及其他信号序列的功能关系。例如,核酸到启动子的有效连接表示多核苷酸和启动子之间的物理和功能关系,从而通过特异性识别并结合启动子的RNA聚合酶从启动子起始DNA的转录,并且其中启动子指导多核苷酸的RNA转录。
在一个具体实施方案中,所使用的载体中编码序列和任何其他期望序列的侧翼是促进在基因组期望位点同源重组的区域,从而提供已整合入基因组中核酸分子构建体的表达(Koller和Smithies,Proc.Natl.Acad.Sa.USA.1989,86:8932-8935;Zijlstra等人,Nature.1989,342:435-438;授予Zarling等人的美国专利号6,244,113;及授予Pati等人的美国专利号6,200,812)。
基因递送
载体递送入患者可是直接的或者间接的,在直接递送的情况下患者直接接触载体或递送复合物,在间接递送的情况下,首先在体外将载体转化细胞,然后移植入患者。这两种方法分别称为体内和先体外后体内的基因治疗。
直接转移在具体实施方案中,载体直接体内施用,进入生物体的细胞并介导基因表达。这可利用本领域已知的和上述讨论的任何多种方法实现,例如通过构建其作为合适表达载体的一部分并施用以使之成为细胞内的,例如通过利用缺陷型的或减毒的逆转录病毒或其他病毒载体(参见美国专利号4,980,286),或通过裸DNA的直接注入,或通过利用微粒轰击(例如基因枪;Biolistic,Dupont);或者包被有脂质或细胞表面受体或转染剂,在生物高分子中包囊化(例如聚-β-1-64-N-乙酰葡糖胺多聚糖;参见美国专利号5,635,493),在脂质体、微粒或微胶囊中包囊化;通过连接到已知进入细胞核的肽或其他配体上施用;或者通过连接到经受受体介导胞吞的配体上施用(参见,例如Wu和Wu,J.Biol.Chem.1987,62:4429-4432),等等。在另一个实施方案中,核酸-配体复合物可这样形成,其中配体包含融合病毒肽以干扰吞饮泡,使核酸避免溶酶体降解,或者配体包含阳离子12-mer肽,例如来源于触角足(antennapedia)的可用于向细胞中传递治疗性DNA(mi等人,Mol.Therapy.2000,2:339-47)。在又一个实施方案中,核酸可以通过寻靶特异性受体而靶向体内,进行细胞特异性吸收和表达(参见,例如PCT申请号WO 92/06180、WO 92/22635、WO 92/20316和WO93/14188)。最近,一项称为磁性转染(magnetofection)的技术已经用于向哺乳动物递送载体。该技术将载体结合至超顺磁纳米颗粒,在磁场的影响下进行递送。该应用降低了递送时间并提高载体效力(Scherer等人,GeneTherapy.2002;9:102-9)。下文对载体的描述考虑另外的寻靶和递送方法学。
在具体实施方案中,核酸可以利用脂质载体施用。脂质载体可以与裸核酸结合(例如质粒DNA)以易于穿过细胞膜。阳离子的、阴离子的或者中性的脂质可以用于该目的。然而,优选阳离子的脂质,因为它们已表明更好的结合通常带有负电荷的DNA。阳离子的脂质也已表明可介导质粒DNA的胞内递送(Feigner和Ringold,Nature.1989;337:387)。对小鼠的阳离子脂质-质粒复合物的静脉注射表明导致该DNA在肺中表达(Brigham等人,Am.J.Med.Sci.1989;298:278)。也参见,Osaka等人,J.Pharm.Sci.1996;85(6):612-618;San等人,Human Gene Therapy.1993;4:781-788;Senior等人,Biochemica et Biophysica Acta.1991;1070:173-179);Kabanov和Kabanov,Bioconjugate Chem.1995;6:7-20;Liu等人,Pharmaceut.Res.1996;13;Remy等人,Bioconjugate Chem.1994;5:647-654;Behr,J-P.,Bioconjugate Chem.1994;5:382-389;Wyman等人,Biochem.1997;36:3008-3017;授予Marshall等人的美国专利号5,939,401l;和授予Scheule等人的美国专利号6,331,524。
典型的阳离子脂质包括在例如美国专利号5,283,185及美国专利号5,767,099中公开的那些,其公开的内容引入本文作为参考。在优选的实施方案中,阳离子脂质是在美国专利号5,767,099中公开的N4-精胺胆固醇氨基甲酸酯(GL-67)。另外的优选脂质包括N4-亚精胺胆甾醇氨基甲酸酯(GL-53)和1-(N4-精胺)-2,3-二月桂甘油氨基甲酸酯(GL-89)。
优选,对于病毒载体的体内给药,合适的免疫抑制处理与病毒载体诸如腺病毒载体联合使用,以避免病毒载体和所转染细胞的免疫钝化。例如,可施用免疫抑制性细胞因子如白细胞介素-12(IL-12)、干扰素-γ(IFN-γ),或者抗CD4抗体以封闭对病毒载体的体液或细胞免疫反应。在那方面,使用工程化以表达最小量抗原的病毒载体是有利的。
间接转移利用如上所述的任何方法可用编码野生型蛋白质的构建体先体外后体内工程化体细胞,然后再植入个体。该方法通常描述于授予Selden等人的WO 93/09222中。另外,用于基于细胞送递的专用ImPACT技术的技术描述于Payumo等人,Clin.Orthopaed.and Related Res.2002;403S:S228-S242。在这样的基因治疗***中,从患者取出体细胞(例如成纤维细胞、肝细胞或内皮细胞),体外培养,用治疗目的基因转染,表征,然后再引入患者。可使用初级细胞(来源于患者或组织并在传代前工程化),和次级细胞(在引入体内前在体外传代)及本领域已知的永生化细胞系。对本发明方法有用的体细胞包括但不限于体细胞诸如成纤维细胞、角质细胞、上皮细胞、内皮细胞、胶质细胞、神经细胞、血液有形成分、肌细胞、其他可以培养的体细胞及体细胞前体细胞。在优选的实施方案中,细胞是成纤维细胞或间质干细胞。
核酸构建体用来转染欲生产编码产物的初级或次级细胞,所述核酸构建体包含外源基因和任选的可选择标记编码核酸以及在初级或次级受体细胞中表达外源基因所必需的附加序列。这样的构建体包含但不限于用于该目的的感染性载体,诸如逆转录病毒、疱疹病毒、腺病毒、腺相关病毒、腮腺炎病毒和脊髓灰质炎病毒载体。
间质干细胞(MSC)是在骨髓中产生的非血液生产的干细胞。MSC可进行分化,并增殖为特化的非血液组织。由于其自我更新能力,转染有逆转录病毒的干细胞是用于治疗的优良候选物。该能力避免基因治疗的重复给药。另一个优点是如果注射的干细胞到达目标器官然后分化,它们可以在该器官代替损伤或畸形的细胞。
作为一个实例,对于戈谢病,正进行试验:用编码Gba基因的逆转录病毒转导来自个体的体干细胞,然后经校正的干细胞返回到患者,在患者体内它们在骨髓定居并产生Gba表达细胞如巨噬细胞。
伴侣送递 当与编码治疗性基因的基因疗法组合给药时,可以根据如上所述的方法和剂型施用特异性药理伴侣。
与底物抑制剂组合
另外,也考虑本发明的小分子伴侣与如背景技术描述的其他小分子底物抑制剂的组合。因为甚至轻微减少溶酶体酶活性就可以导致脂质累积升高,其可接着改变细胞中磷脂平衡或者启动导致细胞凋亡的信号事件。典型的底物抑制剂包括抑制神经酰胺特异性葡萄糖基转移酶(还原糖脂底物)的NB-DNJ(Miglustat)(Kasperzyk等人,Journal of Neurochemistry 2004.89:645-653)。
实施例
通过如下所述的实施例进一步描述本发明。这些实施例的用途仅仅是说明性的并绝不限制本发明或任何举例说明术语的范围和含义。同样地,本发明不局限于本文描述的任何具体优选的实施方案。实际上,本发明的许多修改和变化对阅读过该说明书的本领域技术人员来说将是显而易见的。因此本发明仅仅由所附的权利要求书以及相当于授权权利要求书的全部范围所限定。
实施例1:用特异性药理伴侣处理的L444P转基因小鼠脑中
Gba活性提高的确定
L444P是与2型和3型戈谢病有关的突变。L444P转基因小鼠(在葡糖神经酰胺合成酶无效基础上纯合型的人L444P突变Gba)显示出脑中Gba活性的缺陷。然而,由于葡糖神经酰胺合成酶基因的破坏,这些小鼠没有显示出在例如巨噬细胞中GluCer的累积。伴随的葡糖神经酰胺合成酶混乱是必需的,以前因为由于表皮阻渗透性功能削弱使得L444P转基因小鼠在出生3天内死亡。
在该实验中,利用异法戈明或C-苯甲基-异法戈明处理L444P转基因小鼠,并在第1、3、6和12个月测量替代标记以确定伴侣的效力。另外,也评价了在伴侣处理4周后经2周非伴侣处理“洗脱(washout)”周期后的小鼠中替代标记返祖到未经处理对照水平的情况。
方法
特异性药理伴侣处理 在其饮用水中对小鼠施用异法戈明或C-苯甲基异法戈明,不限量。根据消耗的水体积估算的日剂量约为10mg/kg/天。
脑中Gba活性的测定 在1、3、6和12个月末时,处死小鼠并评价脑中Gba酶活性的提高。收集新鲜的(利用PBS洗去血液)或从冷冻材料解冻的脑组织。切碎组织,并于冰上在200-500μl的McIlvaine(MI)缓冲液(在0.1M柠檬酸盐和0.2M磷酸盐缓冲液中的0.25%牛磺胆酸钠,0.1%Tritonx-100,pH 5.2)中匀浆,然后进行10,000xg离心。收集上清并可在该步骤冷冻。
将来自脑组织匀浆的约1-10μl上清添加到干净的96孔平板用于微量BCA蛋白质测定(Pierce,cat# 23235),根据厂家方案定量总蛋白质的量。作为阴性对照,另一个10μl添加到黑色平板,与10μl 2.5mM的Gba活性抑制剂CBE(6.7ml缓冲液中2.7mg牛弥菜醇(Conduritol)B环氧化物)混合,置于室温(RT)30分钟。然后添加Gba底物即50μl的3mM 4-甲基伞形酮-β-D-葡糖苷(4-MU-β-D-葡糖苷;新鲜制备,粉末溶于0.2ml DMSO,然后利用MI缓冲液定容到合适的体积),而黑色平板在37℃再孵育1小时。孵育后,添加10μl上清到第二个黑色平板中,与10μl的MI缓冲液和50μl 6mM的Gba底物4-MU-β-D-葡糖苷混合,然后在37℃孵育1小时。通过添加70μl pH 10.8的0.2M甘氨酸终止反应。在平板读出器(Victor21420多标记计数器;Wallac)中于F460条件下读出平板。
利用下列公式确定相对的β-葡萄糖活性:
(F460无CBE-F460有CBE)/(A550样本-A550缓冲液)
基于4-MU标准曲线将F460读数转化为4-MU nmole数,而基于蛋白质标准曲线将A550转化为蛋白质mg数。Gba活性的一个单位定义为1小时释放的4-MU nmole数。
洗脱研究 为了确定在停止处理后,以饮用水形式给药的AT2101对L444P小鼠的作用是否并且什么期限发生倒退,进行洗脱研究。九个雄性3月龄L444P小鼠的给药剂量约为10mg/kg/天,给药4周,以等数目的未处理小鼠作为对照。在第4周末处死四个处理的和四个未处理的小鼠,并且剩余动物不进一步用异法戈明处理,即在处死前给予它们另外2周正常的饮用水并评价脑中Gba活性。
结果
脑中Gba活性 在异法戈明处理仅仅两周后,观察到脑中Gba活性显著增加(图1A),这种现象持续4-12周。值得注意的是,在脑中异法戈明处理导致从未处理小鼠中的约1U/mg增加到2和4周处理后的约4.5U/mg,并在12周后进一步达到约6U/mg(p<0.001)。只要施用伴侣,预计增加的Gba活性将持续3、6和12个月。
与此类似,两周后,C-苯甲基异法戈明处理的小鼠也在器官如脾中显示出显著增加的Gba活性,并且在肺和脑中倾向于活性增加(数据未显示)。预计在更一步处理后Gba活性的增加将在其他器官包括脑中观察到,因为在利用AT2206处理两周后,在脑中倾向于活性增加(数据未显示)。
洗脱 类似于上述,在10mg/kg/天处理4周后,L444P转基因小鼠脑中Gba活性显著升高(图1B)。
讨论
这些结果提供的第一个指示是生理水平的伴侣足以穿过血脑屏障提高脑和***器官的Gba活性(例如脾和肝脏)。这是令人惊奇的,因为***施用的药剂为达到在脑中有效往往必须以较高的剂量施用。在低抑制性Gba抑制剂用作伴侣的情况下,在***抑制剂的高剂量将抑制突变Gba,由此阻挠如以前表明的提高酶活性的目的。在用IFG处理的猴中获得了相似的结果,处理后在CSF中发现IFG。
实施例2:在戈谢病成纤维细胞中破坏的溶酶体运输的修复
尽管N370S戈谢病成纤维细胞(来自人类患者)没有表明在细胞质中累积底物(即GluCer),但这些成纤维细胞与野生型成纤维细胞相比显示出异常的溶酶体蛋白质和Gba染色。利用药理伴侣异法戈明处理的N370S成纤维细胞增加了见于溶酶体中Gba的量,并且修复细胞为正常溶酶体染色模式。
方法
细胞培养在5%CO2、于37℃,在具有10%FBS和1%青霉素/链霉素的DMEM培养基中培养N370S成纤维细胞(DMN89.15)。来自健康个体的野生型成纤维细胞系CRL-2097用作对照。将细胞从10cm平板移入12孔有盖平板进行传代培养。利用38ml培养液稀释来自一个汇合10cm平板的细胞。从10mM储液(5%二甲亚砜)按下列浓度添加异法戈明或C-苯甲基-异法戈明到12孔平板的各孔:
C-苯甲基-异法戈明-对照(仅仅第二抗体);未处理的;0.03μM;0.1μM;0.3μM;1.0μM;3.0μM;和10.0μM。
异法戈明-对照(仅仅第二抗体);未处理的;10μM;30μM;100μM;1nM;3nM;和10nM。
培养细胞共约6天。
固定及染色在PBS中洗涤细胞5分钟,在3.7%多聚甲醛(于PBS)中固定15分钟,再一次在PBS中洗涤5分钟,并用0.5%皂苷(saponin)透化5分钟。然后利用含0.1%皂苷的PBS洗涤细胞,与新鲜的0.1%硼氢化钠/0.01%皂苷处理5分钟,并利用0.1%皂苷/1%BSA的PBS洗涤3次,每次5分钟。
细胞在具有1%BSA、500μl第一抗Gba抗体(1∶200)或抗LAMP-1抗体(1∶200;BD Pharmingen,Cat.No.555798)的PBS溶液中孵育1小时,根据厂家说明书利用Lyso红(Cambrex,Rutherford,NJ)对溶酶体染色。孵育后,利用含有0.1%皂苷1%BSA的PBS洗涤细胞3次,然后与第二抗体溶液(1∶500;抗Gba的抗兔AlexaFluor588和抗LAMP-1的抗鼠IgGAlexaFluor594)孵育。将细胞封固于盖玻片,密封并立即观察。
共焦显微镜检利用共焦显微镜观察细胞。设置红色和绿色信号通道为6,并利用强度窗优化激光功率,并且在余下的实验中不调整。在相同的位置分析所有的载玻片并收集所有的图像:没有任何变焦距、利用20x和60x透镜、小孔、最佳象素大小,平均扫描2次、并且如上述的所有实验红色和绿色信号通道同时探测。
在相同的强度显示全部图像,并且通过将光标置于最大数目的细胞上对每个图像产生红色+绿色信号通道强度图。
进一步的测量可通过计算红色(LAMP-1)和绿色(GBA)象素的叠加比率进行。
结果
利用Lyso红染色,与点状染色模式的正常成纤维细胞相比(图2B),汇合5天以上的戈谢病N370S成纤维细胞显示出颗粒状溶酶体染色模式(图2A)。L444P成纤维细胞显示相似的结果(未显示数据)。N370S和正常的成纤维细胞均显示溶酶体LAMP-1染色(分别为图2C、2D)。戈谢病成纤维细胞中显示更多的LAMP-1。
利用30.0μM异法戈明(AT2201)(图2G-H)和3.0μl C-苯甲基异法戈明(AT2206)(图2I-J)处理增加溶酶体中Gba的量,并且与未处理的对照(图2E-F)相比重建正常溶酶体Gba和LAMP-1的点状染色模式,如通过双重染色所显示的那样。
图2K-N显示N370S戈谢病成纤维细胞中Gba染色的改变如下:(K)-对照(仅仅第二抗体);(L)-未处理的N370S成纤维细胞;(M)-30μM异法戈明;和(N)3μM C-苯甲基-异法戈明。Gba染色显示相对未处理的对照在伴侣处理中到溶酶体的定位。L444P戈谢病成纤维细胞获得相似的结果(未显示数据)。
用伴侣处理后正常细胞形态的改善是由于在ER和/或胞液中很可能为聚集形式的突变Gba量或累积减少。因此,该策略可减轻具有杂合的N370S突变的帕金森氏病患者或者具有纯合的N370S突变及帕金森综合征/痴呆的杂合戈谢病患者中的CNS症状。
实施例3:戈谢病成纤维细胞中利用伴侣处理后多聚泛素化蛋白质的增加;蛋白酶体降解途径的修复
抗多聚泛素化蛋白质(PUP)和抗Gba标记的健康人成纤维细胞与来自具有L444P Gba突变的戈谢病患者的成纤维细胞和具有N370S Gba突变的戈谢病患者的成纤维细胞比较。
方法
细胞培养在5%CO2、于37℃,在具有10%FBS和1%PS的DMEM培养基中培养L444P戈谢病成纤维细胞(细胞系GM10915);N370S戈谢病成纤维细胞(细胞系DMN89.15);和来自健康个体的成纤维细胞(CRL-2097)。将细胞从10cm平板移入12孔有无菌盖的平板对进行传代培养。按1∶6稀释来自一个汇合T-75摇瓶的N370S细胞,并再培养4天。
从10mM储液(5%二甲亚砜)按下列浓度添加异法戈明或C-苯甲基-异法戈明到12孔平板的各孔:
C-苯甲基-异法戈明-未处理的;对照(仅仅第二抗体);0.03μM;0.1μM;0.3μM;1.0μM;3.0μM;和10.0μM。
异法戈明-未处理的;对照(仅仅第二抗体);10μM;30μM;100μM;1nM;3nM;和10nM。
固定及染色在PBS中洗涤细胞5分钟,随后在新鲜的3.7%多聚甲醛中固定15分钟。然后在PBS中洗涤细胞一次5分钟,随后在0.2%Triton X-100中透化5分钟。然后再一次在PBS中洗涤5分钟,并用新鲜的0.1%硼氢化钠处理5-10分钟。在染色前利用含有1%BSA的PBS洗涤细胞3次(每次5分钟)。
细胞与500μl如下的第一抗体(利用含有1%BSA的PBS按1∶200稀释)孵育1小时:
1、泛素化蛋白质克隆FK1的小鼠单克隆抗体(AFFINITI ResearchProducts Cat.No.PW 8805)
2、市场上可买到的兔抗Gba抗体,例如8E4
然后利用含有1%BSA的PBS洗涤细胞三次,随后利用1∶500稀释的下列第二抗体孵育1小时:
1、山羊抗小鼠IgM(μ链)AlexaFluor568(Molecular Probes Cat.No.A21043);
2、山羊抗兔IgG(H+L)高交叉吸收的AlexaFluor488(Molecular ProbesCat.No.A11034)
在含有BSA的PBS中洗涤细胞三次,封固,观察之前在4℃保存。
结果
开始的实验表明细胞中多聚泛素化蛋白质(PUP)的浓度在健康细胞中比在染色不是很强烈的戈谢病N370S(图3D和3F)和L4449成纤维细胞中(图3G和3I)更高(很浓)(图3A和3C)。已知蛋白质聚集抑制泛素/蛋白酶体途径。因此,利用伴侣降低聚集对蛋白酶体介导的降解途径有积极的作用。
讨论
L444P突变的戈谢病患者具有广泛的CNS受累情况。这可能是由于人类L444P突变酶比例如N370S更不稳定,使它更可能形成蛋白质聚集体,并从而抑制泛素/蛋白酶体途径(Tsuji等人,N.Eng.J.Med.1987;315:570)。很多其他的神经变性疾病是由导致泛素化蛋白质累积的突变所引起的,并且已有进一步的报道表明蛋白质聚集体可直接削弱泛素/蛋白酶体途径并诱导炎症介质的表达(li等人,The International Journal of Biochemistry & CellBiology.2003;35:547-552)。
若利用特异性药理伴侣稳定小鼠L444P,通过增加到溶酶体的Gba运输减轻泛素/蛋白酶体途径的应激,从而延长突变Gba的半衰期——将其运输的溶酶体,而不是在ER中降解。这解释了与戈谢病成纤维细胞相比在正常成纤维细胞中增加的PUP染色。
其他在临床上没有引起明显CNS症状的Gba突变(即N370S)仍可引起ER和胞液中突变蛋白质的累积,引发泛素/蛋白酶体途径的额外应激或者通过降低细胞单泛素化蛋白质的能力而破坏神经元中的运输。
*****
本发明不限于本文描述的具体实施方案的范围。实际上,除了本文描述的那些,根据前述说明书和附图的本发明的各种改变对本领域技术人员来说将是显而易见的。这样的改变落入所附权利要求书的范围。
应进一步理解的是,所有值都是近似值,并且用于说明目的。
对于所有目的,本申请通篇引用的专利、专利申请、出版物、产品说明和方案公开的内容整体引入本文作为参考。
序列表
<110>阿米库斯治疗学公司
<120>溶酶体酶编码基因突变相关的CNS紊乱的治疗
<130>077376.0352
<150>60/689,120
<151>2005-06-08
<160>4
<170>FastSEQ for Windows Version 4.0
<210>1
<211>8850
<212>DNA
<213>智人(Homo sapiens)
<400>1
tctagaaaga cttcactgag atcatttaaa gaacaaaaag gatggctggg gtccagcgca 60
gtggctcatg cctgtaatcc cagcactttc ggataccaag gcagcagatc acctgaggtc 120
cagagtttca gaccagcctg gccaacatag tgaaacccca tctctactaa aaataaaaaa 180
attagctgag catgttggag ggcacctgta atcccagcta cttgggaggc tgaggcagga 240
gaatcactcg aacccaggag gtggaggttg cagtgagcca agatcacgcc actgcactcc 300
agcctgggca acagagtgag actctgtctc aaaaaacaac aacaacaaaa aatacaaaca 360
agagacaagt agttcccagg tgcctaccaa gtggtcaggc actgcactta cctcactgac 420
tgcagtaacc accctttgag gttgtggcat tgcctccatt ttccaggcaa ggaaatgggc 480
tgagagctgg gattagtcag gtcatgactg tgtgtgccac tcccgctaaa tctcatttga 540
tgtggttcat gaggccacac catggacagc ttcctccttg tgtccactga ggatatggct 600
ttgtacaaca ctttggtttt ttgaacgact ttacaaacct ccctgtcttg tgaggaagga 660
agaacagtta ttaccatctg catctgatga tgaaacaagg gacgctgcag aggagccgca 720
ctgaccactc cctccctcca gtcctgtcat cccactgcca gtgtcccacc ctcttgtgcc 780
ctgcacttca ctggctaata acccccctca ctttttcctc tgtgaagcca tcctggataa 840
ttccccaccc acgaatggtc cctcctcatc tcagagagct ctccatgcac acctgttacc 900
gtttctgtct ttatctgtaa atatctgtgt gtctgacttc catgcctcac acacctctat 960
agggcaaaga ctgtcttaaa catcttggta gtgtcagtat tttgcacagt gaagtttttt 1020
tttttaaatt atatcagctt tatttgtacc tttttgacat ttctatcaaa aaagaagtgt 1080
gcctgctgtg gttcccatcc tctgggattt aggagcctct accccattct ccatgcaaat 1140
ctgtgttcta ggctcttcct aaagttgtca cccatacatg ccctccagag ttttataggg 1200
catataatcg taacagatga gaggaagcca attgcccttt agaaatatgg ctgtgattgc 1260
ctcacttcct gtgtcatgtg acgctcctag tcatcacatg acccatccac atcgggaagc 1320
cggaattact tgcagggcta acctagtgcc tatagctaag gcaggtacct gcatccttgt 1380
ttttgtttag tggatcctct atccttcaga gactctggaa cccctgtggt cttctcttca 1440
tctaatgacc ctgaggggat ggagttttca agtccttcca gagaggtaag agagagagct 1500
cccaatcagc attgtcacag tgcttctgga atcctggcac tggaatttaa tgaatgacag 1560
actctctttg aatccagggc catcatggct ctttgagcaa ggcacagatg gagggagggg 1620
tcgaagttga aatgggtggg aagagtggtg gggagcatcc tgatttgggg tgggcagaga 1680
gttgtcatca gaagggttgc agggagagct gcacccaggt ttctgtgggc cttgtcctaa 1740
tgaatgtggg agaccgggcc atgggcaccc aaaggcagct aagccctgcc caggagagta 1800
gttgaggggt ggagaggggc ttgcttttca gtcattcctc attctgtcct caggaatgtc 1860
ccaagccttt gagtagggta agcatcatgg ctggcagcct cacaggattg cttctacttc 1920
aggcagtgtc gtgggcatca ggtgagtgag tcaaggcagt ggggaggtag cacagagcct 1980
cccttctgcc tcatagtcct ttggtagcct tccagtaagc tggtggtaga cttttagtag 2040
gtgctcaata aatccttttg agtgactgag accaactttg gggtgaggat tttgtttttt 2100
ttcttttgaa acagagtctt actctgttgc ctgggctgga gtgcagtggt gcaattttgg 2160
ctcattccaa cctctgcctc ccagattcaa gcgattctct tgcttcagct tcccaggtag 2220
ctgggattac aggcggccac cactacgccc agctaatttt tgtattttta gtagagacgg 2280
ggtttcacca tgctggcaag gcaggtctca aactcctcac ctcaggtgat ccgcccacct 2340
cggcctccta aagtgctagg attacaggtg tgagcccctg cgcccggcca aggggtgagg 2400
aattttgaaa ccgtgttcag tctctcctag cagatgtgtc cattctccat gtcttcatca 2460
gacctcactc tgcttgtact ccctccctcc caggtgcccg cccctgcatc cctaaaagct 2520
tcggctacag ctcggtggtg tgtgtctgca atgccacata ctgtgactcc tttgaccccc 2580
cgacctttcc tgcccttggt accttcagcc gctatgagag tacacgcagt gggcgacgga 2640
tggagctgag tatggggccc atccaggcta atcacacggg cacaggtaac cattacaccc 2700
ctcaccccct gggccaggct gggtcctcct agaggtaaat ggtgtcagtg atcaccatgg 2760
agtttcccgc tgggtactga tacccttatt ccctgtggat gtcctcaggc ctgctactga 2820
ccctgcagcc agaacagaag ttccagaaag tgaagggatt tggaggggcc atgacagatg 2880
ctgctgctct caacatcctt gccctgtcac cccctgccca aaatttgcta cttaaatcgt 2940
acttctctga agaaggtgag gaggaagggg acaagatgac atagagccat tgaaactttt 3000
cgtttttctt ttcttttttt aaaatttttt tgaggcagaa tctcactctg cccattctgt 3060
cggcgagaca ggagtgcagt ggtgtgatct cccctcacag caacctctgc ctcccaggct 3120
atagtgattc tcctgcctca gcctcctgag tagctggaat tataggcgtg cgccactacc 3180
acctggctaa tttttgtatt tttagtagag acagggtttc atcatgttga ccaggctagt 3240
cttaaactcc tgacctcaaa tgatatacct gccttggcct cccgaagtgc tggaattaca 3300
agtgtgagcc accgagccca gcagacactt ttcttttttc tttttttttt tttgagacag 3360
agtctcgcac tgtcacccag gctggagtgc agtggcacaa tctcagctca ctgcaacctc 3420
cacctcccgg gttcaggtga ttctcctgtc tcagcctctc gagtacctgg gattacaggt 3480
gcctgccacc acgcccggct aattttttgt atttttagta gagacagggt ttcactatgt 3540
tggccaggat gattgcgaac tcctgacctc gtgatctgcc cacatcggcc tcccaaagtg 3600
ctgggattac atgcgtgagc cactgacact tttctttgcc ctttctttgg accctgactt 3660
ctgcccatcc ctgacatttg gttcctgttt taatgccctg tgaaataaga tttcgccgcc 3720
tatcatctgc taactgctac ggactcaggc tcagaaaggc ctgcgcttca cccaggtgcc 3780
agcctccaca ggttccaacc caggagccca agttcccttt ggccctgact cagacactat 3840
taggactggc aagtgataag cagagtccca tactctccta ttgactcgga ctaccatatc 3900
ttgatcatcc ttttctgtag gaatcggata taacatcatc cgggtaccca tggccagctg 3960
tgacttctcc atccgcacct acacctatgc agacacccct gatgatttcc agttgcacaa 4020
cttcagcctc ccagaggaag ataccaagct caaggtaggc attctagctt tttcaggccc 4080
tgagggccct gatgtctggg ggttgagaaa ctgtagggta ggtctgcttg tacagacatt 4140
ttgtcccctg ctgttttgtc ctgggggtgg gagggtggag gctaatggct gaaccggatg 4200
cactggttgg gctagtatgt gttccaactc tgggtgcttc tctcttcact acctttgtct 4260
ctagataccc ctgattcacc gagccctgca gttggcccag cgtcccgttt cactccttgc 4320
cagcccctgg acatcaccca cttggctcaa gaccaatgga gcggtgaatg ggaaggggtc 4380
actcaaggga cagcccggag acatctacca ccagacctgg gccagatact ttgtgaagta 4440
agggatcagc aaggatgtgg gatcaggact ggcctcccat ttagccatgc tgatctgtgt 4500
cccaaccctc aacctagttc cacttccaga tctgcctgtc ctcagctcac ctttctacct 4560
tctgggcctt tcagccttgg gcctgtcaat cttgcccact ccatcaggct tcctgttctc 4620
tcggtctggc ccactttctt tttatttttc ttcttttttt tttttttgag aaggagtctc 4680
tctctctgtc acccaggctg gagtgctgtg gcgccatctt cactcactgt aacctctgcc 4740
tcctgagttc aagcaattct cctgcctcag ccttccaagt agctgggatt ataggcgcct 4800
gccaccaggc ccagctgatt tttctatttt tagtagagac ggggtttcgc caggctgttc 4860
tcgaactcct gaactcaagt gatccacctg cctcggcttc ccaaagtgct gggattacag 4920
gtgtgagcca ccacacccag ctggtctggt ccactttctt ggccggatca ttcatgacct 4980
ttctcttgcc aggttcctgg atgcctatgc tgagcacaag ttacagttct gggcagtgac 5040
agctgaaaat gagccttctg ctgggctgtt gagtggatac cccttccagt gcctgggctt 5100
cacccctgaa catcagcgag acttcattgc ccgtgaccta ggtcctaccc tcgccaacag 5160
tactcaccac aatgtccgcc tactcatgct ggatgaccaa cgcttgctgc tgccccactg 5220
ggcaaaggtg gtaaggcctg gacctccatg gtgctccagt gaccttcaaa tccagcatcc 5280
aaatgactgg ctcccaaact tagagcgatt tctctaccca actatggatt cctagagcac 5340
cattcccctg gacctccagg gtgccatgga tcccacagtt gtcgcttgaa acctttctag 5400
gggctgggcg aggtggctca ctcatgcaaa cccagcactt tgggaagccg aggcgggtga 5460
tcacctgagg tcaggagttt aagaccaccc tggccaacgt gttgaaaccc tgtgtctact 5520
aaaatacaaa aaaaaaaaat tatctgggca tgatggtggg tgtctgtaat cccagctact 5580
caggaggctg agaagggaga atcagttgaa cccgggagat ggtggttgcg gtgagccgag 5640
atcgcgccac tgcactccag cctgggaggc tgagcgagac tccatctcga aacaaaacaa 5700
aacaaaacta tctaggctgg gggtggtggt tcatgtatgt atgtgtatat acatatatat 5760
gtgtttatat gtatatatat atacacacac acacatacat acacacacat acacacacaa 5820
attagctggg tgtggcaccc gtgtagtccc agctactcag gaggctaatg tgggaggatc 5880
agttgaccct aggaagtcaa ggctgcagtg agtcgtgatt gcgccactgt actccagccc 5940
gagtgacaga gtgacatcct gtctcaaaaa caaaaaaaaa tctccccaaa cctctctagt 6000
tgcattcttc ccgtcaccca actccaggat tcctacaaca ggaactagaa gttccagaag 6060
cctgtgtgca aggtccagga tcagttgctc ttcctttgca ggtactgaca gacccagaag 6120
cagctaaata tgttcatggc attgctgtac attggtacct ggactttctg gctccagcca 6180
aagccaccct aggggagaca caccgcctgt tccccaacac catgctcttt gcctcagagg 6240
cctgtgtggg ctccaagttc tgggagcaga gtgtgcggct aggctcctgg gatcgaggga 6300
tgcagtacag ccacagcatc atcacggtaa gccaccccag tctcccttcc tgcaaagcag 6360
acctcagacc tcttactagt ttcaccaaag actgacagaa gcccttcctg tccagctttc 6420
cccagctagc ctgccctttt gagcaactct ggggaaccat gattccctat cttccctttc 6480
cttcacaggt ctgcacacct cattgcccct tttgcaacta ctgaggcact tgcagctgcc 6540
tcagacttct cagctcccct tgagatgcct ggatcttcac acccccaact ccttagctac 6600
taaggaatgt gcccctcaca gggctgacct acccacagct gcctctccca catgtgaccc 6660
ttacctacac tctctgggga cccccagtgt tgagcctttg tctctttgcc tttgtcctta 6720
ccctagaacc tcctgtacca tgtggtcggc tggaccgact ggaaccttgc cctgaacccc 6780
gaaggaggac ccaattgggt gcgtaacttt gtcgacagtc ccatcattgt agacatcacc 6840
aaggacacgt tttacaaaca gcccatgttc taccaccttg gccacttcag gtgagtggag 6900
ggcgggcacc cccattccat accaggccta tcatctccta catcggatgg cttacatcac 6960
tctacaccac gagggagcag gaaggtgttc agggtggaac ctcggaagag gcacacccat 7020
ccccttttgc accatggagg caggaagtga ctaggtagca acagaaaacc ccaatgcctg 7080
aggctggact gcgatgcaga aaagcagggt cagtgcccag cagcatggct ccaggcctag 7140
agagccaggg cagagcctct gcaggagtta tggggtgggt ccgtgggtgg gtgacttctt 7200
agatgagggt ttcatgggag gtaccccgag ggactctgac catctgttcc cacattcagc 7260
aagttcattc ctgagggctc ccagagagtg gggctggttg ccagtcagaa gaacgacctg 7320
gacgcagtgg cactgatgca tcccgatggc tctgctgttg tggtcgtgct aaaccggtga 7380
gggcaatggt gaggtctggg aagtgggctg aagacagcgt tgggggcctt ggcaggatca 7440
cactctcagc ttctcctccc tgctccctag ctcctctaag gatgtgcctc ttaccatcaa 7500
ggatcctgct gtgggcttcc tggagacaat ctcacctggc tactccattc acacctacct 7560
gtggcgtcgc cagtgatgga gcagatactc aaggaggcac tgggctcagc ctgggcatta 7620
aagggacaga gtcagctcac acgctgtctg tgactaaaga gggcacagca gggccagtgt 7680
gagcttacag cgacgtaagc ccaggggcaa tggtttgggt gactcacttt cccctctagg 7740
tggtgccagg ggctggaggc ccctagaaaa agatcagtaa gccccagtgt ccccccagcc 7800
cccatgctta tgtgaacatg cgctgtgtgc tgcttgcttt ggaaactggg cctgggtcca 7860
ggcctagggt gagctcactg tccgtacaaa cacaagatca gggctgaggg taaggaaaag 7920
aagagactag gaaagctggg cccaaaactg gagactgttt gtctttcctg gagatgcaga 7980
actgggcccg tggagcagca gtgtcagcat cagggcggaa gccttaaagc agcagcgggt 8040
gtgcccaggc acccagatga ttcctatggc accagccagg aaaaatggca gctcttaaag 8100
gagaaaatgt ttgagcccag tcagtgtgag tggctttatt ctgggtggca gcaccccgtg 8160
tccggctgta ccaacaacga ggaggcacgg gggcctctgg aatgcatgag agtagaaaaa 8220
ccagtcttgg gagcgtgagg acaaatcatt cctcttcatc ctcctcagcc atgcccaggg 8280
tccgggtgcc tggggcccga gcaggcgttg cccgctggat ggagacaatg ccgctgagca 8340
aggcgtagcc caccatggct gccagtcctg ccagcacaga taggatctgg ttccggcgcc 8400
ggtatggctc ctcctcagtc tctgggcctg ctggtgtctg gcgttgcggt ggtacctcag 8460
ctgagggtca aggaaggaag gtgtgttagg agaactagtt cttggatccc tgcccactct 8520
ccccagggct gcccctccca tctgcccctt acctccatcc caggggaagt agagactgag 8580
aatgtgggta caataggcac agaggttgtg cagcccacgc aggtggacct gcagcttccc 8640
actgggcagc tttgcctgca gcagcagggc caagtagctg aagacgaagg cgtccaagga 8700
ggcagggctg gagcagagag agaagggtgg gatggaggag aaccactggg gtagaagggg 8760
taaagatgga gctggaggaa gagtcagcct tgggaggtgg gctctgggca gcaggcggcc 8820
accaggaagg acaggacaca cagttctaga 8850
<210>2
<211>536
<212>PRT
<213>智人
<400>2
Met Glu Phe Ser Ser Pro Ser Arg Glu Glu Cys Pro Lys Pro Leu Ser
1 5 10 15
Arg Val Ser Ile Met Ala Gly Ser Leu Thr Gly Leu Leu Leu Leu Gln
20 25 30
Ala Val Ser Trp Ala Ser Gly Ala Arg Pro Cys Ile Pro Lys Ser Phe
35 40 45
Gly Tyr Ser Ser Val Val Cys Val Cys Asn Ala Thr Tyr Cys Asp Ser
50 55 60
Phe Asp Pro Pro Thr Phe Pro Ala Leu Gly Thr Phe Ser Arg Tyr Glu
65 70 75 80
Ser Thr Arg Ser Gly Arg Arg Met Glu Leu Ser Met Gly Pro Ile Gln
85 90 95
Ala Asn His Thr Gly Thr Gly Leu Leu Leu Thr Leu Gln Pro Glu Gln
100 105 110
Lys Phe Gln Lys Val Lys Gly Phe Gly Gly Ala Met Thr Asp Ala Ala
115 120 125
Ala Leu Asn Ile Leu Ala Leu Ser Pro Pro Ala Gln Asn Leu Leu Leu
130 135 140
Lys Ser Tyr Phe Ser Glu Glu Gly Ile Gly Tyr Asn Ile Ile Arg Val
145 150 155 160
Pro Met Ala Ser Cys Asp Phe Ser Ile Arg Thr Tyr Thr Tyr Ala Asp
165 170 175
Thr Pro Asp Asp Phe Gln Leu His Asn Phe Ser Leu Pro Glu Glu Asp
180 185 190
Thr Lys Leu Lys Ile Pro Leu Ile His Arg Ala Leu Gln Leu Ala Gln
195 200 205
Arg Pro Val Ser Leu Leu Ala Ser Pro Trp Thr Ser Pro Thr Trp Leu
210 215 220
Lys Thr Asn Gly Ala Val Asn Gly Lys Gly Ser Leu Lys Gly Gln Pro
225 230 235 240
Gly Asp Ile Tyr His Gln Thr Trp Ala Arg Tyr Phe Val Lys Phe Leu
245 250 255
Asp Ala Tyr Ala Glu His Lys Leu Gln Phe Trp Ala Val Thr Ala Glu
260 265 270
Asn Glu Pro Ser Ala Gly Leu Leu Ser Gly Tyr Pro Phe Gln Cys Leu
275 280 285
Gly Phe Thr Pro Glu His Gln Arg Asp Phe Ile Ala Arg Asp Leu Gly
290 295 300
Pro Thr Leu Ala Asn Ser Thr His His Asn Val Arg Leu Leu Met Leu
305 310 315 320
Asp Asp Gln Arg Leu Leu Leu Pro His Trp Ala Lys Val Val Leu Thr
325 330 335
Asp Pro Glu Ala Ala Lys Tyr Val Hi s Gly Ile Ala Val His Trp Tyr
340 345 350
Leu Asp Phe Leu Ala Pro Ala Lys Ala Thr Leu Gly Glu Thr His Arg
355 360 365
Leu Phe Pro Asn Thr Met Leu Phe Ala Ser Glu Ala Cys Val Gly Ser
370 375 380
Lys Phe Trp Glu Gln Ser Val Arg Leu Gly Ser Trp Asp Arg Gly Met
385 390 395 400
Gln Tyr Ser His Ser Ile Ile Thr Asn Leu Leu Tyr His Val Val Gly
405 410 415
Trp Thr Asp Trp Asn Leu Ala Leu Asn Pro Glu Gly Gly Pro Asn Trp
420 425 430
Val Arg Asn Phe Val Asp Ser Pro Ile Ile Val Asp Ile Thr Lys Asp
435 440 445
Thr Phe Tyr Lys Gln Pro Met Phe Tyr His Leu Gly His Phe Ser Lys
450 455 460
Phe Ile Pro Glu Gly Ser Gln Arg Val Gly Leu Val Ala Ser Gln Lys
465 470 475 480
Asn Asp Leu Asp Ala Val Ala Leu Met His Pro Asp Gly Ser Ala Val
485 490 495
Val Val Val Leu Asn Arg Ser Ser Lys Asp Val Pro Leu Thr Ile Lys
500 505 510
Asp Pro Ala Val Gly Phe Leu Glu Thr Ile Ser Pro Gly Tyr Ser Ile
515 520 525
His Thr Tyr Leu Trp Arg Arg Gln
530 535
<210>3
<211>2586
<212>DNA
<213>智人
<220>
<221>misc_feature
<222>2317
<223>n=A、T、C或G
<400>3
cattaggcct atgaattata agatacagtc actttaaaat ccactggaag gctgaagagt 60
gagttaaacc tcttataatg aatatacagt gaaaccagta gaggcatttt atttagggtt 120
cctacaagaa agtgcttaaa tagcatcgac gcctacatgc tacatcctgt tcagtctctg 180
cctctgtgat gcagttggcc agcaaatatc ctccaagtca tcatttgcat agtgctaggg 240
ataaaatgag gagcaatacc aaatgctata cctgccctta tgggtcttat agtccaacgg 300
gagaaaaaga tattatacaa ataatcacgg aaaataaata gaaaacgcat ccttgttttt 360
gtttagtgga tcctctatcc ttcagagact ctggaacccc tgtggtcttc tcttcatcta 420
atgaccctga ggggatggag ttttcaagtc cttccagaga ggaatgtccc aagcctttga 480
gtagggtaag catcatggct ggcagcctca caggtttgct tctacttcag gcagtgtcgt 540
gggcatcagg tgcccgcccc tgcatcccta aaagcttcgg ctacagctcg gtggtgtgtg 600
tctgcaatgc cacatactgt gactcctttg accccccgac ctttcctgcc cttggtacct 660
tcagccgcta tgagagtaca cgcagtgggc gacggatgga gctgagtatg gggcccatcc 720
aggctaatca cacgggcaca ggcctgctac tgaccctgca gccagaacag aagttccaga 780
aagtgaaggg atttggaggg gccatgacag atgctgctgc tctcaacatc cttgccctgt 840
caccccctgc ccaaaatttg ctacttaaat cgtacttctc tgaagaagga atcggatata 900
acatcatccg ggtacccatg gccagctgtg acttctccat ccgcacctac acctatgcag 960
acacccctga tgatttccag ttgcacaact tcagcctccc agaggaagat accaagctca 1020
agatacccct gattcaccga gccctgcagt tggcccagcg tcccgtttca ctccttgcca 1080
gcccctggac atcacccact tggctcaaga ccaatggagc ggtgaatggg aaggggtcac 1140
tcaagggaca gcccggagac atctaccacc agacctgggc cagatacttt gtgaagttcc 1200
tggatgccta tgctgagcac aagttacagt tctgggcagt gacagctgaa aatgagcctt 1260
ctgctgggct gttgagtgga taccccttcc agtgcctggg cttcacccct gaacatcagc 1320
gagacttcat tgcccgtgac ctaggtccta ccctcgccaa cagtactcac cacaatgtcc 1380
gcctactcat gctggatgac caacgcttgc tgctgcccca ctgggcaaag gtggtactga 1440
cagacccaga agcagctaaa tatgttcatg gcattgctgt acattggtac ctggactttc 1500
tggctccagc caaagccacc ctaggggaga cacaccgcct gttccccaac accatgctct 1560
ttgcctcaga ggcctgtgtg ggctccaagt tctgggagca gagtgtgcgg ctaggctcct 1620
gggatcgagg gatgcagtac agccacagca tcatcacgaa cctcctgtac catgtggtcg 1680
gctggaccga ctggaacctt gccctgaacc ccgaaggagg acccaattgg gtgcgtaact 1740
ttgtcgacag tcccatcatt gtagacatca ccaaggacac gttttacaaa cagcccatgt 1800
tctaccacct tggccacttc agcaagttca ttcctgaggg ctcccagaga gtggggctgg 1860
ttgccagtca gaagaacgac ctggacgcag tggcactgat gcatcccgat ggctctgctg 1920
ttgtggtcgt gctaaaccgc tcctctaagg atgtgcctct taccatcaag gatcctgctg 1980
tgggcttcct ggagacaatc tcacctggct actccattca cacctacctg tggcatcgcc 2040
agtgatggag cagatactca aggaggcact gggctcagcc tgggcattaa agggacagag 2100
tcagctcaca cgctgtctgt gactaaagag ggcacagcag ggccagtgtg agcttacagc 2160
gacgtaagcc caggggcaat ggtttgggtg actcactttc ccctctaggt ggtgcccagg 2220
gctggaggcc cctagaaaaa gatcagtaag ccccagtgtc cccccagccc ccatgcttat 2280
gtgaacatgc gctgtgtgct gcttgctttg gaaactngcc tgggtccagg cctagggtga 2340
gctcactgtc cgtacaaaca caagatcagg gctgagggta aggaaaagaa gagactagga 2400
aagctgggcc caaaactgga gactgtttgt ctttcctaga gatgcagaac tgggcccgtg 2460
gagcagcagt gtcagcatca gggcggaagc cttaaagcag cagcgggtgt gcccaggcac 2520
ccagatgatt cctatggcac cagccaggaa aaatggcagc tcttaaagga gaaaatgttt 2580
gagccc 2586
<210>4
<211>516
<212>PRT
<213>智人
<400>4
Met Ala Gly Ser Leu Thr Gly Leu Leu Leu Leu Gln Ala Val Ser Trp
1 5 10 15
Ala Ser Gly Ala Arg Pro Cys Ile Pro Lys Ser Phe Gly Tyr Ser Ser
20 25 30
Val Val Cys Val Cys Asn Ala Thr Tyr Cys Asp Ser Phe Asp Pro Pro
35 40 45
Thr Phe Pro Ala Leu Gly Thr Phe Ser Arg Tyr Glu Ser Thr Arg Ser
50 55 60
Gly Arg Arg Met Glu Leu Ser Met Gly Pro Ile Gln Ala Asn His Thr
65 70 75 80
Gly Thr Gly Leu Leu Leu Thr Leu Gln Pro Glu Gln Lys Phe Gln Lys
85 90 95
Val Lys Gly Phe Gly Gly Ala Met Thr Asp Ala Ala Ala Leu Asn Ile
100 105 110
Leu Ala Leu Ser Pro Pro Ala Gln Asn Leu Leu Leu Lys Ser Tyr Phe
115 120 125
Ser Glu Glu Gly Ile Gly Tyr Asn Ile Ile Arg Val Pro Met Ala Ser
130 135 140
Cys Asp Phe Ser Ile Arg Thr Tyr Thr Tyr Ala Asp Thr Pro Asp Asp
145 150 155 160
Phe Gln Leu His Asn Phe Ser Leu Pro Glu Glu Asp Thr Lys Leu Lys
165 170 175
Ile Pro Leu Ile His Arg Ala Leu Gln Leu Ala Gln Arg Pro Val Ser
180 185 190
Leu Leu Ala Ser Pro Trp Thr Ser Pro Thr Trp Leu Lys Thr Asn Gly
195 200 205
Ala Val Asn Gly Lys Gly Ser Leu Lys Gly Gln Pro Gly AspIle Tyr
210 215 220
His Gln Thr Trp Ala Arg Tyr Phe Val Lys Phe Leu Asp Ala Tyr Ala
225 230 235 240
Glu His Lys Leu Gln Phe Trp Ala Val Thr Ala Glu Asn Glu Pro Ser
245 250 255
Ala Gly Leu Leu Ser Gly Tyr Pro Phe Gln Cys Leu Gly Phe Thr Pro
260 265 270
Glu His Gln Arg Asp Phe Ile Ala Arg Asp Leu Gly Pro Thr Leu Ala
275 280 285
Asn Ser Thr His His Asn Val Arg Leu Leu Met Leu Asp Asp Gln Arg
290 295 300
Leu Leu Leu Pro His Trp Ala Lys Val Val Leu Thr Asp Pro Glu Ala
305 310 315 320
Ala Lys Tyr Val His Gly Ile Ala Val His Trp Tyr Leu Asp Phe Leu
325 330 335
Ala Pro Ala Lys Ala Thr Leu Gly Glu Thr His Arg Leu Phe Pro Asn
340 345 350
Thr Met Leu Phe Ala Ser Glu Ala Cys Val Gly Ser Lys Phe Trp Glu
355 360 365
Gln Ser Val Arg Leu Gly Ser Trp Asp Arg Gly Met Gln Tyr Ser His
370 375 380
Ser Ile Ile Thr Asn Leu Leu Tyr His Val Val Gly Trp Thr Asp Trp
385 390 395 400
Asn Leu Ala Leu Asn Pro Glu Gly Gly Pro Asn Trp Val Arg Asn Phe
405 410 415
Val Asp Ser Pro Ile Ile Val Asp Ile Thr Lys Asp Thr Phe Tyr Lys
420 425 430
Gln Pro Met Phe Tyr His Leu Gly His Phe Ser Lys Phe Ile Pro Glu
435 440 445
Gly Ser Gln Arg Val Gly Leu Val Ala Ser Gln Lys Asn Asp Leu Asp
450 455 460
Ala Val Ala Leu Met His Pro Asp Gly Ser Ala Val Val Val Val Leu
465 470 475 480
Asn Arg Ser Ser Lys Asp Val Pro Leu Thr Ile Lys Asp Pro Ala Val
485 490 495
Gly Phe Leu Glu Thr Ile Ser Pro Gly Tyr Ser Ile His Thr Tyr Leu
500 505 510
Trp His Arg Gln
515
Claims (20)
1、一种用于治疗个体神经紊乱的方法,其中神经紊乱与溶酶体酶编码基因的突变相关,该方法包括对个体施用有效量的结合溶酶体酶的特异性药理伴侣。
2、权利要求1的方法,其中个体是纯合型的突变。
3、权利要求1的方法,其中个体是半合子型的、杂合型的或者复合杂合型的突变。
4、权利要求1的方法,其中突变是构象突变体。
5、权利要求4的方法,其中伴侣增加突变酶从内质网的运输和/或修复酶活性。
6、权利要求4的方法,其中突变导致其他细胞物质的量增加或者聚集。
7、权利要求6的方法,其中细胞物质是脂质或者其他蛋白质。
8、权利要求1的方法,其中溶酶体酶是葡糖脑苷脂酶,而神经紊乱是帕金森氏病或帕金森综合征。
9、权利要求8的方法,其中帕金森氏病是早期发病的帕金森氏病。
10、权利要求1的方法,其中特异性药理伴侣是溶酶体酶的抑制剂。
11、权利要求10的方法,其中抑制剂是可逆性抑制剂。
12、权利要求10的方法,其中抑制剂是竞争性抑制剂。
13、权利要求8的方法,其中特异性药理伴侣是异法戈明或者(5R,6R,7S,8S)-5-羟甲基-2-辛烷基-5,6,7,8-四氢咪唑并[1,2-a]吡啶-6,7,8-三醇。
14、权利要求13的方法,其中个体是杂合型的或者纯合型的N370S突变。
15、权利要求13的方法,其中个体是杂合型的84GG突变。
16、权利要求13的方法,其中个体是杂合型的R496H突变。
17、一种用于诊断与突变溶酶体酶相关的神经紊乱的方法,包括筛选个体,所述个体显示出一个或多个溶酶体酶突变的神经病学症状。
18、权利要求17的方法,其中突变是构象突变。
19、权利要求17的方法,其中筛选是与健康个体生物样品相比测定个体生物样品中降低的酶活性。
20、权利要求17的方法,其中神经紊乱是帕金森综合征或者帕金森氏病。
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CNA2006800292268A Pending CN101541172A (zh) | 2005-06-08 | 2006-06-08 | 溶酶体酶编码基因突变相关的cns紊乱的治疗 |
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EP (1) | EP1888068B1 (zh) |
JP (2) | JP2009509913A (zh) |
KR (2) | KR20130128481A (zh) |
CN (2) | CN101541172A (zh) |
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CA (1) | CA2611011C (zh) |
ES (1) | ES2485369T3 (zh) |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103764166A (zh) * | 2011-06-22 | 2014-04-30 | 通用医疗公司 | 蛋白质病的治疗 |
CN103764166B (zh) * | 2011-06-22 | 2017-10-24 | 通用医疗公司 | 蛋白质病的治疗 |
US9845327B2 (en) | 2011-06-22 | 2017-12-19 | The General Hospital Corporation | Treatment of proteinopathies |
CN114026115A (zh) * | 2019-04-10 | 2022-02-08 | 普利维尔治疗公司 | 用于溶酶体病症的基因疗法 |
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CA2611011A1 (en) | 2006-12-14 |
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US20060287358A1 (en) | 2006-12-21 |
WO2006133446A3 (en) | 2009-05-07 |
KR20080033242A (ko) | 2008-04-16 |
IL187902A0 (en) | 2008-03-20 |
WO2006133446A2 (en) | 2006-12-14 |
KR20130128481A (ko) | 2013-11-26 |
JP2013079246A (ja) | 2013-05-02 |
ES2485369T3 (es) | 2014-08-13 |
EP1888068A2 (en) | 2008-02-20 |
US9597324B2 (en) | 2017-03-21 |
MX2007015602A (es) | 2008-02-21 |
ZA200800174B (en) | 2009-04-29 |
EP1888068A4 (en) | 2009-12-09 |
JP2009509913A (ja) | 2009-03-12 |
US20180133206A1 (en) | 2018-05-17 |
AU2006254796A1 (en) | 2006-12-14 |
AU2006254796B2 (en) | 2012-08-16 |
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