CN110418800A - 治疗溶酶体紊乱的方法 - Google Patents
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Abstract
本文提供了通过将核酸分子离体引入造血干细胞和祖细胞(HSPC)中，然后将HSPC移植到需要治疗的受试者中来治疗溶酶体跨膜蛋白疾病或紊乱的方法。还提供了含有该核酸分子的载体。
Description
相关文献的交叉引用
本申请根据35U.S.C.§119(e)要求于2017年3月15日提交的美国系列号No.62/471,741，以及2017年5月17日提交的美国系列号No.62/507,713的优先权，其各自全部内容通过引用并入本文。
资助信息
本发明是在国立卫生研究院授予的资助号2R01-DK090058和PHS 7K23HL107755的政府支持下完成的。美国政府对本发明享有一定的权利。
序列表
本申请包含已经以ASCII形式进行电子提交的序列表并且其全部内容通过引用并入本文。所述ASCII副本，创建于2018年3月15日，命名为20378-201753_SL.txt，并且其大小为109千字节。
技术领域
本发明大体上涉及与功能障碍的跨膜溶酶体蛋白质相关的溶酶体疾病，更具体地涉及用造血干细胞和祖细胞(HSPC)基因疗法治疗这些疾病。
背景技术
溶酶体膜蛋白在溶酶体生命周期的几个关键步骤(包括腔酸化、代谢物输出、分子马达募集和与其他细胞器融合)起作用。溶酶体贮积病是由溶酶体功能缺陷引起的一组遗传性代谢紊乱。溶酶体是细胞内的酶的囊，其消化大分子并将碎片传递到细胞的其他部分以进行再循环。该过程需要几种关键酶。如果这些酶中的一种有缺陷(例如，由于突变)，大分子在细胞内积累，最终杀死它。
在～50种已知的溶酶体贮积病中，有若干种是由溶酶体膜蛋白功能障碍引起的。一种这样的溶酶体膜蛋白疾病是胱氨酸病，其特征在于体内所有细胞中氨基酸胱氨酸的异常积累导致多器官衰竭。胱氨酸病是由编码胱氨酸转运蛋白(cystinosin)(胱氨酸的溶酶体膜特异性转运蛋白)的CTNS基因突变引起的。如同所有氨基酸一样，胱氨酸的细胞内代谢需要其跨细胞膜转运。在内吞蛋白质降解为溶酶体内的胱氨酸后，通常将其转运至胞质溶胶中。但如果载体蛋白存在缺陷，则胱氨酸会在溶酶体中积累。由于胱氨酸高度不溶，当其在组织溶酶体中的浓度增加时，其溶解度立即被超过，并且在几乎所有器官和组织中形成结晶沉淀物。另一个例子是溶酶体贮积症，它是由LAMP-2基因(一种对自噬流至关重要的溶酶体跨膜蛋白)突变引起的。
迄今为止，对于这些溶酶体疾病没有已知的治愈方法或预防措施，目前的治疗方法是针对治疗相关症状。因此，本领域需要用于治疗溶酶体疾病/紊乱的替代或改进方法。
发明内容
因此，在一个方面，本发明提供了治疗受试者中溶酶体跨膜蛋白疾病或紊乱的方法。该方法包括将相应的功能性人溶酶体跨膜蛋白引入受试者的造血干细胞和祖细胞(HSPC)，并将HSPC移植入受试者，从而治疗溶酶体跨膜蛋白疾病或紊乱。因此，当溶酶体跨膜蛋白疾病或紊乱是胱氨酸病时，相应的功能性人溶酶体跨膜蛋白是胱氨酸转运蛋白(CTNS)；溶酶体跨膜蛋白疾病或紊乱是唾液酸贮积病或婴儿唾液酸贮积病，相应的功能性人溶酶体跨膜蛋白是唾液酸转运蛋白(SLC17A5)；溶酶体跨膜蛋白疾病或紊乱是钴胺素F型疾病，相应的功能性人溶酶体跨膜蛋白是LMBD1；溶酶体跨膜蛋白疾病或紊乱是晚期婴儿神经元蜡样脂褐质沉积症，相应的功能性人溶酶体跨膜蛋白是CLN7；溶酶体跨膜蛋白疾病或紊乱是青少年神经元蜡样脂褐质沉积症，相应的功能性人溶酶体跨膜蛋白是Battenin(CLN3)；溶酶体跨膜蛋白疾病或紊乱是恶性婴儿骨硬化症，相应的功能性人溶酶体跨膜蛋白是ClC-7或OSTM1；溶酶体跨膜蛋白疾病或紊乱是粘脂贮积病IV，相应的功能性人溶酶体跨膜蛋白是TRPML-1；溶酶体跨膜蛋白疾病或紊乱是粘多糖贮积症IIC型，相应的功能性人溶酶体跨膜蛋白是HGSNAT；溶酶体跨膜蛋白疾病或紊乱是Neiman-Pick C型，相应的功能性人溶酶体跨膜蛋白是NPC-1；并且溶酶体跨膜蛋白疾病或紊乱是溶酶体贮积症，相应的功能性人溶酶体跨膜蛋白是LAMP2。
在各种实施方案中，引入步骤可包括使包含编码功能性人溶酶体跨膜蛋白的多核苷酸和功能性启动子的载体与HSPC接触，并使得能够表达功能性人溶酶体跨膜蛋白。在各种实施方案中，溶酶体跨膜蛋白疾病或紊乱是胱氨酸病，并且功能性人溶酶体跨膜蛋白是CTNS。在各种实施方案中，溶酶体跨膜蛋白疾病或紊乱是溶酶体贮积症，并且功能性人溶酶体跨膜蛋白是LAMP2。LAMP2可以是选自由LAMP-2A、LAMP-2B、LAMP-2C组成的组的同种型。受试者可以是哺乳动物，诸如人。在各种实施方案中，载体是选自由慢病毒、腺病毒和AAV载体组成的组的病毒载体。在各种实施方案中，载体是慢病毒载体。在各种实施方案中，载体是腺病毒载体。在各种实施方案中，载体是AAV载体。在各种实施方案中，载体是自失活(SIN)-慢病毒载体，诸如pCCL-CTNS或pCCL-LAMP2。在各种实施方案中，引入步骤是离体进行的。在各种实施方案中，HSPC从受试者的骨髓中分离。
另一方面，本发明提供了表达盒，其包含与编码功能性人溶酶体跨膜蛋白的转基因(transgene)功能性连接的启动子，所述跨膜蛋白选自由CTNS、SLC17A5、LMBRD1、CLN7、CLN3、CLC-7、OSTM1、TRPML1、HGSNAT、NPC1和LAMP2组成的组。还提供了载体，诸如自失活(SIN)-慢病毒载体，其包括与编码功能性人溶酶体跨膜蛋白的多核苷酸功能性连接的启动子，所述功能性人溶酶体跨膜蛋白选自由CTNS、SLC17A5、LMBRD1、CLN7、CLN3。、CLC-7、OSTM1、TRPML1、HGSNAT、NPC1和LAMP2组成的组。在各种实施方案中，功能性人溶酶体跨膜蛋白是CTNS。在各种实施方案中，功能性人溶酶体跨膜蛋白是LAMP2。
另一方面，本发明提供治疗或改善受试者中溶酶体蛋白质疾病或紊乱的方法。该方法包括从受试者的骨髓中分离造血干细胞和HSPC细胞，将功能性人溶酶体跨膜基因引入HSPC，其中，该基因编码对应于溶酶体蛋白疾病或紊乱的蛋白质，并将HSPC移植回受试者，从而治疗或改善溶酶体蛋白质疾病或紊乱。因此，当溶酶体跨膜蛋白疾病或紊乱是胱氨酸病时，功能性人溶酶体跨膜基因是CTNS；溶酶体跨膜蛋白疾病或紊乱是唾液酸贮积病或婴儿唾液酸贮积病，功能性人溶酶体跨膜基因是SLC17A5；溶酶体跨膜蛋白疾病或紊乱是钴胺素F型疾病，功能性人溶酶体跨膜基因是LMBRD1；溶酶体跨膜蛋白疾病或紊乱是婴儿晚期神经元蜡样脂褐质沉积症，功能性人溶酶体跨膜基因是MFSD8；溶酶体跨膜蛋白疾病或紊乱是青少年神经元蜡样脂褐质沉积症，功能性人溶酶体跨膜基因是CLN3；溶酶体跨膜蛋白疾病或紊乱是恶性婴儿骨硬化症，功能性人溶酶体跨膜基因是CLCN7或OSTM1；溶酶体跨膜蛋白疾病或紊乱是粘脂贮积病IV，功能性人溶酶体跨膜基因是MCOLN1；溶酶体跨膜蛋白疾病或紊乱是粘多糖贮积症IIC型，功能性人溶酶体跨膜基因是HGSNAT；溶酶体跨膜蛋白疾病或紊乱是Neiman-Pick C型，功能性人溶酶体跨膜基因是NPC1；以及溶酶体跨膜蛋白疾病或紊乱是溶酶体贮积症，功能性人溶酶体跨膜基因是LAMP2。
在各种实施方案中，HSPC是CD34+细胞。在各种实施方案中，溶酶体蛋白质疾病或紊乱是胱氨酸病，并且功能性人溶酶体跨膜基因是CTNS。在各种实施方案中，溶酶体蛋白疾病或紊乱是溶酶体贮积症，并且功能性人溶酶体跨膜基因是LAMP2。在各种实施方案中，将功能性人CTNS基因引入HSPC的步骤包括使用载体，诸如病毒载体。在各种实施方案中，载体是选自由慢病毒、腺病毒和AAV载体组成的组的病毒载体。在各种实施方案中，治疗后，受试者的眼、皮肤、白细胞、实质组织或胃肠道中的胱氨酸水平降低。在各种实施方案中，剂量为为施用约1.0×106至5.0×106个细胞/kg，诸如2.5×106个细胞/kg作为单剂量。
在治疗之前，受试者可以进行半胱胺治疗，诸如口服半胱胺治疗。剂量施用可以是静脉内施用。在各种实施方案中，在治疗之前和/或之后，在眼、皮肤、白细胞、实质组织和/或胃肠道中测量胱氨酸或胱氨酸晶体。在各种实施方案中，在治疗之前和/或之后在眼中测量胱氨酸或胱氨酸晶体。在各种实施方案中，使用体内共聚焦显微镜测量胱氨酸晶体。在各种实施方案中，可以在治疗之前、期间和/或之后测量胱氨酸水平。在各种实施方案中，使用生物样品(诸如血液，直肠活组织切片或颊粘膜)测量胱氨酸水平。在各种实施方案中，从直肠活组织切片测量胱氨酸水平。
另一方面，本发明提供治疗或改善受试者中溶酶体蛋白质疾病或紊乱的方法。该方法包括使用基因编辑在受试者中产生功能性人溶酶体跨膜基因。因此，当溶酶体跨膜蛋白疾病或紊乱是胱氨酸病时，功能性人溶酶体跨膜基因是CTNS；溶酶体跨膜蛋白疾病或紊乱是唾液酸贮积病病或婴儿唾液酸贮积病，功能性人溶酶体跨膜基因是SLC17A5；溶酶体跨膜蛋白疾病或紊乱是钴胺素F型疾病，功能性人溶酶体跨膜基因是LMBRD1；溶酶体跨膜蛋白疾病或紊乱是婴儿晚期神经元蜡样脂褐质沉积症，功能性人溶酶体跨膜基因是MFSD8；溶酶体跨膜蛋白疾病或紊乱是青少年神经元蜡样脂褐质沉积症，功能性人溶酶体跨膜基因是CLN3；溶酶体跨膜蛋白疾病或紊乱是恶性婴儿骨硬化症，功能性人溶酶体跨膜基因是CLCN7或OSTM1；溶酶体跨膜蛋白疾病或紊乱是粘脂贮积病IV，功能性人溶酶体跨膜基因是MCOLN1；溶酶体跨膜蛋白疾病或紊乱是粘多糖贮积症IIC型，功能性人溶酶体跨膜基因是HGSNAT；溶酶体跨膜蛋白疾病或紊乱是Neiman-Pick C型，功能性人溶酶体跨膜基因是NPC1；并且溶酶体跨膜蛋白疾病或紊乱是溶酶体贮积症，功能性人溶酶体跨膜基因是LAMP2。
另一方面，本发明提供治疗或改善受试者中溶酶体蛋白质疾病或紊乱的方法。该方法包括使用编码基因编辑系统的载体接触来自受试者的表达缺陷型溶酶体跨膜蛋白的细胞，当转染到细胞中时，去除编码内源性溶酶体跨膜蛋白的基因的三核苷酸延伸突变，从而治疗溶酶体蛋白质疾病或紊乱。因此，当溶酶体跨膜蛋白疾病或紊乱是胱氨酸病时，溶酶体跨膜蛋白是胱氨酸转运蛋白(CTNS)；溶酶体跨膜蛋白疾病或紊乱是唾液酸贮积症或婴儿唾液酸贮积症，溶酶体跨膜蛋白是唾液酸转运蛋白(SLC17A5)；溶酶体跨膜蛋白疾病或紊乱是个钴胺素F型疾病，溶酶体跨膜蛋白是LMBD1；溶酶体跨膜蛋白疾病或紊乱是晚期婴儿神经元蜡样脂褐质沉积症，溶酶体跨膜蛋白是CLN7；溶酶体跨膜蛋白疾病或疾病是青少年神经元蜡样脂褐质沉积症，溶酶体跨膜蛋白是Battenin(CLN3)；溶酶体跨膜蛋白疾病或紊乱是恶性婴儿骨硬化症，溶酶体跨膜蛋白是ClC-7或OSTM1；溶酶体跨膜蛋白疾病或紊乱是粘脂贮积病IV，溶酶体跨膜蛋白是TRPML-1；溶酶体跨膜蛋白疾病或紊乱是粘多糖贮积症IIC型，溶酶体跨膜蛋白是HGSNAT；溶酶体跨膜蛋白疾病或紊乱是Neiman-Pick C型，溶酶体跨膜蛋白是NPC-1；并且溶酶体跨膜蛋白疾病或紊乱是溶酶体贮积症，溶酶体跨膜蛋白是LAMP2。
在各种实施方案中，基因编辑系统选自由CRISPR/Cas、锌指核酸酶、工程化大范围核酸酶、ARCUS和转录激活因子样效应核酸酶组成的组。在各种实施方案中，接触步骤包括向受试者施用有效量的载体。在各种实施方案中，接触步骤包括从受试者获得细胞样品，将基因编辑系统转染到细胞样品中，然后将转染的细胞移植到受试者内。在各种实施方案中，细胞样品选自由血细胞和HSPC组成的组。
附图说明
图1A-1D是显示15个月大的Ctns-/-小鼠的肾切片的组织学分析的示意图。图1A和1B显示了苏木精和伊红染色的结果，揭示了Ctns-/-小鼠中的严重异常(图1A)，而HSC移植的Ctns-/-小鼠仅表现出局灶性异常(图1B)。图1C和1D显示亚甲蓝染色的结果，揭示了在Ctns-/-小鼠的肾中存在大量胱氨酸晶体(图1C)，在经治疗的Ctns-/-小鼠中没有存在胱氨酸晶体(图1D)。
图2A和2B是显示角膜中胱氨酸晶体的图示和图解图。图2A显示了Ctns-/-对照及低和高HSC移植小鼠的侧角膜IVCM表示。图2B显示了来自Ctns-/-对照和经移植(低和高)小鼠的双眼的完整IVCM角膜扫描的每层内的表面晶体定量。误差柱代表SEM(*p<0.05，**p<0.005)。
图3是显示甲状腺研究结果的图解图。与野生型小鼠(WT)和移植有表达Ctns的HSC的Ctns-/-小鼠(经移植的Ctns-/-)相比，测量Ctns-/-小鼠中的胱氨酸含量(左图)和TSH水平(右图)。
图4是显示HSC移植对Ctns-/-小鼠胃肠道的影响的图示和图解图。左图：结肠的代表性共聚焦图片：可以看到表达丰富GFP的HSC衍生细胞。右图：与对照相比，HSC移植Ctns-/-小鼠中结肠和肠(intestine)中的胱氨酸含量。*P<0.05。
图5A-5D是显示TNT介导的胱氨酸转运蛋白转移是交叉校正的优选模式的图解和图示图。图5A和5B显示直方图，表示当与GFP-MSC或GFP-巨噬细胞(供体细胞)(每个N＝4个重复)接触共培养测定(图5A)或通过transwell测定的1-μm端口transwell过滤器分离(图5B)铺板时，DsRed-Ctns-/-成纤维细胞(受体细胞)中的胱氨酸含量的百分比降低。值是平均值±标准偏差。*P<0.05；**P<0.01；***p<0.005。图5C显示了从GFP-巨噬细胞延伸到DsRed-Ctns-/-成纤维细胞的TNT(箭头)的共聚焦图像。图5D显示来自共聚焦成像的代表性框架，共聚焦成像显示通过TNT从表达CTNS-GFP的巨噬细胞向Ctns-/-成纤维细胞(箭头)迁移含有胱氨酸转运蛋白-GFP的囊泡。比例尺:(图5C)30μm；(图5D)20μm。
图6A-6C是显示肾的TNT介导的体内转移研究的示意图。图6A显示了用GFPWT HSPC移植后6个月的8个月大的Ctns-/-小鼠的肾的共聚焦图像。GFP为绿色，层粘连蛋白为红色。PTC(管腔，#)用莲花四叶甙-凝集素(LT)(蓝色)标记。图6A-a1、6A-a2和6A a3显示表达eGFP的HSC来源细胞显示出许多延伸。箭头表示TBL穿越。凋亡PTC(*)。图6A-a3显示了表达GFP的绿色结构位于PTC内。图6B-6D显示了从移植有DsRed-Ctns-/-HSPC的Ctns-/-小鼠(对照，图6B)或移植有被慢病毒转导以表达胱氨酸-GFP并对鬼笔环肽染色的DsRed-Ctns-/-HSPC(图6C)获得的肾的Z-堆叠共聚焦图像。含有胱氨酸转运蛋白-GFP的囊泡在PTC的细胞质中丰富(图6C)。图6B和6C显示了蓝色染色的细胞核(DAPI)。比例尺：5μm(图6A)、10μm(图6B和6C)。
图7是显示pCCL-CTNS慢病毒载体结构的示意图。SIN-LTR＝自失活长末端重复；Ψ＝Psi序列；RRE＝rev响应元件；cPPT＝中央多嘌呤管道；EFS＝延伸因子1α短；CTNS cDNA＝人CTNS cDNA；WPRE＝土拨鼠肝炎转录后调控元件。
图8A-8D是显示雄性肾中胱氨酸和胱氨酸晶体定量的图解和图示图。图8A显示，未治疗的Ctns-/-小鼠(KO)与用pCCL-CTNS-HSC治疗相比较的胱氨酸含量。图8B显示用亚甲蓝染色的肾切片上的胱氨酸晶体的定量。与pCCLCTNS治疗的小鼠相反(8C)，在未治疗的Ctns-/-小鼠的肾切片中观察到丰富的胱氨酸晶体(图8D)。误差柱定义为平均值+SD，*P<0.05。
图9A-9B是显示体内毒理学研究结果的图解。图9A-1和9A-2显示了用pCCL-CTNS转导的HSC治疗的Ctns-/-雄性(图9A-1)和雌性(图9A-2)和空白处理的体重。图9B显示用pCCL-CTNS转导的HSC治疗的Ctns-/-小鼠和空白处理的组织中的胱氨酸含量。
图10A-10E是显示WT-HSPC移植受体的心脏和骨骼肌中LAMP2表达的示意图。图10A-10C是显示WT(图10A)、KO(图10B)和WT-HSPC移植的心脏中LAMP2表达的图像，其显示与WT-GFP+巨噬细胞相邻的心肌细胞中表达LAMP2的囊泡(图10C)。箭头展示出RFP+空泡。心脏(图10D)和骨骼肌(图10E)裂解物的Western印迹显示WT-HSPC移植的小鼠受体中LAMP2的表达恢复至接近WT水平。
图11是显示生理评估结果的图解图。与KO(未治疗的)和KO-HSPC受体小鼠相比，在WT-HSPC的小鼠受体中挽救了握力。与WT相比，*p<0.05；与WT-HSPC组相比，#p<0.05。
图12A-12D是显示在WT BMT后增加的自噬流的拯救的图示和图解图。图12A显示了WT、KO、WT-HSPC移植的小鼠和KO-HSPC移植小鼠的心脏的代表性EM图像。图12B显示EM图像的定量，证明WT-HSPC小鼠中AV积累的拯救接近至WT水平。图12C和12D显示Western印迹和结果，证明与KO小鼠相比，WT-HSPC移植的小鼠的LC-II/GAPDH水平降低。与WT相比，*p<0.05；与KO相比，#p<0.05。
具体实施方式
本发明部分基于以下发现：含有编码人胱氨酸转运蛋白(CTNS)或LAMP-2cDNA和功能性启动子的自失活(SIN)-慢病毒载体可用于离体基因-校正患者的自体造血干细胞和祖细胞(HSPC)，然后可以在患者中重新移植以重新填充其骨髓，其是患者剩余生命的“健康”细胞库。这些细胞动员并整合到疾病组织、脑、肌肉、心脏，引起它们的拯救。尽管自体HSPC用于本文的说明性实施例中，但本领域技术人员将认识到其他HSPC也是有用的(例如同种异体的)。
在描述本发明的组合物和方法之前，应理解本发明不限于所述的特定组合物、方法和实验条件，因为这样的组合物、方法和条件可以变化。还应理解，本文使用的术语仅用于描述特定实施方案的目的，而不是限制性的，因为本发明的范围仅限于所附权利要求。
如在本说明书和所附权利要求中使用的，除非上下文另有明确说明，单数形式“a”、“an”和“the”包括复数指代。因此，例如，对“该方法”的引用包括本文所述类型的一种或更多种方法和/或步骤，这些方法在阅读本发明等之后对于本领域技术人员而言将变得显而易见。
与“包括”、“含有”或“特征在于”可互换使用的术语“包含”是包含性或开放式语言，并且不排除另外的、未列举的元素或方法步骤。短语“由......组成”排除了权利要求中未指定的任何要素、步骤或成分。短语“基本上由......组成”将权利要求的范围限制于指定的材料或步骤以及不会实质上影响所要求保护的发明的基本和新颖特征的那些。本发明考虑了与这些短语中的每一个的范围相对应的本发明组合物和方法的实施方案。因此，包含所列举的要素或步骤的组合物或方法考虑了所述组合物或方法基本上由这些要素或步骤组成或由这些要素或步骤组成的特定实施方案。
除非另外定义，否则本文使用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常理解的含义相同的含义。尽管与本文描述的那些类似或等同的任何方法和材料可用于本发明的实践或测试，但现在描述优选的方法和材料。
如本文所用，术语“受试者”或“宿主生物”是指进行本发明方法的任何个体或患者。通常，受试者是人，但是如本领域技术人员所理解的，受试者可以是动物。因此其他动物(包括诸如啮齿类动物(包括小鼠、大鼠、仓鼠和豚鼠)、猫、狗、兔子等哺乳动物，包括牛、马、山羊、绵羊、猪等在内的农场动物，以及灵长类动物(包括猴子、黑猩猩、猩猩(orangutans)和大猩猩))包括在受试者的定义内。
术语“生物样品”是指取自参与者的任何样品，包括但不限于细胞、血液、组织、皮肤、尿液等，或毛发。
术语“颊粘膜”是指脸颊的内衬和口腔的底部。
术语“治疗有效量”或“有效量”是指研究人员、兽医、医生或其他临床医生正在寻求的引起组织、系统、动物或人的生物或医学响应的化合物或药物组合物的量。因此，术语“治疗有效量”在本文中用于表示当在一段时间内重复施用于患病区域时引起疾病状况显著改善的制剂的任何量。该量随所治疗的病症、病症的进展阶段以及所用制剂的类型和浓度而变化。在任何给定的示例中，适当的量对于本领域技术人员来说是显而易见的，或者能够通过常规实验确定。在胱氨酸转运蛋白的情况下，试剂(诸如转导、基因编辑或以其他方式修饰以表达人胱氨酸转运蛋白转基因的造血干细胞群)的治疗有效量的实例，是足以减少患者细胞(诸如肾、肝、肺、脾、肌肉、脑和/或心脏中的细胞)溶酶体中的胱氨酸(例如结晶胱氨酸)数量的量。
“剂量(dosage/dose)”被定义为包括涵盖在定义内的指定的大小、频率或暴露水平。
本文所用“治疗效果”，包括如本文所描述的治疗益处和/或预防性益处。
术语“施用(administration/administering)”定义为包括向需要治疗的受试者提供本发明的化合物或药物组合物的行为。本文所用的短语“肠胃外的施用”和“肠胃外地施用”是指除肠内和局部施用以外的施用方式，通常是口服或注射，包括但不限于静脉内、肌肉内、动脉内、鞘内、囊内、眶内、心内、皮内、腹膜内、经气管、皮下、表皮下，动脉内、囊下、蛛网膜下、脊柱内和胸骨内注射和输注。本文所用的短语“全身的施用”、“全身地施用”、“外周的施用”和“外周地施用”是指化合物、药物或其他物质通过除直接进入中枢神经系统之外的施用，使其进入受试者内(例如，皮下施用)，并因此，它可以进行新陈代谢和其他类似过程。
如果不能获得对细胞类型特异的病毒载体，则可以修饰载体以表达对靶细胞上表达的配体(或受体)特异的受体(或配体)，或者可以将其包封在脂质体内，其也可以修饰以包括这样的配体(或受体)。可以通过各种方法将肽试剂引入细胞中，包括例如通过改造肽以包含蛋白质转导结构域(诸如人免疫缺陷病毒TAT蛋白转导结构域，其可以促进肽转运到细胞中)。此外，还有各种基于生物材料的技术，诸如纳米笼和药物递送晶片(诸如用于脑癌化学治疗剂)，其也可以被修改以适应该技术。
最常评估基因转移的病毒载体是基于DNA的腺病毒(Ad)和腺相关病毒(AAV)和基于RNA的逆转录病毒和慢病毒。慢病毒载体最常用于实现染色体整合。
术语“实质”是指器官的功能部分，其有时包括相同和/或相邻器官的结构部分。
如本文所用，术语“减少”和“抑制”一起使用，因为认识到在某些情况下，减少可以降低至低于特定测定的检测水平。因此，可能并不总是清楚表达水平或活性是否“低于”测定检测水平，或者是否被完全“抑制”。然而，在根据本发明方法的治疗后，它将是清楚可确定的。
如本文所用，“治疗(treatment/treating)”意指将组合物施用于具有不期望病症的受试者或系统。该病症可包括疾病或紊乱(disorder)。“预防(Prevention/preventing)”是指将组合物施用于处于该病症风险的受试者或系统。该病症可包括对疾病或紊乱的易感性。施用组合物至受试者的效果(治疗和/或预防)可以是，但不限于，病症的一种或更多种症状的停止、病症的一种或更多种症状的减轻或预防，病症严重程度的降低、病症的完全消除、特定事件或特征的发展或进展的稳定或延迟，或特定事件或特征将发生的机会减到最小限度。
如本文所用，术语“遗传修饰”用于指以不在自然条件下发生的方式对生物体遗传物质的任何操作。进行这种操作的方法是本领域普通技术人员已知的，并包括但不限于利用具有感兴趣的核酸序列的载体转化细胞的技术。定义中包括各种形式的基因编辑，其中使用工程化的核酸酶或“分子剪刀”在生物体的基因组中插入、缺失或替换DNA。这些核酸酶在基因组中的所需位置产生位点特异性双链断裂(DSB)。诱导的双链断裂通过非同源末端连接(NHEJ)或同源重组(HR)修复，引起靶向突变(即编辑)。
在基因编辑中存在几个工程化核酸酶家族，例如但不限于，大范围核酸酶、锌指核酸酶(ZFN)、基于转录激活因子样效应核酸酶(TALEN)，CRISPR-Cas系统，和ARCUS。然而，应该理解，任何已知的利用工程化核酸酶的基因编辑系统都可以用于本文所述的方法中。
CRISPR(簇状规则间隔短回文重复序列)是包含多个、短的、直接重复的碱基序列的DNA基因座的首字母缩写。原核生物CRISPR/Cas系统已经适合用作真核生物中的基因编辑(沉默、增强或改变特定基因)(参见，例如Cong,Science,15:339(6121):819-823(2013)和Jinek,et al.,Science,337(6096):816-21(2012))。通过用包含Cas基因和特别设计的CRISPR的元件转染细胞，可以在任何所需位置切割和修饰核酸序列。使用CRISPR/Cas系统制备用于基因组编辑的组合物的方法详细描述于美国公开号2016/0340661、美国公开号20160340662、美国公开号2016/0354487、美国公开号2016/0355796、美国公开号20160355797和WO2014/018423中，其全部内容通过引用明确并入本文。
因此，如本文所用，“CRISPR系统”统称为涉及表达或指导CRISPR相关(“Cas”)基因活性的转录物和其他元件，包括编码Cas基因的序列、tracr(反式激活CRISPR)序列(例如，tracrRNA或活性部分tracrRNA)、tracr配对序列(包括在内源CRISPR系统的背景下的“直接重复”和tracrRNA处理的部分直接重复)、向导序列(在内源CRISPR系统的背景下也称为“间隔区”、“向导RNA”或“gRNA”)，或来自CRISPR基因座的其他序列和转录物。与向导序列可操作地连接的一个或更多个tracr配对序列(例如，直接重复-间隔区-直接重复)也可以在加工前称为“pre-crRNA”(pre-CRISPR RNA)或在通过核酸酶处理后称为crRNA。
在一些实施方案中，tracrRNA和crRNA连接并形成嵌合crRNA-tracrRNA杂合体，其中成熟crRNA通过合成茎环与部分tracrRNA融合以模拟天然crRNA:tracrRNA双链体，如Cong,Science,15:339(6121):819-823(2013)和Jinek,et al.,Science,337(6096):816-21(2012)中所述。单个融合的crRNA-tracrRNA构建体也可称为向导RNA或gRNA(或单向导RNA(sgRNA))。在sgRNA内，crRNA部分可以被鉴定为“靶序列”，并且tracrRNA通常被称为“支架”。
一旦鉴定了所需的DNA靶序列，有许多资源可用于帮助从业者确定合适的靶位点。例如，许多公共资源(包括生物信息学生成的靶向超过40％的人类外显子的大约190000个潜在sgRNA的列表)，可用于帮助从业者选择靶位点并设计相关sgRNA以影响位点处的切口或双链断裂。另请参见crispr.u-psud.fr，这是一种旨在帮助科学家在多种物种中找到CRISPR靶向位点并生成合适的crRNA序列的工具。
在一些实施方案中，将驱动CRISPR系统的一种或更多种元件表达的一种或更多种载体引入靶细胞中，使得CRISPR系统的元件的表达引导在一个或更多个靶位点处形成CRISPR复合物。虽然在不同的工程CRISPR系统中细节可以变化，但总体方法是类似的。对使用CRISPR技术靶向DNA序列感兴趣的从业者可以将含有靶序列的短DNA片段插入向导RNA表达质粒中。sgRNA表达质粒含有靶序列(约20个核苷酸)，tracrRNA序列的形式(支架)以及合适的启动子和在真核细胞中适当加工的必需元件。此类载体可商购获得(参见，例如，Addgene)。许多系统依赖于定制的互补寡核苷酸(被退火以形成双链DNA)，然后克隆到sgRNA表达质粒中。来自相同或不同质粒的sgRNA和合适的Cas酶在转染细胞中的共表达引起在所需靶位点处的单链或双链断裂(取决于Cas酶的活性)。
锌指核酸酶(ZFN)是通过将锌指DNA结合结构域与DNA切割结构域融合而产生的人工限制酶。可以工程化锌指结构域以靶向特定的所需DNA序列，并且这使得锌指核酸酶能够靶向复杂基因组内的独特序列。通过利用内源DNA修复机制，这些试剂可用于精确改变高等生物的基因组。最常见的切割结构域是IIS型酶Fok1。Fok1在距离一条链上的识别位点为9个核苷酸和距离另一条链上的识别位点为13个核苷酸处催化DNA的双链切割。参见，例如，美国专利号5,356,802；5,436,150和5,487,994；以及Li et al.Proc.,Natl.Acad.Sci.USA89(1992):4275-4279；Li et al.Proc.Natl.Acad.Sci.USA,90:2764-2768(1993)；Kim etal.Proc.Natl.Acad.Sci.USA.91:883-887(1994a)；Kim et al.J.Biol.Chem.269:31,978-31,982(1994b)，所有这些文献都通过引用并入本文。这些酶中的一种或更多种(或其酶促功能片段)可用作切割结构域的来源。
转录激活因子样效应核酸酶(TALEN)具有与ZFN类似的总体结构，主要区别在于DNA结合结构域来自TAL效应蛋白，转录因子来自植物病原细菌。TALEN的DNA结合结构域是氨基酸重复的串联阵列，每个重复长约34个残基。重复非常相似；通常它们主要在两个位置(第12和13位氨基酸，称为重复变量双残基或RVD)不同。尽管已知NN RVD除鸟嘌呤外还结合腺嘌呤，但每个RVD优先指定结合四种可能的核苷酸之一，这意味着每个TALEN重复结合单个碱基对。与锌指蛋白相比，TAL效应子DNA结合在机理上不太清楚，但它们看似简单的代码可能对工程核酸酶设计非常有益。TALEN还作为二聚体切割，具有相对长的靶序列(迄今为止报道的每个单体最短结合13个核苷酸)并且对于结合位点之间的间隔区长度似乎没有比ZFN更严格的要求。单体和二聚体TALEN可包括超过10个、超过14个、超过20个或超过24个重复。工程化TAL与特定核酸结合的方法描述于Cermak,et al,Nucl.Acids Res.1-11(2011)；美国公布申请号2011/0145940，其公开了TAL效应子和使用它们修饰DNA的方法；Miller etal.Nature Biotechnol 29:143(2011)报道了通过将TAL截短变体连接到Fok1核酸酶的催化结构域来制备用于位点特异性核酸酶结构的TALEN。显示所得TALEN在永生化人细胞中诱导基因修饰。TALE结合结构域的一般设计原理可以在例如WO2011/072246中找到。上述每篇参考文献都通过引用整体并入本文。
本文所述的基因组编辑系统的核酸酶活性切割靶DNA以在靶DNA中产生单链或双链断裂。双链断裂可由细胞以两种方式之一修复：非同源末端连接和同源定向修复。在非同源末端连接(NHEJ)中，通过断裂末端彼此直接连接来修复双链断裂。因此，尽管一些核酸材料可能丢失而导致缺失，但没有新的核酸材料插入该位点。在同源定向修复中，与经切割的靶DNA序列具有同源性的供体多核苷酸用作修复经切割的靶DNA序列的模板，引起遗传信息从供体多核苷酸转移至靶DNA。因此，可以将新的核酸材料插入/复制到该位点。因此，在一些实施方案中，基因组编辑载体或组合物可选地包含供体多核苷酸。由NHEJ和/或同源定向修复引起的靶DNA修饰可用于诱导基因校正、基因置换、基因标记、转基因插入、核苷酸缺失、基因破坏、基因突变等。
因此，通过基因组编辑载体或组合物的DNA的切割可用于通过切割靶DNA序列从靶DNA序列中缺失核酸材料，并使得细胞能够在没有外源提供的供体多核苷酸的情况下修复序列。或者，如果基因组编辑组合物包括供体多核苷酸序列(至少包含与靶DNA序列具有同源性的区段)，则该方法可用于将核酸材料添加(即插入或替换)至靶DNA序列(例如，“敲入”编码蛋白质、siRNA、miRNA等的核酸)，以添加标签(例如，6×His(SEQ ID NO:27)、荧光蛋白质(例如，绿色荧光蛋白；黄色荧光蛋白等)、血凝素(HA)、FLAG等)，为基因添加调控序列(如启动子、多腺苷酸化信号、内部核糖体进入序列(IRES)、2A肽、启动密码子、终止密码子、剪接信号，定位信号等)，以修饰核酸序列(例如，引入突变)等。因此，该组合物可用于以位点特异性(即“靶向”方式)修饰DNA(例如，用于基因疗法的，例如基因敲除、基因敲入、基因编辑、基因标记等)。
ARCUS是源自称为“归巢内切核酸酶”的天然基因组编辑酶的基因组编辑平台。归巢核酸内切酶是在许多真核物种的基因组中编码的位点特异性DNA切割酶，其能够精确识别长DNA序列(12-40个碱基对)。这些非破坏性酶触发基因转换事件，以非常精确的方式修饰基因组，最常见的是通过插入新的DNA序列。因此，ARCUS基因组编辑平台依赖于工程化的ARC核酸酶，其是与归巢核酸内切酶类似的完全合成，但具有改进的特异性以识别任何靶基因内的DNA序列的酶。
术语“多肽”、“肽”和“蛋白质”在本文中可互换使用，指氨基酸残基的聚合物。该术语适用于氨基酸聚合物(其中一个或更多个氨基酸残基是相应天然存在的氨基酸的人工化学模拟物)，以及天然存在的氨基酸聚合物和非天然存在的氨基酸聚合物。
术语“氨基酸”是指天然存在的和合成的氨基酸，以及以与天然存在的氨基酸类似的方式起作用的氨基酸类似物和氨基酸模拟物。天然存在的氨基酸是由遗传密码编码的氨基酸，以及后来被修饰的那些氨基酸，例如羟脯氨酸、α-羧基谷氨酸和O-磷酸丝氨酸。氨基酸类似物是指与天然存在的氨基酸具有相同基本化学结构的化合物，即与氢、羧基、氨基和R基团结合的α碳，例如高丝氨酸、正亮氨酸、蛋氨酸亚砜、蛋氨酸甲基锍。此类类似物具有经修饰的R基团(例如正亮氨酸)或经修饰的肽主链，但保留与天然存在的氨基酸相同的基本化学结构。氨基酸模拟物是指具有与氨基酸的一般化学结构不同的结构但是以与天然存在的氨基酸类似的方式起作用的化学化合物。
氨基酸在本文中可以通过它们通常已知的三字母符号或由IUPAC-IUB生物化学命名委员会推荐的单字母符号表示。同样，核苷酸可以通过它们通常被接受的单字母代码来表示。
如本文所用，“调节基因”或“调节序列”是编码控制其他基因表达的产物(例如转录因子)的核酸序列。
如本文所用，“蛋白质编码序列”或编码特定蛋白质或多肽的序列是当置于合适的调节序列控制下时，转录成mRNA(在DNA的情况下)并在体外或体内被翻译(在mRNA的情况下)成多肽的核酸序列。编码序列的边界由5'末端(N末端)的起始密码子和3'末端(C末端)的翻译终止无义密码子决定。编码序列可包括但不限于来自真核mRNA的cDNA，来自真核DNA的基因组DNA序列和合成的核酸。转录终止序列通常位于编码序列的3'。
如本文所用，“启动子”定义为通常位于基因上游的调节DNA序列，其通过引导RNA聚合酶结合DNA并启动RNA合成来介导转录起始。启动子可以是组成型活性启动子(即，持续地处于活性/“ON”状态的启动子)，它可以是诱导型启动子(即，其状态(活性/“ON”或非活性/“OFF”)受外部刺激(例如，特定化合物或蛋白质的存在)控制的启动子)，它可以是空间限制的启动子(即转录控制元件、增强子等)(例如，组织特异性启动子、特定细胞类型启动子)，它可以是时间限制的启动子(即，在胚胎发育的特定阶段或在生物过程的特定阶段期间，启动子处于“ON”状态或“OFF”状态。因此，在各种实施方案中，启动子可以是驱动转基因表达的干细胞特异性启动子。例如，可以使用不同强度的组成型启动子。根据本发明的表达载体和质粒可以包括一种或更多种组成型启动子(诸如病毒启动子，或来自哺乳动物基因的启动子，其通常在促进转录方面具有活性)。示例性启动子包括但不限于人延长因子1α启动子(EFS)、SV40早期启动子、小鼠乳腺肿瘤病毒长末端重复序列(LTR)启动子；腺病毒主要晚期启动子(Ad MLP)；单纯疱疹病毒(HSV)启动子、与感兴趣基因异源的内源性细胞启动子、巨细胞病毒(CMV)启动子(诸如CMV立即早期启动子区域(CMVIE))、劳斯肉瘤病毒(RSV)启动子、合成启动子、杂合启动子等。
如本文所用，术语“基因”意指包含结构基因的编码区的脱氧核糖核苷酸序列。“基因”还可以包括位于5'和3'末端的编码区附近的非翻译序列，使得该基因对应于全长mRNA的长度。位于编码区5'并且存在于mRNA上的序列称为5'非翻译序列。位于编码区3'或下游并且存在于mRNA上的序列称为3'非翻译序列。术语“基因”包括基因的cDNA和基因组形式。基因的基因组形式或克隆含有被称为“内含子”或“插入区域”或“插入序列”的非编码序列中断的编码区。内含子是转录成异源核RNA(hnRNA)的基因片段；内含子可能含有调节元件，诸如增强子。从核或初级转录物移除或“剪接”内含子；因此内含子不存在于信使RNA(mRNA)转录物中。mRNA在翻译过程中起作用以指定新生多肽中氨基酸的序列或顺序。
如本文所用，术语“功能性连接”和“可操作地连接”可互换使用，并且指两个或更多个DNA片段之间的功能关系，特别是待表达的基因序列和控制其表达的那些序列。例如，如果它在合适的宿主细胞或其它表达系统中刺激或调节编码序列的转录，则包括顺式作用转录控制元件的任何组合的启动子/增强子序列，与编码序列可操作地连接。与转录的基因序列可操作连接的启动子调节序列与转录序列在物理上连续。
“保守修饰的变体”适用于氨基酸和核酸序列。关于特定的核酸序列，保守修饰的变体是指编码相同或基本相同的氨基酸序列的核酸，或者在核酸不编码氨基酸序列的情况下，指基本上相同的序列。由于遗传密码的简并性，大量功能相同的核酸编码任何给定的蛋白质。例如，密码子GCA、GCC、GCG和GCU都编码氨基酸丙氨酸。因此，在密码子指定丙氨酸的每个位置，密码子可以改变为所述的任何相应密码子而不改变编码的多肽。这种核酸变异是“沉默变异”，其是保守修饰变异的一种。本文中编码多肽的每个核酸序列也描述了核酸的每种可能的沉默变异。技术人员将认识到，核酸中的每个密码子(除了AUG，其通常是甲硫氨酸的唯一密码子，和TGG，其通常是色氨酸的唯一密码子)可以被修饰以产生功能相同的分子。因此，编码多肽的核酸的每个沉默变异隐含在每个所描述的序列中。
关于氨基酸序列，技术人员将认识到在编码序列中改变、添加或缺失单个氨基酸或少量氨基酸的核酸、肽、多肽或蛋白质序列的个体取代、缺失或添加，是“保守修饰的变体”，其中改变由化学上相似氨基酸取代氨基酸引起。提供功能相似的氨基酸的保守取代表是本领域熟知的。此类保守修饰的变体是对本发明的多态变体、种间同源物和等位基因的补充，并且不排除多态变体、种间同源物和等位基因。
如本文所用的术语“抗体”是指多克隆和单克隆抗体及其片段，及其免疫结合等同物。术语“抗体”是指同质分子实体，或混合物(诸如由多种不同分子实体组成的多克隆血清产物，并且广泛地包括天然存在形式的抗体(例如，IgG、IgA、IgM、IgE)和重组抗体(诸如单链抗体、嵌合和人源化抗体和多特异性抗体))。术语“抗体”还指所有前述的片段和衍生物，并且可以进一步包含其保留特异性结合表位的能力的任何修饰的或衍生的变体。抗体衍生物可包含与抗体缀合的蛋白质或化学部分。单克隆抗体能够选择性地结合靶抗原或表位。抗体可包括但不限于多克隆抗体、单克隆抗体(mAb)、人源化或嵌合抗体、骆驼抗体、单链抗体(scFv)、Fab片段、F(ab')2片段、二硫键连接的Fv(sdFv)片段(例如，由Fab表达文库产生)、抗独特型(抗Id)抗体、胞内抗体、纳米抗体、合成抗体和任何上述的表位结合片段。
如本文所用，术语“人源化小鼠”(Hu-小鼠)是开发用于携带功能性人基因、细胞、组织和/或器官的小鼠。人源化小鼠通常用作人类治疗的生物学和医学研究中的小动物模型。免疫缺陷小鼠通常用作人细胞或组织的接受者，因为它们由于缺乏宿主免疫力而相对容易地接受异源细胞。
HSC具有多能性(即，一种HSC可以分化成所有功能性血细胞)和自我更新(即，HSC可以分裂并产生相同的子细胞，而没有分化)的能力。通过一系列谱系定向(lineagecommitment)步骤，HSC产生逐渐丧失自我更新潜力的后代，并且其分化能力逐渐变得越来越受限，产生多潜能和谱系定向的祖细胞，并最终成熟的功能性循环血细胞。
造血干细胞和祖细胞(HSPC)自我更新和分化的能力是终生造血的形成和维持的基础，并且这些过程的失调可能导致严重的临床后果。HSPC对于它们在移植时重建造血系统的能力也非常有价值，这使得它们能够在临床中用于治疗多种紊乱，包括骨髓衰竭、骨髓增生性紊乱和其他影响血细胞的获得性或遗传性紊乱。
如本文所用，“多能细胞”是指源自通过激活含有所有雌性或雄性来源的DNA的细胞产生的胚胎的细胞，所述细胞可以未分化状态在体外长时间(理论上无限期的时间)维持，未分化的状态的细胞可以产生不同的分化组织类型，即外胚层、中胚层和内胚层。“胚胎干细胞”(ES细胞)是源自早期植入前胚胎的胚泡的内细胞团的多能干细胞。
如本文所用，“自体移植”是指使用受试者自身干细胞的移植。预先收集这些细胞并在稍后阶段返回。因此，“同种异体移植”是指干细胞的供体和受体是不同的人的移植。示例性同种异体细胞包括但不限于同基因细胞、MHC匹配细胞等。
如本文所用，“药学上可接受的载体”包括任何标准药物载体，诸如磷酸盐缓冲盐水溶液、水和乳液(诸如油/水或水/油乳液)，和各种类型的润湿剂。
如本文所用，“溶酶体蛋白质紊乱”或“溶酶体蛋白质疾病”是指由溶酶体功能缺陷引起的任何代谢紊乱。也称为“溶酶体贮积症”，这些疾病/紊乱通常由溶酶体功能障碍引起，通常是由于脂质、糖蛋白(含糖蛋白质)或所谓的粘多糖代谢所需的单一酶缺乏的结果。示例性溶酶体贮积症包括但不限于胱氨酸病、唾液酸贮积病、婴儿唾液酸贮积病、钴胺素F型病、神经元蜡样脂褐质沉积病(婴儿晚期和青少年型)、恶性婴儿骨硬化症、粘脂贮积病IV、粘多糖贮积症IIIC型(Sanfilippo综合征C)、Niemann-Pick C型和溶酶体贮积症(Ruivo,et al.Biochimica et Biophysica Acta 1793(2009)636-649，通过引用并入本文)。
例如，胱氨酸病是一种常染色体代谢疾病，属于溶酶体贮积症的家族。即使使用半胱胺治疗，胱氨酸病对患病的个体(主要是儿童和年轻人)，也具有破坏性影响。胱氨酸病的患病率为1:100000至1:200000。参与胱氨酸病的基因是编码7-跨膜溶酶体胱氨酸转运蛋白(胱氨酸转运蛋白)的基因CTNS。最严重和最常见的胱氨酸病形式是婴儿型，也称为肾病性胱氨酸病。儿童在6-8个月时出现肾Fanconi综合征，其特征是严重的液体和电解质紊乱，生长迟缓和佝偻病。肾小球功能的逐渐丧失导致肾功能衰竭；根据NAPRTCS(北美儿科肾试验和合作研究)，1.4％的透析儿童(2011年度透析报告)和2.1％的肾移植手术(2010年度移植报告)患有胱氨酸病。作为临床实体的胱氨酸病也是由于体内所有细胞的溶酶体中胱氨酸积累引起的多器官进行性功能障碍；患病患者在细胞中储存的胱氨酸是正常量的50-100倍。
胱氨酸储存导致在所有组织中形成胱氨酸晶体。胱氨酸病的主要临床并发症包括糖尿病、甲状腺功能减退，肌病和中枢神经系统恶化。角膜胱氨酸晶体出现在生命的第一个十年，导致畏光和视觉障碍。与肌肉萎缩直接相关的吞咽困难，是胱氨酸病死亡的主要原因。除了胱氨酸积聚之外，细胞功能障碍诸如异常囊泡运输、自噬和TFEB(转录因子EB)信号传导也被描述为导致胱氨酸病的发病机制。
目前对于胱氨酸病的治疗是药物半胱胺(巯基乙胺)，其降低细胞内胱氨酸含量。然而，该疗法仅延迟疾病进展并且对肾Fanconi综合征没有效果，也不能预防患病患者的终末期肾衰竭。半胱胺还被证明对改善CTNS缺陷细胞中的细胞功能障碍是无效的，证明胱氨酸病的细胞缺陷不仅是由于胱氨酸积累，而且还是由于缺乏与关键细胞成分直接相互作用的胱氨酸转运蛋白本身。
此外，半胱胺必须每6小时服用一次，包括在晚上服用，并且导致不良的体臭以及严重的胃肠道副作用(诸如呕吐和腹泻)，这使得治疗依从性变得困难。2013年，延迟释放的半胱胺制剂获得FDA批准，需要每12小时给药一次。虽然减少了剂量，改善了患者生活质量，但对疾病的影响与立即释放的半胱胺类似，患者仍然会出现胃副作用。此外，这种药物的成本非常高，每位患者每年300000美元至600000美元。
胱氨酸病的眼病变需要每小时局部施用半胱胺滴眼液，这会引起刺激和灼烧，因此依从性非常具有挑战性。每名患者每年的眼药水费用约为50000美元。半胱胺和所有与胱氨酸病相关的并发症的支持性治疗需要患者每天服用多达60粒；孩子们经常需要放置胃管以便能够耐受药物并获得必需的热量摄入。随着年龄的增长，医疗并发症的严重程度和数量都会增加，导致新的和不断增加的症状和治疗。有无休止的医生预约、G管喂养、频繁的抽血、生长激素注射、骨痛、每日呕吐、眼痛和严重的胃肠道副作用。随着疾病的进展，他们的身体会恶化。成人最严重的并发症是肌病、肺部问题和角膜囊肿病的进展。肾衰竭患者需要透析或移植，这两者都具有显著的负面健康影响，并且由于供体器官的严重短缺，患者可能需要等待三到六年才能进行移植。因此，目前的护理标准不能预防疾病的进展，并且显著影响仍在成年早期死亡的胱氨酸病患者的生活质量。
溶酶体贮积症与其他溶酶体膜蛋白疾病具有许多相似性，并且其特征在于影响许多细胞组分的降解的自噬紊乱，因此不会导致单个基质的积累。溶酶体贮积症最近被描述为自噬性空泡性肌病。溶酶体贮积症是由编码溶酶体相关膜蛋白2(LAMP-2)的基因突变引起的，导致LAMP-2蛋白表达降低。LAMP-2表达的丧失破坏了自噬流，削弱了细胞对应激反应以及去除受损的细胞成分的能力。
因此，本发明证明一次性造血干细胞和祖细胞(HSPC)移植具有成为与有缺陷的溶酶体跨膜蛋白相关的疾病或紊乱的终生治愈性疗法的潜力。该疗法可进一步预防肾移植和与胱氨酸病相关的长期并发症，包括意外地清除角膜胱氨酸晶体。这也应该使得患者能够无需口服半胱胺、半胱胺滴眼液和用于治疗与疾病相关症状的任何其他药物。因此，患者的生活质量大大提高，治疗成本大大降低。
由于胱氨酸病的多系统性质和补偿在每个组织中胱氨酸转运蛋白不存在而所需的所有药物，研究了基因治疗方法。基因治疗有可能成为第三个千年治疗罕见和常见严重疾病的重要新方法，因为它的范围远远超出常规药物的范围，并提供了相比同种异体HSC移植，风险有限的治疗性干细胞治疗的前景。因此，造血干细胞和祖细胞(HSPC)因其易于分离、自我更新能力和安全性而成为用于再生医学和细胞替代疗法的理想候选者。此外，基因治疗可以解决未满足的医疗需求，诸如在胱氨酸病的情况下，尤其是该策略克服了经匹配的HSC供体的不可用性并且使得治疗可能对所有患者可用。
使用胱氨酸病的啮齿动物模型(Cstns-/-小鼠)，已经显示移植表达功能性Ctns基因的HSC引起骨髓衍生细胞的丰富组织整合，胱氨酸积累显著减少(高达97％清除率)，以及长期肾的保留。实际上，虽然未经治疗的Cstns-/-小鼠进展至终末期肾衰竭，但移植了野生型HSC的年龄匹配的Cstns-/-小鼠在移植后超过一年后维持正常的肾功能。与未治疗的Cstns-/-小鼠在肾中始终观察到大量的胱氨酸晶体相比，在经治疗的小鼠的肾中几乎没有或没有观察到胱氨酸晶体。最近还证实了HSC移植可以挽救Cstns-/-小鼠的眼部缺陷。经治疗的Cstns-/-小鼠表现出从上皮层到中间基质的胱氨酸晶体几乎完全消除(分别减少100％至72％)，以及正常的角膜厚度和眼内压。还研究了移植的HSC对甲状腺的影响。Cstns-/-小鼠存在持续的TSH活化，伴有甲状腺细胞肥大、增生和血管增生。相反，用移植的HSC治疗的Cstns-/-小鼠表现出胱氨酸和TSH值的正常化以及正常的组织学。这些研究首次证明单一HSC移植可以预防与胱氨酸病相关的多器官变性。
因此，本发明评估了小鼠模型中HSPC移植对胱氨酸病(Cstns-/-小鼠)的影响。使用胱氨酸病小鼠模型(Cstns-/-小鼠)，本发明证明野生型(WT)鼠造血干细胞(mHSCs)的移植引起骨髓衍生细胞的丰富组织整合，组织胱氨酸积累显著减少(减少高达97％)和长期肾、眼和甲状腺保留。考虑到与同种异体HSC移植相关的死亡率和发病率的风险(诸如移植物抗宿主病(GVHD))，开发了用于离体修饰的HSC的自体移植方案。使用自失活的慢病毒载体(SIN-LV)引入CTNS cDNA，pCCL-CTNS(骨架pCCL-EFS-X-WPRE)的功能形式，已显示在Cstns-/-小鼠中的功效。
使用从健康供体和胱氨酸病患者的外周血分离的人CD34+HSPC的体外研究现已完成，并且Cstns-/-小鼠中的连续移植已显著进展。因此，本文提供的数据证明了通过使用pCCL-CTNS LV离体转导修饰的来自患有胱氨酸病的G-CSF动员的外周血干细胞(PBSC)的CD34+HSC移植的功效。
胱氨酸病和溶酶体贮积症均分别由跨膜溶酶体蛋白(胱氨酸转运蛋白和LAMP-2)中的功能丧失突变引起。实际上，胱氨酸转运蛋白定位于在交叉校正(cross-correction)期间转移的LAMP-2阳性囊泡。因此，本发明还证明从患有溶酶体贮积症的患者收获骨髓并分选CD34+造血干细胞(HPSC)。收获后，使用病毒转导载体对患者HPSC进行遗传修饰，所述病毒转导载体包括但不限于携带LAMP-2基因的任何正常变体和/或任何LAMP-2剪接同种型(LAMP-2A，LAMP-2B，LAMP-2C)的慢病毒和其他逆转录病毒，将下文统称为“野生型LAMP-2”或“WT LAMP-2”，插入收获的HPSC的基因组中。感染后，病毒载体将野生型LAMP-2转基因插入宿主细胞基因组中的限制基因组破坏的特定位点。然后该插入使得野生型LAMP-2转基因能够由宿主细胞稳定表达。翻译后，将野生型LAMP-2蛋白质转运至溶酶体膜，在其中嵌入并呈现其正常的细胞内位置。将野生型LAMP-2蛋白引入溶酶体膜可恢复自噬流，使细胞正常发挥功能。
在引入野生型LAMP-2基因后，将HPSC移植回收获它们的患者。然后这些细胞重新植入患者的骨髓并开始产生祖细胞。这些祖细胞中的一些分化成携带野生型LAMP-2基因的单核细胞。具有野生型LAMP-2基因的单核细胞进入循环并随后侵入外周组织，在那里它们转化为组织驻留的巨噬细胞。这些巨噬细胞通过多种机制，包括但不限于隧道纳米管的形成、囊泡释放和直接的细胞-细胞粘附，将它们携带膜结合的野生型LAMP-2蛋白的溶酶体转移到患病外周细胞。野生型LAMP-2蛋白也可以以另外的形式在巨噬细胞和患病的外周细胞之间转移，包括但不限于游离蛋白或与其他蛋白、膜或细胞器结合。含有野生型LAMP-2的溶酶体或其他形式的野生型LAMP-2的转移恢复了患病细胞中的正常自噬流，使得溶酶体贮积症得到部分或完全改善。
因此，在一个方面，本发明提供了治疗受试者中溶酶体跨膜蛋白疾病或紊乱的方法。该方法包括将对应于待治疗紊乱的功能性人跨膜蛋白离体引入受试者的HSPC，然后将HSPC移植入受试者，从而治疗溶酶体跨膜蛋白疾病或紊乱。因此，例如，当待治疗的疾病或紊乱是胱氨酸病时，待引入的功能性人跨膜蛋白是CTNS。在各种实施方案中，载体是自失活(SIN)-慢病毒载体，诸如pCCL-CTNS(在CTNS的情况下)。同样，当待治疗的疾病或紊乱是溶酶体贮积症时，待引入的功能性人跨膜蛋白是LAMP-2。在各种实施方案中，引入步骤可包括使包含编码功能性蛋白质的多核苷酸(例如，CTNS或LAMP-2)与功能性启动子(例如，功能性蛋白质普遍存在或内源的启动子)的载体与HSPC接触，并使得能够表达功能性蛋白质。因此，本发明内容提供了用于离体基因修饰的HSPC的自体移植以引入与特定溶酶体跨膜蛋白疾病或紊乱相关的功能性蛋白质的方法。
在各种实施方案中，溶酶体跨膜蛋白疾病或紊乱包括但不限于胱氨酸病、唾液酸贮积病、婴儿唾液酸贮积病、钴胺素F型病、神经元蜡样脂褐质沉积病(婴儿晚期和青少年型)、恶性婴儿骨硬化病、粘脂贮积病IV、粘多糖贮积症IIIC型(Sanfilippo综合征C)、Niemann-Pick C型和溶酶体贮积症。不受理论束缚，在胱氨酸病和游离唾液酸贮积病中，胱氨酸和酸性单糖的转运蛋白分别被阻断或延迟。推定的钴胺素转运蛋白和乙酰基的杂合转运蛋白/转移酶分别在钴胺素F型疾病和IIIC型粘多糖贮积症中是有缺陷的。在骨硬化病的神经变性形式中，质子/氯化物交换剂的突变损害了V型ATP酶维持质子泵送所需的电荷平衡，从而导致骨吸收空隙中和。然而，导致溶酶体贮积和神经变性的机制仍不清楚。粘脂贮积病IV是由名为TRPML1的溶酶体阳离子通道的突变引起的；它的门控特性仍然知之甚少，并且将这种通道与脂质贮积和膜交通缺陷联系起来的离子种类也存在争议。最后，溶酶体贮积症的自噬缺陷显然源于LAMP2在溶酶体/自噬体融合中的作用，可能继发于基于动力蛋白的向心运动中的作用(Ruivo,et al.Biochimica et Biophysica Acta 1793(2009)636-649，通过引用并入本文)。
表1列出了用离体引入相应的功能性人跨膜蛋白治疗的示例性溶酶体跨膜蛋白疾病或紊乱。
表1
由于其优异的基因转移效率和更好的生物安全性，来源自慢病毒的载体已经取代了用于基因治疗的γ-逆转录病毒载体。实际上，迄今为止在临床试验或动物模型中观察到的所有白血病并发症的病例都涉及使用含有强增强子/启动子的LTR的逆转录病毒载体，其可以引发远程增强子活化。相反，缺失LTR的第三代慢病毒载体SIN-LV仅含有一个内部增强子/启动子，这降低了与附近细胞基因相互作用的发生率，从而降低了致癌整合的风险。SIN-LV还设计用于防止在用生产所必需的三种包装质粒生产病毒上清液期间产生具有复制能力的慢病毒(RCL)的可能性。慢病毒载体有效地转导HSPC并且不改变其再增殖特性，这使得这种类型的载体成为干细胞基因治疗的有吸引力的载体。
使用SIN-LV进行基因校正人HSPC的临床试验正在美国和欧洲针对包括HIV-1、β-地中海贫血、免疫缺陷、代谢疾病和癌症在内的几种病症进行。对于免疫缺陷病症，目前已有35例患者接受了SIN-LV修饰的HSPC移植。肾上腺脑白质营养不良(ALD)患者的临床试验已经在2名患者的约20％的造血细胞中实现了稳定的基因校正。经过三年的随访，脑脱髓鞘停止进一步发展，这代表了与同种异体移植后观察到的临床结果相当的临床结果；没有证据表明克隆占优势。最近，在移植后32个月的3名患者中报道了Wilskott-Aldrich综合征的临床试验。基因修饰的HSPC(25-50％)的稳定和长期植入引起血小板计数改善，防止出血和感染，以及湿疹的消退。最近另一项临床成功在三名患有异染性脑白质营养不良症状的症状发生前患者中报道。转导的细胞衍生的血细胞植入达到45％至80％，并且长达24个月后，蛋白质活性在脑脊液中重建至高于正常值，并具有明显的治疗益处。
最近在MCK小鼠中使用AAV载体的基因治疗成功不仅在给予症状发生前动物时预防了心力衰竭，而且在发病后给予时也逆转了心肌病。虽然令人鼓舞，但这种方法存在潜在的安全性和后勤问题：i)通过直接病毒注射到患病部位的局部递送在进入诸如心脏和大脑等部位时具有某些挑战，并且仅导致组织特异性挽救，ii)由于必需的载体高水平而导致载体合成和安全性问题，全身性AAV递送在人类中仍然困难。相比之下，HSPC基因治疗方法具有以下关键优势：i)通过单次输注干细胞治疗所有并发症；ii)基因校正在受控环境中离体发生，使得能够在移植前进行细胞表征，iii)经基因-校正的HSPC在移植后存在于骨髓龛中，在那里它们自我更新并成为患者生命中健康细胞的储库，iv)与同种异体移植相比，它避免了免疫反应。因此，自体HSPC基因治疗可以为溶酶体跨膜蛋白疾病或紊乱提供治疗。
表1中列出的人蛋白质的氨基酸和核酸序列是本领域已知的。参见，例如，GenBank登录号：Y15924.1，人CTNS基因，外显子3，侧翼内含子区和连接的CDS，其提供氨基酸序列(SEQ ID NO:1)：
MIRNWLTIFILFPLKLVEKCESSVSLTVPPVVKLENGSSTNVSLTLRPPLNATLVITFEITFRSKNITILELPDEVVVPPGVTNSSFQVTSQNVGQLTVYLHGNHSNQTGPRIRFLVIRSSAISIINQVIGWIYFVAWSISFYPQVIMNWRRKSVIGLSFDFVALNLTGFVAYSVFNIGLLWVPYIKEQFLLKYPNGVNPVNSNDVFFSLHAVVLTLIIIVQCCLYERGGQRVSWPAIGFLVLAWLFAFVTMIVAAVGVITWLQFLFCFSYIKLAVTLVKYFPQAYMNFYYKSTEGWSIGNVLLDFTGGSFSLLQMFLQSYNNDQWTLIFGDPTKFGLGVFSIVFDVVFFIQHFCLYRKRPGYDQLN
GenBank登录号：AJ222967.1，人CTNS mRNA，其提供核酸序列(SEQ ID NO:2)：
GenBank登录号：CAB62540.1，人唾液酸转运蛋白，提供氨基酸序列(SEQ ID NO:3)：
GenBank登录号：AJ387747.1，人唾液酸转运蛋白mRNA，其提供核酸序列(SEQ IDNO:4)：
GenBank登录号：CCP79466.1，人LMBD1，其提供氨基酸序列(SEQ ID NO:5)：
GAASAELVIGWCIFGPLLLAIFAFCWIYVRKYQSQRESEVVSTITAIFSLAIALITSALLPVDIFLVSYMKNQNGTFKDWANANVSRQIEDTVLYGYYTLYSVILFCVFFWIPFVYFYYEEKDDDDTSKCTQIKTAFKYTLGFAVICALLLLVGAFVPLNVPNNKNSTEWEKVKFLFEELGSSHGLAALSFSISSLTLIGMLAAITYTAYGMSALPLNLIKGTRSAAYERLENTEDIEEVEQHIQTIKSKSKDGRPLPARDKRALKQFEERLRTLRKRERHLEYIENSWWTKFCGALRPLKIIWGIFFILVALLFIISLFLSNLDKALHSAGIDSGFIIFGANLSNPLNMLLPVLQTVFPLDYILITIIIMYFIFTSMAGIRNIGIWFFWVRLYKIRRGRTRPQALLFLCMILLLIVLHTSYMIYSLAPQYVMYGSQNYLIESNITYDDHKNNSAFPVPKRCDADAPEDQCTVTRTYLFLHKFWFFSAAYYFGNWAFLVVFLIGLIVSCCKGKKSVIEGVDEDDSDISDDEPSVYSV
GenBank登录号：HAAF01007642.1，人LMBD1转录的RNA，其提供核酸序列(SEQ IDNO:6)：
GenBank登录号：AAH295036.1，人CLN7，其提供氨基酸序列(SEQ ID NO:7)：
GenBank登录号：BC029503.1，人CLN7 mRNA，其提供核酸序列(SEQ ID NO:8)：
GenBank登录号：AAB51075.1，人CLN3，其提供氨基酸序列(SEQ ID NO:9)：
MGGCAGSRRRFSDSEGEETVPEPRLPLLDHQGAHWKNAVGFWLLGLCNNFSYVVMLSAAHDILSHKRTSGNQSHVDPGPTPIPHNSSSRFDCNSVSTAAVLLADILPTLVIKLLAPLGLHLLPYSPRVLVSGICAAGSFVLVAFSHSVGTSLCGVVFASISSGLGEVTFLSLTAFYPRAVISWWSSGTGGAGLLGALSYLGLTQAGLSPQQTLLSMLGIPALLLASYFLLLTSPEAQDPGGEEEAESAARQPLIRTEAPESKPGSSSSLSLRERWTVFKGLLWYIVPLVVVYFAEYFINQGLFELLFFWNTSLSHAQQYRWYQMLYQAGVFASRSSLRCCRIRFTWALALLQCLNLVFLLADVWFGFLPSIYLVFLIILYEGLLGGAAYVNTFHNIALETSDEHREFAMAATCISDTLGISLSGLLALPLHDFLCQLS
GenBank登录号：U32680.1，人CLN3 mRNA完整cds，其提供核酸序列(SEQ ID NO:10)：
GenBank登录号：AAF34711.1，人CLCN7，其提供氨基酸序列(SEQ ID NO:11)：
MANVSKKVSWSGRDRDDEEAAPLLRRTARPGGGTPLLNGAGPGAARQSPRSALFRVGHMSSVELDDELLDPDMDPPHPFPKEIPHNEKLLSLKYESLDYDNSENQLFLEEERRINHTAFRTVEIKRWVICALIGILTGLVACFIDIVVENLAGLKYRVIKGNIDKFTEKGGLSFSLLLWATLNAAFVLVGSVIVAFIEPVAAGSGIPQIKCFLNGVKIPHVVRLKTLVIKVSGVILSVVGGLAVGKEGPMIHSGSVIAAGISQGRSTSLKRDFKIFEYFRRDTEKRDFVSAGAAAGVSAAFGAPVGGVLFSLEEGASFWNQFLTWRIFFASMISTFTLNFVLSIYHGNMWDLSSPGLINFGRFDSEKMAYTIHEIPVFIAMGVVGGVLGAVFNALNYWLTMFRIRYIHRPCLQVIEAVLVAAVTATVAFVLIYSSRDCQPLQGGSMSYPLQLFCADGEYNSMAAAFFNTPEKSVVSLFHDPPGSYNPLTLGLFTLVYFFLACWTYGLTVSAGVFIPSLLIGAAWGRLFGISLSYLTGAAIWADPGKYALMGAAAQLGGIVRMTLSLTVIMMEATSNVTYGFPIMLVLMTAKIVGDVFIEGLYDMHIQLQSVPFLHWEAPVTSHSLTAREVMSTPVTCLRRREKVGVIVDVLSDTASNHNGFPVVEHADDTQPARLQGLILRSQLIVLLKHKVFVERSNLGLVQRRLRLKDFRDAYPRFPPIQSIHVSQDERECTMDLSEFMNPSPYTVPQEASLPRVFKLFRALGLRHLVVVDNRNQVVGLVTRKDLARYRLGKRGLEELSLAQT
GenBank登录号：AF224741.1，人CLCN7 mRNA完整cds，其提供核酸序列(SEQ IDNO:12)：
GenBank登录号：AAH68581.1，人OSTM1，其提供氨基酸序列(SEQ ID NO:13)：
GenBank登录号：BC068581.1，人OSTM1 mRNA，其提供核酸序列(SEQ ID NO:14)：
GenBank登录号：AAG00797.1，人MCOLN1，其提供氨基酸序列(SEQ ID NO:15)：
MTAPAGPRGSETERLLTPNPGYGTQAGPSPAPPTPPEEEDLRRRLKYFFMSPCDKFRAKGRKPCKLMLQVVKILVVTVQLILFGLSNQLAVTFREENTIAFRHLFLLGYSDGADDTFAAYTREQLYQAIFHAVDQYLALPDVSLGRYAYVRGGGDPWTNGSGLALCQRYYHRGHVDPANDTFDIDPMVVTDCIQVDPPERPPPPPSDDLTLLESSSSYKNLTLKFHKLVNVTIHFRLKTINLQSLINNEIPDCYTFSVLITFDNKAHSGRIPISLETQAHIQECKHPSVFQHGDNSFRLLFDVVVILTCSLSFLLCARSLLRGFLLQNEFVGFMWRQRGRVISLWERLEFVNGWYILLVTSDVLTISGTIMKIGIEAKNLASYDVCSILLGTSTLLVWVGVIRYLTFFHNYNILIATLRVALPSVMRFCCCVAVIYLGYCFCGWIVLGPYHVKFRSLSMVSECLFSLINGDDMFVTFAAMQAQQGRSSLVWLFSQLYLYSFISLFIYMVLSLFIALITGAYDTIKHPGGAGAEESELQAYIAQCQDSPTSGKFRRGSGSACSLLCCCGRDPSEEHSLLVN
GenBank登录号：AF287269.1，人MCOLN1 mRNA，完整cds，其提供核酸序列(SEQ IDNO:16)：
GenBank登录号：Q68CP4.2，人HGSNAT，提供氨基酸序列(SEQ ID NO:17)：
GenBank登录号：NM_152419，人HGSNAT mRNA，其提供核酸序列(SEQ ID NO:18)：
GenBank登录号：AAB63982.1，人NPC1，其提供氨基酸序列(SEQ ID NO:19)：
MTARGLALGLLLLLLCPAQVFSQSCVWYGECGIAYGDKRYNCEYSGPPKPLPKDGYDLVQELCPGFFFGNVSLCCDVRQLQTLKDNLQLPLQFLSRCPSCFYNLLNLFCELTCSPRQSQFLNVTATEDYVDPVTNQTKTNVKELQYYVGQSFANAMYNACRDVEAPSSNDKALGLLCGKDADACNATNWIEYMFNKDNGQAPFTITPVFSDFPVHGMEPMNNATKGCDESVDEVTAPCSCQDCSIVCGPKPQPPPPPAPWTILGLDAMYVIMWITYMAFLLVFFGAFFAVWCYRKRYFVSEYTPIDSNIAFSVNASDKGEASCCDPVSAAFEGCLRRLFTRWGSFCVRNPGCVIFFSLVFITACSSGLVFVRVTTNPVDLWSAPSSQARLEKEYFDQHFGPFFRTEQLIIRAPLTDKHIYQPYPSGADVPFGPPLDIQILHQVLDLQIAIENITASYDNETVTLQDICLAPLSPYNTNCTILSVLNYFQNSHSVLDHKKGDDFFVYADYHTHFLYCVRAPASLNDTSLLHDPCLGTFGGPVFPWLVLGGYDDQNYNNATALVITFPVNNYYNDTEKLQRAQAWEKEFINFVKNYKNPNLTISFTAERSIEDELNRESDSDVFTVVISYAIMFLYISLALGHIKSCRRLLVDSKVSLGIAGILIVLSSVACSLGVFSYIGLPLTLIVIEVIPFLVLAVGVDNIFILVQAYQRDERLQGETLDQQLGRVLGEVAPSMFLSSFSETVAFFLGALSVMPAVHTFSLFAGLAVFIDFLLQITCFVSLLGLDIKRQEKNRLDIFCCVRGAEDGTSVQASESCLFRFFKNSYSPLLLKDWMRPIVIAIFVGVLSFSIAVLNKVDIGLDQSLSMPDDSYMVDYFKSISQYLHAGPPVYFVLEEGHDYTSSKGQNMVCGGMGCNNDSLVQQIFNAAQLDNYTRIGFAPSSWIDDYFDWVKPQSSCCRVDNITDQFCNASVVDPACVRCRPLTPEGKQRPQGGDFMRFLPMFLSDNPNPKCGKGGHAAYSSAVNILLGHGTRVGATYFMTYHTVLQTSADFIDALKKARLIASNVTETMGINGSAYRVFPYSVFYVFYEQYLTIIDDTIFNLGVSLGAIFLVTMVLLGCELWSAVIMCATIAMVLVNMFGVMWLWGISLNAVSLVNLVMSCGISVEFCSHITRAFTVSMKGSRVERAEEALAHMGSSVFSGITLTKFGGIVVLAFAKSQIFQIFYFRMYLAMVLLGATHGLIFLPVLLSYIGPSVNKAKSCATEERYKGTERERLLNF
GenBank登录号：AF002020.1，人NPC1 mRNA，完整cds，其提供核酸序列(SEQ IDNO:20)：
GenBank登录号：CAA54416.1，人LAMP-2A，其提供氨基酸序列(SEQ ID NO:21)：
GenBank登录号：X77196.1，人LAMP2 mRNA，其提供核酸序列(SEQ ID NO:22)：
GenBank登录号：AAA91149.1，人LAMP-2B，其提供氨基酸序列(SEQ ID NO:23)：
MVCFRLFPVPGSGLVLVCLVLGAVRSYALELNLTDSENATCLYAKWQMNFTVRYETTNKTYKTVTISDHGTVTYNGSICGDDQNGPKIAVQFGPGFSWIANFTKAASTYSIDSVSFSYNTGDNTTFPDAEDKGILTVDELLAIRIPLNDLFRCNSLSTLEKNDVVQHYWDVLVQAFVQNGTVSTNEFLCDKDKTSTVAPTIHTTVPSPTTTPTPKEKPEAGTYSVNNGNDTCLLATMGLQLNITQDKVASVININPNTTHSTGSCRSHTALLRLNSSTIKYLDFVFAVKNENRFYLKEVNISMYLVNGSVFSIANNNLSYWDAPLGSSYMCNKEQTVSVSGAFQINTFDLRVQPFNVTQGKYSTAQECSLDDDTILIPIIVGAGLSGLIIVIVIAYVIGRRKSYAGYQTL
GenBank登录号：U36336.1，人LAMP-2B mRNA，完整cds，其提供核酸序列(SEQ IDNO:24)：
GenBank登录号：AAS67876.1，人LAMP-2C，其提供氨基酸序列(SEQ ID NO:25)：
MVCFRLFPVPGSGLVLVCLVLGAVRSYALELNLTDSENATCLYAKWQMNFTVRYETTNKTYKTVTISDHGTVTYNGSICGDDQNGPKIAVQFGPGFSWIANFTKAASTYSIDSVSFSYNTGDNTTFPDAEDKGILTVDELLAIRIPLNDLFRCNSLSTLEKNDVVQHYWDVLVQAFVQNGTVSTNEFLCDKDKTSTVAPTIHTTVPSPTTTPTPKEKPEAGTYSVNNGNDTCLLATMGLQLNITQDKVASVININPNTTHSTGSCRSHTALLRLNSSTIKYLDFVFAVKNENRFYLKEVNISMYLVNGSVFSIANNNLSYWDAPLGSSYMCNKEQTVSVSGAFQINTFDLRVQPFNVTQGKYSTAEECSADSDLNFLIPVAVGVALGFLIIVVFISYMIGRRKSRTGYQSV
GenBank登录号：AY561849.1，人LAMP-2C mRNA，完整cds，其提供核酸序列(SEQ IDNO:26)：
在另一个方面，治疗受试者中的溶酶体跨膜蛋白疾病或紊乱的方法包括用编码基因编辑系统的载体与表达与受试者的特定疾病或紊乱相关的蛋白质(参见表1)的细胞接触，当转染到细胞中时，去除内源蛋白的突变(例如，三核苷酸重复扩增突变)，从而治疗溶酶体跨膜蛋白疾病或紊乱。在各种实施方案中，基因编辑系统选自由CRISPR/Cas、锌指核酸酶和-转录激活因子样效应核酸酶组成的组。接触步骤可以离体进行，首先从受试者获得细胞样品，将基因编辑系统转染到细胞样品中，然后将转染的细胞移植到受试者内，从而治疗溶酶体跨膜蛋白疾病或紊乱。细胞样品可以是表达与溶酶体跨膜蛋白疾病或紊乱相关的蛋白质的任何细胞，诸如受试者的血细胞或HSPC。
在另一个方面，本发明提供了治疗或改善受试者中溶酶体蛋白质疾病或紊乱的方法。该方法包括将一群HSPC移植到受试者中，其中通过引入编码相应的功能性人溶酶体跨膜蛋白的转基因对HSPC进行遗传修饰，从而治疗溶酶体跨膜蛋白疾病或紊乱。因此，当溶酶体跨膜蛋白疾病或紊乱是胱氨酸病时，功能性人溶酶体跨膜基因是CTNS；溶酶体跨膜蛋白疾病或紊乱是唾液酸贮积病或婴儿唾液酸贮积病，功能性人溶酶体跨膜基因是SLC17A5；溶酶体跨膜蛋白疾病或紊乱是钴胺素F型疾病，功能性人溶酶体跨膜基因是LMBRD1；溶酶体跨膜蛋白疾病或紊乱是婴儿晚期神经元蜡样脂褐质沉积症，功能性人溶酶体跨膜基因是MFSD8；溶酶体跨膜蛋白疾病或紊乱是青少年神经元蜡样脂褐质沉积症，功能性人溶酶体跨膜基因是CLN3；溶酶体跨膜蛋白疾病或紊乱是恶性婴儿骨硬化症，功能性人溶酶体跨膜基因是CLCN7或OSTM1；溶酶体跨膜蛋白疾病或紊乱是粘脂贮积病IV，功能性人溶酶体跨膜基因是MCOLN1；溶酶体跨膜蛋白疾病或紊乱是粘多糖贮积症IIC型，功能性人溶酶体跨膜基因是HGSNAT；溶酶体跨膜蛋白疾病或紊乱是Neiman-Pick C型，功能性人溶酶体跨膜基因是NPC1；并且溶酶体跨膜蛋白疾病或紊乱是溶酶体贮积症，功能性人溶酶体跨膜基因是LAMP2。在各种实施方案中，HSPC从受试者中分离，诸如从受试者的骨髓中分离。
尽管本发明已经关于胱氨酸病和溶酶体贮积症进行了证明，但应该理解，这些方法适用于表1中列出的任何病症或病症。因此，该策略使HSPC变成智能和广泛递送载体以在分化成进入循环的单核细胞并随后侵入外周组织后(在那里它们转化成组织驻留的巨噬细胞)获得稳定和持续的交叉校正。这些巨噬细胞通过多种机制(包括但不限于隧道纳米管的形成、囊泡释放和直接的细胞-细胞粘附)，将它们的溶酶体转移到患病的外周细胞中，所述溶酶体携带相应的蛋白质。因此，这项工作证明了用于治疗溶酶体跨膜蛋白疾病或紊乱的HSPC基因治疗策略的开发。
以下实施例旨在说明而非限制本发明。
实施例1
用于测试治疗方法的胱氨酸病的临床前模型
已经在胱氨酸病的小鼠模型(Ctns-/-小鼠)上测试了干细胞治疗方法。该小鼠模型被设计为产生有缺陷的胱氨酸转运蛋白，因此不能将胱氨酸正确地从溶酶体中转运出来。该缺陷导致胱氨酸病的特征性的胱氨酸的积累和胱氨酸晶体的形成。胱氨酸积聚从出生就存在并随着年龄而增加。最初的Ctns-/-小鼠已经回交以产生纯C57BL/6Ctns-/-小鼠品系(如生物化学(血清尿素和肌酐升高)和组织学上观察到的，其在6个月大的时候发生肾功能障碍)，并且这些小鼠在18个月时处于终末期肾衰竭。肾Fanconi综合征也在大约6个月大开始(多尿、磷酸尿和蛋白尿)，近端肾小管细胞出现去分化，并且在患有导致管状肾小球的胱氨酸病的小鼠和人中发现表现出典型的“天鹅颈”畸形。最后，在Ctns-/-小鼠的肾中可以观察到炎性细胞的严重浸润。Ctns-/-小鼠也会出现眼部缺损，伴有角膜胱氨酸晶体沉积和甲状腺功能障碍，与患病患者的观察结果类似。
实施例2
BMC、HSC和MSC移植对胱氨酸病的影响
为了确定在胱氨酸病的情况下用于移植的合适细胞群，在2个月大的经辐射的Ctns-/-小鼠中进行同基因骨髓细胞(BMC)、Sca1+造血干细胞(HSC)和间充质干细胞(MSC)移植。从绿色荧光蛋白(GFP)-转基因野生型(WT)小鼠或来自Ctns-/-小鼠中分离的细胞作为对照。移植后4个月进行疾病参数分析。MSC对该疾病仅具有短期有限的有益影响。相反，在WTBMC和HSC治疗的小鼠中测试的所有器官中组织胱氨酸含量显著降低(取决于组织，降低57％至94％)。所有器官均存在丰富的GFP+骨髓衍生细胞，并且肾功能得到改善。即使胱氨酸转运蛋白是跨膜溶酶体蛋白而不是分泌酶，这是HSC可以挽救胱氨酸病的第一个概念验证。
实施例3
Ctns-/-小鼠中HSC移植的长期效果
然后确定该治疗对于小鼠的一生是否稳定并且是否会引起多器官保留。
肾分析：WT HSC的移植能够提供肾功能和结构的长期保护，并且在移植后直至15个月防止肾病的进展(测试的最后时间点；图1)。然而，有效的治疗取决于实现相对高水平的供体衍生的Ctns表达细胞(>50％)的血细胞植入，其与肾内发现的表达Ctns的细胞的量直接相关。相反，肾保留不依赖于移植时小鼠的年龄。实际上，在干细胞治疗后，长达10个月大的小鼠可能表现出正常的肾功能，这表明如果组织损伤没有巩固(consolidated)，则可以挽救肾。还显示所有组织中的胱氨酸含量显著降低(从肾中的54％到肝中的96.5％)，证明包括一次性HSC移植的治疗，引起对小鼠寿命的长期且稳定的低水平组织胱氨酸。此外，在来自经治疗小鼠的所有肾中几乎没有观察到胱氨酸晶体，而在来自未治疗的Ctns-/-小鼠的肾中始终观察到大量的胱氨酸晶体。
眼分析：GFP+WT HSC移植引起Ctns-/-小鼠眼的长期保留。不仅在经治疗小鼠的角膜内而且在巩膜、睫状体、视网膜、脉络膜和晶状体中检测到丰富的GFP+骨髓来源的细胞。为了量化角膜内的胱氨酸晶体，进行活体小鼠体内共聚焦显微镜(IVCM)。如先前对肾所证实的，有效的治疗取决于供体衍生的血细胞植入水平。虽然植入水平低(<50％；低；n＝5)的Ctns-/-小鼠表现出晶体计数的部分减少，但具有高植入水平(>50％；高；n＝5)的小鼠几乎显示出从上皮层到中间基质的晶体完全消除(分别为100％至72％的清除率；图2)。移植后一年，HSC治疗的Ctns-/-小鼠表现出正常的角膜厚度和结构以及正常的眼压。这项工作是首次证明移植的HSC可以挽救角膜缺陷并为眼再生医学带来新的前景。
甲状腺分析：由于甲状腺也在胱氨酸病中受到影响，因此分析了来自Ctns-/-小鼠和HSC移植小鼠的甲状腺功能和结构。在Ctns-/-小鼠中显示持续的促甲状腺激素(TSH)激活合并甲状腺球蛋白合成增加的形态学证据。囊泡变化包括甲状腺细胞肥大、增生、胶体耗竭和血管增生。相反，通过HSC移植治疗的Ctns-/-小鼠呈现出几乎正常的组织学和胱氨酸和TSH值的正常化(图3)。
胃肠道分析：胃肠粘膜活组织切片可用于测量基因修饰的干细胞组织植入及其对参与HSC基因治疗的胱氨酸病临床试验的受试者中胱氨酸和胱氨酸晶体水平的影响。先前已经描述了用于评估肠粘膜活组织切片上的组织胱氨酸晶体水平的组织学技术。结果表明，胱氨酸晶体计数可能与肾功能有关，并可能有助于评估对半胱胺治疗的响应。因此，在患有胱氨酸病的受试者中，在基因校正的HSC移植之前和之后每6个月计划直肠活检。一次可以获得多达9个活组织切片，因此可以在每个时间点测量该组织中的载体拷贝数(VCN)、CTNS表达、胱氨酸含量和胱氨酸晶体。为了确定该组织是否代表治疗功效，研究了GFP+WTHSC移植对Ctns-/-小鼠胃肠道的影响。移植后6个月，在肠和结肠组织中观察到丰富的GFP+HSC衍生细胞，并且与这些区室中的对照相比，经治疗小鼠中胱氨酸含量显著降低(图4)。
皮肤分析：在皮肤上使用体内共聚焦显微术作为非侵入性成像技术，用于对参与临床试验的患有胱氨酸病的受试者HSC移植之前和之后组织胱氨酸晶体的可视化和定量。Chiaverini等(Journal of the American Academy of Dermatology 68,e111(2013))表明该技术能够检测患有胱氨酸病的患者的皮肤胱氨酸沉积。为此目的，使用适于皮肤成像的反射共聚焦成像仪(3000)来测试患有胱氨酸病的患者。在HSC移植的Ctns-/-小鼠中也显示，在皮肤中植入了丰富的GFP+骨髓衍生细胞，引起该组织中胱氨酸的显著减少(HSC治疗的Ctns-/-中79±0.87，对比在对照中193±78，p<0.05)。
实施例4
清髓性预处理方案：Ctns-/-小鼠中的功效和毒性
将Ctns-/-小鼠暴露于目前临床用于HSC移植的清髓性药物，白消安(Bu)和环磷酰胺(Cy)，以测试药物介导的骨髓清除是否使得能够在临床前模型中有效植入表达Ctns的HSC，减少组织胱氨酸并确定是否由于胱氨酸病而发生任何意外的毒性。将药物腹膜内(IP)注射到Ctns-/-小鼠和WT小鼠中作为对照。在移植后4个月分析小鼠，证明：i)与WT对照相比，Ctns-/-小鼠对Bu或Cy没有任何毒性；ii)肾功能与未治疗的年龄匹配的WT对照相似；iii)两种情况下的骨髓细胞清除都是成功的，并且在外周血中测得的供体细胞植入率为Bu/Cy94.2±1.6％和仅Bu 94.0±0.8％；和iv)与未治疗的相比，经治疗的Ctns-/-小鼠在所有测试组织中具有胱氨酸的显著减少。因此，Bu和Cy在小鼠模型中对于胱氨酸病和药物介导的骨髓清除没有毒性，并且Ctns-/-小鼠中的HSC移植引起所有组织中胱氨酸的显著降低。
可以使用没有环磷酰胺的白消安可以进行骨髓细胞清除给药。环磷酰胺不会清除造血干细胞(即，不会形成植入空间)，并且具有免疫抑制和抗白血病。由于HSC移植是自体的，并且不是针对白血病的，因此不需要环磷酰胺，因为它会给预处理方案增加不必要的毒性。此外，由于常用的预处理方案如白消安，直接引起严重的肾毒性是不寻常的。请注意，Donald Kohn博士的镰状细胞试验(ClinicalTrials.gov Identifier：NCT02247843)仅使用白消安，而bluebird bio，Inc.的镰状细胞和地中海贫血试验(ClinicalTrials.govIdentifier：NCT02151526)也使用没有环磷酰胺的白消安。
实施例5
治疗作用机制
HSC拯救胱氨酸病的功效程度令人惊讶，特别是考虑到HSC移植拯救非造血组织的能力仍然存在争议，并且胱氨酸转运蛋白是跨膜溶酶体蛋白。为了阐明HSC介导的组织修复的机制，开发了一种新的小鼠模型，其中Ctns-/-小鼠在DsRed背景上回交，以便普遍表达DsRed报告基因(Harrison et al.,Mol Ther 21,433(2013))。当移植来自GFP转基因小鼠的表达GFP的HSC时，这产生了一种双荧光小鼠模式，不仅使我们能够在体内环境中追踪移植的HSC的命运，而且还能够敏感地鉴定和明确区分诸如融合、分化和转分化事件。
使用该模型，首次表明HSC在组织内分化成巨噬细胞(Naphade et al.,StemCells 33,301(2015))。然后使用WT GFP-巨噬细胞和DsRed-Ctns-/-成纤维细胞进行体外共培养实验。当WT巨噬细胞与Ctns-/-成纤维细胞共培养时，在FACS分选的成纤维细胞中胱氨酸水平降低～75％(图5A)。相反，当使用transwell多孔将两个群体物理分离为微泡时，胱氨酸水平仅降低～20％(图5B)。这些研究结果表明，即使胱氨酸转运蛋白是溶酶体跨膜蛋白，也会发生交叉校正，并且直接的细胞:细胞接触是交叉校正的主要途径。使用共聚焦显微镜(图5C)，观察到称为隧穿纳米管(TNT)(～40μm)的巨噬细胞延伸的长膜突起，其与成纤维细胞建立接触。为了确定TNT是否可以介导携带胱氨酸转运蛋白的囊泡的物理转移，将DsRed-Ctns-/-成纤维细胞与用表达胱氨酸-GFP融合蛋白(CTNS-GFP-巨噬细胞)的慢病毒载体稳定转导的巨噬细胞共培养。活共聚焦显微镜显示含有胱氨酸转运蛋白-GFP的囊泡可沿TNT向DsRed-Ctns-/-成纤维细胞迁移(图5D)。LysoTracker染色将这些囊泡鉴定为溶酶体(Naphade et al.,Stem Cells 33,301(2015))。
关于体内TNT的已知很少。因此检查了是否可以在体内检测到涉及纳米管的细胞间囊泡交换，以便解释Ctns-/-小鼠中的长期肾保留。最初的重点是肾，不仅是因为近端肾小管细胞(PTC)早期发生胱氨酸病，而且还因为它们通过致密的管状基底层(TBL)进行物理隔离。在双色移植小鼠中，观察到GFP+骨髓衍生的细胞在近端小管内周围但从不在近端小管内，并且从HSC衍生的巨噬细胞发出许多管状延伸并穿过TBL(图6A-a1至6A-a3)。在PTC内观察到含有GFP的结构，表明细胞质从巨噬细胞物理转移到上皮细胞中(图6A-a3)。为了测试该假设，用稳定表达胱氨酸转运蛋白-GFP融合蛋白的DsRed-Ctns-/-HSPC(图4C)或用DsRed-Ctns-/-HSPC移植Ctns-/-小鼠(图4B)。在PTC中观察到许多胱氨酸-GFP-囊泡(图4C)(Naphadeet al.,Stem Cells 33,301(2015))。这是通过穿透TBL的TNT将蛋白质从间质巨噬细胞直接转移到上皮细胞的第一个证据，以便纠正导致PTC变性的遗传缺陷。在Ctns-/-小鼠中获得了对于眼部缺陷(Rocca et al.,Investigative ophthalmology&visual science 56,7214(2015))和甲状腺挽救(Chevronnay et al.,Endocrinology In press,(2016))的HSC介导的治疗作用机制的相似数据。这些关于HSC介导的组织修复的发现为再生医学带来了新的前景，因为它们应该适用于涉及细胞内细胞器缺陷的其他多室疾病。
实施例6
造血干细胞移植的临床研究
上述工作代表了使用HSC移植作为胱氨酸病治疗的第一个概念验证。为了最小化移植物抗宿主(GVHD)的风险，要求受试者具有在10个等位基因中的10个与HLA匹配的同胞骨髓供体。本研究旨在包括6名受试者，这些受试者是有明显的疾病进展迹象的18岁及以上的成年人，或不能耐受半胱胺的13至17岁的青少年。然而，鉴于疾病的罕见性和严格的供体要求，到目前为止候选人与他们的兄弟姐妹并不完全匹配。此外，尽管存在严重的医学问题，在定期使用药物半胱胺的引入允许患者活到成年期的情况下，同种异体HSC移植的风险-效益比可能不适合年轻患者(Cherqui，Kidney Int 81,127)(2012))。实际上，与同种异体移植相关的发病率和死亡率存在显著风险。GVHD是一个主要的并发症；在最近的研究中，急性GVHD II-IV级患者发生率为20％-32％，慢性GVHD发生率为16％-59％，两者均显著影响受者的存活率((Cutler et al.,Blood 109,3108(2007)；Geyer et al.,Br J Haematol155,218(2011)；和Schleuning et al.,Bone Marrow Transplant 43,717(2009))。因此，优选的候选疗法将利用患者自身的干细胞进行自体HSC移植，从而降低移植物排斥和GVHD的风险。
实施例7
病毒载体选择
考虑到与同种异体HSC移植相关的风险并考虑HSC基因治疗的临床前数据，经修饰以表达功能性胱氨酸转运蛋白的自体HSC的移植代表了更安全的方法。
关于基因治疗，源自慢病毒的载体由于其优异的基因转移效率和改善的生物安全性而已经取代γ-逆转录病毒载体(Case et al.,Proc Natl Acad Sci USA 96,2988(1999)；Miyoshi,et al.Science 283,682(1999)；Naldini et al.,Science 272,263(1996)；和Varma et al.,Nature 389,239(1997))。特别地：
1、迄今为止在临床试验或基因治疗动物模型中观察到的所有白血病并发症的病例都涉及使用γ-逆转录病毒载体，诸如含有强增强子/启动子的长末端重复序列(LTR)的莫洛尼白血病病毒(MLV)逆转录病毒，其中强增强子/启动子触发远端增强子激活(Hacein-Bey-Abina et al.,J Clin Invest 118,3132(2008)；Li et al.,Science 296,497(2002))。
2、相反，第三代慢病毒载体，自失活(SIN)-慢病毒载体(LV)，其LTR缺失，仅含有一个内部增强子/启动子，可降低与附近细胞相互作用的发生率并因此降低了致癌整合的风险(Modlich et al.,Blood 108,2545(2006)；Montini et al.,J Clin Invest 119,964(2009))。此外，与MLV相反，慢病毒与肿瘤发生无关。重要的是，尽管已知记忆T细胞多年携带整合病毒，但白血病并不是HIV患者公认的副作用。
3、SIN-LTR还被设计用于防止在病毒上清液的产生过程中产生具有复制能力的慢病毒(RCL)的可能性。实际上，具有三种包装质粒的瞬时转染系统通常用于载体生产-gag、pol和rev(Dull et al.,J Virol 72,8463(1998))。含有编码包膜和水泡性口炎病毒糖蛋白(VSV-G)的基因的第四种质粒经常用作包膜的选择。到目前为止，在输注载体转导的细胞产物后，RCL从未报道过患者中常用的病毒生产系统(Sastry et al.,Mol Ther 8,830(2003))。
4、LV有效转导HSC并且不改变其再增殖特性(Montini et al.,J Clin Invest119,964(2009)；Gonzalez-Murillo et al.,Blood 112,3138(2008))。
5、使用SIN-LV以转导人HSPC的临床试验正在美国和欧洲针对包括HIV-1、β-地中海贫血、免疫缺陷、代谢疾病和癌症在内的几种病症进行(DiGiusto et al.,Viruses 5,2898(2013)；Drakopoulou et al.,Current molecular medicine 13,1314(2013)；Porteret al.,N Engl J Med 365,725(2011)；和Zhang et al.,Gene Ther 20,963(2013))。对于免疫缺陷病症，目前已有35例患者接受了SIN-LV修饰的HSPC移植(Bigger et al.,Discovery medicine 17,207(2014))。使用SIN-LV离体校正X-肾上腺脑白质营养不良患者的HSC的临床试验显示，两名登记患者的脑脱髓鞘停止，随访3年无进一步发展；以及没有证据表明克隆优势(Cartier et al.,Methods Enzymol 507,187(2012)；Cartier et al.,Science 326,818(2009))。最近，在移植后32个月的3名患者中报道了Wilskott-Aldrich综合征的临床试验。基因修饰的HSPC(25-50％)的稳定和长期植入引起血小板计数改善，防止出血和感染，以及湿疹的消除(Aiuti et al.,Science 341,1233151(2013))。最近另一项临床成功在三名患有异染性脑白质营养不良症状的症状发生前患者中报道。转导的细胞衍生的血细胞植入达到45％至80％，并且长达24个月后，蛋白质活性在脑脊液中重建至高于正常值，并具有明显的治疗益处(Biffi et al.,Science 341,1233158(2013))。
制备了pCCL-CTNS慢病毒载体(已经亚克隆人CTNS cDNA的第三代SIN-慢病毒载体)，pCCL-CTNS(图7)，以供施用。载体骨架pCCL-EFS-X-WPRE，由Zufferey et al.(J Virol72,9873(1998))描述，由Donald Kohn博士(UCLA)提供。将增加病毒DNA核输入的中央多嘌呤管道(cPPT)片段添加到CCL载体骨架中(Demaison et al.,Hum Gene Ther 13,803(2002))。土拨鼠肝炎病毒翻译后调节元件(WPRE)用于提高滴度和基因表达。然而，它的开放阅读框架被消除了(Zanta-Boussif et al.,Gene Ther 16,605(2009))，因为它与土拨鼠肝炎病毒X蛋白(一种参与肝肿瘤发展的转录激活因子)重叠(Kingsman et al.,GeneTher 12,3(2005))。转基因表达由普遍表达的短的内含子更短(intron-less)的人延长因子1α启动子(EFS，242bp)驱动(Wakabayashi-Ito，S.Nagata，J Biol Chem 269,29831(1994))。缺乏许多表达质粒中使用的较大元件的内含子和增强子的EFS启动子，已被证明可以指导鼠HSC中报告基因的高水平转录，并且与γ-逆转录病毒LTR相比具有显著降低的反式激活潜力(Zychlinski et al.,Mol Ther,(2008))。
具有该骨架的载体用于由Kohn博士进行的临床试验：i)对于腺苷脱氨酶(ADA)-严重联合免疫缺陷(SCID)，通过EFS-ADA慢病毒载体添加正常人ADA cDNA后对骨髓CD34+干/祖细胞的自体移植(BB IND 15440；NCT01852071)；ii)自体骨髓干细胞(CD34+)培养的W/细胞因子；转导表达人β-珠蛋白的W/自失活(SIN)慢病毒载体(LENTI/BetaAS3-FB)；随后白消安(BB IND 16028；NCT02247843)。
实施例8
pCCL-CTNS转导的HSC的移植的临床前研究
使用我们针对mHSC的优化方案，用pCCL-CTNS离体转导从Ctns-/-小鼠分离的Sca1+HSC，并移植到1至4个月大的Ctns-/-小鼠中。在移植后4个月(组1；n＝8)和8个月(组2；n＝12)分析脑、眼、心、肾、肝、肌肉和脾中的胱氨酸含量。作为对照，使用年龄匹配的未治疗的Ctns-/-小鼠(n＝7和n＝12)或移植WT HSC的Ctns-/-小鼠(n＝4和n＝4)。与Ctns-/-对照相比，在用pCCL-CTNS转导的HSC治疗的小鼠中测试的所有组织中胱氨酸含量的降低是统计学显著的(图8A)。还测试了用对照载体pCCL-GFP转导的Ctns-/-HSC对组织胱氨酸水平的影响，以排除任何转基因的存在导致胱氨酸降低的可能性。与未治疗的Ctns-/-小鼠相比，在移植了pCCL-GFP-Ctns-/-HSC的小鼠任何组织中未观察到减少(Harrison et al.,Mol Ther 21,433(2013))。
通过测量移植后8个月的雄性血清中的肌酸酐、尿素和磷酸盐水平以及24小时尿液中的肌酸酐清除率并与年龄匹配的WT雄性进行比较(n＝6)，来评估肾小球和肾小管功能。与WT小鼠相比，未治疗的Ctns-/-小鼠中所有参数均增加并且肌酸酐清除率降低。与对照相比，在经pCCL-CTNS治疗的Ctns-/-小鼠中，血清肌酸酐、尿磷和尿量显著降低，显示出基因修饰的HSC对Ctns-/-小鼠肾功能的有益作用。在经治疗的Ctns-/-小鼠比较对照中证实了肾切片中存在的胱氨酸晶体的显著减少(图8B和8C)。请注意，我们发现Ctns-/-小鼠中，雌性肾中的胱氨酸含量比雄性的肾高5倍，因此必须分别对雄性和雌性进行肾研究(Harrison etal.,Mol Ther 21,433(2013))。
使用慢病毒特异性引物对从pCCL-CTNS-移植的Ctns-/-小鼠收集的血液中分离的基因组DNA进行定量PCR(qPCR)，以确定每个细胞的载体拷贝数(VCN)。平均VCN为1.573±1.868，落在VCN 1-3的靶标范围内。为了确定是否可以在组织中预测慢病毒水平，在不同组织中的pCCL水平之间进行线性回归分析，作为血液VCN水平的函数。证实了血液中存在的慢病毒水平与组织中存在的水平之间的直接相关性(Harrison et al.,Mol Ther 21,433(2013))，其可用于跟踪参加临床试验的未来受试者。
实施例9
临床前的药理学和毒理学
使用从印第安纳大学载体生产设施(IUVPF)获得的在可比较的良好生产规范(GMPc)下生产的一批pCCL-CTNS慢病毒载体制剂进行用pCCL-CTNS基因修饰的离体HSC的药理学/毒理学研究，由Kenneth Cornetta博士指导。为安全起见向FDA提出的靶标VCN范围包括在1至3之间。
体外永生化(IVIM)测定、遗传毒性测试，由辛辛那提儿童医院医学中心的翻译试验开发和支持实验室进行。该测定法包括转导的鼠Lin-BMC的大规模培养扩增2周，然后在96孔板中以100或10个细胞/孔的密度培养长达7周(Arumugam et al.,Mol Ther 17,1929(2009)；Modlich et al.,Mol Ther 17,1919(2009))。计数阳性孔并计算重放细胞的频率并与阴性(空白转导的)和阳性对照(MLV载体)比较。使用GMPc pCCL-CTNS制剂一式三份进行IVIM测定，VCN范围为1-3。用该构建体不产生永生化克隆，因此证明了优异的安全性。
目前正在用涉及连续移植的Ctns-/-小鼠中的Sca1+mHSC组成的类似细胞治疗产品进行体内药理学/毒理学研究。将用经pCCL-CTNS转导的Ctns-/-mHSC(VCN为1-3)移植的15-20只Ctns-/-小鼠(10只雄性和10只雌性)和具有空白转导的Ctns-/-mHSC的20只小鼠作为主要受体。随后，将来自这些小鼠的骨髓细胞移植到继代Ctns-/-小鼠中。必须在移植后6个月，通过全面的分子、临床和组织学分析对原代和继代小鼠进行全面分析。到目前为止，我们有32个主要受体达到6个月的时间点：11只移植了pCCL-CTNS转导的Ctns-/-mHSC(VCN为1-3)的Ctns-/-小鼠，和21只空白处理的小鼠，和18只继代小鼠。到目前为止尚未检测到不良事件，数据显示该产品的功效，因为用pCCL-CTNS-HSC治疗的小鼠的体重更高，并且测试的组织中的胱氨酸含量显著低于空白处理的对照(图9A-9B)。因此，对于达9个额外的用pCCL-CTNS转导的HSC治疗的Ctns-/-原代受体和15个继代受体，我们必须达到6个月的时间点。
实施例10
制作：流程开发
使用GMPc pCCL-CTNS制剂，优化方案以转导来自健康供体的人CD34+HSC以获得包含在1至3之间的VCN。该方案涉及在MOI 20下进行一次命中的载体转导20小时。然后使用从五个健康供体和四个胱氨酸病患者分离的人CD34+外周血干细胞(PBSC)进行群落形成单位(CFU)测定，并且与空白转导的对照相比，用pCCL-CTNS LV均未显示异常增殖或分化潜能。此外，患者细胞中的载体整合位点(VIS)分析显示，在原癌基因5'端附近没有富集整合位点。然而，虽然该方案引起健康CD34+细胞的平均VCN为2，但胱氨酸病患者的平均VCN为0.96。因此，该方案进一步优化了胱氨酸病患者的细胞以实现更高水平的转导，因为我们已经证明表达CTNS的更高水平的细胞引起更好的治疗响应(Yeagy et al.,Kidney Int 79,1198(2011)；Rocca et al.,Investigative ophthalmology&visual science 56,7214(2015)；Harrison et al.,Mol Ther 21,433(2013))。该方案涉及以MOI 20的两次命中载体转导，每次总共24小时，并且获得患者细胞的平均VCN为1.9。现在，用这个新方案将重复CFU实验和VIS。
对于临床试验，根据GMP设施的标准操作程序进行转导方案，并使用针对胱氨酸病患者的CD34+细胞的最佳方案。注意，在征召第一名患者之前，使用GMP级pCCL-CTNS载体制剂进行大规模转导的最佳条件以及最佳方案在小规模下和GMP设施中使用来自的健康供体的人CD34+细胞的Proficiency Runs进行验证。临床试验将包括6名患有胱氨酸病的患者，4名成人和2名青少年。这将是针对胱氨酸病的自体干细胞和基因疗法治疗策略的首次人体临床试验。如果成功，这种治疗可能是一种终身疗法，可以消除或减少肾恶化和肾移植的需要，以及与胱氨酸病相关的长期并发症。另外，pCCL-CTNS修饰的CD34+HSC移植提供有益和保护作用的机制可适用于其他遗传性多器官退行性紊乱。
实施例11
用于溶酶体贮积症的HSPC移植
该实验的目的是确定是否可以通过HSPC移植来拯救溶酶体贮积症并确定是否发生溶酶体交叉校正。使用本文所述的小鼠模型，已经证明Lamp2 KO小鼠的心脏表现出异常线粒体的数量增加，以及线粒体和线粒体呼吸的损伤，这与先前在溶酶体贮积症患者的经诱导多能干细胞(hiPSC)来源的心肌细胞中的研究一致(Cherqui，Kidney Int 81,127(2012))，证实了小鼠模型与人类疾病之间的相似性。
为了评估WT HSPC拯救溶酶体贮积症的能力，使用先前描述的方案移植(Yeagy etal.,Kidney Int 79,1198(2011)；Naphade et al.,Stem Cells 33,301(2015)；Case etal.,Proc Natl Acad Sci U S A 96,2988(1999))，用分离自普遍表达细胞质eGFP的同基因C57BL/6WT(来自Jackson Laboratory的Tg(ACTB-EGFP)1Osb/J)的Sca1+HSPC(WT-HSPC)移植两个月龄致死辐射的Lamp2 KO小鼠，同基因C57BL/6WT。作为阴性对照，Lamp2 KO小鼠也用来自组成型表达eGFP(KO-HSPC)的Lamp2 KO小鼠的Sca1+HSPC移植。使用先前描述的技术测定骨骼肌强度，并且与WT和已接受WT HSPC的Lamp2小鼠相比，证明Lamp2 KO小鼠的握力显著降低(图11)。通过Western印迹分析评估，在移植有WT HSPC的Lamp2 KO小鼠的心脏和骨骼肌中，LAMP2蛋白表达恢复至接近WT水平(图10D-10E)。
为了证明LAMP2在受体Lamp2 KO小鼠的心肌细胞内表达，而不仅仅是驻留在那些心脏中的供体巨噬细胞内，进行了免疫荧光研究，证明心肌细胞中的LAMP2+囊泡(α-辅肌动蛋白：白色)位于供体巨噬细胞附近的(图10A-10C)。EM分析显示与Lamp2 KO小鼠相比，接受WT HSPC的Lamp2 KO小鼠的空泡减少(图11A和11B)，表现出与WT小鼠相似的外观。通过评估LC3-II/GAPDH水平证实了Lamp2 KO小鼠的WT HSPC移植后改善的自噬流(图11C-11D)。总之，这些研究证明了用WT HSPC移植治疗的Lamp2 KO小鼠的生理和代谢功能的恢复。
尽管已参考上述实施例描述了本发明，但应理解，修改和变化包含在本发明的精神和范围内。因此，本发明仅受以上权利要求的限制。
SEQUENCE LISTING
<110> 加利福尼亚大学董事会
<120> 治疗溶酶体紊乱的方法
<130> 20378-201753
<150> 62/471,741
<151> 2017-03-05
<150> 62/507,713
<151> 2017-05-17
<160> 27
<170> PatentIn version 3.5
<210> 1
<211> 367
<212> PRT
<213> 智人
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Met Ile Arg Asn Trp Leu Thr Ile Phe Ile Leu Phe Pro Leu Lys Leu
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Pro Leu Asn Ala Thr Leu Val Ile Thr Phe Glu Ile Thr Phe Arg Ser
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Lys Asn Ile Thr Ile Leu Glu Leu Pro Asp Glu Val Val Val Pro Pro
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Leu Thr Val Tyr Leu His Gly Asn His Ser Asn Gln Thr Gly Pro Arg
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Ile Arg Phe Leu Val Ile Arg Ser Ser Ala Ile Ser Ile Ile Asn Gln
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Val Ile Gly Trp Ile Tyr Phe Val Ala Trp Ser Ile Ser Phe Tyr Pro
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Gln Val Ile Met Asn Trp Arg Arg Lys Ser Val Ile Gly Leu Ser Phe
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Asp Phe Val Ala Leu Asn Leu Thr Gly Phe Val Ala Tyr Ser Val Phe
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Asn Ile Gly Leu Leu Trp Val Pro Tyr Ile Lys Glu Gln Phe Leu Leu
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Lys Tyr Pro Asn Gly Val Asn Pro Val Asn Ser Asn Asp Val Phe Phe
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Leu Tyr Glu Arg Gly Gly Gln Arg Val Ser Trp Pro Ala Ile Gly Phe
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Leu Val Leu Ala Trp Leu Phe Ala Phe Val Thr Met Ile Val Ala Ala
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Val Gly Val Ile Thr Trp Leu Gln Phe Leu Phe Cys Phe Ser Tyr Ile
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Lys Leu Ala Val Thr Leu Val Lys Tyr Phe Pro Gln Ala Tyr Met Asn
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Phe Tyr Tyr Lys Ser Thr Glu Gly Trp Ser Ile Gly Asn Val Leu Leu
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Asp Phe Thr Gly Gly Ser Phe Ser Leu Leu Gln Met Phe Leu Gln Ser
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Tyr Asn Asn Asp Gln Trp Thr Leu Ile Phe Gly Asp Pro Thr Lys Phe
325 330 335
Gly Leu Gly Val Phe Ser Ile Val Phe Asp Val Val Phe Phe Ile Gln
340 345 350
His Phe Cys Leu Tyr Arg Lys Arg Pro Gly Tyr Asp Gln Leu Asn
355 360 365
<210> 2
<211> 2611
<212> DNA
<213> 智人
<400> 2
cgcctctccc aaagtctagc cgggcagggg aacgcggtgc attcctgacc ggcacctggc 60
gaggctcatg cgtcccgtga gggcggttcc tcgagcctgg gggcgctcag attgctttgg 120
agacgctgag agaacctttg cgagagcgcc ggttgacgtg cggagtgcgg ggctccgggg 180
gactgagcag cacgagaccc catcctcccc tccgggtttt cacactgggc gaagggagga 240
ctcctgagct ctgcctcttc cagtaacatt gaggattact gtgttttgtg agagctcgct 300
aggcgcccta agcaacagag ttctgagaaa tcgagaaaca tgataaggaa ttggctgact 360
atttttatcc tttttcccct gaagctcgta gagaaatgtg agtcaagcgt cagcctcact 420
gttcctcctg tcgtaaagct ggagaacggc agctcgacca acgtcagcct caccctgcgg 480
ccaccattaa atgcaaccct ggtgatcact tttgaaatca catttcgttc caaaaatatt 540
actatccttg agctccccga tgaagttgtg gtgcctcctg gagtgacaaa ctcctctttt 600
caagtgacat ctcaaaatgt tggacaactt actgtttatc tacatggaaa tcactccaat 660
cagaccggcc cgaggatacg ctttcttgtg atccgcagca gcgccattag catcataaac 720
caggtgattg gctggatcta ctttgtggcc tggtccatct ccttctaccc tcaggtgatc 780
atgaattgga ggcggaaaag tgtcattggt ctgagcttcg acttcgtggc tctgaacctg 840
acaggcttcg tggcctacag tgtattcaac atcggcctcc tctgggtgcc ctacatcaag 900
gagcagtttc tcctcaaata ccccaacgga gtgaaccccg tgaacagcaa cgacgtcttc 960
ttcagcctgc acgcggttgt cctcacgctg atcatcatcg tgcagtgctg cctgtatgag 1020
cgcggtggcc agcgcgtgtc ctggcctgcc atcggcttcc tggtgctcgc gtggctcttc 1080
gcatttgtca ccatgatcgt ggctgcagtg ggagtgatca cgtggctgca gtttctcttc 1140
tgcttctcct acatcaagct cgcagtcacg ctggtcaagt attttccaca ggcctacatg 1200
aacttttact acaaaagcac tgagggctgg agcattggca acgtgctcct ggacttcacc 1260
gggggcagct tcagcctcct gcagatgttc ctccagtcct acaacaacga ccagtggacg 1320
ctgatcttcg gagacccaac caagtttgga ctcggggtct tctccatcgt cttcgacgtc 1380
gtcttcttca tccagcactt ctgtttgtac agaaagagac cggggtatga ccagctgaac 1440
tagcacccag ggacccagtg tacccagcct ctggcctcgt gccctgctgg ggaaggcctc 1500
acccagcgaa ggccggagaa gcggttgggc cctggcacac agggctggct cagtgtgcgg 1560
acagaggaga ccactctgct cctggggcca gaggccattc aatagcctgc cttcgtccgg 1620
gcccctcctg ggcctccccg gccaggcacg tggcaccgtc gccttgacac cgccatctct 1680
tttctttaag gcttcaggca gcgcgcacag gctctggcag ccgtctcagg caggactggg 1740
caccaagctt gcagccgaag gccttgcccc aaactaccag cgtttctgca agcagcttga 1800
agggctgacc ttgcagccgg gtgagccaag ggcactttgc tgccaccgct gcattcccag 1860
agatcaagca gcccggtgcc gtggccagtg aactcagagg tgctggtgga cgggctagga 1920
ctttggggtt aggccatggg gctctttctc tgaaggccac tttcctgacg tactctctgt 1980
acataactca gcgtccgtga ctgcagtaac agccagccct acccagagta tttctgagcc 2040
atgaggggcc caccagattg gttctgaatt ggattcatgc ccagcgcatt agcatagtaa 2100
ctcctttcag attttttgga gggacgtttg gaagtggctt actctcttct gccctctctc 2160
ctacctccac cttctcagat gagccccatc tgagcacatc cagctgctcc ttacccagca 2220
tctggagtac aggacatagc tctctcctgc taccagtctg tgccttagag gtcgttaggc 2280
ctgccaaacg gcgaccagct cccctggagc gagggcaggc cccttccctc tctttcccca 2340
gacacctact tgagactcac caatttctgg cctgttcagg agcctcagat aagtatttgt 2400
acttgagacc acctcacaca atctgtatgg gcccaaccct gatctcaaac ctccttccct 2460
ctgcccaaag ctgtccttcc tatggcagga ggggtggggg tcccaggacg tgcctcatac 2520
atgacttgag cttgtcagtc cactgagttt ccttctacga gatcaacgcg aggggcctgt 2580
atcttgaatt aaagcctact cgcttccttt c 2611
<210> 3
<211> 495
<212> PRT
<213> 智人
<400> 3
Met Arg Ser Pro Val Arg Asp Leu Ala Arg Asn Asp Gly Glu Glu Ser
1 5 10 15
Thr Asp Arg Thr Pro Leu Leu Pro Gly Ala Pro Arg Ala Glu Ala Ala
20 25 30
Pro Val Cys Cys Ser Ala Arg Tyr Asn Leu Ala Ile Leu Ala Phe Phe
35 40 45
Gly Phe Phe Ile Val Tyr Ala Leu Arg Val Asn Leu Ser Val Ala Leu
50 55 60
Val Asp Met Val Asp Ser Asn Thr Thr Leu Glu Asp Asn Arg Thr Ser
65 70 75 80
Lys Ala Cys Pro Glu His Ser Ala Pro Ile Lys Val His His Asn Gln
85 90 95
Thr Gly Lys Lys Tyr Gln Trp Asp Ala Glu Thr Gln Gly Trp Ile Leu
100 105 110
Gly Ser Phe Phe Tyr Gly Tyr Ile Ile Thr Gln Ile Pro Gly Gly Tyr
115 120 125
Val Ala Ser Lys Ile Gly Gly Lys Met Leu Leu Gly Phe Gly Ile Leu
130 135 140
Gly Thr Ala Val Leu Thr Leu Phe Thr Pro Ile Ala Ala Asp Leu Gly
145 150 155 160
Val Gly Pro Leu Ile Val Leu Arg Ala Leu Glu Gly Leu Gly Glu Gly
165 170 175
Val Thr Phe Pro Ala Met His Ala Met Trp Ser Ser Trp Ala Pro Pro
180 185 190
Leu Glu Arg Ser Lys Leu Leu Ser Ile Ser Tyr Ala Gly Ala Gln Leu
195 200 205
Gly Thr Val Ile Ser Leu Pro Leu Ser Gly Ile Ile Cys Tyr Tyr Met
210 215 220
Asn Trp Thr Tyr Val Phe Tyr Phe Phe Gly Thr Ile Gly Ile Phe Trp
225 230 235 240
Phe Leu Leu Trp Ile Trp Leu Val Ser Asp Thr Pro Gln Lys His Lys
245 250 255
Arg Ile Ser His Tyr Glu Lys Glu Tyr Ile Leu Ser Ser Leu Arg Asn
260 265 270
Gln Leu Ser Ser Gln Lys Ser Val Pro Trp Val Pro Ile Leu Lys Ser
275 280 285
Leu Pro Leu Trp Ala Ile Val Val Ala His Phe Ser Tyr Asn Trp Thr
290 295 300
Phe Tyr Thr Leu Leu Thr Leu Leu Pro Thr Tyr Met Lys Glu Ile Leu
305 310 315 320
Arg Phe Asn Val Gln Glu Asn Gly Phe Leu Ser Ser Leu Pro Tyr Leu
325 330 335
Gly Ser Trp Leu Cys Met Ile Leu Ser Gly Gln Ala Ala Asp Asn Leu
340 345 350
Arg Ala Lys Trp Asn Phe Ser Thr Leu Cys Val Arg Arg Ile Phe Ser
355 360 365
Leu Ile Gly Met Ile Gly Pro Ala Val Phe Leu Val Ala Ala Gly Phe
370 375 380
Ile Gly Cys Asp Tyr Ser Leu Ala Val Ala Phe Leu Thr Ile Ser Thr
385 390 395 400
Thr Leu Gly Gly Phe Cys Ser Ser Gly Phe Ser Ile Asn His Leu Asp
405 410 415
Ile Ala Pro Ser Tyr Ala Gly Ile Leu Leu Gly Ile Thr Asn Thr Phe
420 425 430
Ala Thr Ile Pro Gly Met Val Gly Pro Val Ile Ala Lys Ser Leu Thr
435 440 445
Pro Asp Asn Thr Val Gly Glu Trp Gln Thr Val Phe Tyr Ile Ala Ala
450 455 460
Ala Ile Asn Val Phe Gly Ala Ile Phe Phe Thr Leu Phe Ala Lys Gly
465 470 475 480
Glu Val Gln Asn Trp Ala Leu Asn Asp His His Gly His Arg His
485 490 495
<210> 4
<211> 2512
<212> DNA
<213> 智人
<400> 4
cggctacttt gcgccaatcc tacgagaact cccagaactc cgcttcccta gtccaaccca 60
agccagagtt gcccacacct aagatggcgg cggggggcgg agtcggcgcg gccgcctctg 120
ggcgggaccg cggggactag acgtggccgc ggggcggtgt catcgccccc gccccgcccg 180
gtccagccag ctcggcccgg gggcttcggg ctgtcgggcc ggcgctccct tctctgccag 240
gtggcgagta cacctgctca cgtaggcgtc atgaggtctc cggttcgaga cctggcccgg 300
aacgatggcg aggagagcac ggaccgcacg cctcttctac cgggcgcccc acgggccgaa 360
gccgctccag tgtgctgctc tgctcgttac aacttagcaa ttttggcctt ttttggtttc 420
ttcattgtgt atgcattacg tgtgaatctg agtgttgcgt tagtggatat ggtagattca 480
aatacaactt tagaagataa tagaacttcc aaggcgtgtc cagagcattc tgctcccata 540
aaagttcatc ataatcaaac gggtaagaag taccaatggg atgcagaaac tcaaggatgg 600
attctcggtt ccttttttta tggctacatc atcacacaga ttcctggagg atatgttgcc 660
agcaaaatag gggggaaaat gctgctagga tttgggatcc ttggcactgc tgtcctcacc 720
ctgttcactc ccattgctgc agatttagga gttggaccac tcattgtact cagagcacta 780
gaaggactag gagagggtgt tacatttcca gccatgcatg ccatgtggtc ttcttgggct 840
ccccctcttg aaagaagcaa acttcttagc atttcatatg caggagcaca gcttgggaca 900
gtaatttctc ttcctctttc tggaataatt tgctactata tgaattggac ttatgtcttc 960
tacttttttg gtactattgg aatattttgg tttcttttgt ggatctggtt agttagtgac 1020
acaccacaaa aacacaagag aatttcccat tatgaaaagg aatacattct ttcatcatta 1080
agaaatcagc tttcttcaca gaagtcagtg ccgtgggtac ccattttaaa atccctgcca 1140
ctttgggcta tcgtagttgc acacttttct tacaactgga ctttttatac tttattgaca 1200
ttattgccta cttatatgaa ggagatccta aggttcaatg ttcaagagaa tgggttttta 1260
tcttcattgc cttatttagg ctcttggtta tgtatgatcc tgtctggtca agctgctgac 1320
aatttaaggg caaaatggaa tttttcaact ttatgtgttc gcagaatttt tagccttata 1380
ggaatgattg gacctgcagt attcctggta gctgctggct tcattggctg tgattattct 1440
ttggccgttg ctttcctaac tatatcaaca acactgggag gcttttgctc ttctggattt 1500
agcatcaacc atctggatat tgctccttcg tatgctggta tcctcctggg catcacaaat 1560
acatttgcca ctattccagg aatggttggg cccgtcattg ctaaaagtct gacccctgat 1620
aacactgttg gagaatggca aaccgtgttc tatattgctg ctgctattaa tgtttttggt 1680
gccattttct ttacactatt cgccaaaggt gaagtacaaa actgggctct caatgatcac 1740
catggacaca gacactgaag gaaccaataa ataatcctgc ctctattaat gtatttttat 1800
ttatcatgta acctcaaagt gccttctgta ttgtgtaagc attctatgtc tttttttaat 1860
tgtacttgta ttagattttt aaggcctata atcatgaaat atcactagtt gccagaataa 1920
taaaatgaac tgtgtttaat tatgaataat atgtaagcta ggacttctac tttaggttca 1980
catacctgcc tgctagtcgg gcaacatgaa gtaggacagt tctgttgatt ttttagggcc 2040
atactaaagg gaatgagctg aaacagacct cctgatacct ttgcttaatt aaactagatg 2100
ataattctca ggtactgata aacacctgtt gttgttcact ttcctcataa aaattgtcag 2160
ctctctctga cacttagacc tcaaacttta gcatctctgt ggagctgcca tccactgtat 2220
aatttcgcct ggcaactgga ctgaggggag tgtgcccagg cagctgccaa gcactccctc 2280
cctggcttca gggtcagagt gcccagcgtt tatcagaggc agcatccaag cccagagcca 2340
gtgtcgactc ttcggctggt gcctttcctc tgaggggcta tcaatgtgta gataaagccc 2400
tgagtaggca agagcagtga gatccactgc tatggtcttg atacatcctc aaactttccc 2460
ttcccagcac agaggaatat tggctggcat gcaacctgca aaagaaaaat gc 2512
<210> 5
<211> 537
<212> PRT
<213> 智人
<400> 5
Gly Ala Ala Ser Ala Glu Leu Val Ile Gly Trp Cys Ile Phe Gly Pro
1 5 10 15
Leu Leu Leu Ala Ile Phe Ala Phe Cys Trp Ile Tyr Val Arg Lys Tyr
20 25 30
Gln Ser Gln Arg Glu Ser Glu Val Val Ser Thr Ile Thr Ala Ile Phe
35 40 45
Ser Leu Ala Ile Ala Leu Ile Thr Ser Ala Leu Leu Pro Val Asp Ile
50 55 60
Phe Leu Val Ser Tyr Met Lys Asn Gln Asn Gly Thr Phe Lys Asp Trp
65 70 75 80
Ala Asn Ala Asn Val Ser Arg Gln Ile Glu Asp Thr Val Leu Tyr Gly
85 90 95
Tyr Tyr Thr Leu Tyr Ser Val Ile Leu Phe Cys Val Phe Phe Trp Ile
100 105 110
Pro Phe Val Tyr Phe Tyr Tyr Glu Glu Lys Asp Asp Asp Asp Thr Ser
115 120 125
Lys Cys Thr Gln Ile Lys Thr Ala Phe Lys Tyr Thr Leu Gly Phe Ala
130 135 140
Val Ile Cys Ala Leu Leu Leu Leu Val Gly Ala Phe Val Pro Leu Asn
145 150 155 160
Val Pro Asn Asn Lys Asn Ser Thr Glu Trp Glu Lys Val Lys Phe Leu
165 170 175
Phe Glu Glu Leu Gly Ser Ser His Gly Leu Ala Ala Leu Ser Phe Ser
180 185 190
Ile Ser Ser Leu Thr Leu Ile Gly Met Leu Ala Ala Ile Thr Tyr Thr
195 200 205
Ala Tyr Gly Met Ser Ala Leu Pro Leu Asn Leu Ile Lys Gly Thr Arg
210 215 220
Ser Ala Ala Tyr Glu Arg Leu Glu Asn Thr Glu Asp Ile Glu Glu Val
225 230 235 240
Glu Gln His Ile Gln Thr Ile Lys Ser Lys Ser Lys Asp Gly Arg Pro
245 250 255
Leu Pro Ala Arg Asp Lys Arg Ala Leu Lys Gln Phe Glu Glu Arg Leu
260 265 270
Arg Thr Leu Arg Lys Arg Glu Arg His Leu Glu Tyr Ile Glu Asn Ser
275 280 285
Trp Trp Thr Lys Phe Cys Gly Ala Leu Arg Pro Leu Lys Ile Ile Trp
290 295 300
Gly Ile Phe Phe Ile Leu Val Ala Leu Leu Phe Ile Ile Ser Leu Phe
305 310 315 320
Leu Ser Asn Leu Asp Lys Ala Leu His Ser Ala Gly Ile Asp Ser Gly
325 330 335
Phe Ile Ile Phe Gly Ala Asn Leu Ser Asn Pro Leu Asn Met Leu Leu
340 345 350
Pro Val Leu Gln Thr Val Phe Pro Leu Asp Tyr Ile Leu Ile Thr Ile
355 360 365
Ile Ile Met Tyr Phe Ile Phe Thr Ser Met Ala Gly Ile Arg Asn Ile
370 375 380
Gly Ile Trp Phe Phe Trp Val Arg Leu Tyr Lys Ile Arg Arg Gly Arg
385 390 395 400
Thr Arg Pro Gln Ala Leu Leu Phe Leu Cys Met Ile Leu Leu Leu Ile
405 410 415
Val Leu His Thr Ser Tyr Met Ile Tyr Ser Leu Ala Pro Gln Tyr Val
420 425 430
Met Tyr Gly Ser Gln Asn Tyr Leu Ile Glu Ser Asn Ile Thr Tyr Asp
435 440 445
Asp His Lys Asn Asn Ser Ala Phe Pro Val Pro Lys Arg Cys Asp Ala
450 455 460
Asp Ala Pro Glu Asp Gln Cys Thr Val Thr Arg Thr Tyr Leu Phe Leu
465 470 475 480
His Lys Phe Trp Phe Phe Ser Ala Ala Tyr Tyr Phe Gly Asn Trp Ala
485 490 495
Phe Leu Val Val Phe Leu Ile Gly Leu Ile Val Ser Cys Cys Lys Gly
500 505 510
Lys Lys Ser Val Ile Glu Gly Val Asp Glu Asp Asp Ser Asp Ile Ser
515 520 525
Asp Asp Glu Pro Ser Val Tyr Ser Val
530 535
<210> 6
<211> 1979
<212> DNA
<213> 智人
<400> 6
ggcgcggctt cggcggagct ggtgatcggc tggtgcatat ttggcccctt actactggct 60
atttttgcat tctgttggat atatgttcgt aaataccaaa gtcagcggga aagtgaagtt 120
gtctccacca taacggcaat tttttctctg gcgattgcac ttatcacatc agcacttctt 180
ccagtggata tatttttggt ttcttacatg aaaaatcaaa atggtacatt taaggactgg 240
gccaatgcta atgtcagcag acagatcgag gacactgtgt tatatggtta ctacacctta 300
tattctgtta tattattctg tgtgtttttc tggatccctt ttgtctactt ctactatgaa 360
gaaaaggatg atgatgatac tagtaaatgt actcaaatta aaactgcatt caagtatact 420
ttgggatttg ctgtaatttg tgcacttctt cttttagttg gagcttttgt tcctctaaat 480
gttcctaata acaaaaattc tacagagtgg gaaaaagtga agttcctgtt tgaagaactt 540
ggaagtagtc atggtttagc tgcattgtca ttttctatta gttctctgac cttgattgga 600
atgttggcag ctataactta cacagcctat ggcatgtctg cattaccttt aaatctaata 660
aaaggcacta gaagcgctgc ttacgaacgt ttagaaaaca ctgaagacat tgaagaagtg 720
gagcaacaca ttcaaacgat taaatcaaaa agcaaagatg gtcggccttt gccagcaagg 780
gataaacgcg ccttaaaaca atttgaagaa aggttaagaa cacttaggaa aagagagagg 840
cacttagaat acattgaaaa cagctggtgg acaaaatttt gtggtgctct gcgtcccctg 900
aagatcattt ggggaatatt tttcatctta gttgcattgc tgtttataat ttctctcttc 960
ctgtcaaatt tggataaagc ccttcattca gctggaatag attctggttt tataattttt 1020
ggagctaact tgagtaatcc actgaatatg cttttgcctg tactacaaac agtgtttcct 1080
cttgattata ttcttataac aattattatt atgtacttta tttttacttc aatggcggga 1140
attcgaaata tcggcatatg gttcttttgg gttagactat ataaaattag aagaggtaga 1200
accaggcccc aggccctctt atttctttgc atgatacttc tgcttattgt ccttcacact 1260
agctacatga tttatagtct tgctccccaa tatgtcatgt atggaagcca aaattactta 1320
atagagagca atataactta tgatgaccat aaaaacaatt cagccttccc tgtgccaaag 1380
agatgtgatg ctgatgcccc tgaagaccaa tgtactgtta cgcggacata cctgttcctt 1440
cacaagttct ggttctttag tgctgcatac tattttggta actgggcttt tcttgtggta 1500
ttcttgattg gattaattgt atcctgttgt aaagggaaga aatcagtcat tgaaggagta 1560
gatgaagatg attcagacat aagtgatgat gagccctctg tctattctgt ttgagagcct 1620
ctgtcttagg ggttttataa tgctgactga atgtctatta tgcatttttt aaagtgttaa 1680
actaacatta ggatgaactg actagcttca tcaaaaatgg gagcatggct attaaaaaaa 1740
ctatattttt tatgttatct gaagtaacat tattgtatca tagattaaca tttaaaattg 1800
ctgtaataat tctatgtaaa tataaaacta tggactttgt gagggaatgt ttgtggaaat 1860
cttttttctc tagtgtataa tagtgttgaa ttgattaaaa gtcttccaga attaatattc 1920
cctcttgtca cttcttaaaa acataataaa tcacttctac ctgtgcaaaa aaaaaaaaa 1979
<210> 7
<211> 518
<212> PRT
<213> 智人
<400> 7
Met Ala Gly Leu Arg Asn Glu Ser Glu Gln Glu Pro Leu Leu Gly Asp
1 5 10 15
Thr Pro Gly Ser Arg Glu Trp Asp Ile Leu Glu Thr Glu Glu His Tyr
20 25 30
Lys Ser Arg Trp Arg Ser Ile Arg Ile Leu Tyr Leu Thr Met Phe Leu
35 40 45
Ser Ser Val Gly Phe Ser Val Val Met Met Ser Ile Trp Pro Tyr Leu
50 55 60
Gln Lys Ile Asp Pro Thr Ala Asp Thr Ser Phe Leu Gly Trp Val Ile
65 70 75 80
Ala Ser Tyr Ser Leu Gly Gln Met Val Ala Ser Pro Ile Phe Gly Leu
85 90 95
Trp Ser Asn Tyr Arg Pro Arg Lys Glu Pro Leu Ile Val Ser Ile Leu
100 105 110
Ile Ser Val Ala Ala Asn Cys Leu Tyr Ala Tyr Leu His Ile Pro Ala
115 120 125
Ser His Asn Lys Tyr Tyr Met Leu Val Ala Arg Gly Leu Leu Gly Ile
130 135 140
Gly Ala Gly Asn Val Ala Val Val Arg Ser Tyr Thr Ala Gly Ala Thr
145 150 155 160
Ser Leu Gln Glu Arg Thr Ser Ser Met Ala Asn Ile Ser Met Cys Gln
165 170 175
Ala Leu Gly Phe Ile Leu Gly Pro Val Phe Gln Thr Cys Phe Thr Phe
180 185 190
Leu Gly Glu Lys Gly Val Thr Trp Asp Val Ile Lys Leu Gln Ile Asn
195 200 205
Met Tyr Thr Thr Pro Val Leu Leu Ser Ala Phe Leu Gly Ile Leu Asn
210 215 220
Ile Ile Leu Ile Leu Ala Ile Leu Arg Glu His Arg Val Asp Asp Ser
225 230 235 240
Gly Arg Gln Cys Lys Ser Ile Asn Phe Glu Glu Ala Ser Thr Asp Glu
245 250 255
Ala Gln Val Pro Gln Gly Asn Ile Asp Gln Val Ala Val Val Ala Ile
260 265 270
Asn Val Leu Phe Phe Val Thr Leu Phe Ile Phe Ala Leu Phe Glu Thr
275 280 285
Ile Ile Thr Pro Leu Thr Met Asp Met Tyr Ala Trp Thr Gln Glu Gln
290 295 300
Ala Val Leu Tyr Asn Gly Ile Ile Leu Ala Ala Leu Gly Val Glu Ala
305 310 315 320
Val Val Ile Phe Leu Gly Val Lys Leu Leu Ser Lys Lys Ile Gly Glu
325 330 335
Arg Ala Ile Leu Leu Gly Gly Leu Ile Val Val Trp Val Gly Phe Phe
340 345 350
Ile Leu Leu Pro Trp Gly Asn Gln Phe Pro Lys Ile Gln Trp Glu Asp
355 360 365
Leu His Asn Asn Ser Ile Pro Asn Thr Thr Phe Gly Glu Ile Ile Ile
370 375 380
Gly Leu Trp Lys Ser Pro Met Glu Asp Asp Asn Glu Arg Pro Thr Gly
385 390 395 400
Cys Ser Ile Glu Gln Ala Trp Cys Leu Tyr Thr Pro Val Ile His Leu
405 410 415
Ala Gln Phe Leu Thr Ser Ala Val Leu Ile Gly Leu Gly Tyr Pro Val
420 425 430
Cys Asn Leu Met Ser Tyr Thr Leu Tyr Ser Lys Ile Leu Gly Pro Lys
435 440 445
Pro Gln Gly Val Tyr Met Gly Trp Leu Thr Ala Ser Gly Ser Gly Ala
450 455 460
Arg Ile Leu Gly Pro Met Phe Ile Ser Gln Val Tyr Ala His Trp Gly
465 470 475 480
Pro Arg Trp Ala Phe Ser Leu Val Cys Gly Ile Ile Val Leu Thr Ile
485 490 495
Thr Leu Leu Gly Val Val Tyr Lys Arg Leu Ile Ala Leu Ser Val Arg
500 505 510
Tyr Gly Arg Ile Gln Glu
515
<210> 8
<211> 1909
<212> DNA
<213> 智人
<400> 8
aggttacaag cagcagatcc caccttcagt cctggctctg acaagccctc cagcttcacg 60
ccacccggga tgggagaaag caggtgtcgc gagagttggg cgcaagacgc cttgtaggga 120
gtgtaactat ggccggcctg cggaacgaaa gtgaacagga gccgctctta ggcgacacac 180
ctggaagcag agaatgggac attttagaga ctgaagagca ttataagagc cgatggagat 240
ctattaggat tttatatctt actatgtttc tcagcagtgt agggttttct gtagtgatga 300
tgtccatatg gccatatctc caaaagattg atccgacagc tgatacaagt tttttgggct 360
gggttattgc ttcatatagt cttggccaaa tggtagcttc acctatattt ggtttatggt 420
ctaattatag accaagaaaa gagcctctta ttgtctccat cttgatttcc gtggcagcca 480
actgcctcta tgcatatctc cacatcccag cttctcataa taaatactac atgctggttg 540
ctcgtggatt gttgggaatt ggagcaggaa atgtagcagt tgttagatca tatactgctg 600
gtgctacttc ccttcaggaa agaacaagtt ccatggcaaa cataagcatg tgtcaagcat 660
taggttttat tctaggtcca gtttttcaga cttgttttac attccttgga gaaaaaggtg 720
tgacatggga tgtgattaaa ctgcagataa acatgtatac aacaccagtt ttacttagcg 780
ccttcctggg aattttaaat attattctga tccttgccat actaagagaa catcgtgtgg 840
atgactcagg aagacagtgt aaaagtatta attttgaaga agcaagtaca gatgaagctc 900
aggttcccca aggaaatatt gaccaggttg ctgttgtggc catcaatgtt ctgttttttg 960
tgactctatt tatctttgcc ctttttgaaa ccatcattac tccattaaca atggatatgt 1020
atgcctggac tcaagaacaa gctgtgttat ataatggcat aatacttgct gctcttgggg 1080
ttgaagccgt tgttattttc ttaggagtta agttgctttc caaaaagatt ggcgagcgtg 1140
ctattctact gggaggactc atcgttgtat gggttggctt ctttatcttg ttaccttggg 1200
gaaatcaatt tcccaaaata cagtgggaag atttgcacaa taattcaatc cctaatacca 1260
catttgggga aattattatt ggtctttgga agtctccaat ggaagatgac aatgaaagac 1320
caactggttg ctcgattgaa caagcctggt gcctctacac cccggtgatt catctggccc 1380
agttccttac atcagctgtg ctaataggat taggctatcc agtctgcaat cttatgtcct 1440
atactctata ttcaaaaatt ctaggaccaa aacctcaggg tgtatacatg ggctggttaa 1500
cagcatctgg aagtggagcc cggattcttg ggcctatgtt catcagccaa gtgtatgctc 1560
actggggacc acgatgggca ttcagcctgg tgtgtggaat aatagtgctc accatcaccc 1620
tcctgggagt ggtttacaaa agactcattg ctctttctgt aagatatggg aggattcagg 1680
aataaactag ctaagactgt gatggaaact acttgctgtg tggcacttcc tggtctaaag 1740
ctctgctaga caattgcggt gagccagtct ccaagaatca gactacagat attgcagatt 1800
ttgaagaaca agaacatatg ttgaataaca gagagaattc tacatgtcat tgtgaatagt 1860
aggttatata aaaacatact agatgataat ttcaaaaaaa aaaaaaaaa 1909
<210> 9
<211> 438
<212> PRT
<213> 智人
<400> 9
Met Gly Gly Cys Ala Gly Ser Arg Arg Arg Phe Ser Asp Ser Glu Gly
1 5 10 15
Glu Glu Thr Val Pro Glu Pro Arg Leu Pro Leu Leu Asp His Gln Gly
20 25 30
Ala His Trp Lys Asn Ala Val Gly Phe Trp Leu Leu Gly Leu Cys Asn
35 40 45
Asn Phe Ser Tyr Val Val Met Leu Ser Ala Ala His Asp Ile Leu Ser
50 55 60
His Lys Arg Thr Ser Gly Asn Gln Ser His Val Asp Pro Gly Pro Thr
65 70 75 80
Pro Ile Pro His Asn Ser Ser Ser Arg Phe Asp Cys Asn Ser Val Ser
85 90 95
Thr Ala Ala Val Leu Leu Ala Asp Ile Leu Pro Thr Leu Val Ile Lys
100 105 110
Leu Leu Ala Pro Leu Gly Leu His Leu Leu Pro Tyr Ser Pro Arg Val
115 120 125
Leu Val Ser Gly Ile Cys Ala Ala Gly Ser Phe Val Leu Val Ala Phe
130 135 140
Ser His Ser Val Gly Thr Ser Leu Cys Gly Val Val Phe Ala Ser Ile
145 150 155 160
Ser Ser Gly Leu Gly Glu Val Thr Phe Leu Ser Leu Thr Ala Phe Tyr
165 170 175
Pro Arg Ala Val Ile Ser Trp Trp Ser Ser Gly Thr Gly Gly Ala Gly
180 185 190
Leu Leu Gly Ala Leu Ser Tyr Leu Gly Leu Thr Gln Ala Gly Leu Ser
195 200 205
Pro Gln Gln Thr Leu Leu Ser Met Leu Gly Ile Pro Ala Leu Leu Leu
210 215 220
Ala Ser Tyr Phe Leu Leu Leu Thr Ser Pro Glu Ala Gln Asp Pro Gly
225 230 235 240
Gly Glu Glu Glu Ala Glu Ser Ala Ala Arg Gln Pro Leu Ile Arg Thr
245 250 255
Glu Ala Pro Glu Ser Lys Pro Gly Ser Ser Ser Ser Leu Ser Leu Arg
260 265 270
Glu Arg Trp Thr Val Phe Lys Gly Leu Leu Trp Tyr Ile Val Pro Leu
275 280 285
Val Val Val Tyr Phe Ala Glu Tyr Phe Ile Asn Gln Gly Leu Phe Glu
290 295 300
Leu Leu Phe Phe Trp Asn Thr Ser Leu Ser His Ala Gln Gln Tyr Arg
305 310 315 320
Trp Tyr Gln Met Leu Tyr Gln Ala Gly Val Phe Ala Ser Arg Ser Ser
325 330 335
Leu Arg Cys Cys Arg Ile Arg Phe Thr Trp Ala Leu Ala Leu Leu Gln
340 345 350
Cys Leu Asn Leu Val Phe Leu Leu Ala Asp Val Trp Phe Gly Phe Leu
355 360 365
Pro Ser Ile Tyr Leu Val Phe Leu Ile Ile Leu Tyr Glu Gly Leu Leu
370 375 380
Gly Gly Ala Ala Tyr Val Asn Thr Phe His Asn Ile Ala Leu Glu Thr
385 390 395 400
Ser Asp Glu His Arg Glu Phe Ala Met Ala Ala Thr Cys Ile Ser Asp
405 410 415
Thr Leu Gly Ile Ser Leu Ser Gly Leu Leu Ala Leu Pro Leu His Asp
420 425 430
Phe Leu Cys Gln Leu Ser
435
<210> 10
<211> 1689
<212> DNA
<213> 智人
<400> 10
cccctagaca agccggagct gggaccggca atcgggcgtt gatccttgtc acctgtcgca 60
gaccctcatc cctcccgtgg gagccccctt tggacactct atgaccctgg accctcgggg 120
gacctgaact tgatgcgatg ggaggctgtg caggctcgcg gcggcgcttt tcggattccg 180
agggggagga gaccgtcccg gagccccggc tccctctgtt ggaccatcag ggcgcgcatt 240
ggaagaacgc ggtgggcttc tggctgctgg gcctttgcaa caacttctct tatgtggtga 300
tgctgagtgc cgcccacgac atccttagcc acaagaggac atcgggaaac cagagccatg 360
tggacccagg cccaacgccg atcccccaca acagctcatc acgatttgac tgcaactctg 420
tctctacggc tgctgtgctc ctggcggaca tcctccccac actcgtcatc aaattgttgg 480
ctcctcttgg ccttcacctg ctgccctaca gcccccgggt tctcgtcagt gggatttgtg 540
ctgctggaag cttcgtcctg gttgcctttt ctcattctgt ggggaccagc ctgtgtggtg 600
tggtcttcgc tagcatctca tcaggccttg gggaggtcac cttcctctcc ctcactgcct 660
tctaccccag ggccgtgatc tcctggtggt cctcagggac tgggggagct gggctgctgg 720
gggccctgtc ctacctgggc ctcacccagg ccggcctctc ccctcagcag accctgctgt 780
ccatgctggg tatccctgcc ctgctgctgg ccagctattt cttgttgctc acatctcctg 840
aggcccagga ccctggaggg gaagaagaag cagagagcgc agcccggcag cccctcataa 900
gaaccgaggc cccggagtcg aagccaggct ccagctccag cctctccctt cgggaaaggt 960
ggacagtatt caagggtctg ctgtggtaca ttgttccctt ggtcgtagtt tactttgccg 1020
agtatttcat taaccaggga ctttttgaac tcctcttttt ctggaacact tccctgagtc 1080
acgctcagca ataccgctgg taccagatgc tgtaccaggc tggcgtcttt gcctcccgct 1140
cttctctccg ctgctgtcgc atccgtttca cctgggccct ggccctgctg cagtgcctca 1200
acctggtgtt cctgctggca gacgtgtggt tcggctttct gccaagcatc tacctcgtct 1260
tcctgatcat tctgtatgag gggctcctgg gaggcgcagc ctacgtgaac accttccaca 1320
acatcgccct ggagaccagt gatgagcacc gggagtttgc aatggcggcc acctgcatct 1380
ctgacacact ggggatctcc ctgtcggggc tcctggcttt gcctctgcat gacttcctct 1440
gccagctctc ctgatactcg ggatcctcag gacgcaggtc acattcacct gtgggcagag 1500
ggacaggtca gacacccagg cccaccccag agaccctcca tgaactgtgc tcccagcctt 1560
cccggcaggt ctgggagtag ggaagggctg aagccttgtt tccttgcagg ggggccagcc 1620
attgtctccc acttggggag tttcttcctg gcatcatgcc ttctgaataa atgccgattt 1680
tgtccatgg 1689
<210> 11
<211> 805
<212> PRT
<213> 智人
<400> 11
Met Ala Asn Val Ser Lys Lys Val Ser Trp Ser Gly Arg Asp Arg Asp
1 5 10 15
Asp Glu Glu Ala Ala Pro Leu Leu Arg Arg Thr Ala Arg Pro Gly Gly
20 25 30
Gly Thr Pro Leu Leu Asn Gly Ala Gly Pro Gly Ala Ala Arg Gln Ser
35 40 45
Pro Arg Ser Ala Leu Phe Arg Val Gly His Met Ser Ser Val Glu Leu
50 55 60
Asp Asp Glu Leu Leu Asp Pro Asp Met Asp Pro Pro His Pro Phe Pro
65 70 75 80
Lys Glu Ile Pro His Asn Glu Lys Leu Leu Ser Leu Lys Tyr Glu Ser
85 90 95
Leu Asp Tyr Asp Asn Ser Glu Asn Gln Leu Phe Leu Glu Glu Glu Arg
100 105 110
Arg Ile Asn His Thr Ala Phe Arg Thr Val Glu Ile Lys Arg Trp Val
115 120 125
Ile Cys Ala Leu Ile Gly Ile Leu Thr Gly Leu Val Ala Cys Phe Ile
130 135 140
Asp Ile Val Val Glu Asn Leu Ala Gly Leu Lys Tyr Arg Val Ile Lys
145 150 155 160
Gly Asn Ile Asp Lys Phe Thr Glu Lys Gly Gly Leu Ser Phe Ser Leu
165 170 175
Leu Leu Trp Ala Thr Leu Asn Ala Ala Phe Val Leu Val Gly Ser Val
180 185 190
Ile Val Ala Phe Ile Glu Pro Val Ala Ala Gly Ser Gly Ile Pro Gln
195 200 205
Ile Lys Cys Phe Leu Asn Gly Val Lys Ile Pro His Val Val Arg Leu
210 215 220
Lys Thr Leu Val Ile Lys Val Ser Gly Val Ile Leu Ser Val Val Gly
225 230 235 240
Gly Leu Ala Val Gly Lys Glu Gly Pro Met Ile His Ser Gly Ser Val
245 250 255
Ile Ala Ala Gly Ile Ser Gln Gly Arg Ser Thr Ser Leu Lys Arg Asp
260 265 270
Phe Lys Ile Phe Glu Tyr Phe Arg Arg Asp Thr Glu Lys Arg Asp Phe
275 280 285
Val Ser Ala Gly Ala Ala Ala Gly Val Ser Ala Ala Phe Gly Ala Pro
290 295 300
Val Gly Gly Val Leu Phe Ser Leu Glu Glu Gly Ala Ser Phe Trp Asn
305 310 315 320
Gln Phe Leu Thr Trp Arg Ile Phe Phe Ala Ser Met Ile Ser Thr Phe
325 330 335
Thr Leu Asn Phe Val Leu Ser Ile Tyr His Gly Asn Met Trp Asp Leu
340 345 350
Ser Ser Pro Gly Leu Ile Asn Phe Gly Arg Phe Asp Ser Glu Lys Met
355 360 365
Ala Tyr Thr Ile His Glu Ile Pro Val Phe Ile Ala Met Gly Val Val
370 375 380
Gly Gly Val Leu Gly Ala Val Phe Asn Ala Leu Asn Tyr Trp Leu Thr
385 390 395 400
Met Phe Arg Ile Arg Tyr Ile His Arg Pro Cys Leu Gln Val Ile Glu
405 410 415
Ala Val Leu Val Ala Ala Val Thr Ala Thr Val Ala Phe Val Leu Ile
420 425 430
Tyr Ser Ser Arg Asp Cys Gln Pro Leu Gln Gly Gly Ser Met Ser Tyr
435 440 445
Pro Leu Gln Leu Phe Cys Ala Asp Gly Glu Tyr Asn Ser Met Ala Ala
450 455 460
Ala Phe Phe Asn Thr Pro Glu Lys Ser Val Val Ser Leu Phe His Asp
465 470 475 480
Pro Pro Gly Ser Tyr Asn Pro Leu Thr Leu Gly Leu Phe Thr Leu Val
485 490 495
Tyr Phe Phe Leu Ala Cys Trp Thr Tyr Gly Leu Thr Val Ser Ala Gly
500 505 510
Val Phe Ile Pro Ser Leu Leu Ile Gly Ala Ala Trp Gly Arg Leu Phe
515 520 525
Gly Ile Ser Leu Ser Tyr Leu Thr Gly Ala Ala Ile Trp Ala Asp Pro
530 535 540
Gly Lys Tyr Ala Leu Met Gly Ala Ala Ala Gln Leu Gly Gly Ile Val
545 550 555 560
Arg Met Thr Leu Ser Leu Thr Val Ile Met Met Glu Ala Thr Ser Asn
565 570 575
Val Thr Tyr Gly Phe Pro Ile Met Leu Val Leu Met Thr Ala Lys Ile
580 585 590
Val Gly Asp Val Phe Ile Glu Gly Leu Tyr Asp Met His Ile Gln Leu
595 600 605
Gln Ser Val Pro Phe Leu His Trp Glu Ala Pro Val Thr Ser His Ser
610 615 620
Leu Thr Ala Arg Glu Val Met Ser Thr Pro Val Thr Cys Leu Arg Arg
625 630 635 640
Arg Glu Lys Val Gly Val Ile Val Asp Val Leu Ser Asp Thr Ala Ser
645 650 655
Asn His Asn Gly Phe Pro Val Val Glu His Ala Asp Asp Thr Gln Pro
660 665 670
Ala Arg Leu Gln Gly Leu Ile Leu Arg Ser Gln Leu Ile Val Leu Leu
675 680 685
Lys His Lys Val Phe Val Glu Arg Ser Asn Leu Gly Leu Val Gln Arg
690 695 700
Arg Leu Arg Leu Lys Asp Phe Arg Asp Ala Tyr Pro Arg Phe Pro Pro
705 710 715 720
Ile Gln Ser Ile His Val Ser Gln Asp Glu Arg Glu Cys Thr Met Asp
725 730 735
Leu Ser Glu Phe Met Asn Pro Ser Pro Tyr Thr Val Pro Gln Glu Ala
740 745 750
Ser Leu Pro Arg Val Phe Lys Leu Phe Arg Ala Leu Gly Leu Arg His
755 760 765
Leu Val Val Val Asp Asn Arg Asn Gln Val Val Gly Leu Val Thr Arg
770 775 780
Lys Asp Leu Ala Arg Tyr Arg Leu Gly Lys Arg Gly Leu Glu Glu Leu
785 790 795 800
Ser Leu Ala Gln Thr
805
<210> 12
<211> 3277
<212> DNA
<213> 智人
<400> 12
gccggcgctt cccggccggt gtcgctccgc ggcgggccat ggccaacgtc tctaagaagg 60
tgtcctggtc cggccgggac cgggacgacg aggaggcggc gccgctgctg cggaggacgg 120
cgcggcccgg cggggggacg ccgctgctga acggggctgg gcccggggct gcgcgccagt 180
caccacgttc tgcgcttttc cgagtcggac atatgagcag cgtggagctg gatgatgaac 240
ttttggaccc ggatatggac cctccacatc ccttccccaa ggagatccca cacaacgaga 300
agctcctgtc cctcaagtat gagagcttgg actatgacaa cagtgagaac cagctgttcc 360
tggaggagga gcggcggatc aatcacacgg ccttccggac ggtggagatc aagcgctggg 420
tcatctgcgc cctcattggg atcctcacgg gcctcgtggc ctgcttcatt gacatcgtgg 480
tggaaaacct ggctggcctc aagtacaggg tcatcaaggg caatatcgac aagttcacag 540
agaagggcgg actgtccttc tccctgttgc tgtgggccac gctgaacgcc gccttcgtgc 600
tcgtgggctc tgtgattgtg gctttcatag agccggtggc tgctggcagc ggaatccccc 660
agatcaagtg cttcctcaac ggggtgaaga tcccccacgt ggtgcggctc aagacgttgg 720
tgatcaaagt gtccggtgtg atcctgtccg tggtcggggg cctggccgtg ggaaaggaag 780
ggccgatgat ccactcaggt tcagtgattg ccgccgggat ctctcaggga aggtcaacgt 840
cactgaaacg agatttcaag atcttcgagt acttccgcag agacacagag aagcgggact 900
tcgtctccgc aggggctgcg gccggagtgt cagcggcgtt tggagccccc gtgggtgggg 960
tcctgttcag cttggaggag ggtgcgtcct tctggaacca gttcctgacc tggaggatct 1020
tctttgcttc catgatctcc acgttcaccc tgaattttgt tctgagcatt taccacggga 1080
acatgtggga cctgtccagc ccaggcctca tcaacttcgg aaggtttgac tcggagaaaa 1140
tggcctacac gatccacgag atcccggtct tcatcgccat gggcgtggtg ggcggtgtgc 1200
ttggagctgt gttcaatgcc ttgaactact ggctgaccat gtttcgaatc aggtacatcc 1260
accggccctg cctgcaggtg attgaggccg tgctggtggc cgccgtcacg gccacagttg 1320
ccttcgtgct gatctactcg tcgcgggatt gccagcccct gcaggggggc tccatgtcct 1380
acccgctgca gctcttttgt gcagatggcg agtacaactc catggctgcg gccttcttca 1440
acaccccgga gaagagcgtg gtgagcctct tccacgaccc gccaggctcc tacaaccccc 1500
tgaccctcgg cctgttcacg ctggtctact tcttcctggc ctgctggacc tacgggctca 1560
cggtgtctgc cggggtcttc atcccgtccc tgctcatcgg ggctgcctgg ggccggctct 1620
ttgggatctc cctgtcctac ctcacggggg cggcgatctg ggcggacccc ggcaaatacg 1680
ccctgatggg agctgctgcc cagctgggcg ggattgtgcg gatgacactg agcctgaccg 1740
tcatcatgat ggaggccacc agcaacgtga cctacggctt ccccatcatg ctggtgctca 1800
tgaccgccaa gatcgtgggc gacgtcttca ttgagggcct gtacgacatg cacattcagc 1860
tgcagagtgt gcccttcctg cactgggagg ccccggtcac ctcacactca ctcactgcca 1920
gggaggtgat gagcacacca gtgacctgcc tgaggcggcg tgagaaggtc ggcgtcattg 1980
tggacgtgct gagcgacacg gcgtccaatc acaacggctt ccccgtggtg gagcatgccg 2040
atgacaccca gcctgcccgg ctccagggcc tgatcctgcg ctcccagctc atcgttctcc 2100
taaagcacaa ggtgtttgtg gagcggtcca acctgggcct ggtacagcgg cgcctgaggc 2160
tgaaggactt ccgagacgcc tacccgcgct tcccacccat ccagtccatc cacgtgtccc 2220
aggacgagcg ggagtgcacc atggacctct ccgagttcat gaacccctcc ccctacacgg 2280
tgccccagga ggcgtcgctc ccacgggtgt tcaagctgtt ccgggccctg ggcctgcggc 2340
acctggtggt ggtggacaac cgcaatcagg ttgtcgggtt ggtgaccagg aaggacctcg 2400
ccaggtaccg cctgggaaag agaggcttgg aggagctctc gctggcccag acgtgaggcc 2460
cagccctgcc cataatgggc actggcgctg gcaccccggc ccttctgcat ttcctcccgg 2520
agtcactggt ttctcggccc aaaccatgct ccccagcagt ggcaatggcg agcaccctgc 2580
agctgggcgg gcaggcggca ggcgcggaac tgaccctctc gcgggactga ccctgttgtg 2640
ggcagtggtc tccccccttg gcgcctcctt gcgcaggccc agcctccact ctcctcgtct 2700
aggtttcttt acctccaggg atcagctgtg tgtgtgtgac ctccctaccg ggctatcggc 2760
ctcttgggag ccagcggcag ggccggcacc tgcgtgcctg tgcccgtgtg cgtgagacag 2820
agcccttgcc cctgctgctg ccccgagggc tgccctgccc tggaagggcc cctctgcctc 2880
cacaccagtg gagtcttcga gacttgggag ctgcttggcc tcattttcag ccatgagcag 2940
acggcctgtg gtccctgggc ctgaggcacg gactcgtagc accagggttt ggaggctgcg 3000
accgccccgg agagcagctt cacactggcg ccacagagga gccccacgtg cactccccgg 3060
cctgcatccg gcttgggtac acaggcccag aggactgggg tgactcacgg gccctgtgct 3120
gtgatgttga gagctgagaa aaacctccaa ggccctgagc cccatgccca gccctgcctt 3180
ggtcccccaa tccccagagc ttggagtctg ggccccacac ccagccctgc cttggtccct 3240
gagcctcaaa gcgtggaatt gctgccctgt ggacact 3277
<210> 13
<211> 334
<212> PRT
<213> 智人
<400> 13
Met Glu Pro Gly Pro Thr Ala Ala Gln Arg Arg Cys Ser Leu Pro Pro
1 5 10 15
Trp Leu Pro Leu Gly Leu Leu Leu Trp Ser Gly Leu Ala Leu Gly Ala
20 25 30
Leu Pro Phe Gly Ser Ser Pro His Arg Val Phe His Asp Leu Leu Ser
35 40 45
Glu Gln Gln Leu Leu Glu Val Glu Asp Leu Ser Leu Ser Leu Leu Gln
50 55 60
Gly Gly Gly Leu Gly Pro Leu Ser Leu Pro Pro Asp Leu Pro Asp Leu
65 70 75 80
Asp Pro Glu Cys Arg Glu Leu Leu Leu Asp Phe Ala Asn Ser Ser Ala
85 90 95
Glu Leu Thr Gly Cys Leu Val Arg Ser Ala Arg Pro Val Arg Leu Cys
100 105 110
Gln Thr Cys Tyr Pro Leu Phe Gln Gln Val Val Ser Lys Met Asp Asn
115 120 125
Ile Ser Arg Ala Ala Gly Asn Thr Ser Glu Ser Gln Ser Cys Ala Arg
130 135 140
Ser Leu Leu Met Ala Asp Arg Met Gln Ile Val Val Ile Leu Ser Glu
145 150 155 160
Phe Phe Asn Thr Thr Trp Gln Glu Ala Asn Cys Ala Asn Cys Leu Thr
165 170 175
Asn Asn Ser Glu Glu Leu Ser Asn Ser Thr Val Tyr Phe Leu Asn Leu
180 185 190
Phe Asn His Thr Leu Thr Cys Phe Glu His Asn Leu Gln Gly Asn Ala
195 200 205
His Ser Leu Leu Gln Thr Lys Asn Tyr Ser Glu Val Cys Lys Asn Cys
210 215 220
Arg Glu Ala Tyr Lys Thr Leu Ser Ser Leu Tyr Ser Glu Met Gln Lys
225 230 235 240
Met Asn Glu Leu Glu Asn Lys Ala Glu Pro Gly Thr His Leu Cys Ile
245 250 255
Asp Val Glu Asp Ala Met Asn Ile Thr Arg Lys Leu Trp Ser Arg Thr
260 265 270
Phe Asn Cys Ser Val Pro Cys Ser Asp Thr Val Pro Val Ile Ala Val
275 280 285
Ser Val Phe Ile Leu Phe Leu Pro Val Val Phe Tyr Leu Ser Ser Phe
290 295 300
Leu His Ser Glu Gln Lys Lys Arg Lys Leu Ile Leu Pro Lys Arg Leu
305 310 315 320
Lys Ser Ser Thr Ser Phe Ala Asn Ile Gln Glu Asn Ser Asn
325 330
<210> 14
<211> 2869
<212> DNA
<213> 智人
<400> 14
ggctgtccgc ggtgccggct gggggcggag aggcggcggt gggctccctg gggtgtgtga 60
gcccggtgat ggagccgggc ccgacagccg cgcagcggag gtgttcgttg ccgccgtggc 120
tgccgctggg gctgctgctg tggtcggggc tggccctggg cgcgctcccc ttcggcagca 180
gtccgcacag ggtcttccac gacctcctgt cggagcagca gttgctggag gtggaggact 240
tgtccctgtc cctcctgcag ggtggagggc tggggcctct gtcgctgccc ccggacctgc 300
cggatctgga tcctgagtgc cgggagctcc tgctggactt cgccaacagc agcgcagagc 360
tgacagggtg tctggtgcgc agcgcccggc ccgtgcgcct ctgtcagacc tgctaccccc 420
tcttccaaca ggtcgtcagc aagatggaca acatcagccg agccgcgggg aatacttcag 480
agagtcagag ttgtgccaga agtctcttaa tggcagatag aatgcaaata gttgtgattc 540
tctcagaatt ttttaatacc acatggcagg aggcaaattg tgcaaattgt ttaacaaaca 600
acagtgaaga attatcaaac agcacagtat atttccttaa tctatttaat cacaccctga 660
cctgctttga acataacctt caggggaatg cacatagtct tttacagaca aaaaattatt 720
cagaagtatg caaaaactgc cgtgaagcat acaaaactct gagtagtctg tacagtgaaa 780
tgcaaaaaat gaatgaactt gagaataagg ctgaacctgg aacacattta tgcattgatg 840
tggaagatgc aatgaacatc actcgaaaac tatggagtcg aactttcaac tgttcagtcc 900
cttgcagtga cacagtgcct gtaattgctg tttctgtgtt cattctcttt ctacctgttg 960
tcttctacct tagtagcttt cttcactcag agcaaaagaa acgcaaactc attctgccca 1020
aacgtctcaa gtccagtacc agttttgcaa atattcagga aaattcaaac tgagacctac 1080
aaaatggaga attgacatat cacgtgaatg aatggtggaa gacacaactt ggtttcagaa 1140
agaagataaa ctgtgatttg acaagtcaag ctcttaagaa atacaaggac ttcagatcca 1200
tttttaaata agaattttcg atttttcttt ccttttccac ttctttctaa cagatttgga 1260
tatttttaat ttccaggcat agcagtgtta tctattttaa tgtgtatttg tcacaataac 1320
agaacatgca agaacaatca ttattttatt ttataggcat ttgattacta ttctagactt 1380
ctggtatctt cttactaaca taagtatctc aagtagaaaa gtttttgaaa actaacattt 1440
aaaaattaat cagttacagt aaagactttg aaaaagaaat gtacttgtta ggaagtagct 1500
taattacccc ccattgcagt attattgtta tatatatagt taatatgttg tacatcacaa 1560
taatatataa ttcagtctct agtttcccta gagtcatttt tgaaaccact gattgcaaac 1620
ctccctgaca atttttaaaa gtagtaagcc acattacatt tatctttgta aaaagattta 1680
tggtaactgg tttcttactt gacttttata aatagtattt tacatcttat ttttgccttt 1740
atttcataag taatttaaaa atcactggat tgctttatta tattcagggc aatatggatt 1800
atttttatac caaggatttg catcgtgaat taaattaagt tatttggcaa tttataattt 1860
attactactt taaatcaaat gtagcattat cacactgtat ttaaattgtc attttttaaa 1920
ggaatatttt cttcttaaga tatatagagg attttggaga agagagacag gaggggtaaa 1980
accagcttaa ggttcagcga gcagaaaggg acctgagagg atgctcactg taagactgtt 2040
ggacagtggt gtgtattgag gggatgaatc ggaacgatag tctcatgcag aaaatagtga 2100
gattaagatc atccttattg tttctaaatt atttcaatca gatgaaagtg atacgattga 2160
aatgaaatca catagttcgt gctcagaaat tctattttgg tatgtttgta ttagccttta 2220
gaaaaaacac tccgtttcag aattgttcac agttttattt cttaggtttt tagagttcag 2280
gatttcattt attaatttct tcttgctttt ttggtggaaa taggctttgt tgtaaacatt 2340
aagaatataa aatctcctct atatagaaac aagaattttg ttaaaaagag aatttgaatc 2400
ccttcctata ctataaaatg ctctataggg agacaaagtg tttctttttt cttttatgtt 2460
tactgtttat gtggagtgaa atataaggct cttggatgta taacatactc aaaagctgtt 2520
acactttctc tgatctgctg tgatccactg aaaatgtgct ggggtttgtt ctgctgtcac 2580
tgtttatgct gctggaactt agcactgtct tgatttgaag catatgattg agagccattt 2640
gaagcaatct tcattaatgc agataaaaca agtttacatg tgcagagtta gaaaatgaca 2700
tgttcaattc tgtaagtggt gactttttga gcacctttca gtattatgta tttgtaaaaa 2760
ccattgtttt tggatataaa gctaataagc actttaaaaa aaaaaaaaaa aaaaaaaaaa 2820
aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaagaaaaaa aaaaaaaaa 2869
<210> 15
<211> 580
<212> PRT
<213> 智人
<400> 15
Met Thr Ala Pro Ala Gly Pro Arg Gly Ser Glu Thr Glu Arg Leu Leu
1 5 10 15
Thr Pro Asn Pro Gly Tyr Gly Thr Gln Ala Gly Pro Ser Pro Ala Pro
20 25 30
Pro Thr Pro Pro Glu Glu Glu Asp Leu Arg Arg Arg Leu Lys Tyr Phe
35 40 45
Phe Met Ser Pro Cys Asp Lys Phe Arg Ala Lys Gly Arg Lys Pro Cys
50 55 60
Lys Leu Met Leu Gln Val Val Lys Ile Leu Val Val Thr Val Gln Leu
65 70 75 80
Ile Leu Phe Gly Leu Ser Asn Gln Leu Ala Val Thr Phe Arg Glu Glu
85 90 95
Asn Thr Ile Ala Phe Arg His Leu Phe Leu Leu Gly Tyr Ser Asp Gly
100 105 110
Ala Asp Asp Thr Phe Ala Ala Tyr Thr Arg Glu Gln Leu Tyr Gln Ala
115 120 125
Ile Phe His Ala Val Asp Gln Tyr Leu Ala Leu Pro Asp Val Ser Leu
130 135 140
Gly Arg Tyr Ala Tyr Val Arg Gly Gly Gly Asp Pro Trp Thr Asn Gly
145 150 155 160
Ser Gly Leu Ala Leu Cys Gln Arg Tyr Tyr His Arg Gly His Val Asp
165 170 175
Pro Ala Asn Asp Thr Phe Asp Ile Asp Pro Met Val Val Thr Asp Cys
180 185 190
Ile Gln Val Asp Pro Pro Glu Arg Pro Pro Pro Pro Pro Ser Asp Asp
195 200 205
Leu Thr Leu Leu Glu Ser Ser Ser Ser Tyr Lys Asn Leu Thr Leu Lys
210 215 220
Phe His Lys Leu Val Asn Val Thr Ile His Phe Arg Leu Lys Thr Ile
225 230 235 240
Asn Leu Gln Ser Leu Ile Asn Asn Glu Ile Pro Asp Cys Tyr Thr Phe
245 250 255
Ser Val Leu Ile Thr Phe Asp Asn Lys Ala His Ser Gly Arg Ile Pro
260 265 270
Ile Ser Leu Glu Thr Gln Ala His Ile Gln Glu Cys Lys His Pro Ser
275 280 285
Val Phe Gln His Gly Asp Asn Ser Phe Arg Leu Leu Phe Asp Val Val
290 295 300
Val Ile Leu Thr Cys Ser Leu Ser Phe Leu Leu Cys Ala Arg Ser Leu
305 310 315 320
Leu Arg Gly Phe Leu Leu Gln Asn Glu Phe Val Gly Phe Met Trp Arg
325 330 335
Gln Arg Gly Arg Val Ile Ser Leu Trp Glu Arg Leu Glu Phe Val Asn
340 345 350
Gly Trp Tyr Ile Leu Leu Val Thr Ser Asp Val Leu Thr Ile Ser Gly
355 360 365
Thr Ile Met Lys Ile Gly Ile Glu Ala Lys Asn Leu Ala Ser Tyr Asp
370 375 380
Val Cys Ser Ile Leu Leu Gly Thr Ser Thr Leu Leu Val Trp Val Gly
385 390 395 400
Val Ile Arg Tyr Leu Thr Phe Phe His Asn Tyr Asn Ile Leu Ile Ala
405 410 415
Thr Leu Arg Val Ala Leu Pro Ser Val Met Arg Phe Cys Cys Cys Val
420 425 430
Ala Val Ile Tyr Leu Gly Tyr Cys Phe Cys Gly Trp Ile Val Leu Gly
435 440 445
Pro Tyr His Val Lys Phe Arg Ser Leu Ser Met Val Ser Glu Cys Leu
450 455 460
Phe Ser Leu Ile Asn Gly Asp Asp Met Phe Val Thr Phe Ala Ala Met
465 470 475 480
Gln Ala Gln Gln Gly Arg Ser Ser Leu Val Trp Leu Phe Ser Gln Leu
485 490 495
Tyr Leu Tyr Ser Phe Ile Ser Leu Phe Ile Tyr Met Val Leu Ser Leu
500 505 510
Phe Ile Ala Leu Ile Thr Gly Ala Tyr Asp Thr Ile Lys His Pro Gly
515 520 525
Gly Ala Gly Ala Glu Glu Ser Glu Leu Gln Ala Tyr Ile Ala Gln Cys
530 535 540
Gln Asp Ser Pro Thr Ser Gly Lys Phe Arg Arg Gly Ser Gly Ser Ala
545 550 555 560
Cys Ser Leu Leu Cys Cys Cys Gly Arg Asp Pro Ser Glu Glu His Ser
565 570 575
Leu Leu Val Asn
580
<210> 16
<211> 2051
<212> DNA
<213> 智人
<400> 16
agatcagctg atgccggagg gtttgaagcc gcgccgcgag ggagcgaggt cgcagtgaca 60
gcggcgggcg atcggaccca ggctgccccg ccgtacccgc ctgcgtcccg cgctcccgcc 120
ccagcatgac agccccggcg ggtccgcgcg gctcagagac cgagcggctt ctgaccccca 180
accccgggta tgggacccag gcggggcctt caccggcccc tccgacaccc ccagaagagg 240
aagaccttcg ccgtcgtctc aaatactttt tcatgagtcc ctgcgacaag tttcgagcca 300
agggccgcaa gccctgcaag ctgatgctgc aagtggtcaa gatcctggtg gtcacggtgc 360
agctcatcct gtttgggctc agtaatcagc tggctgtgac attccgggaa gagaacacca 420
tcgccttccg acacctcttc ctgctgggct actcggacgg agcggatgac accttcgcag 480
cctacacgcg ggagcagctg taccaggcca tcttccatgc tgtggaccag tacctggcgt 540
tgcctgacgt gtcactgggc cggtatgcgt atgtccgtgg tgggggtgac ccttggacca 600
atggctcagg gcttgctctc tgccagcggt actaccaccg aggccacgtg gacccggcca 660
acgacacatt tgacattgat ccgatggtgg ttactgactg catccaggtg gatccccccg 720
agcggccccc tccgcccccc agcgacgatc tcaccctctt ggaaagcagc tccagttaca 780
agaacctcac gctcaaattc cacaagctgg tcaatgtcac catccacttc cggctgaaga 840
ccattaacct ccagagcctc atcaataatg agatcccgga ctgctatacc ttcagcgtcc 900
tgatcacgtt tgacaacaaa gcacacagtg ggcggatccc catcagcctg gagacccagg 960
cccacatcca ggagtgtaag caccccagtg tcttccagca cggagacaac agcttccggc 1020
tcctgtttga cgtggtggtc atcctcacct gctccctgtc cttcctcctc tgcgcccgct 1080
cactccttcg aggcttcctg ctgcagaacg agtttgtggg gttcatgtgg cggcagcggg 1140
gacgggtcat cagcctgtgg gagcggctgg aatttgtcaa tggctggtac atcctgctcg 1200
tcaccagcga tgtgctcacc atctcgggca ccatcatgaa gatcggcatc gaggccaaga 1260
acttggcgag ctacgacgtc tgcagcatcc tcctgggcac ctcgacgctg ctggtgtggg 1320
tgggcgtgat ccgctacctg accttcttcc acaactacaa tatcctcatc gccacactgc 1380
gggtggccct gcccagcgtc atgcgcttct gctgctgcgt ggctgtcatc tacctgggct 1440
actgcttctg tggctggatc gtgctggggc cctatcatgt gaagttccgc tcactctcca 1500
tggtgtctga gtgcctgttc tcgctcatca atggggacga catgtttgtg acgttcgccg 1560
ccatgcaggc gcagcagggc cgcagcagcc tggtgtggct cttctcccag ctctaccttt 1620
actccttcat cagcctcttc atctacatgg tgctcagcct cttcatcgcg ctcatcaccg 1680
gcgcctacga caccatcaag catcccggcg gcgcaggcgc agaggagagc gagctgcagg 1740
cctacatcgc acagtgccag gacagcccca cctccggcaa gttccgccgc gggagcggct 1800
cggcctgcag ccttctctgc tgctgcggaa gggacccctc ggaggagcat tcgctgctgg 1860
tgaattgatt cgacctgact gccgttggac cgtaggccct ggactgcaga gacccccgcc 1920
cccgaccccg cttatttatt tgtagggttt gcttttaagg atcggctccc tgtcgcgccc 1980
gaggagggcc tggacctttc gtgtcggacc cttgggggcg gggagactgg gtggggaggg 2040
tgttgaataa a 2051
<210> 17
<211> 663
<212> PRT
<213> 智人
<400> 17
Met Thr Gly Ala Arg Ala Ser Ala Ala Glu Gln Arg Arg Ala Gly Arg
1 5 10 15
Ser Gly Gln Ala Arg Ala Ala Glu Arg Ala Ala Gly Met Ser Gly Ala
20 25 30
Gly Arg Ala Leu Ala Ala Leu Leu Leu Ala Ala Ser Val Leu Ser Ala
35 40 45
Ala Leu Leu Ala Pro Gly Gly Ser Ser Gly Arg Asp Ala Gln Ala Ala
50 55 60
Pro Pro Arg Asp Leu Asp Lys Lys Arg His Ala Glu Leu Lys Met Asp
65 70 75 80
Gln Ala Leu Leu Leu Ile His Asn Glu Leu Leu Trp Thr Asn Leu Thr
85 90 95
Val Tyr Trp Lys Ser Glu Cys Cys Tyr His Cys Leu Phe Gln Val Leu
100 105 110
Val Asn Val Pro Gln Ser Pro Lys Ala Gly Lys Pro Ser Ala Ala Ala
115 120 125
Ala Ser Val Ser Thr Gln His Gly Ser Ile Leu Gln Leu Asn Asp Thr
130 135 140
Leu Glu Glu Lys Glu Val Cys Arg Leu Glu Tyr Arg Phe Gly Glu Phe
145 150 155 160
Gly Asn Tyr Ser Leu Leu Val Lys Asn Ile His Asn Gly Val Ser Glu
165 170 175
Ile Ala Cys Asp Leu Ala Val Asn Glu Asp Pro Val Asp Ser Asn Leu
180 185 190
Pro Val Ser Ile Ala Phe Leu Ile Gly Leu Ala Val Ile Ile Val Ile
195 200 205
Ser Phe Leu Arg Leu Leu Leu Ser Leu Asp Asp Phe Asn Asn Trp Ile
210 215 220
Ser Lys Ala Ile Ser Ser Arg Glu Thr Asp Arg Leu Ile Asn Ser Glu
225 230 235 240
Leu Gly Ser Pro Ser Arg Thr Asp Pro Leu Asp Gly Asp Val Gln Pro
245 250 255
Ala Thr Trp Arg Leu Ser Ala Leu Pro Pro Arg Leu Arg Ser Val Asp
260 265 270
Thr Phe Arg Gly Ile Ala Leu Ile Leu Met Val Phe Val Asn Tyr Gly
275 280 285
Gly Gly Lys Tyr Trp Tyr Phe Lys His Ala Ser Trp Asn Gly Leu Thr
290 295 300
Val Ala Asp Leu Val Phe Pro Trp Phe Val Phe Ile Met Gly Ser Ser
305 310 315 320
Ile Phe Leu Ser Met Thr Ser Ile Leu Gln Arg Gly Cys Ser Lys Phe
325 330 335
Arg Leu Leu Gly Lys Ile Ala Trp Arg Ser Phe Leu Leu Ile Cys Ile
340 345 350
Gly Ile Ile Ile Val Asn Pro Asn Tyr Cys Leu Gly Pro Leu Ser Trp
355 360 365
Asp Lys Val Arg Ile Pro Gly Val Leu Gln Arg Leu Gly Val Thr Tyr
370 375 380
Phe Val Val Ala Val Leu Glu Leu Leu Phe Ala Lys Pro Val Pro Glu
385 390 395 400
His Cys Ala Ser Glu Arg Ser Cys Leu Ser Leu Arg Asp Ile Thr Ser
405 410 415
Ser Trp Pro Gln Trp Leu Leu Ile Leu Val Leu Glu Gly Leu Trp Leu
420 425 430
Gly Leu Thr Phe Leu Leu Pro Val Pro Gly Cys Pro Thr Gly Tyr Leu
435 440 445
Gly Pro Gly Gly Ile Gly Asp Phe Gly Lys Tyr Pro Asn Cys Thr Gly
450 455 460
Gly Ala Ala Gly Tyr Ile Asp Arg Leu Leu Leu Gly Asp Asp His Leu
465 470 475 480
Tyr Gln His Pro Ser Ser Ala Val Leu Tyr His Thr Glu Val Ala Tyr
485 490 495
Asp Pro Glu Gly Ile Leu Gly Thr Ile Asn Ser Ile Val Met Ala Phe
500 505 510
Leu Gly Val Gln Ala Gly Lys Ile Leu Leu Tyr Tyr Lys Ala Arg Thr
515 520 525
Lys Asp Ile Leu Ile Arg Phe Thr Ala Trp Cys Cys Ile Leu Gly Leu
530 535 540
Ile Ser Val Ala Leu Thr Lys Val Ser Glu Asn Glu Gly Phe Ile Pro
545 550 555 560
Val Asn Lys Asn Leu Trp Ser Leu Ser Tyr Val Thr Thr Leu Ser Ser
565 570 575
Phe Ala Phe Phe Ile Leu Leu Val Leu Tyr Pro Val Val Asp Val Lys
580 585 590
Gly Leu Trp Thr Gly Thr Pro Phe Phe Tyr Pro Gly Met Asn Ser Ile
595 600 605
Leu Val Tyr Val Gly His Glu Val Phe Glu Asn Tyr Phe Pro Phe Gln
610 615 620
Trp Lys Leu Lys Asp Asn Gln Ser His Lys Glu His Leu Thr Gln Asn
625 630 635 640
Ile Val Ala Thr Ala Leu Trp Val Leu Ile Ala Tyr Ile Leu Tyr Arg
645 650 655
Lys Lys Ile Phe Trp Lys Ile
660
<210> 18
<211> 5228
<212> DNA
<213> 智人
<400> 18
agggcggggc gcagcgggca ggcaagggcg gccgagcggg cggcgggcat gagcggggcg 60
ggcagggcgc tggccgcgct gctgctggcc gcgtccgtgc tgagcgccgc gctgctggcc 120
cccggcggct cttcggggcg cgatgcccag gccgcgccgc cacgagactt agacaaaaaa 180
agacatgcag agctgaagat ggatcaggct ttgctactca tccataatga acttctctgg 240
accaacttga ccgtctactg gaaatctgaa tgctgttatc actgcttgtt tcaggttctg 300
gtaaacgttc ctcagagtcc aaaagcaggg aagcctagtg ctgcagctgc ctctgtcagc 360
acccagcacg gatctatcct gcagctgaac gacaccttgg aagagaaaga agtttgtagg 420
ttggaataca gatttggaga atttggaaac tattctctct tggtaaagaa catccataat 480
ggagttagtg aaattgcctg tgacctggct gtgaacgagg atccagttga tagtaacctt 540
cctgtgagca ttgcattcct tattggtctt gctgtcatca ttgtgatatc ctttctgagg 600
ctcttgttga gtttggatga ctttaacaat tggatttcta aagccataag ttctcgagaa 660
actgatcgcc tcatcaattc tgagctggga tctcccagca ggacagaccc tctcgatggt 720
gatgttcagc cagcaacgtg gcgtctatct gccctgccgc cccgcctccg cagcgtggac 780
accttcaggg ggattgctct tatactcatg gtctttgtca attatggagg aggaaaatat 840
tggtacttca aacatgcaag ttggaatggg ctgacagtgg ctgacctcgt gttcccgtgg 900
tttgtattta ttatgggatc ttccattttt ctatcgatga cttctatact gcaacggggg 960
tgttcaaaat tcagattgct ggggaagatt gcatggagga gtttcctgtt aatctgcata 1020
ggaattatca ttgtgaatcc caattattgc cttggtccat tgtcttggga caaggtgcgc 1080
attcctggtg tgctgcagcg attgggagtg acatactttg tggttgctgt gttggagctc 1140
ctctttgcta aacctgtgcc tgaacattgt gcctcggaga ggagctgcct ttctcttcga 1200
gacatcacgt ccagctggcc ccagtggctg ctcatcctgg tgctggaagg cctgtggctg 1260
ggcttgacat tcctcctgcc agtccctggg tgccctactg gttatcttgg tcctgggggc 1320
attggagatt ttggcaagta tccaaattgc actggaggag ctgcaggcta catcgaccgc 1380
ctgctgctgg gagacgatca cctttaccag cacccatctt ctgctgtact ttaccacacc 1440
gaggtggcct atgaccccga gggcatcctg ggcaccatca actccatcgt gatggccttt 1500
ttaggagttc aggcaggaaa aatactattg tattacaagg ctcggaccaa agacatcctg 1560
attcgattca ctgcttggtg ttgtattctt gggctcattt ctgttgctct gacgaaggtt 1620
tctgaaaatg aaggctttat tccagtaaac aaaaatctct ggtccctttc gtatgtcact 1680
acgctcagtt cttttgcctt cttcatcctg ctggtcctgt acccagttgt ggatgtgaag 1740
gggctgtgga caggaacccc attcttttat ccaggaatga attccattct ggtatatgtc 1800
ggccacgagg tgtttgagaa ctacttcccc tttcagtgga agctgaagga caaccagtcc 1860
cacaaggagc acctgactca gaacatcgtc gccactgccc tctgggtgct cattgcctac 1920
atcctctata gaaagaagat tttttggaaa atctgatggc tcccactgag atgtgctgct 1980
ggaagactct agtaggcctg cagggaggac tgaagcagcc tttgttaaag ggaagcattc 2040
attaggaaat tgactggctg cgtgtttaca gactctgggg gaagacactg atgtcctcaa 2100
actggttaac tgtgacacgg ctcgccagaa ctctgcctgt ctatttgtga cttacagatt 2160
tgaaatgtaa ttgtcttttt tcctccatct tctgtggaaa tggatgtctt tggaacttca 2220
ttccgaggag ataagcttta actttccaaa agggaattgc catgggtgtt tttcttctgt 2280
ggtgagtgaa acaatctgag gtctggttct tgctgacctt gttgccctgc aaacttcctt 2340
tccacgtgta cgcgcacacc aacacgaaat gccatcactc ctactgcggc tgctatgaag 2400
cttactggtt gtgatgtgtt ataatttagt ctgttttttt gattgaatgc agtttaatgt 2460
ttccagaaag ccaaagtaat tttcttttca gatatgcaag gctttggtgg gtccaaaaaa 2520
tgtctatcac aagccatttt ttccttttcc tctctcgaaa agttaaaata tctatgtgtt 2580
attcccaaac cctcttacct atgtatctgc ctgtctgtcc atcatcttcc ttcctcccta 2640
tctctgtgta tctggatggc agccgctgcc caggggagtg gctgtgggga gggcaggtac 2700
tgtctttgcc tgtgggtcca gctgagccat ccctgctggg tgatgctggg caagaccctt 2760
ggcccgtctg ggccttggct tcctcacttg tgaaatgagc gggaagatga ctctcagttc 2820
cttccacctc ttagacatgg tgaggtaaca gacatcaaaa gcttttctga aatcttcaga 2880
agaaatagtt ccattacaga aaactcttca aaataaatag tagtgaaaac ttttaaaaac 2940
tctcattgga gtaagtcttt tcaagatgat cctccacaat ggaggcagcg ttcctacttg 3000
tcatcacaca gctgaagaca ttgtttctta ggtgtgaaat cggggacaaa ggacaaacag 3060
agacacacgg cattgttcat gggaggcatc gtcaccctcc tgggtgttct gtgggaattt 3120
cctgtgtgag gaaaacgtgg ccacagggtt gtgctgtacc cacccttccc cggcgagatg 3180
gccctcggcc tgtgccgctg cttccaccct cgccactcca tggcagcttt tggtctgttt 3240
ccggctctgc cctctgccct gaactctcat ccggcttgta cctgcctgct ggacccctcc 3300
acctggaggc cagcccatgt ctcaggccca gccctagcct cttctcctca aattctaagt 3360
gttttctctt taggtttccc tggctttgtg aatggatcat gtgtctctag gtataaacct 3420
gacatcatct ttccacccgg cttacctcca ccagatctcc ccagttctgt ctccatcttc 3480
tacctgcagc tgctctgttc tcatggtcac tgctgcatca ctgagtctgg acccttgtta 3540
tcattttcaa actggcctcc ttccctcgtt ccccacttct taaagtcacc tgtccattgc 3600
caccagatta agctttctcc agccagatca cctctctctg agaaacctcc attgacatgg 3660
aaacaccatt gtctggcaca catactcaca tactcacctt cccgtcttga tccccacaca 3720
tctttccagc ctcccctccc actccactcc ctgctctctc ctccacctcc ccatcctctt 3780
gtctcccctc ccctctgaat ccagcccagc ggggcttctc ctgcctccat cacatcacag 3840
aagtacctcc tgcttctggt tttaattaga gccttccccg attacatttt cctctgaatt 3900
ttttcctatc tacatttgat ctgtcatgtt taaaccccct acttctaagg gaacttctct 3960
aatctcttat cctcatcccc aaatagtgtt ttcttcctct gggttcttat aatgttggta 4020
tcaatctcac agcatttagt gcttcctgcc tggtgtgaca gttacctgtg tgcatgtgca 4080
atttctaatt tcccacgcta gactgtgagc ttcctaaggc aagaatcatg ccttgttggt 4140
ttctgtattc ctcatggtgc caaacacagt gccttctaca ttgcaggcgc tgaataaaca 4200
tttttaaagc aaaatgatgt ggatttttaa aataaatatt taagtgctgg taagatgagc 4260
atgtatccgg ggtgcccatg aaatgttctt ggggccgtgt ggggacagtc gtcattcctc 4320
ctcctgccac ccttttcttt cagtgagtca ctgtggatgg tcccagctgt gtcatcccaa 4380
agttcagcag ggaaagctga gctgggcctc tccaggtgag ttttctagaa gcatttctca 4440
aactgtgggt tacatcaact tgggtgtctt gagctgtaag gaaggaactc cggagtcagc 4500
tgggctacag gggagcttct ctaagtcctg cgggaggcca gacccagcct gagcttgctg 4560
ttagctagcg gaggcagctg ctggtggccc aggtgctcga caccaggcat cccctctcct 4620
cccacgaagg gtgtgccata atccccttca acaggaaatg cttcccagaa gcctctcagc 4680
agcctcccct cctgtcctat cagctagaag cgcctcgctt gtcccaagac cagcagggac 4740
agggaactgt ccgagcccgt ggctgtgtgg aggaaggcga cccccagcac aagattggtt 4800
tcctttggga agggaagagg gagtgtgttg gggtaagggg tagagcagag gaatggtcag 4860
ggggcaacaa ccgctgacag ctgcaacagg tgcatggcat ctcacaggga ggcagggagg 4920
tgcgagctcc taagtaatgg agcaaaaaaa ttctattctg tagaatgggg agagaaaatg 4980
tgacatttta attttttttt gcatttatat tcctaattcc tacttaaagt gaatatactg 5040
ccgctgtaga tcataaaatg tatcttttcc atggccaaca aggggcatct tttataaatg 5100
cataataacc cagtttgtat caaagggtat cgacttaagt gaaatttcaa catgctgtta 5160
ctttttcctt ttaatgtaat tctgttttcc aaataaatgg gggagacaaa tggaaaaaaa 5220
aaaaaaaa 5228
<210> 19
<211> 1278
<212> PRT
<213> 智人
<400> 19
Met Thr Ala Arg Gly Leu Ala Leu Gly Leu Leu Leu Leu Leu Leu Cys
1 5 10 15
Pro Ala Gln Val Phe Ser Gln Ser Cys Val Trp Tyr Gly Glu Cys Gly
20 25 30
Ile Ala Tyr Gly Asp Lys Arg Tyr Asn Cys Glu Tyr Ser Gly Pro Pro
35 40 45
Lys Pro Leu Pro Lys Asp Gly Tyr Asp Leu Val Gln Glu Leu Cys Pro
50 55 60
Gly Phe Phe Phe Gly Asn Val Ser Leu Cys Cys Asp Val Arg Gln Leu
65 70 75 80
Gln Thr Leu Lys Asp Asn Leu Gln Leu Pro Leu Gln Phe Leu Ser Arg
85 90 95
Cys Pro Ser Cys Phe Tyr Asn Leu Leu Asn Leu Phe Cys Glu Leu Thr
100 105 110
Cys Ser Pro Arg Gln Ser Gln Phe Leu Asn Val Thr Ala Thr Glu Asp
115 120 125
Tyr Val Asp Pro Val Thr Asn Gln Thr Lys Thr Asn Val Lys Glu Leu
130 135 140
Gln Tyr Tyr Val Gly Gln Ser Phe Ala Asn Ala Met Tyr Asn Ala Cys
145 150 155 160
Arg Asp Val Glu Ala Pro Ser Ser Asn Asp Lys Ala Leu Gly Leu Leu
165 170 175
Cys Gly Lys Asp Ala Asp Ala Cys Asn Ala Thr Asn Trp Ile Glu Tyr
180 185 190
Met Phe Asn Lys Asp Asn Gly Gln Ala Pro Phe Thr Ile Thr Pro Val
195 200 205
Phe Ser Asp Phe Pro Val His Gly Met Glu Pro Met Asn Asn Ala Thr
210 215 220
Lys Gly Cys Asp Glu Ser Val Asp Glu Val Thr Ala Pro Cys Ser Cys
225 230 235 240
Gln Asp Cys Ser Ile Val Cys Gly Pro Lys Pro Gln Pro Pro Pro Pro
245 250 255
Pro Ala Pro Trp Thr Ile Leu Gly Leu Asp Ala Met Tyr Val Ile Met
260 265 270
Trp Ile Thr Tyr Met Ala Phe Leu Leu Val Phe Phe Gly Ala Phe Phe
275 280 285
Ala Val Trp Cys Tyr Arg Lys Arg Tyr Phe Val Ser Glu Tyr Thr Pro
290 295 300
Ile Asp Ser Asn Ile Ala Phe Ser Val Asn Ala Ser Asp Lys Gly Glu
305 310 315 320
Ala Ser Cys Cys Asp Pro Val Ser Ala Ala Phe Glu Gly Cys Leu Arg
325 330 335
Arg Leu Phe Thr Arg Trp Gly Ser Phe Cys Val Arg Asn Pro Gly Cys
340 345 350
Val Ile Phe Phe Ser Leu Val Phe Ile Thr Ala Cys Ser Ser Gly Leu
355 360 365
Val Phe Val Arg Val Thr Thr Asn Pro Val Asp Leu Trp Ser Ala Pro
370 375 380
Ser Ser Gln Ala Arg Leu Glu Lys Glu Tyr Phe Asp Gln His Phe Gly
385 390 395 400
Pro Phe Phe Arg Thr Glu Gln Leu Ile Ile Arg Ala Pro Leu Thr Asp
405 410 415
Lys His Ile Tyr Gln Pro Tyr Pro Ser Gly Ala Asp Val Pro Phe Gly
420 425 430
Pro Pro Leu Asp Ile Gln Ile Leu His Gln Val Leu Asp Leu Gln Ile
435 440 445
Ala Ile Glu Asn Ile Thr Ala Ser Tyr Asp Asn Glu Thr Val Thr Leu
450 455 460
Gln Asp Ile Cys Leu Ala Pro Leu Ser Pro Tyr Asn Thr Asn Cys Thr
465 470 475 480
Ile Leu Ser Val Leu Asn Tyr Phe Gln Asn Ser His Ser Val Leu Asp
485 490 495
His Lys Lys Gly Asp Asp Phe Phe Val Tyr Ala Asp Tyr His Thr His
500 505 510
Phe Leu Tyr Cys Val Arg Ala Pro Ala Ser Leu Asn Asp Thr Ser Leu
515 520 525
Leu His Asp Pro Cys Leu Gly Thr Phe Gly Gly Pro Val Phe Pro Trp
530 535 540
Leu Val Leu Gly Gly Tyr Asp Asp Gln Asn Tyr Asn Asn Ala Thr Ala
545 550 555 560
Leu Val Ile Thr Phe Pro Val Asn Asn Tyr Tyr Asn Asp Thr Glu Lys
565 570 575
Leu Gln Arg Ala Gln Ala Trp Glu Lys Glu Phe Ile Asn Phe Val Lys
580 585 590
Asn Tyr Lys Asn Pro Asn Leu Thr Ile Ser Phe Thr Ala Glu Arg Ser
595 600 605
Ile Glu Asp Glu Leu Asn Arg Glu Ser Asp Ser Asp Val Phe Thr Val
610 615 620
Val Ile Ser Tyr Ala Ile Met Phe Leu Tyr Ile Ser Leu Ala Leu Gly
625 630 635 640
His Ile Lys Ser Cys Arg Arg Leu Leu Val Asp Ser Lys Val Ser Leu
645 650 655
Gly Ile Ala Gly Ile Leu Ile Val Leu Ser Ser Val Ala Cys Ser Leu
660 665 670
Gly Val Phe Ser Tyr Ile Gly Leu Pro Leu Thr Leu Ile Val Ile Glu
675 680 685
Val Ile Pro Phe Leu Val Leu Ala Val Gly Val Asp Asn Ile Phe Ile
690 695 700
Leu Val Gln Ala Tyr Gln Arg Asp Glu Arg Leu Gln Gly Glu Thr Leu
705 710 715 720
Asp Gln Gln Leu Gly Arg Val Leu Gly Glu Val Ala Pro Ser Met Phe
725 730 735
Leu Ser Ser Phe Ser Glu Thr Val Ala Phe Phe Leu Gly Ala Leu Ser
740 745 750
Val Met Pro Ala Val His Thr Phe Ser Leu Phe Ala Gly Leu Ala Val
755 760 765
Phe Ile Asp Phe Leu Leu Gln Ile Thr Cys Phe Val Ser Leu Leu Gly
770 775 780
Leu Asp Ile Lys Arg Gln Glu Lys Asn Arg Leu Asp Ile Phe Cys Cys
785 790 795 800
Val Arg Gly Ala Glu Asp Gly Thr Ser Val Gln Ala Ser Glu Ser Cys
805 810 815
Leu Phe Arg Phe Phe Lys Asn Ser Tyr Ser Pro Leu Leu Leu Lys Asp
820 825 830
Trp Met Arg Pro Ile Val Ile Ala Ile Phe Val Gly Val Leu Ser Phe
835 840 845
Ser Ile Ala Val Leu Asn Lys Val Asp Ile Gly Leu Asp Gln Ser Leu
850 855 860
Ser Met Pro Asp Asp Ser Tyr Met Val Asp Tyr Phe Lys Ser Ile Ser
865 870 875 880
Gln Tyr Leu His Ala Gly Pro Pro Val Tyr Phe Val Leu Glu Glu Gly
885 890 895
His Asp Tyr Thr Ser Ser Lys Gly Gln Asn Met Val Cys Gly Gly Met
900 905 910
Gly Cys Asn Asn Asp Ser Leu Val Gln Gln Ile Phe Asn Ala Ala Gln
915 920 925
Leu Asp Asn Tyr Thr Arg Ile Gly Phe Ala Pro Ser Ser Trp Ile Asp
930 935 940
Asp Tyr Phe Asp Trp Val Lys Pro Gln Ser Ser Cys Cys Arg Val Asp
945 950 955 960
Asn Ile Thr Asp Gln Phe Cys Asn Ala Ser Val Val Asp Pro Ala Cys
965 970 975
Val Arg Cys Arg Pro Leu Thr Pro Glu Gly Lys Gln Arg Pro Gln Gly
980 985 990
Gly Asp Phe Met Arg Phe Leu Pro Met Phe Leu Ser Asp Asn Pro Asn
995 1000 1005
Pro Lys Cys Gly Lys Gly Gly His Ala Ala Tyr Ser Ser Ala Val
1010 1015 1020
Asn Ile Leu Leu Gly His Gly Thr Arg Val Gly Ala Thr Tyr Phe
1025 1030 1035
Met Thr Tyr His Thr Val Leu Gln Thr Ser Ala Asp Phe Ile Asp
1040 1045 1050
Ala Leu Lys Lys Ala Arg Leu Ile Ala Ser Asn Val Thr Glu Thr
1055 1060 1065
Met Gly Ile Asn Gly Ser Ala Tyr Arg Val Phe Pro Tyr Ser Val
1070 1075 1080
Phe Tyr Val Phe Tyr Glu Gln Tyr Leu Thr Ile Ile Asp Asp Thr
1085 1090 1095
Ile Phe Asn Leu Gly Val Ser Leu Gly Ala Ile Phe Leu Val Thr
1100 1105 1110
Met Val Leu Leu Gly Cys Glu Leu Trp Ser Ala Val Ile Met Cys
1115 1120 1125
Ala Thr Ile Ala Met Val Leu Val Asn Met Phe Gly Val Met Trp
1130 1135 1140
Leu Trp Gly Ile Ser Leu Asn Ala Val Ser Leu Val Asn Leu Val
1145 1150 1155
Met Ser Cys Gly Ile Ser Val Glu Phe Cys Ser His Ile Thr Arg
1160 1165 1170
Ala Phe Thr Val Ser Met Lys Gly Ser Arg Val Glu Arg Ala Glu
1175 1180 1185
Glu Ala Leu Ala His Met Gly Ser Ser Val Phe Ser Gly Ile Thr
1190 1195 1200
Leu Thr Lys Phe Gly Gly Ile Val Val Leu Ala Phe Ala Lys Ser
1205 1210 1215
Gln Ile Phe Gln Ile Phe Tyr Phe Arg Met Tyr Leu Ala Met Val
1220 1225 1230
Leu Leu Gly Ala Thr His Gly Leu Ile Phe Leu Pro Val Leu Leu
1235 1240 1245
Ser Tyr Ile Gly Pro Ser Val Asn Lys Ala Lys Ser Cys Ala Thr
1250 1255 1260
Glu Glu Arg Tyr Lys Gly Thr Glu Arg Glu Arg Leu Leu Asn Phe
1265 1270 1275
<210> 20
<211> 4673
<212> DNA
<213> 智人
<400> 20
tttgctcctg ctcctccgct cctcctgcgc ggggtgctga aacagcccgg ggaagtagag 60
ccgcctccgg ggagcccaac cagccgaacg ccgccggcgt cagcagcctt gcgcggccac 120
agcatgaccg ctcgcggcct ggcccttggc ctcctcctgc tgctactgtg tccagcgcag 180
gtgttttcac agtcctgtgt ttggtatgga gagtgtggaa ttgcatatgg ggacaagagg 240
tacaattgcg aatattctgg cccaccaaaa ccattgccaa aggatggata tgacttagtg 300
caggaactct gtccaggatt cttctttggc aatgtcagtc tctgttgtga tgttcggcag 360
cttcagacac taaaagacaa cctgcagctg cctctacagt ttctgtccag atgtccatcc 420
tgtttttata acctactgaa cctgttttgt gagctgacat gtagccctcg acagagtcag 480
tttttgaatg ttacagctac tgaagattat gttgatcctg ttacaaacca gacgaaaaca 540
aatgtgaaag agttacaata ctacgtcgga cagagttttg ccaatgcaat gtacaatgcc 600
tgccgggatg tggaggcccc ctcaagtaat gacaaggccc tgggactcct gtgtgggaag 660
gacgctgacg cctgtaatgc caccaactgg attgaataca tgttcaataa ggacaatgga 720
caggcacctt ttaccatcac tcctgtgttt tcagattttc cagtccatgg gatggagccc 780
atgaacaatg ccaccaaagg ctgtgacgag tctgtggatg aggtcacagc accatgtagc 840
tgccaagact gctctattgt ctgtggcccc aagccccagc ccccacctcc tcctgctccc 900
tggacgatcc ttggcttgga cgccatgtat gtcatcatgt ggatcaccta catggcgttt 960
ttgcttgtgt tttttggagc attttttgca gtgtggtgct acagaaaacg gtattttgtc 1020
tccgagtaca ctcccatcga tagcaatata gctttttctg ttaatgcaag tgacaaagga 1080
gaggcgtcct gctgtgaccc tgtcagcgca gcatttgagg gctgcttgag gcggctgttc 1140
acacgctggg ggtctttctg cgtccgaaac cctggctgtg tcattttctt ctcgctggtc 1200
ttcattactg cgtgttcgtc aggcctggtg tttgtccggg tcacaaccaa tccagttgac 1260
ctctggtcag cccccagcag ccaggctcgc ctggaaaaag agtactttga ccagcacttt 1320
gggcctttct tccggacgga gcagctcatc atccgggccc ctctcactga caaacacatt 1380
taccagccat acccttcggg agctgatgta ccctttggac ctccgcttga catacagata 1440
ctgcaccagg ttcttgactt acaaatagcc atcgaaaaca ttactgcctc ttatgacaat 1500
gagactgtga cacttcaaga catctgcttg gcccctcttt caccgtataa cacgaactgc 1560
accattttga gtgtgttaaa ttacttccag aacagccatt ccgtgctgga ccacaagaaa 1620
ggggacgact tctttgtgta tgccgattac cacacgcact ttctgtactg cgtacgggct 1680
cctgcctctc tgaatgatac aagtttgctc catgaccctt gtctgggtac gtttggtgga 1740
ccagtgttcc cgtggcttgt gttgggaggc tatgatgatc aaaactacaa taacgccact 1800
gcccttgtga ttaccttccc tgtcaataat tactataatg atacagagaa gctccagagg 1860
gcccaggcct gggaaaaaga gtttattaat tttgtgaaaa actacaagaa tcccaatctg 1920
accatttcct tcactgctga acgaagtatt gaagatgaac taaatcgtga aagtgacagt 1980
gatgtcttca ccgttgtaat tagctatgcc atcatgtttc tatatatttc cctagccttg 2040
gggcacatca aaagctgtcg caggcttctg gtggattcga aggtctcact aggcatcgcg 2100
ggcatcttga tcgtgctgag ctcggtggct tgctccttgg gtgtcttcag ctacattggg 2160
ttgcccttga ccctcattgt gattgaagtc atcccgttcc tggtgctggc tgttggagtg 2220
gacaacatct tcattctggt gcaggcctac cagagagatg aacgtcttca aggggaaacc 2280
ctggatcagc agctgggcag ggtcctagga gaagtggctc ccagtatgtt cctgtcatcc 2340
ttttctgaga ctgtagcatt tttcttagga gcattgtccg tgatgccagc cgtgcacacc 2400
ttctctctct ttgcgggatt ggcagtcttc attgactttc ttctgcagat tacctgtttc 2460
gtgagtctct tggggttaga cattaaacgt caagagaaaa atcggctaga catcttttgc 2520
tgtgtcagag gtgctgaaga tggaacaagc gtccaggcct cagagagctg tttgtttcgc 2580
ttcttcaaaa actcctattc tccacttctg ctaaaggact ggatgagacc aattgtgata 2640
gcaatatttg tgggtgttct gtcattcagc atcgcagtcc tgaacaaagt agatattgga 2700
ttggatcagt ctctttcgat gccagatgac tcctacatgg tggattattt caaatccatc 2760
agtcagtacc tgcatgcggg tccgcctgtg tactttgtcc tggaggaagg gcacgactac 2820
acttcttcca aggggcagaa catggtgtgc ggcggcatgg gctgcaacaa tgattccctg 2880
gtgcagcaga tatttaacgc ggcgcagctg gacaactata cccgaatagg cttcgccccc 2940
tcgtcctgga tcgacgatta tttcgactgg gtgaagccac agtcgtcttg ctgtcgagtg 3000
gacaatatca ctgaccagtt ctgcaatgct tcagtggttg accctgcctg cgttcgctgc 3060
aggcctctga ctccggaagg caaacagagg cctcaggggg gagacttcat gagattcctg 3120
cccatgttcc tttcggataa ccctaacccc aagtgtggca aagggggaca tgctgcctat 3180
agttctgcag ttaacatcct ccttggccat ggcaccaggg tcggagccac gtacttcatg 3240
acctaccaca ccgtgctgca gacctctgct gactttattg acgctctgaa gaaagcccga 3300
cttatagcca gtaatgtcac cgaaaccatg ggcattaacg gcagtgccta ccgagtattt 3360
ccttacagtg tgttttatgt cttctacgaa cagtacctga ccatcattga cgacactatc 3420
ttcaacctcg gtgtgtccct gggcgcgata tttctggtga ccatggtcct cctgggctgt 3480
gagctctggt ctgcagtcat catgtgtgcc accatcgcca tggtcttggt caacatgttt 3540
ggagttatgt ggctctgggg catcagtctg aacgctgtat ccttggtcaa cctggtgatg 3600
agctgtggca tctccgtgga gttctgcagc cacataacca gagcgttcac ggtgagcatg 3660
aaaggcagcc gcgtggagcg cgcggaagag gcacttgccc acatgggcag ctccgtgttc 3720
agtggaatca cacttacaaa atttggaggg attgtggtgt tggcttttgc caaatctcaa 3780
attttccaga tattctactt caggatgtat ttggccatgg tcttactggg agccactcac 3840
ggattaatat ttctccctgt cttactcagt tacatagggc catcagtaaa taaagccaaa 3900
agttgtgcca ctgaagagcg atacaaagga acagagcgcg aacggcttct aaatttctag 3960
ccctctcgca gggcatcctg actgaactgt gtctaagggt cggtcggttt accactggac 4020
gggtgctgca tcggcaaggc caagttgaac accggatggt gccaaccatc ggttgtttgg 4080
cagcagcttt gaacgtagcg cctgtgaact caggaatgca cagttgactt gggaagcagt 4140
attactagat ctggaggcaa ccacaggaca ctaaacttct cccagcctct tcaggaaaga 4200
aacctcattc tttggcaagc aggaggtgac actagatggc tgtgaatgtg atccgctcac 4260
tgacactctg taaaggccaa tcaatgcact gtctgtcctc tcctttttag gagtaagcca 4320
tcccacaagt tctataccat atttttagtg acagttgagg ttgtagatac actttataac 4380
attttatagt ttaaagagct ttattaatgc aataaattaa ctttgtacac atttttatat 4440
aaaaaaacag caagtgattt cagaatgttg taggcctcat tagagcttgg tctccaaaaa 4500
tctgtttgaa aaaagcaaca tgttcttcac agtgttcccc tagaaaggaa gagatttaat 4560
tgccagttag atgtggcatg aaatgaggga caaagaaagc atctcgtagg tgtgtctact 4620
gggttttaac ttatttttct ttaataaaat acattgtttt cctaaaaaaa aaa 4673
<210> 21
<211> 410
<212> PRT
<213> 智人
<400> 21
Met Val Cys Phe Arg Leu Phe Pro Val Pro Gly Ser Gly Leu Val Leu
1 5 10 15
Val Cys Leu Val Leu Gly Ala Val Arg Ser Tyr Ala Leu Glu Leu Asn
20 25 30
Leu Thr Asp Ser Glu Asn Ala Thr Cys Leu Tyr Ala Lys Trp Gln Met
35 40 45
Asn Phe Thr Val Arg Tyr Glu Thr Thr Asn Lys Thr Tyr Lys Thr Val
50 55 60
Thr Ile Ser Asp His Gly Thr Val Thr Tyr Asn Gly Ser Ile Cys Gly
65 70 75 80
Asp Asp Gln Asn Gly Pro Lys Ile Ala Val Gln Phe Gly Pro Gly Phe
85 90 95
Ser Trp Ile Ala Asn Phe Thr Lys Ala Ala Ser Thr Tyr Ser Ile Asp
100 105 110
Ser Val Ser Phe Ser Tyr Asn Thr Gly Asp Asn Thr Thr Phe Pro Asp
115 120 125
Ala Glu Asp Lys Gly Ile Leu Thr Val Asp Glu Leu Leu Ala Ile Arg
130 135 140
Ile Pro Leu Asn Asp Leu Phe Arg Cys Asn Ser Leu Ser Thr Leu Glu
145 150 155 160
Lys Asn Asp Val Val Gln His Tyr Trp Asp Val Leu Val Gln Ala Phe
165 170 175
Val Gln Asn Gly Thr Val Ser Thr Asn Glu Phe Leu Cys Asp Lys Asp
180 185 190
Lys Thr Ser Thr Val Ala Pro Thr Ile His Thr Thr Val Pro Ser Pro
195 200 205
Thr Thr Thr Pro Thr Pro Lys Glu Lys Pro Glu Ala Gly Thr Tyr Ser
210 215 220
Val Asn Asn Gly Asn Asp Thr Cys Leu Leu Ala Thr Met Gly Leu Gln
225 230 235 240
Leu Asn Ile Thr Gln Asp Lys Val Ala Ser Val Ile Asn Ile Asn Pro
245 250 255
Asn Thr Thr His Ser Thr Gly Ser Cys Arg Ser His Thr Ala Leu Leu
260 265 270
Arg Leu Asn Ser Ser Thr Ile Lys Tyr Leu Asp Phe Val Phe Ala Val
275 280 285
Lys Asn Glu Asn Arg Phe Tyr Leu Lys Glu Val Asn Ile Ser Met Tyr
290 295 300
Leu Val Asn Gly Ser Val Phe Ser Ile Ala Asn Asn Asn Leu Ser Tyr
305 310 315 320
Trp Asp Ala Pro Leu Gly Ser Ser Tyr Met Cys Asn Lys Glu Gln Thr
325 330 335
Val Ser Val Ser Gly Ala Phe Gln Ile Asn Thr Phe Asp Leu Arg Val
340 345 350
Gln Pro Phe Asn Val Thr Gln Gly Lys Tyr Ser Thr Ala Gln Asp Cys
355 360 365
Ser Ala Asp Asp Asp Asn Phe Leu Val Pro Ile Ala Val Gly Ala Ala
370 375 380
Leu Ala Gly Val Leu Ile Leu Val Leu Leu Ala Tyr Phe Ile Gly Leu
385 390 395 400
Lys His His His Ala Gly Tyr Glu Gln Phe
405 410
<210> 22
<211> 1868
<212> DNA
<213> 智人
<400> 22
ccgattcctg gcttttgcaa ggctgtggtc ggtggtcatc agtgctcttg acccaggtcc 60
agcgagcctt ttccctggtg ttgcagctgt tgttgtaccg ccgccgtcgc cgccgtcgcc 120
gcctgctctg cggggtcatg gtgtgcttcc gcctcttccc ggttccgggc tcagggctcg 180
ttctggtctg cctagtcctg ggagctgtgc ggtcttatgc attggaactt aatttgacag 240
attcagaaaa tgccacttgc ctttatgcaa aatggcagat gaatttcaca gtacgctatg 300
aaactacaaa taaaacttat aaaactgtaa ccatttcaga ccatggcact gtgacatata 360
atggaagcat ttgtggggat gatcagaatg gtcccaaaat agcagtgcag ttcggacctg 420
gcttttcctg gattgcgaat tttaccaagg cagcatctac ttattcaatt gacagcgtct 480
cattttccta caacactggt gataacacaa catttcctga tgctgaagat aaaggaattc 540
ttactgttga tgaacttttg gccatcagaa ttccattgaa tgaccttttt agatgcaata 600
gtttatcaac tttggaaaag aatgatgttg tccaacacta ctgggatgtt cttgtacaag 660
cttttgtcca aaatggcaca gtgagcacaa atgagttcct gtgtgataaa gacaaaactt 720
caacagtggc acccaccata cacaccactg tgccatctcc tactacaaca cctactccaa 780
aggaaaaacc agaagctgga acctattcag ttaataatgg caatgatact tgtctgctgg 840
ctaccatggg gctgcagctg aacatcactc aggataaggt tgcttcagtt attaacatca 900
accccaatac aactcactcc acaggcagct gccgttctca cactgctcta cttagactca 960
atagcagcac cattaagtat ctagactttg tctttgctgt gaaaaatgaa aaccgatttt 1020
atctgaagga agtgaacatc agcatgtatt tggttaatgg ctccgttttc agcattgcaa 1080
ataacaatct cagctactgg gatgcccccc tgggaagttc ttatatgtgc aacaaagagc 1140
agactgtttc agtgtctgga gcatttcaga taaatacctt tgatctaagg gttcagcctt 1200
tcaatgtgac acaaggaaag tattctacag ctcaagactg cagtgcagat gacgacaact 1260
tccttgtgcc catagcggtg ggagctgcct tggcaggagt acttattcta gtgttgctgg 1320
cttattttat tggtctcaag caccatcatg ctggatatga gcaattttag aatctgcaac 1380
ctgattgatt atataaaaat acatgcaaat aacaagattt tcttacctct cagttgttga 1440
aacactttgc ttcttaaaat tgatatgttg aaactttaat tcttttatca atcccagcat 1500
tttgagatca gtctttatta ataaaacctg ttctctttaa tcagcttaaa atccaaagtg 1560
tcatatttac tggtcctgga gacaaacttg ttcaaaagaa catcaacgtg caatgtttta 1620
aggtctatct taagaagccc tggccaaatt ttgatcctaa ccttgaagta tgccttgaac 1680
ttattaacat ggccattata agaataaaat atgtagttgt gtcttaatgg aattaataaa 1740
tgtcatttca ctactggtgt tctgttttca atgtataagg actatagtga tttaaactca 1800
tcaatgtgcc tttgcataaa gttgattaaa taaatattga tgtggtataa atgcccatca 1860
gatatgct 1868
<210> 23
<211> 410
<212> PRT
<213> 智人
<400> 23
Met Val Cys Phe Arg Leu Phe Pro Val Pro Gly Ser Gly Leu Val Leu
1 5 10 15
Val Cys Leu Val Leu Gly Ala Val Arg Ser Tyr Ala Leu Glu Leu Asn
20 25 30
Leu Thr Asp Ser Glu Asn Ala Thr Cys Leu Tyr Ala Lys Trp Gln Met
35 40 45
Asn Phe Thr Val Arg Tyr Glu Thr Thr Asn Lys Thr Tyr Lys Thr Val
50 55 60
Thr Ile Ser Asp His Gly Thr Val Thr Tyr Asn Gly Ser Ile Cys Gly
65 70 75 80
Asp Asp Gln Asn Gly Pro Lys Ile Ala Val Gln Phe Gly Pro Gly Phe
85 90 95
Ser Trp Ile Ala Asn Phe Thr Lys Ala Ala Ser Thr Tyr Ser Ile Asp
100 105 110
Ser Val Ser Phe Ser Tyr Asn Thr Gly Asp Asn Thr Thr Phe Pro Asp
115 120 125
Ala Glu Asp Lys Gly Ile Leu Thr Val Asp Glu Leu Leu Ala Ile Arg
130 135 140
Ile Pro Leu Asn Asp Leu Phe Arg Cys Asn Ser Leu Ser Thr Leu Glu
145 150 155 160
Lys Asn Asp Val Val Gln His Tyr Trp Asp Val Leu Val Gln Ala Phe
165 170 175
Val Gln Asn Gly Thr Val Ser Thr Asn Glu Phe Leu Cys Asp Lys Asp
180 185 190
Lys Thr Ser Thr Val Ala Pro Thr Ile His Thr Thr Val Pro Ser Pro
195 200 205
Thr Thr Thr Pro Thr Pro Lys Glu Lys Pro Glu Ala Gly Thr Tyr Ser
210 215 220
Val Asn Asn Gly Asn Asp Thr Cys Leu Leu Ala Thr Met Gly Leu Gln
225 230 235 240
Leu Asn Ile Thr Gln Asp Lys Val Ala Ser Val Ile Asn Ile Asn Pro
245 250 255
Asn Thr Thr His Ser Thr Gly Ser Cys Arg Ser His Thr Ala Leu Leu
260 265 270
Arg Leu Asn Ser Ser Thr Ile Lys Tyr Leu Asp Phe Val Phe Ala Val
275 280 285
Lys Asn Glu Asn Arg Phe Tyr Leu Lys Glu Val Asn Ile Ser Met Tyr
290 295 300
Leu Val Asn Gly Ser Val Phe Ser Ile Ala Asn Asn Asn Leu Ser Tyr
305 310 315 320
Trp Asp Ala Pro Leu Gly Ser Ser Tyr Met Cys Asn Lys Glu Gln Thr
325 330 335
Val Ser Val Ser Gly Ala Phe Gln Ile Asn Thr Phe Asp Leu Arg Val
340 345 350
Gln Pro Phe Asn Val Thr Gln Gly Lys Tyr Ser Thr Ala Gln Glu Cys
355 360 365
Ser Leu Asp Asp Asp Thr Ile Leu Ile Pro Ile Ile Val Gly Ala Gly
370 375 380
Leu Ser Gly Leu Ile Ile Val Ile Val Ile Ala Tyr Val Ile Gly Arg
385 390 395 400
Arg Lys Ser Tyr Ala Gly Tyr Gln Thr Leu
405 410
<210> 24
<211> 4006
<212> DNA
<213> 智人
<400> 24
ccgattcctg gcttttgcaa ggctgtggtc ggtggtcatc agtgctcttg acccaggtcc 60
agcgagcctt ttccctggtg ttgcagctgt tgttgtaccg ccgccgtcgc cgccgtcgcc 120
gcctgctctg cggggtcatg gtgtgcttcc gcctcttccc ggttccgggc tcagggctcg 180
ttctggtctg cctagtcctg ggagctgtgc ggtcttatgc attggaactt aatttgacag 240
attcagaaaa tgccacttgc ctttatgcaa aatggcagat gaatttcaca gtacgctatg 300
aaactacaaa taaaacttat aaaactgtaa ccatttcaga ccatggcact gtgacatata 360
atggaagcat ttgtggggat gatcagaatg gtcccaaaat agcagtgcag ttcggacctg 420
gcttttcctg gattgcgaat tttaccaagg cagcatctac ttattcaatt gacagcgtct 480
cattttccta caacactggt gataacacaa catttcctga tgctgaagat aaaggaattc 540
ttactgttga tgaacttttg gccatcagaa ttccattgaa tgaccttttt agatgcaata 600
gtttatcaac tttggaaaag aatgatgttg tccaacacta ctgggatgtt cttgtacaag 660
cttttgtcca aaatggcaca gtgagcacaa atgagttcct gtgtgataaa gacaaaactt 720
caacagtggc acccaccata cacaccactg tgccatctcc tactacaaca cctactccaa 780
aggaaaaacc agaagctgga acctattcag ttaataatgg caatgatact tgtctgctgg 840
ctaccatggg gctgcagctg aacatcactc aggataaggt tgcttcagtt attaacatca 900
accccaatac aactcactcc acaggcagct gccgttctca cactgctcta cttagactca 960
atagcagcac cattaagtat ctagactttg tctttgctgt gaaaaatgaa aaccgatttt 1020
atctgaagga agtgaacatc agcatgtatt tggttaatgg ctccgttttc agcattgcaa 1080
ataacaatct cagctactgg gatgcccccc tgggaagttc ttatatgtgc aacaaagagc 1140
agactgtttc agtgtctgga gcatttcaga taaatacctt tgatctaagg gttcagcctt 1200
tcaatgtgac acaaggaaag tattctacag cccaagagtg ttcgctggat gatgacacca 1260
ttctaatccc aattatagtt ggtgctggtc tttcaggctt gattatcgtt atagtgattg 1320
cttacgtaat tggcagaaga aaaagttatg ctggatatca gactctgtaa cactaatcaa 1380
tacgtgatct ctgttacaaa agaaaaaagc aagtacaagt tccaacatgc aatactggtc 1440
aacttaaggt atatttagtt gcagtccagc tctttagaat gggtggtatg ggggatttca 1500
aacttaaaca aaaaactatc aactacaaat tagttgcctg actttggttt ttccaaccaa 1560
ggaatttaaa actgttattt ttacagcaaa agatgtgcaa aatcactgga ttataagttc 1620
tattttactg tcttgaatta gtatttcagt gttttcattt tagacattca gactaaaaat 1680
acaccgttta gaaaaaacaa tttttgaaaa agagattttt tttccctgca ggtagttgag 1740
ttgaacaaca tgttctaccg tggatttgta cttgctcctt ttgctctttt tgtgtgtgtg 1800
tgtgtgtgtg tgtgtgtgtg tgtgattttt gtttgcaggt taacttagct actttggcat 1860
tgctgcatat ttgacctttg agagatataa tagtagattt gaacaggggc tggtattatt 1920
atgttcttag caataaatgc ttttctaatg ccttttgaat acatttgtat ttatgtggct 1980
gtaatgacaa aagatacaaa agctttttaa aatttagagt aggtattaat cttattgttt 2040
aatctttttt ttaaaaaaac tggatatttc aatcttttaa attgcaatat ataagactat 2100
tccaactggg catttcaatc cattttttag gtgctttaga gataattgct tgccagtgcc 2160
aattgagggc attagtactt tgtgctcata aattggcctc tgtatgcagt actaaaatta 2220
atgcagattt ctctttagcc ttccaacatt tcttgttgat agtgatgtat tttattattt 2280
tctttttctt aagaaatgcc agtgtgtcct agaacctaga taacgaagtg cacttacact 2340
tataaaataa cttgcatcta ggctgggcgt ggcggctcac gcctgtaatc ccagcacttt 2400
gggaggccga agtgggtgga tcacttgagg ccaggagttt gagaccagcc tggccaacat 2460
ggtgaaaccc catctctatc agaaatacaa aaaattagct gggcatggtg gtgggcgcct 2520
gtaatcccag ttactcggga ggctgaggca ggagaatcac ttgaacccgg gaggcagagg 2580
ttgcggtgag ccaagagcgc accattgcac tccagccttg ggcgacaaaa acgaaactcc 2640
atcttcaaaa caaaacaaaa caaaacaaac aaacaaacaa aacttgcatc ttaaccaaaa 2700
gtcttggttt tatcttaatc cattaaaagt tggtcttgtt tccagcttgc attgattgct 2760
acaacatcac taatttggct ttcacattta aatggttctg tgctaatcaa aactttcgtt 2820
gttattattc gttatggtag aatcattttt aattcacgtg ctttgtgttc agttttgtgg 2880
tctgagagat gtaccaattg tcaaattacc gtgtaccacc taatgtttat aggagaaagc 2940
aaaatacatc agcttggtag ttaacacatc aaatatttct tgctgcttct aggagaactt 3000
ttttggtgtg tgttggaatg gctgagcaaa tattaaaatt gttaatatgc agccatatat 3060
ggaaggttcc tgtggggttg ttttttcgtg tttttttttt ttgtggtggg attatgtgcc 3120
tcccattcac tagaaaatga gaaaattgtc tgggttccaa aatattgaca ttgaatggat 3180
caatacacac acacagacat atatatatat atatgcacac atatataggc agttgcatgc 3240
ctagcatggg tattttataa ccatataact gagttatatt ggaattataa atattttccg 3300
tcacttaaat ttgttctttg tttagcctga aaacctttat ggctcaagat cagattcctg 3360
actaacccct ctcttagagc tacagcgagc tgcattacca gcttaaaaca cttcttaggg 3420
attaaatata gatgtaattt ttcaaaatcg tttttaattt aaactgtgtt ttagtgtaaa 3480
attgttaacc ttgtaagatg gataatgtgt ataagaatgt aggccttaac tatttcacat 3540
gagtcaaaac aaagcagctt taaaaaaata attggaagca caatgcatgg cactgactga 3600
atgctgttaa tatttctaaa agtttctaca ttcagattat atgcctgatt catagtaaaa 3660
tacctctaat aaacactgtt ttatagaaaa cctgacttca gtgaatattt ttgtatttta 3720
catgggccag tttatatact gctatttaca ctattatttc ctatagctac atgttctttg 3780
taccttttgt agttttattt gtattactag attcatacct tgatggtaac gctctatctg 3840
gttttgggtg tttttcatgt tttagcattt gtataaagaa actggtccat gtaaatactt 3900
tccatgtttt ttcttcaaat gtttaaacca ctagttgatg tatggtatct ttagatattt 3960
gcctgtctgt ttgctcaaaa ttgcttctaa aacaataaag attctt 4006
<210> 25
<211> 411
<212> PRT
<213> 智人
<400> 25
Met Val Cys Phe Arg Leu Phe Pro Val Pro Gly Ser Gly Leu Val Leu
1 5 10 15
Val Cys Leu Val Leu Gly Ala Val Arg Ser Tyr Ala Leu Glu Leu Asn
20 25 30
Leu Thr Asp Ser Glu Asn Ala Thr Cys Leu Tyr Ala Lys Trp Gln Met
35 40 45
Asn Phe Thr Val Arg Tyr Glu Thr Thr Asn Lys Thr Tyr Lys Thr Val
50 55 60
Thr Ile Ser Asp His Gly Thr Val Thr Tyr Asn Gly Ser Ile Cys Gly
65 70 75 80
Asp Asp Gln Asn Gly Pro Lys Ile Ala Val Gln Phe Gly Pro Gly Phe
85 90 95
Ser Trp Ile Ala Asn Phe Thr Lys Ala Ala Ser Thr Tyr Ser Ile Asp
100 105 110
Ser Val Ser Phe Ser Tyr Asn Thr Gly Asp Asn Thr Thr Phe Pro Asp
115 120 125
Ala Glu Asp Lys Gly Ile Leu Thr Val Asp Glu Leu Leu Ala Ile Arg
130 135 140
Ile Pro Leu Asn Asp Leu Phe Arg Cys Asn Ser Leu Ser Thr Leu Glu
145 150 155 160
Lys Asn Asp Val Val Gln His Tyr Trp Asp Val Leu Val Gln Ala Phe
165 170 175
Val Gln Asn Gly Thr Val Ser Thr Asn Glu Phe Leu Cys Asp Lys Asp
180 185 190
Lys Thr Ser Thr Val Ala Pro Thr Ile His Thr Thr Val Pro Ser Pro
195 200 205
Thr Thr Thr Pro Thr Pro Lys Glu Lys Pro Glu Ala Gly Thr Tyr Ser
210 215 220
Val Asn Asn Gly Asn Asp Thr Cys Leu Leu Ala Thr Met Gly Leu Gln
225 230 235 240
Leu Asn Ile Thr Gln Asp Lys Val Ala Ser Val Ile Asn Ile Asn Pro
245 250 255
Asn Thr Thr His Ser Thr Gly Ser Cys Arg Ser His Thr Ala Leu Leu
260 265 270
Arg Leu Asn Ser Ser Thr Ile Lys Tyr Leu Asp Phe Val Phe Ala Val
275 280 285
Lys Asn Glu Asn Arg Phe Tyr Leu Lys Glu Val Asn Ile Ser Met Tyr
290 295 300
Leu Val Asn Gly Ser Val Phe Ser Ile Ala Asn Asn Asn Leu Ser Tyr
305 310 315 320
Trp Asp Ala Pro Leu Gly Ser Ser Tyr Met Cys Asn Lys Glu Gln Thr
325 330 335
Val Ser Val Ser Gly Ala Phe Gln Ile Asn Thr Phe Asp Leu Arg Val
340 345 350
Gln Pro Phe Asn Val Thr Gln Gly Lys Tyr Ser Thr Ala Glu Glu Cys
355 360 365
Ser Ala Asp Ser Asp Leu Asn Phe Leu Ile Pro Val Ala Val Gly Val
370 375 380
Ala Leu Gly Phe Leu Ile Ile Val Val Phe Ile Ser Tyr Met Ile Gly
385 390 395 400
Arg Arg Lys Ser Arg Thr Gly Tyr Gln Ser Val
405 410
<210> 26
<211> 1236
<212> DNA
<213> 智人
<400> 26
atggtgtgct tccgcctctt cccggttccg ggctcagggc tcgttctggt ctgcctagtc 60
ctgggagctg tgcggtctta tgcattggaa cttaatttga cagattcaga aaatgccact 120
tgcctttatg caaaatggca gatgaatttc acagtacgct atgaaactac aaataaaact 180
tataaaactg taaccatttc agaccatggc actgtgacat ataatggaag catttgtggg 240
gatgatcaga atggtcccaa aatagcagtg cagttcggac ctggcttttc ctggattgcg 300
aattttacca aggcagcatc tacttattca attgacagcg tctcattttc ctacaacact 360
ggtgataaca caacatttcc tgatgctgaa gataaaggaa ttcttactgt tgatgaactt 420
ttggccatca gaattccatt gaatgacctt tttagatgca atagtttatc aactttggaa 480
aagaatgatg ttgtccaaca ctactgggat gttcttgtac aagcttttgt ccaaaatggc 540
acagtgagca caaatgagtt cctgtgtgat aaagacaaaa cttcaacagt ggcacccacc 600
atacacacca ctgtgccatc tcctactaca acacctactc caaaggaaaa accagaagct 660
ggaacctatt cagttaataa tggcaatgat acttgtctgc tggctaccat ggggctgcag 720
ctgaacatca ctcaggataa ggttgcttca gttattaaca tcaaccccaa tacaactcac 780
tccacaggca gctgccgttc tcacactgct ctacttagac tcaatagcag caccattaag 840
tatctagact ttgtctttgc tgtgaaaaat gaaaaccgat tttatctgaa ggaagtgaac 900
atcagcatgt atttggttaa tggctccgtt ttcagcattg caaataacaa tctcagctac 960
tgggatgccc ccctgggaag ttcttatatg tgcaacaaag agcagactgt ttcagtgtct 1020
ggagcatttc agataaatac ctttgatcta agggttcagc ctttcaatgt gacacaagga 1080
aagtattcta cagctgaaga atgttctgct gactctgacc tcaactttct tattcctgtt 1140
gcagtgggtg tggccttggg cttccttata attgttgtct ttatctctta tatgattgga 1200
agaaggaaaa gtcgtactgg ttatcagtct gtgtaa 1236
<210> 27
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 27
His His His His His His
1 5
Claims (51)
1.一种治疗受试者的溶酶体跨膜蛋白疾病或紊乱的方法，所述方法包括：
将相应的功能性人溶酶体跨膜蛋白引入所述受试者的造血干细胞和祖细胞(HSPC)中；以及
将所述HSPC移植到所述受试者内，
从而治疗所述溶酶体跨膜蛋白疾病或紊乱。
2.权利要求1所述的方法，其中：
(a)当所述溶酶体跨膜蛋白疾病或紊乱是胱氨酸病时，所述相应的功能性人溶酶体跨膜蛋白是胱氨酸转运蛋白(CTNS)；
(b)当所述溶酶体跨膜蛋白疾病或紊乱是唾液酸贮积病或婴儿唾液酸贮积病时，所述相应的功能性人溶酶体跨膜蛋白是唾液酸转运蛋白(SLC17A5)；
(c)当所述溶酶体跨膜蛋白疾病或紊乱是钴胺素F型疾病时，所述相应的功能性人溶酶体跨膜蛋白是LMBD1；
(d)当所述溶酶体跨膜蛋白疾病或紊乱是晚期婴儿神经元蜡样脂褐质沉积症时，所述相应的功能性人溶酶体跨膜蛋白是CLN7；
(e)当所述溶酶体跨膜蛋白疾病或紊乱是青少年神经元蜡样脂褐质沉积症时，所述相应的功能性人溶酶体跨膜蛋白是Battenin(CLN3)；
(f)当所述溶酶体跨膜蛋白疾病或紊乱是恶性婴儿骨硬化症时，所述相应的功能性人溶酶体跨膜蛋白是ClC-7或OSTM1；
(g)当所述溶酶体跨膜蛋白疾病或紊乱是粘脂贮积病IV时，所述相应的功能性人溶酶体跨膜蛋白是TRPML-1；
(h)当所述溶酶体跨膜蛋白疾病或紊乱是粘多糖贮积症IIC型时，所述相应的功能性人溶酶体跨膜蛋白是HGSNAT；
(i)当所述溶酶体跨膜蛋白疾病或紊乱是Neiman-Pick C型时，所述相应的功能性人溶酶体跨膜蛋白是NPC-1；和
(j)当所述溶酶体跨膜蛋白疾病或紊乱是溶酶体贮积症时，所述相应的功能性人溶酶体跨膜蛋白是LAMP2。
3.权利要求1所述的方法，其中，所述引入的步骤包括使包含编码功能性人溶酶体跨膜蛋白的多核苷酸和功能性启动子的载体与所述HSPC接触，并使得能够表达所述功能性人溶酶体跨膜蛋白。
4.权利要求1所述的方法，其中，所述溶酶体跨膜蛋白疾病或紊乱是胱氨酸病，并且所述功能性人溶酶体跨膜蛋白是CTNS。
5.权利要求1所述的方法，其中，所述溶酶体跨膜蛋白疾病或紊乱是溶酶体贮积症，并且所述功能性人溶酶体跨膜蛋白是LAMP2。
6.权利要求5所述的方法，其中，LAMP-2是选自由LAMP-2A、LAMP-2B、LAMP-2C组成的组的同种型。
7.权利要求所述1的方法，其中，所述受试者是哺乳动物。
8.权利要求7所述的方法，其中，所述受试者是人。
9.权利要求1所述的方法，其中，所述载体是选自由慢病毒、腺病毒和AAV载体组成的组的病毒载体。
10.权利要求9所述的方法，其中，所述载体是自失活(SIN)-慢病毒载体。
11.权利要求4所述的方法，其中，所述载体是自失活(SIN)-慢病毒载体。
12.权利要求11所述的方法，其中，所述载体是pCCL-CTNS。
13.权利要求5所述的方法，其中，所述载体是自失活(SIN)-慢病毒载体。
14.权利要求13所述的方法，其中，所述载体是pCCL-LAMP2。
15.权利要求1所述的方法，其中，所述引入的步骤是离体进行的。
16.权利要求1所述的方法，其中，所述HSPC是从所述受试者的骨髓中分离的。
17.一种载体，所述载体包含与编码功能性人溶酶体跨膜蛋白的多核苷酸功能性连接的启动子，所述功能性人溶酶体跨膜蛋白选自由CTNS、SLC17A5、LMBRD1、CLN7、CLN3、CLC-7、OSTM1、TRPML1、HGSNAT、NPC1和LAMP2组成的组。
18.权利要求17所述的载体，其中，所述载体是选自慢病毒、腺病毒和AAV载体组成的组的病毒载体。
19.权利要求17所述的载体，其中，所述载体是自失活(SIN)-慢病毒载体。
20.权利要求19所述的载体，其中，所述载体是pCCL-CTNS。
21.一种经分离的哺乳动物宿主细胞，所述经分离的哺乳动物宿主细胞含有权利要求17-20中任一项所述的表达载体。
22.权利要求21所述的经分离的哺乳动物宿主细胞，其中，所述细胞是HSPC。
23.一种治疗或改善受试者中溶酶体蛋白质疾病或紊乱的方法，所述方法包括：
从所述受试者的骨髓中分离造血干细胞和祖细胞(HSPC)；
将功能性人溶酶体跨膜基因引入所述HSPC，其中，所述基因编码对应于所述溶酶体蛋白质疾病或紊乱的蛋白质；以及
将所述HSPC移植回所述受试者，
从而治疗或改善所述溶酶体蛋白质疾病或紊乱。
24.如权利要求23所述的方法，其中：
(a)当所述溶酶体跨膜蛋白疾病或紊乱是胱氨酸病时，所述功能性人溶酶体跨膜蛋白基因是CTNS；
(b)当所述溶酶体跨膜蛋白疾病或紊乱是唾液酸贮积病或婴儿唾液酸贮积病时，所述功能性人溶酶体跨膜蛋白基因是SLC17A5；
(c)当所述溶酶体跨膜蛋白疾病或紊乱是钴胺素F型疾病时，所述功能性人溶酶体跨膜蛋白基因是LMRBD1；
(d)当所述溶酶体跨膜蛋白疾病或紊乱是晚期婴儿神经元蜡样脂褐质沉积症时，所述功能性人溶酶体跨膜蛋白基因是MFSD8；
(e)当所述溶酶体跨膜蛋白疾病或紊乱是青少年神经元蜡样脂褐质沉积症时，所述功能性人溶酶体跨膜蛋白基因是CLN3；
(f)当所述溶酶体跨膜蛋白疾病或紊乱是恶性婴儿骨硬化症时，所述功能性人溶酶体跨膜蛋白基因是CLCN7或OSTM1；
(g)当所述溶酶体跨膜蛋白疾病或紊乱是粘脂贮积病IV时，所述功能性人溶酶体跨膜蛋白基因是MCOLN1；
(h)当所述溶酶体跨膜蛋白疾病或紊乱是粘多糖贮积症IIC型时，所述功能性人溶酶体跨膜蛋白基因是HGSNAT；
(i)当所述溶酶体跨膜蛋白疾病或紊乱是Neiman-Pick C型时，所述功能性人溶酶体跨膜蛋白基因是NPC1；和
(j)当所述溶酶体跨膜蛋白疾病或紊乱是溶酶体贮积症时，所述功能性人溶酶体跨膜蛋白基因是LAMP2。
25.权利要求23所述的方法，其中，所述HSPC是CD34+细胞。
26.权利要求24所述的方法，其中，所述溶酶体蛋白疾病或紊乱是胱氨酸病，并且所述功能性人溶酶体跨膜基因是CTNS。
27.权利要求24所述的方法，其中，所述溶酶体蛋白疾病或紊乱是溶酶体贮积症，并且所述功能性人溶酶体跨膜基因是LAMP2。
28.权利要求26所述的方法，其中，将所述功能性人CTNS基因引入所述HSPC的步骤包括使用载体。
29.权利要求28所述的方法，其中，所述载体是选自由慢病毒、腺病毒和AAV载体组成的组的病毒载体。
30.权利要求29所述的方法，其中，所述载体是慢病毒载体。
31.权利要求30所述的方法，其中，所述载体是自失活(SIN)-慢病毒载体。
32.权利要求26所述的方法，其中，在治疗后，所述受试者的眼、皮肤、白细胞、实质组织或胃肠道中的胱氨酸水平降低。
33.权利要求26所述的方法，其中，剂量为约1.0×106至5.0×106个细胞/kg。
34.权利要求33所述的方法，其中，所述剂量为施用约2.5×106个细胞/kg作为单剂量。
35.权利要求26所述的方法，其中，所述受试者患有肾病性胱氨酸病。
36.权利要求26所述的方法，其中，所述受试者在治疗前进行半胱胺治疗。
37.权利要求36所述的方法，其中，所述受试者接受口服半胱胺治疗。
38.权利要求26所述的方法，其中，施用是静脉内施用。
39.权利要求26所述的方法，其中，在治疗之前和/或之后，于眼、皮肤、白细胞、实质组织和/或胃肠道中测量胱氨酸或胱氨酸晶体。
40.权利要求39所述的方法，其中，在治疗之前、期间和/或之后测量胱氨酸水平。
41.权利要求39所述的方法，其中，使用生物样品测量胱氨酸水平。
42.权利要求41所述的方法，其中，所述生物样品是血液、直肠活组织切片或颊粘膜。
43.权利要求39所述的方法，其中，使用体内共聚焦显微镜测量胱氨酸晶体。
44.一种治疗或改善受试者中溶酶体蛋白质疾病或紊乱的方法，所述方法包括：
使用基因编辑在所述受试者中产生功能性人溶酶体跨膜基因。
45.权利要求44所述的方法，其中，
(a)当所述溶酶体跨膜蛋白疾病或紊乱是胱氨酸病时，所述功能性人溶酶体跨膜蛋白基因是CTNS；
(b)当所述溶酶体跨膜蛋白疾病或紊乱是唾液酸贮积病或婴儿唾液酸贮积病时，所述功能性人溶酶体跨膜蛋白基因是SLC17A5；
(c)当所述溶酶体跨膜蛋白疾病或紊乱是钴胺素F型疾病时，所述功能性人溶酶体跨膜蛋白基因是LMBRD1；
(d)当所述溶酶体跨膜蛋白疾病或紊乱是晚期婴儿神经元蜡样脂褐质沉积症时，所述功能性人溶酶体跨膜蛋白基因是MFSD8；
(e)当所述溶酶体跨膜蛋白疾病或紊乱是青少年神经元蜡样脂褐质沉积症时，所述功能性人溶酶体跨膜蛋白基因是CLN3；
(f)当所述溶酶体跨膜蛋白疾病或紊乱是恶性婴儿骨硬化症时，所述功能性人溶酶体跨膜蛋白基因是CLCN7或OSTM1；
(g)当所述溶酶体跨膜蛋白疾病或紊乱是粘脂贮积病IV时，所述功能性人溶酶体跨膜蛋白基因是MCOLN1；
(h)当所述溶酶体跨膜蛋白疾病或紊乱是粘多糖贮积症IIC型时，所述功能性人溶酶体跨膜蛋白基因是HGSNAT；
(i)当所述溶酶体跨膜蛋白疾病或紊乱是Neiman-Pick C型时，所述功能性人溶酶体跨膜蛋白基因是NPC-1；和
(j)当所述溶酶体跨膜蛋白疾病或紊乱是溶酶体贮积症时，所述功能性人溶酶体跨膜蛋白基因是LAMP2。
46.一种治疗或改善受试者中溶酶体蛋白质疾病或紊乱的方法，所述方法包括使表达来自所述受试者的缺陷型溶酶体跨膜蛋白的细胞与编码基因编辑系统的载体接触，所述基因编辑系统在转染入细胞时除去内源基因的三核苷酸延伸突变从而治疗所述溶酶体蛋白疾病或紊乱，所述内源基因编码所述溶酶体跨膜蛋白。
47.权利要求46所述的方法，其中，
(a)当所述溶酶体跨膜蛋白疾病或紊乱是胱氨酸病时，所述溶酶体跨膜蛋白是胱氨酸转运蛋白(CTNS)；
(b)当所述溶酶体跨膜蛋白疾病或紊乱是唾液酸贮积病或婴儿唾液酸贮积病时，所述溶酶体跨膜蛋白是唾液酸转运蛋白(SLC17A5)；
(c)当所述溶酶体跨膜蛋白疾病或紊乱是钴胺素F型疾病时，所述溶酶体跨膜蛋白是LMBD1；
(d)当所述溶酶体跨膜蛋白疾病或紊乱是晚期婴儿神经元蜡样脂褐质沉积症时，所述溶酶体跨膜蛋白是CLN7；
(e)当所述溶酶体跨膜蛋白疾病或紊乱是青少年神经元蜡样脂褐质沉积症时，所述溶酶体跨膜蛋白是Battenin(CLN3)；
(f)当所述溶酶体跨膜蛋白疾病或紊乱是恶性婴儿骨硬化症时，所述溶酶体跨膜蛋白是ClC-7或OSTM1；
(g)当所述溶酶体跨膜蛋白疾病或紊乱是粘脂贮积病IV时，所述溶酶体跨膜蛋白是TRPML-1；
(h)当所述溶酶体跨膜蛋白疾病或紊乱是粘多糖贮积症IIC型时，所述溶酶体跨膜蛋白是HGSNAT；
(i)当所述溶酶体跨膜蛋白疾病或紊乱是Neiman-Pick C型时，所述溶酶体跨膜蛋白是NPC-1；和
(j)当所述溶酶体跨膜蛋白疾病或紊乱是溶酶体贮积症时，所述溶酶体跨膜蛋白是LAMP2。
48.权利要求47所述的方法，其中，所述基因编辑系统选自由CRISPR/Cas、锌指核酸酶和转录激活因子样效应核酸酶。
49.权利要求47所述的方法，其中，所述接触的步骤包括给所述受试者施用有效量的所述载体。
50.权利要求47所述的方法，其中，所述接触的步骤包括从所述受试者获得细胞样品，将所述基因编辑系统转染到所述细胞样品中，然后将经转染的细胞移植到所述受试者内。
51.权利要求46所述的方法，其中，所述细胞样品选自由血细胞和HSPC组成的组。
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| PCT/US2018/022598 WO2018170239A1 (en) | 2017-03-15 | 2018-03-15 | Methods of treating lysosomal disorders |
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| WO2020160458A1 (en) * | 2019-02-01 | 2020-08-06 | Avrobio, Inc. | Compositions and methods for treating neurocognitive disorders |
| US20220177922A1 (en) * | 2019-03-07 | 2022-06-09 | National University Corporation Tokyo Medical And Dental University | High-throughput gene-editing technique |
| US20200299727A1 (en) * | 2019-03-21 | 2020-09-24 | The Regents Of The University Of Colorado, A Body Corporate | Methods of treating danon disease |
| WO2020210218A1 (en) * | 2019-04-12 | 2020-10-15 | The Regents Of The University Of California | Methods for treating inherited eye defects |
| CN114786710A (zh) * | 2019-10-17 | 2022-07-22 | 西湖生物医药科技(杭州)有限公司 | 工程改造红细胞用于治疗溶酶体贮积病 |
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