CN115943213A - 视网膜神经节细胞的再生 - Google Patents
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Abstract
本文提供了用于通过激活转录因子如Atoh7、Brn3B、Sox4、Sox11或Ils1中的一种或多种从视网膜神经元细胞再生视网膜神经节细胞(RGC)的组合物和方法。视网膜神经元细胞可以是中间神经元细胞,例如无长突细胞、水平细胞和双极细胞。再生的RGC可以将轴突投射到离散的皮层下脑区并建立视网膜‑大脑连接。它们可以对视觉刺激做出反应并将电信号传输到大脑中。因此,再生的RGC可以替代受损或退化的RGC,从而治疗视力障碍或失明。这些方法同样适用于退化、受损或老化的RGC,以刺激它们再生功能性轴突,从而使这些RGC恢复活力。
Description
本发明要求2020年1月16日提交的202010047628.2的优先权,其内容整体纳入本文。
背景技术
视网膜神经节细胞(RGC)是视网膜的最终输出神经元,其处理视觉信息并将其传输到离散的大脑视觉区域以形成视觉。RGC的缺失是一组被广泛归类为视神经病变的疾病中失明的主要原因,这些疾病包括青光眼、遗传性视神经病变以及由毒素、营养缺陷和创伤引起的疾病。这些患者的视力丧失是不可逆转的,因为人类和所有哺乳动物都缺乏在成年期产生RGC的能力。人们对开发再生疗法以恢复此类患者的视力丧失非常感兴趣。
开发用于视神经病变的再生疗法的一种有吸引力的方法是替换丢失的神经节细胞并使用内源性细胞将视网膜重新连接到大脑。已经做出了巨大的努力来识别视网膜干/祖细胞并了解视网膜神经元是如何在各种模式生物中产生的。先前的研究表明,鱼类和两栖动物等低等脊椎动物在受伤后会在功能上再生其视网膜,而穆勒神经胶质(Müllerglia)是再生视网膜神经元的细胞来源。相比之下,哺乳动物中的穆勒神经胶质(Müllerglia)没有这种能力,包括人类在内的哺乳动物也没有其他视网膜干/祖细胞库,可以在成年阶段再生视网膜神经元。目前的共识是,在成熟的哺乳动物视网膜中通常几乎没有持续添加神经元。
迫切需要治疗这些疾病和病症并恢复患者的视力。
发明内容
本公开报道了视网膜神经节细胞(RGC)可以通过激活转录因子例如Atoh7、Brn3B、Sox4、Sox11或Ils1中的一种或多种从视网膜神经元再生的发现。再生的RGC可以将轴突投射到离散的皮层下脑区并建立视网膜-大脑连接。它们可以对视觉刺激做出反应并将电信号传输到大脑中。因此,再生的RGC可以替代受损或退化的RGC,从而治疗视力障碍或失明。
在另一个意想不到的发现中,这些转录因子的激活也可以重新激活退化、受损或老化的RGC,使它们能够再生功能性轴突。因此,当向受试者施用可以激活这些转录因子的治疗剂时,它们可以使退化、受损或老化的RGC恢复活力,同时将附近的中间神经元细胞重编程为再生的RGC。这些试剂的这种双重作用可以更有效地实现所需的治疗效果。
根据本公开的一个实施方案,提供了一种制备对视觉信号有反应的哺乳动物细胞的方法,包括增加视网膜神经元细胞的一种或多种选自由以下组成的组的基因的生物学活性:POU 4类同源框2(Brn3B)、SRY框转录因子4(Sox4)、Atonal BHLH转录因子7(Atoh7)、SRY框转录因子11(Sox11)和ISL LIM同源框1(Ils1)。
在一些实施方案中,所述一种或多种基因包含Brn3B和Sox4。在一些实施方案中,所述一种或多种基因进一步包含Atoh7。
在一些实施方案中,视网膜神经元细胞是中间神经元细胞,例如无长突细胞、水平细胞或双极细胞。在一些实施方案中,视网膜神经元细胞是退化的、受损的或老化的视网膜神经节细胞(RGC)。在一些实施方案中,视网膜神经元细胞是Lgr5+无长突细胞。在一些实施方案中,视网膜神经元细胞是Prokr2+置换的无长突细胞。
在另一个实施方案中,本公开提供了一种用于改善视网膜神经节细胞(RGC)功能的方法,该视网膜神经节细胞可以是退化的、受损的、老化的或正常的/健康的,其需要改善的功能。在一些实施方案中,该方法需要在RGC中增加一种或多种选自由Atoh7、Brn3B、Sox4、Sox11和Ils1组成的组的基因的生物学活性。
在一些实施方案中,增加一种或多种基因的生物学活性包括向视网膜神经元细胞中引入一种或多种编码基因的多核苷酸,例如cDNA,其可以在质粒或病毒载体中提供,例如腺相关的病毒(AAV)载体。
还提供了一种用于治疗有需要的受试者的视力障碍或失明的方法,包括向受试者的视网膜施用能够增加一种或多种选自由Brn3B、Sox4、Atoh7、Sox11和Ils1组成的组的基因的生物学活性的试剂。
在一些实施方案中,视力障碍或失明是由退化的视网膜神经节细胞(RGC)引起的。在一些实施方案中,视力障碍或失明与选自由视神经病(包括青光眼)、遗传性视神经病和由毒素、营养缺陷和外伤引起的病症组成的组的病况相关。
在一个实施方案中,还提供了一种核酸构建体,其包含编码Brn3B和Sox4蛋白的编码序列,以及与每个编码序列相关的启动子,其中每个启动子在视网膜神经元细胞中是有活性的。
另一个实施方案提供了由核酸构建体转染的细胞。又一个实施方案提供了一种对视觉信号有反应的细胞,其通过本文公开的方法制备。
这些和其他实施方案在下文中进一步描述。
附图说明
图1.Lgr5+无长突中间神经元在成年小鼠中转分化为其他神经元亚型。a,视网膜横截面图像,其显示内核层中的Lgr5+无长突中间神经元。b,c,来自Lgr5EGFP-IRES-CreERT2;Rosa26-tdTomato小鼠的视网膜横截面图像。箭头突出显示来自Lgr5+无长突中间神经元的双极(b)和水平(c)细胞的生成。d,视网膜平铺(flat-mount retina)样本的图像,聚焦在视网膜神经节细胞层上。从内核层迁移到神经节细胞层的Lgr5+无长突中间神经元被标记为绿色。e,Lgr5+无长突细胞响应全场闪光的代表性膜电位。插图:染料填充后记录的细胞的荧光图像。f,Lgr5+无长突细胞响应全场闪光的代表性兴奋性突触后电流(EPSC,蓝色)和抑制性突触后电流(IPSC,红色)。总6个记录的细胞中共有5个对全场LED光刺激有反应。图e和f中的箭头:刺激伪影。ONL:外核层;OPL:外丛状层;INL:内核层;IPL:内丛状层;GCL:神经节细胞层。比例尺,图a、b和c中=30μm,图d中=200μm,图e中=10μm。
图2.在体内将Lgr5+无长突中间神经元重编程为RGC。a,体内神经元重编程的策略。首先给Lgr5EGFP-IRES-CreERT2;Rosa26-tdTomato小鼠喂食他莫昔芬(TM)五次(从第-11天(D-11)到第-7天(D-7)),用Rosa26-tdTomato报告基因标记Lgr5+无长突中间神经元,以协助身份追踪。一周后,在D1小鼠被玻璃体内注射表达Cre依赖性转录因子的AAV,然后从D3到D7进行TM喂养,以激活AAV递送的基因,特别是在Lgr5+无长突中间神经元中。病毒注射后6周处死小鼠进行分析。b,使用依赖于Cre的反向开放阅读框(DIO)系统的AAV表达载体图。c,转录因子的单一和各种组合的重编程效率。提供的数据是视神经中tdTomato+轴突的数量(每组中n=4只小鼠中有8个)。在注射AAV-DIO-EGFP的小鼠的视神经中未检测到tdTomato+轴突。(D-F)实验小鼠的视网膜平铺样本的图像,聚焦在视网膜神经节细胞层上。e,图D中区域的高倍放大视图,箭头指向再生RGC的tdTomato+轴突。f,单个再生RGC的突出显示。g-i,用对RPBMS(g)、Brn3A(h)和CART(i)特异的抗体对再生RGC进行免疫组织学染色。**P<0.001;NS,不显著。图c中的缩写:B=Brn3B,S4=Sox4,BS4=Brn3B+Sox4,ABS4=Atoh7+Brn3B+Sox4,ABS4S11Is=Atoh7+Brn3B+Sox4+Sox11+Isl1。比例尺,在图d中=200μm,在图e中=150μm,在图f中=50μm,在图g、h和i中=40μm。
图3.再生的RGC将轴突投射到大脑中。a,视神经内再生的RGC轴突的共聚焦图像。b-f,大脑视觉区域中再生的RGC轴突的投射,显示背侧和腹外侧膝状体核(dLGN和vLGN,分别为图b和c)、橄榄顶盖前核(OPN,图d)和上丘(SC,图e和f)中的tdTomato+轴突末端。图f中的箭头突出显示SC区域中再生的RGC轴突末端上的棒头状(bouton-like)结构。g-i,SC脑切片的PSD-95染色。tdTomato+静脉曲张与PSD-95染色密切相关,但不重叠。来自3种不同动物的大脑样本具有相同的染色模式。比例尺,图a到e中=200μm,图f中=40μm,图g和h中=10μm。
图4.将Prokr2+置换的无长突中间神经元重编程为RGC。来自Prokr2CreERT2;Rosa26-tdTomato小鼠的视网膜平铺样本的共聚焦图像;tdTomato+置换的无长突细胞以红色显示。Prokr2-tdTomao+置换的无长突细胞在视网膜平铺样本上没有任何轴突。b,在图a中突出显示区域。c,来自注射了共表达转录因子和EGFP的AAV的Prokr2CreERT2小鼠的视网膜平铺样品的共聚焦图像。再生的RGC将轴突延伸到视神经盘。d,在图c中突出显示区域。e,视神经内再生的RGC的轴突。f-k,再生的RGC的轴突在各种大脑视网膜受体区域的投射,包括dLGN和vLGN(f)、OPN(g)以及SC区域的上层(图h和i)和下层(图j和k)。图i和k中的图像是高放大率视图。比例尺,在图a和c中=1000μm,在图e到g和图j中=200μm,在图h中=100μm,在图i和k中=40μm。
图5.再生的RGC将视觉信息传递到大脑并与突触后神经元建立功能连接。a,三个示例性轴突末端响应于不同方向的漂移光栅的钙信号轨迹。青色斑块标记刺激呈现的周期,底部的值指示刺激方向。请注意,此图中显示的三个末端具有稳健的的“开启”响应。b,与图A中的图相同,只是此处显示的末端具有稳健的“关闭”响应。c,d,具有定向选择性(c)和方向选择性(d)的三个轴突末端的钙信号痕迹。e,SC神经元中光诱发突触后AMPA受体反应的代表性EPSC。箭头表示多突触前输入的突触后反应。f,SC神经元中光诱发突触后NMDA受体反应的代表性EPSC。g,SC神经元中光诱发突触后动作电位的例子。h,i,光诱发AMPA受体反应的EPSC振幅(h)和峰值数(i)的总结(来自7只动物的n=11)。j,光诱发NMDA受体反应的EPSC振幅总结(来自3只动物的n=3)。数据是平均值±sem。
图6.在青光眼小鼠模型中再生功能性RGC。a-d.视网膜样本的共聚焦图像。a,正常Lgr5EGFP-IRES-CreERT2;Rosa26-tdTomato小鼠的视网膜。b,7天前因眼压升高(IPI)受损的小鼠视网膜。c,7天前被IPI损伤但每天接受瑞帕舒地尔治疗的小鼠的视网膜。d,受IPI损伤但接受瑞帕舒地尔治疗和注射表达RGC命运决定(fate-specification)转录因子(AAV-DIO-TFs)的AAV的小鼠的视网膜。AAV注射后6周处死小鼠。e、f,来自接受AAV-DIO-EGFP(e)和AAV-DIO-TF(f)的眼睛的视神经的共聚焦图像。g-k,来自Lgr5EGFP-IRES-CreERT2;Rosa26-tdTomato小鼠的大脑切片的共聚焦图像,该小鼠左眼注射了AAV-DIO-EGFP,右眼注射了AAV-DIO-TFs。大多数再生的RGC轴突投射到大脑的对侧(左侧),一小部分投射到同侧(右侧)。呈现的大脑视觉区域是紧随视交叉(g)、视轨(h)、dLGN、vLGN和投射到顶盖前区(i)、dLGN(j)和SC(k)之后的视轨。l-n,SC神经元的光诱发突触后反应,包括AMPA受体介导的EPSC(l)、NMDA受体介导的EPSC(n)和动作电位(n)。比例尺,在图d,j和k中=100μm,在图e和f中=200μm,在图g中=400μm,在图h和i中=600μm。
图7.Lgr5+无长突中间神经元的形态及其向神经节细胞层的迁移。a-c,在Lgr5EGFP -IRES-CreERT2;Rosa26-tdTomato小鼠中用tdTomato报告基因稀疏标记的Lgr5+无长突中间神经元的共聚焦图像。用tdTomato报告基因对Lgr5+无长突细胞进行稀疏标记是通过只用他莫昔芬喂养小鼠一次来实现的。图像取自平铺的视网膜样本,聚焦在Lgr5+无长突细胞所在的内核层。d,来自Lgr5EGFP-IRES-CreERT2;Rosa26-tdTomato小鼠的视网膜横截面的共聚焦图像。箭头突出显示用tdTomato报告基因标记的Lgr5+无长突细胞。该细胞的树突状突起到达神经节细胞层。e-g,来自Lgr5EGFP-IRES-CreERT2小鼠的平铺的视网膜样本的共聚焦图像,聚焦在神经节细胞层上。箭头突出显示神经节细胞层中Lgr5+无长突细胞的存在。g,20个月大的小鼠神经节细胞层中的一组Lgr5+无长突细胞。h,每个视网膜神经节细胞层中Lgr5+无长突细胞的数量。神经节细胞层中Lgr5+无长突细胞呈年龄依赖性增加,表明这些细胞可能从内核层迁移到神经节细胞层。比例尺,图a至c中=20μm,图d中=30μm,图e至f中=50μm。
图8.Lgr5EGFP-IRES-CreERT2;Rosa26-tdTomato小鼠中的神经元身份重编程。a,b,来自注射了AAV-DIO-EGFP的小鼠的视网膜平铺样本(a)和视神经(b)的代表性图像。在这些小鼠中未检测到tdTomato+轴突。c-e,注射高剂量AAV-DIO-EGFP(7x1012pfu,2μl)的小鼠视神经的代表性图像。由于AAV-DIO质粒在DNA扩增和病毒载体生产(翻转载体)过程中的自重组,当注入大量AAV粒子时,少量(个位数以内)原始RGC及其轴突可以通过不依赖Cre的转基因表达注射AAV-DIO-EGFP进行标记。然而,这些EGFP+轴突不表达tdTomato,表明它们不是来自再生的RGC。f-h,突出显示的Lgr5-EGFP和tdTomato双阳性细胞存在于内丛状层(IPL)中,表明编程触发了Lgr5+无长突细胞从内核层(INL)迁移到视网膜神经节层(RGL)。i-l,再生的RGC表达α-RGC标记SMI-32的共聚焦图像。m-r,玻璃体内注射AAV-DIO-tdTomato的Lgr5EGFP-IRES-CreERT2小鼠视网膜横截面的共聚焦图像,以检查AAV递送基因表达的特异性和效率。在5次他莫昔芬喂养后,AAV递送的tdTomato基因特异性标记Lgr5+无长突细胞。p-r,从图m至o的同一只眼睛拍摄的更高放大率图像。s,图m至r中EGFP+/tdTomato+细胞的统计数据。使用该表达系统,大约21.3%的Lgr5+无长突细胞可以被AAV递送的tdTomato标记。t,玻璃体内注射AAV-DIO-Brn3B和AAV-DIO-Sox4的Lgr5EGFP-IRES-CreERT2;Rosa26-tdTomato小鼠中Brn3B和Sox4表达水平的统计。通过定量PCR测量Brn3B和Sox4表达,并在玻璃体内注射AAV-DIO-EGFP的对照小鼠中归一化为1。比例尺,在图a中=150μm,在图b中=200μm,在图c至e中=300μm,在图f至l中=40μm,在图o中=400μm,在图r中=50μm。
图9.再生的RGC将轴突生长至离散的大脑视觉区域所花费的时间。在一只眼睛中对Lgr5EGFP-IRES-CreERT2;Rosa26-tdTomato小鼠玻璃体内注射AAV-DIO-Brn3B和AAV-DIO-Sox4,随后喂食莫昔芬5次以激活基因表达。在不同时间点处死小鼠以制备大脑切片,并通过共聚焦显微镜检查tdTomato+轴突的存在。a,病毒注射后30天处死的小鼠的大脑切片的共聚焦图像。对侧脑侧(图中左侧)中的tdTomato+轴突已穿过外侧膝状体核。在同一张大脑载玻片的同侧未检测到tdTomato+轴突。b,来自与图a中相同的小鼠的上丘(SC)区域的共聚焦图像。此时没有tdTomato+轴突到达SC。c,病毒注射后35天处死的小鼠大脑切片的共聚焦图像。突出显示的是LGN后部(外侧膝状体核)和对侧脑侧中SC前部(图片左侧)的区域。tdTomato+轴突也可以在同侧大脑侧检测到,但数量显著降低。d,再生的RGC轴突投射的时间过程。再生的RGC轴突到达OC(视交叉)、LGN和SC所需的时间是通过计算病毒注射后在这些位置首次观察到再生的RGC轴突的时间来确定的。再生的RGC轴突大约在第18天达到OC,在第28天达到LGN,在第35天达到SC(每组n=8)。
图10.Prokr2敲入小鼠品系的构建和在体内将Prokr2+置换的无长突中间神经元重编程为RGC。a,制作Prokr2CreERT2小鼠品系的靶向策略图。CreERT2编码区被敲入Prokr2基因座的起始密码子。标记了靶向5'臂和CreERT2区域的Southern印迹探针的位置。b,带有5'臂探针(上)和CreERT2探针(下)的Southern印迹膜的图像。新群体建立者1、2、3和4具有正确的基因组靶向,并被用于进一步的育种。c-e,来自具有抗RBPMS抗体的Prokr2CreERT2;Rosa26-tdTomato小鼠的视网膜横截面的免疫组织学染色。Prokr2-tdTomato+细胞不表达RGC标记RBPMS。f-h,Prokr2CreERT2;Rosa26-tdTomato小鼠的脑冠状切片(f)、上丘(g)和视神经(h)的共聚焦图像。Prokr2-tdTomato+细胞存在于大脑和视神经中。i,j,玻璃体内注射AAV-DIO-EGFP的Prokr2CreERT2小鼠的图像。由于AAV-DIO质粒在DNA扩增和病毒载体生产过程中的自重组,翻转的AAV-DIO-EGFP载体标记非常少的原始视网膜神经节细胞(i)及其轴突(j)。k,Prokr2CreERT2小鼠的重编程策略和AAV表达载体图。在第1天(D1)向小鼠玻璃体内注射AAV,随后喂食他莫昔芬(TM)以激活由Cre依赖性AAV-DIO系统在D3至D7递送的基因的表达。在D42或以后处死小鼠进行分析。l,转录因子组合的重编程效率。在对照组中,翻转的AAV-DIO-EGFP标记的内源性RGC很少。比例尺,图d中=40μm,图f中=800μm,图g中=200μm,图h中=100μm,图i中=1000μm,图j中=100μm。
图11.RGC的钙成像和光遗传学分析。a,体内钙成像设置示意图。b,SC区域中再生的RGC末端的代表性图像。c,3只小鼠中记录的所有响应末端的定向选择指数(OSI)的直方图分布。d,图c中显示的所有末端数据的OSI累积百分比图。e、f,其RGC被ChR2标记的C57B6/J小鼠的SC神经元中光诱发的突触后AMPA受体反应(e)和突触后动作电位(f)的代表性EPSC。比例尺=10μm。
图12.损伤原始RGC后的体内重编程。Pvalb在RGC的某些亚型中表达,因此,PvalbCreERT2;Rosa26-tdTomato小鼠用于建立眼压升高(IPI)引起的损伤RGC及其轴突的状况。a,来自PvalbCreERT2;Rosa26-tdTomato小鼠的视神经共聚焦图像。Pvalb-tdTomato+RGC的轴突是完整的。b,在眼压升高(IPI)造成损伤后7天,来自PvalbCreERT2;Rosa26-tdTomato小鼠的视神经共聚焦图像。所有轴突都被IPI损伤。c-e,来自PvalbCreERT2;Rosa26-tdTomato小鼠的视网膜平铺样本的共聚焦图像。Pvalb-tdTomato在未受损的正常小鼠中标记RGC及其轴突(c)。眼内压升高(IPI)引起的损伤7天后,小鼠视网膜中的Pvalb-tdTomato+RGC急剧减少(d)。瑞帕舒地尔治疗减缓了Pvalb-tdTomato+RGCs的退化,但幸存的RGC仍然没有完整的轴突(e)。f,通过IPI损伤原始的RGC后的Lgr5EGFP-IRES-CreERT2;Rosa26-tdTomato小鼠体内神经元重编程图。首先给Lgr5EGFP-IRES-CreERT2;Rosa26-tdTomato小鼠喂食他莫昔芬(TM)五次(从第-11天(D-11)到第-7天(D-7)),用Rosa26-tdTomato报告基因标记Lgr5+无长突中间神经元,以协助身份追踪。一周后,在D1小鼠的RGC及其轴突因眼压升高而受损。小鼠在D7接受玻璃体内注射表达Cre依赖性转录因子的AAV,并从D9到D13喂食他莫昔芬(TM)以激活基因表达。在D49或之后处死小鼠进行分析。为了保护Lgr5+无长突中间神经元和其他视网膜神经元,从D1到D49,每天用瑞帕舒地尔滴眼液治疗小鼠。比例尺=100μm。
图13.视网膜平铺样本和视神经的共聚焦图像。a)PV-CreERT2;Rosa26-tdTomato小鼠视网膜平铺中的小清蛋白(pavalbumin)(PV)阳性RGC及其轴突。b)眼压升高后,许多RGC死亡,其轴突退化。c)Atoh7+Brn3B+Sox4在存活的RGC中的表达导致这些细胞再生/再生轴突。d)PV-CreERT2;Rosa26-tdTomato小鼠视神经中的PV阳性RGC轴突。e)眼压升高导致RGC损伤后,RGC的轴突在视神经内退化。F)在幸存的RGC中过表达Atoh7+Brn3B+Sox4后,视神经内再生的RGC轴突。
图14.将再生的RGC轴突投射到大脑视觉区域。a)背侧和腹外侧膝状体核中再生的RGC轴突。b)上丘核中再生的RGC轴突。
详细说明
定义
除非另有定义,本文使用的所有技术和科学术语具有与本领域普通技术人员通常理解的相同含义。如本文所用,除非另有说明,否则以下术语具有以下含义。与本文所述的那些相似或等效的任何方法、装置和材料都可以用于实践本文所述的组合物和方法。提供以下定义是为了便于理解本文经常使用的某些术语,并不意味着限制本公开的范围。本文提及的所有参考文献均通过引用整体纳入。
如本文所用,术语“包括”旨在表示组合物和方法包括所列举的元素,但不排除其他元素。当用于定义组合物和方法时,“基本上由...组成”应意味着排除对组合具有任何基本意义的其他元素。例如,基本上由本文定义的元素组成的组合物不排除不会实质影响要求保护的发明的基本和新颖特征的其他元素。“由……组成”是指不包括超过痕量的其他成分和所列举的实质性方法步骤。由这些过渡术语中的每一个定义的实施方案都在本发明的范围内。
术语“约”是指在给定值或范围的±10%、±5%或±1%内。在一个实施方案中,大约是指给定值或范围的±10%。在另一个实施方案中,大约是指给定值或范围的±5%。在另一个实施方案中,大约是指给定值或范围的±1%。
“表达控制序列”是指调节与其可操作连接的核苷酸序列的表达的核酸序列。当表达控制序列控制和调节核苷酸序列的转录和/或翻译时,表达控制序列与核苷酸序列“可操作地连接”。因此,表达控制序列可以包括启动子、增强子、内部核糖体进入位点(IRES)、转录终止子、蛋白质编码基因前面的起始密码子、内含子的剪接信号和终止密码子。术语“表达控制序列”旨在至少包括其存在旨在影响表达的序列,并且还可以包括额外的有利组分。例如,前导序列和融合伴侣序列是表达控制序列。该术语还可以包括核酸序列的设计,以便从序列中去除不希望的、潜在的框内和框外的起始密码子。它还可以包括核酸序列的设计,以便去除不希望的潜在剪接位点。它包括指导添加polyA尾的序列或多腺苷酸化序列(pA),即mRNA 3'端的一串腺嘌呤残基,其可称为polyA序列。它还可以设计用于增强mRNA稳定性。适用于昆虫细胞的影响转录和翻译稳定性的表达控制序列,例如启动子,以及影响翻译的序列,例如Kozak序列,是本领域技术人员熟知的。表达控制序列可以具有这样的性质,即调节与其可操作地连接的核苷酸序列,从而实现较低的表达水平或较高的表达水平。
如本文所用,术语“启动子”或“转录调控序列”是指起控制一种或多种编码序列转录作用的核酸片段,并且位于相对于编码序列的转录起始位点的转录方向的上游,并且在结构上通过存在DNA依赖性RNA聚合酶、转录起始位点和任何其他DNA序列的结合位点(包括但不限于转录因子结合位点、阻遏蛋白和激活蛋白结合位点)来鉴定,以及本领域技术人员已知的任何其他核苷酸序列,其直接或间接作用以调节从启动子的转录量,包括例如衰减子或增强子,但也包括沉默基因。“组成型”启动子是在大多数生理和发育条件下在大多数组织中具有活性的启动子。“诱导型”启动子是生理或发育调节的启动子,例如通过应用化学诱导剂。“组织特异性”启动子仅在特定类型的组织或细胞中具有活性。
“载体”是用于将过客核酸序列(即DNA或RNA)转移到宿主细胞中的核酸分子(通常是DNA或RNA)。三种常见的载体类型包括质粒、噬菌体和病毒。优选地,载体是病毒。包含启动子和克隆位点(其中多核苷酸可操作地连接到其中)两者的载体是本领域公知的。此类载体能够在体外或体内转录RNA,并且可从诸如Stratagene(La Jolla,Calif.)和PromegaBiotech(Madison,Wis.)等来源商购获得。为了优化表达和/或体外转录,去除、添加或改变克隆的5'和/或3'非翻译部分以消除额外的、潜在的不适当的替代翻译起始密码子或可能在转录或翻译水平上干扰或减少表达的其他序列可能是有用的。或者,可以在起始密码子的5'处紧接地插入共有核糖体结合位点以增强表达。
“病毒载体”是指包含以下部分或全部的载体:编码基因产物的病毒基因、控制序列和病毒包装序列。“细小病毒载体”定义为重组产生的细小病毒或细小病毒颗粒,其包含在体内、离体或体外待递送到宿主细胞中的多核苷酸。细小病毒载体的例子包括例如腺相关病毒载体。本文中,细小病毒载体构建体是指包含病毒基因组或其部分和转基因的多核苷酸。
术语“施用”是指将试剂引入患者。可以施用有效量,这可以由治疗医师等确定。当与化合物或片剂(和语法等同物)结合使用时,相关的术语和短语“施用(administering)”和“施用(administration of)”均指直接施用,其可以是由医学专业人员向患者施用或由患者自行施用。
“治疗有效量”或“有效量”是指药物或试剂的量,所述药物或试剂当通过本文所述的药物组合物局部施用至患有症状的患者时,将具有预期的治疗效果,例如缓解、改善、减轻或消除患者的病况的一种或多种症状。完全的治疗效果不一定立即发生,而可能仅在治疗有效量连续递送一段时间后发生。对于缓释或控释制剂,“治疗有效量”或“有效量”可以指在一段时间内有效的总量,其以可确定和可控的释放速率从递送运载体缓慢释放到疾病部位,该可确定和可控的释放速率不断向疾病部位提供有效量的药物。在一些实施方案中,“治疗有效量”或“有效量”是指在给定时间段例如每天释放到疾病部位的量。
术语“药学上可接受的”是指对人体施用通常是安全且无毒的。
“治疗(Treatment)”、“治疗(treating)”和“治疗(treat)”被定义为用试剂作用于疾病、病症或病况以减少或改善疾病、病症或病况和/或其症状的有害或任何不希望的效果。
从其他视网膜神经元细胞再生视网膜神经节细胞(RGC)
视网膜神经节细胞(RGC)及其轴突的退化引起青光眼和各种视神经病变中的视力丧失。目前没有可用于恢复受这些疾病影响的患者视力丧失的治疗方法。再生RGC并将视网膜重新连接到大脑展示了一种理想的治疗策略;然而,哺乳动物没有准备在成年期产生新神经元的视网膜干/祖细胞库。
在随附的实验示例中证明了RGC可以通过视网膜神经元的直接谱系重编程来再生。无长突和置换的无长突中间神经元成功转化为RGC,其将轴突投射到大脑视网膜受体区域。它们将视觉信息传递到大脑以响应视觉刺激,并能够在正常动物和青光眼动物模型中将电信号传输到突触后神经元,在青光眼动物模型中原始RGC已因眼内压升高而受损。
因此,根据本公开的一个实施方案,提供了一种重编程非RGC神经元细胞以变得对视觉信号有响应的方法。在一个实施方案中,重编程需要激活非RGC神经细胞中的一种或多种转录因子(或增加其生物学活性)。在一些实施方案中,转录因子是原神经转录因子。
示例转录因子是POU结构域转录因子,例如Brn3B。Brn3B(POU4类同源框2,或POU4F2、BRN3.2,或Brn-3b)是POU结构域转录因子家族的成员,并参与维持视网膜中的视觉系统神经元。人的代表性Brn3B基因具有蛋白质序列NP_004566.2和mRNA序列NM_004575.3。小鼠的代表性Brn3B基因具有蛋白质序列NP_620394.2和mRNA序列NM_138944.3。
另一个示例转录因子是SOX(SRY-相关HMG-框)转录因子,例如Sox4。Sox4(SRY-框转录因子4,或CSS10或EVI16)是SOX(SRY相关HMG-框)转录因子家族的成员,并参与胚胎发育的调节和细胞命运的确定。人的代表性Sox4基因具有蛋白质序列NP_003098.1和mRNA序列NM_003107.3。小鼠的代表性Sox4基因具有蛋白质序列NP_033264.2和mRNA序列NM_009238.3。
SOX(SRY-相关HMG-框)转录因子家族的另一个示例成员是Sox11。Sox11(SRY-框转录因子11,或CSS9或MRD27)是SOX(SRY相关HMG-框)转录因子家族的成员,并参与胚胎发育的调节和细胞命运的确定。人的代表性Sox11基因具有蛋白质序列NP_003099.1和mRNA序列NM_003108.4。小鼠的代表性Sox11基因具有蛋白质序列NP_033260.4和mRNA序列NM_009234.6。
另一个示例转录因子是碱性螺旋环螺旋转录因子,例如Atoh7。Atoh7(atonalbHLH转录因子7,或Math5、NCRNA、RNANC、PHPVAR或bHLHa13)是转录因子的碱性螺旋-环-螺旋家族的成员,并控制光感受器的发育。该基因在视网膜神经节细胞和视神经形成中起核心作用。人的代表性Atoh7基因具有蛋白质序列NP_660161.1和mRNA序列NM_145178.4。小鼠的代表性Atoh7基因具有蛋白质序列NP_058560.1或NP_001351577.1和mRNA序列NM_016864.3或NM_001364648.2。
另一个示例转录因子是LIM/同源结构域转录因子,例如Ils1。Ils1(ISL LIM同源框1,或Isl-1或ISLET1)是转录因子的LIM/同源结构域家族的成员,与胰岛素基因的增强子区域等结合,可能在调节胰岛素基因表达中起重要作用。Ils1是胰腺细胞谱系发育的核心,是运动神经元生成所必需的。人的代表性Ils1基因具有蛋白质序列NP_002193.2和mRNA序列NM_002202.3。小鼠的代表性Ils1基因具有蛋白质序列NP_067434.3和mRNA序列NM_021459.4。
这些示例性转录因子的示例性蛋白质和核酸序列在下表1中提供。
表1示例序列
增加基因的生物学活性的方法是本领域已知的。增加的生物学活性可以是增加的蛋白质的表达或增加的蛋白质的功能,或两者兼而有之。
在一些实施方案中,至少一种转录因子在细胞中被激活。在一个实施方案中,Brn3B的生物学活性增加。在一个实施方案中,Sox4的生物学活性增加。在一个实施方案中,Atoh7的生物学活性增加。在一个实施方案中,Sox11的生物学活性增加。在一个实施方案中,Ils1的生物学活性增加。
在一些实施方案中,至少两种转录因子的生物学活性增加。这两种可能是Brn3B和Sox4,Brn3B和Atoh7,Brn3B和Sox11,Brn3B和Ils1,Sox4和Atoh7,Sox4和Sox11,Sox4和Ils1,Atoh7和Sox11,Atoh7和Ils1,或Sox11和Ils1。
在一些实施方案中,至少三种转录因子的生物学活性增加。这三种可以是Brn3B、Sox4和Atoh7、Brn3B、Sox4和Sox11,或Brn3B、Sox4和Ils1,但不限于此。在一些实施方案中,至少四种转录因子的生物学活性增加。在一些实施方案中,所有五种转录因子的生物学活性增加。
内源性转录因子的激活
在一个实施例中,相应内源基因的表达被激活或增强。例如,人类巨细胞病毒(CMV)增强子/启动子(被称为CMV)是具有高转录活性的天然哺乳动物启动子。CMV增强子是多种哺乳动物细胞中的强增强子,已广泛用于驱动多种哺乳动物细胞中各种基因的异位表达,以及驱动转基因动物广泛组织中外源基因的异位表达。在一些实施例中,CMV增强子的转录活性可以通过将天然NF-κB结合位点改变为人工选择的具有高结合亲和力的NF-κB结合序列来进一步提高(Wang等人,Protein Expression and Purification 142:16-24,2018)。美国专利号10329595还报道了两种改进的CMV启动子(SEQ ID NO:26和27)的产生。其他有用的基因启动子和增强子也是本领域已知的。
在一些实施方案中,启动子或增强子是调节在神经元中持续表达的基因表达的启动子或增强子。在神经元(例如无长突细胞)中表达的示例基因包括Pax6、Tcfap2b、Gad1、GlyT1、RBPMS和Prox1。另一个示例基因是突触蛋白1。示例启动子/增强子在表2中提供。
表2示例启动子/增强子
基因表达启动子或增强子可以通过常规敲入技术或CRISPR方法引入靶基因。
还有大量基于CRISPR的基因激活技术。在一个实施例中,一种无活性的Cas蛋白(例如,Cas9)与适当的转录效应结构域融合。常用的转录激活结构域包括VP64、NF-κB的p65域、EB病毒R反式激活因子(Rta)和热休克因子1(HSF1)的激活结构域。在内源性环境中,多个转录因子和辅因子同步工作以刺激基因转录。事实上,将多个独特的转录激活因子招募到启动子的CRISPR工具优于那些带有单个转录激活因子结构域或相同效应子的冗余拷贝的工具。靶向同一启动子上的多个位点也增加了CRISPR的基因激活。最有效的CRISPR效应子之一是CRISPR协同激活介导因子(SAM)复合物,它将三个独特的转录激活子结构域招募到靶基因启动子。在该系统中,一个转录激活因子VP64(VP16的多聚体形式)直接融合到dCas9。
在另一个实施例中,dCas9-p300 CRISPR基因激活系统(Signa Aldrich,Hilton,Isaac B.,等Nature Biotechnology(2015))基于dCas9与人类E1A相关蛋白p300的催化组蛋白乙酰转移酶(HAT)核心结构域的融合。这种方法在相对于转录起始位点(TSS)的近端和远端位置激活基因。
外源转录因子的引入
增加转录因子的生物学活性(或表达)的更常规技术是引入编码转录因子或转录因子蛋白的外源序列。可以通过将蛋白质封装在运载体(例如脂质体)中来将蛋白质引入细胞中。转录因子的示例蛋白质序列在表1中提供。
编码序列,例如cDNA或mRNA,也可以被引入靶细胞。转录因子的示例编码序列在表1中提供。在一些实施方案中,制备包括一种或多种这些转录因子的编码序列的核酸构建体。编码序列可以与合适的启动子或增强子功能性连接。在一些实施方案中,启动子或增强子对靶细胞是特异性的,例如视网膜中间神经元。表2中提供了示例启动子。
构建体可以是质粒,或者优选地是病毒载体。合适的病毒载体包括慢病毒载体和AAV载体。
本文中的“重组腺相关病毒(AAV)载体”(或“rAAV载体”)是指包含一个或多个目标多核苷酸序列、目标基因产物、目标基因或“转基因”的载体,该目标基因或转基因侧翼为至少一种细小病毒或AAV反向末端重复序列(ITR)。当存在于表达AAV rep和cap基因产物(即AAV Rep和Cap蛋白)的昆虫宿主细胞中时,此类rAAV载体可以被复制并包装成感染性病毒颗粒。当rAAV载体被整合到更大的核酸构建体中(例如,在染色体中或在另一个载体中,例如用于克隆或转染的质粒或杆状病毒),那么rAAV载体通常被称为“前载体”,其在存在AAV包装功能和必要的辅助功能的情况下,可以通过复制和封装来“拯救”。优选地,目标基因产物的两侧是AAV ITR。任何AAV ITR均可用于本发明的构建体,包括来自AAV1、AAV2、AAV3、AAV4、AAV5、AAV6、AAV7、AAV8、AAV9、AAV10、AAV11和/或AAV12的ITR。
用于本技术的AAV基因治疗载体可以在哺乳动物细胞或昆虫细胞中产生。两种方法均在本领域中描述。例如,Grimm等人(2003Molecular Therapy 7(6):839-850)公开了一种以无辅助病毒且光学可控的方式产生AAV载体的策略,其基于仅将两种质粒转染到293T细胞中。他们公开了一种生产包含AAV2 ITR和AAV5衣壳蛋白的杂合AAV载体的方法。更多信息也可以在Blits等人(2010)(Journal of Neuroscience methods 185(2):257-263)中找到。术语“杂交”和“假分型”在本文中可互换使用,用于表示Rep蛋白、ITR和/或衣壳蛋白具有不同血清型的载体。例如,ITR和Rep蛋白属于AAV2,衣壳蛋白属于AAV5。术语“嵌合”在本文中用于描述单个基因,例如衣壳,由至少两个衍生自不同血清型的序列组成。
AAV可以例如根据以下方法在哺乳动物细胞中产生,但不限于此:载体基因组包含转基因表达盒,侧翼是衍生自AAV血清型2的两个反向末端重复(ITR)。为了保持高效的包装效率,病毒载体基因组的总长度不得超过4.7kB的野生型基因组大小。单个衣壳由比例为1:1:10的VP1(62kDa)、VP2(73kDa)或VP3(87kDa)的60种病毒蛋白组成。AAV载体的制造过程基于将两种质粒Ca(PO4)2转染到滚瓶(850cm2表面积)中的人胚胎肾生产细胞(HEK293)中,然后通过过滤和层析技术纯化衣壳化的载体基因组。第一质粒是病毒载体质粒并且包含侧翼为AAV2 ITR的表达构建体。第二质粒是包装质粒并且编码所需血清型的AAV rep 2型和cap5型基因以及腺病毒早期辅助基因E2A、VA、E4(pDP5)。生产细胞系的基因组包含腺病毒E1以提供辅助功能。在含有10%胎牛血清(FCS)的Iscove’s Modified Dulbecco’s Medium(IMDM)中用两种质粒共转染后,将细胞在无血清Dulbecco’s modified Eagle's medium(DMEM)中培养三天以进行载体生产。平均而言,在滚瓶中产生的载体产生每个细胞3×103个载体基因组或每个滚瓶4×1011个载体基因组的产量(通过qPCR量化)。随后,细胞培养物通过含有Triton-X-100的缓冲液裂解,并通过低速离心去除细胞碎片。澄清的块状物(bulk)通过AVB Sepharose亲和层析纯化,并使用400kDa中空纤维模块(例如来自SpectrumLaboratories)通过浓缩和渗滤配制成PBS/5%蔗糖。
可以在本发明中用于在昆虫细胞中产生rAAV载体的AAV ITR和Rep序列可以来源于任何AAV血清型的基因组。通常,AAV血清型在氨基酸和核酸水平上具有显著同源性的基因组序列。这提供了一组相同的遗传功能来产生在物理和功能上基本相同的病毒粒子。对于各种AAV血清型的基因组序列和基因组相似性的综述,参见例如GenBank登录号U89790;GenBank登录号J01901;GenBank登录号AF043303;GenBank登录号AF085716;Chiorini等人(1997,J.Vir.71:6823-33);Srivastava等人(1983,J.Vir.45:555-64);Chiorini等人(1999,J.Vir.73:1309-1319);Rutledge等人(1998,J.Vir.72:309-319);和Wu等人(2000,J.Vir.74:8635-47)。rAAV血清型1、2、3、4和5是用于本发明上下文的AAV核苷酸序列的优选来源。优选地,用于本发明上下文的AAV ITR序列源自AAV1、AAV2和/或AAV5。更优选地,用于本发明的ITR序列是AAV2 ITR。同样,Rep(Rep78/68和Rep52/40)编码序列优选地源自AAV1、AAV2和/或AAV5,更优选AAV2。
AAV Rep和ITR序列在大多数血清型中特别保守。各种AAV血清型的Rep78蛋白具有例如超过89%的同一性,并且在AAV2、AAV3A、AAV3B和AAV6之间的基因组水平上的总核苷酸序列同一性约为82%(Bantel-Schaal等,1999,J.Virol.,73(2):939-947)。此外,已知许多AAV血清型的Rep序列和ITR在哺乳动物细胞中产生AAV颗粒时可有效地交叉互补(即功能替代)来自其他血清型的相应序列。US2003148506报道称,AAV Rep和ITR序列还可以有效地交叉互补昆虫细胞中的其他AAV Rep和ITR序列。
已知AAV VP蛋白可确定AAV病毒粒子的细胞嗜性(tropicity)。在不同的AAV血清型中,VP蛋白编码序列的保守性明显低于Rep蛋白和基因。用于本发明上下文的编码病毒蛋白(VP)VP1、VP2和VP3衣壳蛋白的序列源自AAV5。最优选地,VP1、VP2和VP3是AAV5 VP1、VP2和VP3。或者,VP1、VP2和VP3是野生型AAV5序列。Rep和ITR序列交叉互补其他血清型的相应序列的能力允许产生包含一种血清型的衣壳蛋白和另一种AAV血清型的ITR序列的假型rAAV颗粒。这种假型rAAV颗粒是本发明的一部分。
每种AAV血清型可能更适合一种或多种特定组织。例如,AAV2、AAV3、AAV4、AAV5、AAV7和AAV8可能适用于视网膜;AAV1、AAV2、AAV4、AAV5、AAV7和AAV10可能适用于神经元;AAV2、AAV4、AAV8和AAV9可能适用于大脑;AAV3、AAV5、AAV6、AAV9和AAV10可能适用于肺;AAV1、AAV6、AAV9和AAV10可能适用于心脏;AAV2、AAV3和AAV6-10可能适用于肝脏;除AAV5外的所有血清型都可能适用于肌肉组织;AAV2和AAV10可能适用于肾脏;以及AAV1、AAV7和AAV9可能适用于胰腺。
在一个实施方案中,AAV是血清型AAV2。在一个实施方案中,AAV是血清型AAV3。在一个实施方案中,AAV是血清型AAV4。在一个实施方案中,AAV是血清型AAV5。在一个实施方案中,AAV是血清型AAV7。在一个实施方案中,AAV是血清型AAV8。
在一些实施方案中,AAV载体是AAV2.7m8载体,其是在腺相关病毒(AAV)表面可变区VIII(VR-VIII)中具有10个氨基酸插入的工程化衣壳,导致AAV2的抗原区的改变和玻璃体内施用后有效转导视网膜细胞的能力(Bennett等人,J Struct Biol,2020年2月1日;209(2):107433.doi:10.1016/j.jsb.2019.107433.Epub 2019年12月16日)。在一些实施方案中,AAV载体是从八种不同的野生型天然病毒改组改造而来的AAV-DJ(2型/8型/9型嵌合体)(Katada Y等人,2019.PeerJ 7:e6317)。在一些实施方案中,AAV载体是AAV7m8载体(Ramachandran等人,Hum Gene Ther.2017年2月;28(2):154-167.doi:10.1089/hum.2016.111.Epub 2016年10月17日)。
靶细胞
可以用视网膜中的非RGC细胞进行重编程,例如任何不是RGC的视网膜神经元。在一些实施方案中,这样的视网膜神经元是中间神经元细胞。中间神经元细胞的例子是无长突细胞、双极细胞和水平细胞。在一些实施方案中,非RGC细胞是光感受器。此外,在一些实施方案中,非RGC细胞可以是穆勒细胞。
在一些实施方案中,无长突细胞是Lgr5+无长突细胞。在一些实施方案中,无长突细胞是Prokr2+置换的无长突细胞。在一些实施方案中,无长突细胞是Lgr5+无长突细胞,并且Brn3B和Sox4两者的生物学活性(表达)在Lgr5+无长突细胞中增加。在一些实施方案中,无长突细胞是Prokr2+置换的无长突细胞,并且Brn3B和Sox4两者的生物学活性(表达)在Prokr2+置换的无长突细胞中增加。在一些实施方案中,无长突细胞是Prokr2+置换的无长突细胞,并且所有Brn3B、Sox4和Atoh7的生物学活性(表达)在Prokr2+置换的无长突细胞中增加。
靶细胞可以在体外或体内重编程。在体外重编程中,细胞被转化为再生的RGC,其可被植入有需要的受试者体内。当在体内被重编程时,再生的RGC可以替代受损或退化的RGC,从而治疗视力障碍或失明。
视网膜神经节细胞(RGC)的再生
在另一个令人惊讶的发现中,本发明人展示本公开的转录因子的激活在重新激活的受损的RGC中也是有效的(实施例2)。重新激活的RGC能够再生功能性轴突,这些轴突投射到视神经并与大脑相连。
因此,本发明的另一实施方案提供一种改善视网膜神经节细胞(RGC)功能的方法。RGC可能是退化的、受损的、老化的,甚至是需要改善功能的正常/健康的RGC。在一些实施方案中,该方法需要在RGC中增加一种或多种选自由Atoh7、Brn3B、Sox4、Sox11和Ils1组成的组的基因的生物学活性。
增加基因的生物学活性的方法是本领域已知的。增加的生物学活性可以是增加的蛋白质的表达或增加的蛋白质的功能,或两者兼而有之。
在一些实施方案中,至少一种转录因子在细胞中被激活。在一个实施方案中,Brn3B的生物学活性增加。在一个实施方案中,Sox4的生物学活性增加。在一个实施方案中,Atoh7的生物学活性增加。在一个实施方案中,Sox11的生物学活性增加。在一个实施方案中,Ils1的生物学活性增加。
在一些实施方案中,至少两种转录因子的生物学活性增加。这两种可能是Brn3B和Sox4,Brn3B和Atoh7,Brn3B和Sox11,Brn3B和Ils1,Sox4和Atoh7,Sox4和Sox11,Sox4和Ils1,Atoh7和Sox11,Atoh7和Ils1,或Sox11和Ils1。
在一些实施方案中,至少三种转录因子的生物学活性增加。这三种可以是Brn3B、Sox4和Atoh7、Brn3B、Sox4和Sox11,或Brn3B、Sox4和Ils1,但不限于此。在一些实施方案中,至少四种转录因子的生物学活性增加。在一些实施方案中,所有五种转录因子的生物学活性增加。
上文更详细地描述了用于激活内源转录因子和引入外源转录因子的示例方法。该方法可以是体外的或体内的。
组合物和再生/恢复活力的细胞
还提供了可以促进本公开的技术的实施的试剂、试剂和组合物。在一些实施方案中,还提供了通过本技术再生或恢复活力的RGC细胞。
本公开的一个实施方案提供了一种核酸构建体,该构建体可以被引入靶细胞中用于所需的细胞重编程。在一些实施方案中,核酸构建体包括编码任何一种、两种、三种、四种或所有本文公开的转录因子的编码序列。在一个实施方案中,核酸构建体包括Brn3B的编码序列。在一个实施方案中,核酸构建体包括Sox4的编码序列。在一个实施方案中,核酸构建体包括Atoh7的编码序列。在一个实施方案中,核酸构建体包括Sox11的编码序列。在一个实施方案中,核酸构建体包括Ils1的编码序列。这些转录因子的示例蛋白和编码序列在表1中提供。
在一个实施方案中,核酸构建体包括至少两种转录因子的编码序列,这些转录因子可以是Brn3B和Sox4、Brn3B和Atoh7、Brn3B和Sox11、Brn3B和Ils1、Sox4和Atoh7、Sox4和Sox11、Sox4和Ils1、Atoh7和Sox11、Atoh7和Ils1,或Sox11和Ils1。在一些实施方案中,核酸构建体包括至少三种转录因子的编码序列,所述转录因子可以是Brn3B、Sox4和Atoh7、Brn3B、Sox4和Sox11,或Brn3B、Sox4和Ils1,但不限于此。在一些实施方案中,核酸构建体包括至少四种转录因子的编码序列。在一些实施方案中,核酸构建体包括所有五种转录因子的编码序列。
在一些实施方案中,核酸构建体包括与每个编码序列相关的启动子或增强子。启动子或增强子在视网膜中间神经元细胞中是有活性的。非限制性实例是Pax6、Tcfap2b、Gad1、GlyT1、RBPMS和Prox1的启动子,或表2中提供的那些。在具体的实施例中,启动子是突触蛋白1启动子。
在一些实施例中,核酸构建体包括表达载体,其可以是质粒载体或病毒载体,例如AAV载体。AAV可以选自由AAV1、AAV2、AAV3、AAV4、AAV5、AAV6、AAV7、AAV8、AAV9、AAV10、AAV11和AAV12组成的组。
在一个实施方案中,AAV是血清型AAV2。在一个实施方案中,AAV是血清型AAV3。在一个实施方案中,AAV是血清型AAV4。在一个实施方案中,AAV是血清型AAV5。在一个实施方案中,AAV是血清型AAV7。在一个实施方案中,AAV是血清型AAV8。
在一些实施方案中,AAV载体是AAV2.7m8载体,其是在腺相关病毒(AAV)表面可变区VIII(VR-VIII)中具有10个氨基酸插入的工程化衣壳,导致AAV2的抗原区的改变和玻璃体内施用后有效转导视网膜细胞的能力(Bennett等人,J Struct Biol,2020年2月1日;209(2):107433.doi:10.1016/j.jsb.2019.107433.Epub 2019年12月16日)。在一些实施方案中,AAV载体是从八种不同的野生型天然病毒改组改造而来的AAV-DJ(2型/8型/9型嵌合体)(Katada Y等人,2019.PeerJ 7:e6317)。在一些实施方案中,AAV载体是AAV7m8载体(Ramachandran等人,Hum Gene Ther.2017年2月;28(2):154-167.doi:10.1089/hum.2016.111.Epub 2016年10月17日)。
还提供了用载体转染的细胞,以及通过本技术重编程或再生的细胞。在一个实施方案中,提供了对视觉信号有反应的哺乳动物细胞。在一个实施方案中,通过增加本文公开的一种或多种基因在视网膜细胞(例如视网膜中间神经元细胞)或退化的、损伤的或老化的RGC中的生物学活性来制备细胞。在另一个实施方案中,视网膜细胞是穆勒细胞。在又一个实施方案中,视网膜细胞是光感受器。在一些实施方案中,重编程的细胞是再生的视网膜神经节细胞(RGC)。在一些实施方案中,重编程的细胞是恢复活力的视网膜神经节细胞(RGC)。
在一些实施方案中,再生或恢复活力的RGC可以将轴突投射到离散的皮层下脑区。在一些实施方案中,再生或恢复活力的RGC可以建立视网膜-大脑连接。在一些实施方案中,再生或恢复活力的RGC可以响应视觉刺激并将电信号传输到大脑中。
在一些实施方案中,哺乳动物细胞是动物细胞。在一些实施方案中,哺乳动物细胞是人细胞。
治疗和用途
RGC的缺失是一组被广泛归类为视神经病变的疾病中失明的主要原因,这些疾病包括青光眼、遗传性视神经病变以及由毒素、营养缺陷和创伤引起的疾病。因此,本技术可用于治疗视力障碍或视力丧失(失明)。
在一些实施方案中,治疗或使用需要向患者(例如,进入患者的视网膜或瞳孔)施用能够增加本文公开的一种或多种基因的生物学活性的试剂,例如Brn3B、Sox4、Atoh7、Sox11和Ils1。在一些实施方案中,至少两种转录因子的生物学活性增加。这两种可能是Brn3B和Sox4,Brn3B和Atoh7,Brn3B和Sox11,Brn3B和Ils1,Sox4和Atoh7,Sox4和Sox11,Sox4和Ils1,Atoh7和Sox11,Atoh7和Ils1,或Sox11和Ils1。在一些实施方案中,至少三种转录因子的生物学活性增加。这三种可以是Brn3B、Sox4和Atoh7、Brn3B、Sox4和Sox11,或Brn3B、Sox4和Ils1,但不限于此。在一些实施方案中,至少四种转录因子的生物学活性增加。在一些实施方案中,所有五种转录因子的生物学活性增加。
上面已经讨论了示例性试剂,例如将启动子或增强子引入一种或多种相应的内源性转录因子(例如,CRISPR系统)的核酸构建体,编码一种或多种转录因子和转录因子的被表达的蛋白质的核酸构建体。
施用可以是局部应用、眼科应用或玻璃体内注射,但不限于此。
在一些实施方案中,试剂是AAV载体或包括AAV载体的药物组合物。在一些实施方案中,施用的AAV载体或药物组合物可以是从1×106至1×1020基因组拷贝(gc)/kg,或从1×107至1×1020,或从1×108至1×1020,或从1×108至1×1019,或从1×109至1×1019,或从1×109至1×1018,或从1×1010至1×1018,或从1×1011至1×1017,或从1×1012至1×1017,或从1×1013至1×1016,2×1013至2×1015,8×1013到6×1014gc/kg受试者体重。需要注意的是,剂量值可能随着要缓解的病症的严重程度而变化。对于任何特定的受试者,可以根据个体需要和施用或监督组合物施用的人的专业判断随时间调整具体的剂量方案。本文所述的剂量范围仅是示例性的,并不限制医学从业者可以选择的剂量范围。
在一些实施方案中,治疗需要将本文公开的重编程的视网膜细胞(例如,再生的RPC)植入患者的眼睛中,其中视网膜(retain)细胞在体外被重编程。
实施例
实施例1视网膜中间神经元细胞的重编程
这个实施例表明,其他视网膜神经元可以用作视网膜神经节细胞再生的内源细胞来源。通过对RGC分化重要的转录因子的异位表达,无长突和置换的无长突中间神经元可以重编程为RGC。再生的RGC将轴突投射到离散的皮层下大脑区域。它们对视觉刺激作出反应并能够将电信号传输到大脑中,无论是在正常条件下还是在青光眼动物模型中,其中原始RGC已因眼内压升高而受损。
方法
小鼠和饲养。Lgr5EGFP-IRES-CreERT2敲入小鼠品系、PvalbCreERT2敲入小鼠品系和Rosa26-tdTomato报告基因小鼠品系从杰克逊实验室获得。Lgr5EGFP-IRES-CreERT2小鼠和PvalbCreERT2小鼠与Rosa26-tdTomato小鼠杂交分别产生Lgr5EGFP-IRES-CreERT2;Rosa26-tdTomato小鼠和PvalbCreERT2;Rosa26-tdTomato小鼠。
Prokr2CreERT2小鼠品系是使用CRISPR/Cas9技术通过同源重组产生的。简而言之,将体外转录的Cas9 mRNA、sgRNA和供体载体质粒混合并注射到来自C57BL/6J小鼠的受精卵的原核中。供体载体质粒被设计为将随后是PolyA序列的CreERT2的编码区插入Prokr2基因座的ATG起始密码子。注射的受精卵培养至胚泡期3.5天,随后转移至假孕雌性的子宫中。具有正确基因组靶向的F0小鼠进一步与C57BL/6J小鼠杂交以产生F1Prokr2CreERT2小鼠。Prokr2CreERT2小鼠与Rosa26-tdTomato小鼠杂交以产生Prokr2CreERT2;Rosa26-tdTomato小鼠。Prokr2翻译起始位点周围的DNA序列为: (SEQ ID NO:23)。翻译起始位点以粗体显示,使用的sgRNA的靶序列用下划线突出显示。供体载体质粒包含5'4kb同源臂、CreERT2-polyA盒和用融合(In-Fusion)克隆方法构建的3'4kb同源臂。
所有小鼠都被安置在具有12小时光照/12小时黑暗循环的动物设施中。动物实验在8-12个月大的雄性和雌性小鼠中进行,所有动物实验程序均经上海科技大学动物护理与使用委员会批准。
AAV载体的构建和生产。将小鼠Atoh7、Brn3B、Sox4、Sox11、Ils1和EGFP的编码序列亚克隆到CAG驱动的Cre依赖性表达载体(Addgene#22222)中,替换原来的Arch-GFP序列。为了从单个AAV载体共表达转录因子和EGFP,将P2A片段放置在两个编码序列之间。
对于AAV病毒颗粒的生产,使用PEI用AAV转基因质粒、pAAV7m8血清型质粒和pHelper质粒转染HEK293T细胞。48-72小时后收集细胞。用碘克沙醇密度梯度离心纯化病毒颗粒,并通过qPCR滴定。
玻璃体内AAV注射。通过腹腔注射氯胺酮(80mg/kg)和甲苯噻嗪(8mg/kg)的混合物对小鼠进行麻醉,并通过局部施用盐酸苯肾上腺素滴眼液(2.5%)扩大其瞳孔。用0.5%盐酸丙美卡因滴眼液进行短暂局部麻醉后,进行角膜穿刺以降低眼压,并用34号针头将1.5ulAAV病毒颗粒注入玻璃体空间。对于AAV混合物的注射,在混合之前,首先将每种AAV稀释至1x1012颗粒/ml。
青光眼模型。使用模拟临床上急性闭角型青光眼的眼内压升高(IPI)诱导的缺血/再灌注(I/R)模型损伤小鼠RGC。通过对先前报道的方案进行微小修改,用针将小鼠的眼前房环化,该针通过管连接到升高的盐水(含0.1%肝素)储液罐。通过将盐水储液罐的高度提高到眼睛上方150厘米,内视网膜血流停止(缺血)。60分钟后移除针头以安装循环(再灌注)。该方案导致所有RGC轴突退化和其他视网膜神经元死亡。为了防止其他视网膜神经元细胞凋亡,每天一次将Rock抑制剂盐酸瑞帕舒地尔二水合物(Ripasudil hydrochloridedehydrate)(在PBS中0.4%)的溶液施用至小鼠的眼表面。
免疫组织化学和成像。在经心脏灌注盐水(ddH2O中0.9%NaCl的)和随后的4%PFA后,收集小鼠的眼睛、视神经和大脑,并在4%PFA中后固定24小时。将眼睛和大脑组织置于30%蔗糖中进行冷冻保护,并使用切片机低温恒温器切片,厚度分别为10和30μm。根据标准方案进行免疫组织化学染色。使用以下抗体:兔抗RBPMS(Abcam,1:400)标记RGC,小鼠抗Brn3a(Santa Cruz Biotechnology,1:200)标记RGC,兔抗SMI-32(Abcam,1:400)标记α-RGC,兔抗黑视蛋白(Abcam,1:500)标记ipRGC,兔抗CART(可卡因和安非他明调节的转录本)(Phoenix Peptide,1:2500)标记ON-OFF DSGC,小鼠抗PSD95(Abcam,1:400)标记突触后细胞膜。对于二次检测,Alexa Fluor 647驴抗兔(IFKineTM,1:400)、Alexa Fluor 647驴抗鼠(IFKineTM,1:400)或Alexa Fluor 488驴抗兔(Abcam,1:400))被使用。用蔡司LSM880共聚焦显微镜、尼康旋转圆盘(CSU W1 Sora)共聚焦显微镜或STED SP8显微镜对免疫染色的组织切片进行成像。
体内钙成像。对于手术,小鼠用氨基甲酸乙酯(1.5g/kg)麻醉,并放置在立体定向装置中,眼睛用眼药膏覆盖。用黑色牙科水泥(添加Fe3O4以阻挡光线)将定制的钛头板粘合到头骨上,大致以λ为中心,平行于小鼠的长轴。在后内侧SC和下丘上进行3mm开颅,然后将直径为3mm的盖玻片轻轻压在硬脑膜上,并用黑色牙科水泥密封开颅。一块遮光布贴在头板上,以避免功能性双光子成像过程中视觉刺激造成的光污染。
视觉刺激是使用Matlab(Mathworks)功能Psychtoolbox生成的,并显示在距离对侧眼睛15厘米处的校正17英寸液晶显示器(戴尔,1280×1024像素,75Hz刷新率)上。刺激是呈现在灰色均匀背景上的全屏正弦波漂移光栅(空间频率:0.05周期/°,时间频率:2Hz)。光栅呈现5次重复,持续时间为1秒,刺激间隔为1-2秒。刺激以45°的规则间隔在8个方向上与4个方向正交。
使用定制的LotosScan显微镜(LotosScan,苏州生物医学工程技术研究所)监测来自轴突末端的荧光的双光子成像,并与锁模Ti:Sa激光器(Chameleon VISION-S,Coherent)耦合。激发波长固定在920nm。使用40X、0.8NA物镜(尼康)进行成像。光束尺寸足够大,足以溢出40X物镜的后孔径。以50Hz(480×240像素,0.225μm/像素)的帧速率获取图像。
在Matlab(Mathworks)和ImageJ(美国国立卫生研究院)中分析图像。为了校正成像数据中的横向运动,使用Turboreg软件(ImageJ插件)应用基于刚体变换的逐帧对齐。末端是根据尺寸、形状和亮度手动识别的。通过平均每帧中末端掩码内的像素强度值来提取单独的末端时间进程。如果在成像过程中大脑搏动明显,则不使用这些数据。使用先前报道的方法40减去Neuropil信号。在此校正后,对每个刺激呈现的反应(Ft)通过刺激开始前0.2秒内的反应(F0)进行归一化。对于每种刺激,通过平均对所有刺激条件和试验的反应来计算荧光的平均变化(ΔF/F)。在空白和刺激呈现期间通过ANOVA定义视觉反应细胞(P<0.05)。
Lgr5+无长突中间神经元的全细胞膜片钳记录。小鼠在被安乐死之前黑暗适应了2小时以上。然后在含有126mM NaCl、1.25mM NaH2PO4、2.5mM KCl、2mM CaCl2、2mM MgCl2、10mM葡萄糖和26mM NaHCO3的人工脑脊液(ACSF)中在红外光下进行视网膜解剖。用剃刀刀片手动切割视网膜切片,然后将其附着在一张滤纸上,将滤纸转移到显微镜台上的记录室中,并用含氧(95%O2/5%CO2)ACSF灌注。使用双光子显微镜鉴定INL中的Lgr5-tdTomato+细胞,并在红外光下靶向全细胞膜片钳记录。移液器(4-7MΩ)充满细胞内溶液,其中含有120mM Cs-甲磺酸盐、5mM NaCl、10mM HEPES、5mM EGTA、5mM QX314、0.5mM CaCl2、4mM ATP、0.5mM GTP用于电压钳记录或123mM K-葡萄糖酸盐,10mM KCl,10mM HEPES,2mM EGTA,1mMCaCl2,1mM MgCl2,4mM ATP,0.5mM GTP,用于电流钳记录。以上使用的所有试剂均来自Sigma。将Alexa488 hydradize(0.2mM,ThermoFisher)添加到细胞内溶液中,以可视化被记录细胞的形态。使用Multiclamp 700A放大器和pClamp 10软件套件(Molecular Devices)采集和处理信号。信号以1kHz过滤并以10kHz采样(Digidata 1440A,Molecular Devices)。EPSCs记录在Cl-的反向电位(-67mV),IPSCs记录在0mV。由记录计算机控制的白色LED灯用于提供全场光刺激。
SC神经元的体外全细胞膜片钳记录。用含有92mM氯化胆碱、2.5mM KCl、1.2mMNaH2PO4、30mM NaHCO3、10mM MgSO4、0.5mM CaCl2、25mM葡萄糖、5mM抗坏血酸钠、3mM丙酮酸钠和2mM硫脲的冰冷的氧合的(95%O2,5%CO2)切割溶液对深度麻醉的小鼠进行心脏灌注。通过加入浓HCl将切割溶液的pH值调节至7.3-7.4,并将渗透压调节至310-315mOsm。从头骨中取出后,使用振动刀片切片机(VT1200 S,Leica Biosystems)在切割溶液中将含有SC区域的大脑组织切成300μm冠状切片。然后将切片在相同的切割溶液中在31-32℃下孵育15分钟,然后转移到含有室温氧合的保持溶液(92mM NaCl、30mM NaHCO3、1.25mM NaH2PO4、2.5mMKCl、2mM MgSO4、2mM CaCl2和25mM葡萄糖、20mM HEPES、5mM抗坏血酸钠、3mM丙酮酸钠和2mM硫脲,pH值为7.3-7.4,渗透压值为310-315mOsm)的保持室中。储存一小时后,将切片转移到含有室温氧合的记录溶液(119mM NaCl、24mM NaHCO3、1.25mM NaH2PO4、2.5mM KCl、2mMMgSO4、2mM CaCl2和12.5mM葡萄糖)的记录室中。三到五片含有SC区域的切片通常由一只动物制成。记录取自包含中间SC区域的大脑切片。
突触反应的全细胞膜片钳记录是使用2-4MΩ玻璃移液管进行的,其内部溶液为125mM K-葡萄糖酸盐、20mM KCl、0.5mM EGTA、10mM HEPES-NaOH、10mM P-肌酸,4mM ATP-Mg和0.3mM GTP(pH 7.3)。蓝色刺激光由470nm LED(Thorlabs,35mW/mm2)产生并通过40X物镜(OLYMPUS)施加。发现5ms的刺激持续时间能够使记录的突触后反应饱和。神经元的输入电阻范围为1-5GΩ,串联电阻小于20MΩ。使用以下方案进行记录:膜电位首先保持在-70mV以记录光诱发的AMPA受体介导的突触电流(在此保持电位下,NMDA受体可能被镁阻断)。然后将膜保持电位切换到+55mV以记录AMPA和NMDA受体介导的电流的混合物。在这种情况下,然后将AMPA受体拮抗剂CNQX(10mM)添加到记录溶液中以阻断AMPA受体介导的突触电流,从而检测NMDA受体介导的EPSC。接下来,将记录切换到电流钳模式以检测动作电位。AMPA受体拮抗剂CNQX(Tocris)和NMDA受体拮抗剂D-APV(Tocris)的应用是通过将各自的药物添加到沐浴记录溶液中来进行的。所有记录均使用Axon700B放大器进行,并使用Digidata1440模数板进行数字化。使用pClamp软件进行刺激和数据采集,并以50kHz进行数字化。所有设备和软件均来自Axon Instruments/Molecular Devices(Molecular Devices,CA)。
统计数据。使用双尾学生t检验比较两组之间的差异。
结果
在体内将Lgr5+无长突中间神经元重编程为RGC。我们首先使用了Lgr5EGFP -IRES-CreERT2;Rosa26-tdTomato小鼠品系,用于测试RGC是否可以从无长突中间神经元再生。Lgr5在位于内核层玻璃体侧的视网膜细胞亚群中表达(图1a)。这些Lgr5+细胞不仅表现出典型的无长突中间神经元形态(图1a-c和7a-d),而且还具有响应光刺激的活跃突触连接(图1e、f)。它们可以接受兴奋性和抑制性突触后电流(EPSC和IPSC),并被它们去极化或超极化(图1e,f),如靶向膜片钳记录所示,表明它们确实是成熟的无长突中间神经元。然而,当用tdTomato报告基因标记Lgr5+无长突中间神经元并在成年小鼠中追踪谱系时,几个月后可以检测到极少数(在任何给定时间点每个视网膜少于一个细胞)tdTomato+双极细胞和水平细胞(图1b、c),表明一些Lgr5+无长突细胞可以关闭Lgr5表达并转分化为其他视网膜谱系,表现出有限的再生潜力。随着小鼠年龄的增长,可以在视网膜神经节细胞层中检测到少量Lgr5+无长突细胞,这表明它们可能能够从内核层迁移到视网膜神经节层(图1d和7e-g)。视网膜神经节细胞层中Lgr5+细胞的数量随着年龄的增长而增加(图7h),其中一些细胞会关闭Lgr5的表达,但它们永远不会变成RGC。
为了研究Lgr5+无长突中间神经元是否可以重编程为RGC,我们设计了一种体内谱系追踪和重编程策略(图2a)。我们首先用Rosa26-tdTomato报告基因标记Lgr5+无长突神经元,然后使用通过腺相关病毒(AAV)递送的Cre依赖的双floxed(double-floxed)反向开放阅读框(DIO)表达系统,在这些细胞中异位表达对RGC命运决定至关重要的基因(图2b)。我们通过检查平铺视网膜样本中具有RGC形态的tdTomato+细胞的存在以及稍后时间点视神经中tdTomato+轴突的存在,分析了Lgr5+无长突细胞产生的RGC。
我们没有观察到平铺视网膜样品中的任何tdTomato+RGC细胞和玻璃体内注射AAV-DIO-EGFP的对照小鼠的视神经中的tdTomato+轴突(图2c和8a-e)。然而,可以在注射AAV的小鼠的视网膜样本中检测到具有RGC形态的tdTomato+细胞,表达一组对RGC命运决定很重要的基因(Atoh7、Brn3B、Sox4、Sox11和Isl1)。诱导基因表达六周后,在视网膜样本中观察到具有RGC形态的tdTomato+细胞(图2d-f)。这些细胞向视盘投射轴突状投射并延伸到视神经中(图3a)。它们的细胞体位于视网膜神经节细胞层,可以用RGC特异性标志物RBPMS和Brn3A染色(图2g,h)。因此,这些细胞可能被视为新生成的RGC。
平均而言,在病毒注射后6周,每个视网膜再生了约180个新的RGC(图2c)。当体内重编程开始时,该数量远高于存在于视网膜神经节层中的Lgr5+无长突细胞(2-3个月大小鼠的视网膜神经节细胞层中约有10-15个细胞)(图7h)。这一结果表明,RGC命运决定因子在Lgr5+无长突细胞中的异位表达可以触发其中一些细胞从内核层迁移到神经节细胞层。为了支持这一观点,在内丛状层中检测到具有较低Lgr5-EGFP表达水平的tdTomato+细胞(图8f-h)。
我们测试了单个转录因子及其组合的重编程活性,发现即使是单个转录因子(Brn3B或Sox4)也能够将Lgr5+无长突中间神经元重编程为RGC,但效率非常低(图2c)。Brn3B和Sox4的组合极大地协同重编程活动。将Atoh7添加到Brn3B+Sox4组合中并没有进一步提高重编程效率(图2c)。因此,除非另有说明,否则我们在其余实验中使用Brn3B+Sox4组合。
RGC是一种异质类型的视网膜神经元,可分为不同的亚型。我们用亚型特异性抗体进行了免疫组织学分析,发现再生的RGC可以用抗CART(用于打开关闭定向选择性神经节细胞)和抗SMI-32(用于α神经节细胞)鉴定(图2i和8i-l),但我们没有检测到任何表达黑视蛋白的内在光敏神经节细胞。总之,这些结果表明特定转录因子的异位表达能够将Lgr5+无长突中间神经元重编程为RGC,并且再生的RGC具有亚型特异性。
再生的RGC将轴突投射到大脑中的视觉核中。为了确定再生的RGC是否可以在大脑中适当地重新连接,我们检查了沿视觉传导通路的再生的RGC的轴突及其对主要大脑视网膜受体区域的投射。病毒注射六周后,再生的RGC的许多轴突已经穿过整个视神经,通过视交叉,并导航到大脑中的视核,包括背侧和腹外侧膝状体核(dLGN和vLGN)、顶盖前区、和上丘(SC)(图3)。我们没有观察到再生的RGC轴突异常投射到与视觉通路无关的大脑区域。在视网膜受体区域内,沿着再生的RGC的轴突树枝状结构观察到微米级的静脉曲张。这些静脉曲张与突触后密度蛋白PSD-95(图3g-i)的染色密切相关,表明它们是推定的突触前棒头。
我们通过分析病毒注射后大脑切片上这些区域何时首次检测到再生的RGC轴突,确定了再生的RGC轴突投射到三个重要的大脑视觉位置,视交叉(OC)、LGN和SC的时间进程。我们发现RGC轴突到达OC大约需要18天,到达LGN需要28天,到达最远端视觉目标SC需要35天(图9)。总之,这些数据表明Lgr5+无长突中间神经元衍生的RGC能够将轴突投射到适当的大脑区域,建立视网膜-大脑连接。
将Prokr2+置换的无长突中间神经元重编程为RGC。我们考虑是否也可以将其他视网膜神经元重编程为RGC。置换的无长突中间神经元可以作为RGC替代的更好细胞来源,因为它们位于RGC层。为了测试这种神经元亚型是否可以重编程为RGC,我们生成了Prokr2CreERT2敲入小鼠系(图10a,b)。Prokr2CreERT2小鼠在Prokr2基因的内源性转录控制下表达他莫昔芬诱导的CreERT2重组酶,该基因在置换的无长突中间神经元亚组中表达。正如预期的那样,在用他莫昔芬治疗的成年Prokr2CreERT2;Rosa26-tdTomato小鼠中,tdTomato+细胞位于视网膜神经节细胞层。它们没有视觉投射并且不表达RGC标志物RBPMS(图4a、b和图10c-e)。
除了在视网膜中表达外,Prokr2还在视神经和大脑的细胞中表达(图10f-h)。这使我们无法使用Rosa26-tdTomato报告基因来跟踪再生的RGC的轴突。为了克服这个障碍,我们在编程过程中通过与转录因子共表达EGFP来标记再生的RGC(图10k)。我们使用两种转录因子组合(Brn3B+Sox4和Atoh7+Brn3B+Sox4)进行重编程,发现这两种组合都可以有效地将Prokr2+置换的无长突中间神经元重编程为RGC(图4c,d)。然而,与Lgr5+无长突中间神经元不同,在Brn3B+Sox4组合中加入Atoh7显著提高了重编程效率(图10l)。Prokr2+置换的无长突中间神经元衍生的RGC还将轴突投射延伸到视神经和各种大脑视觉靶标(图4e-k)。因此,这些结果表明,可以通过在体内重编程多个视网膜神经元亚型来再生RGC。
再生的RGC将视觉信息传递给大脑。为了研究再生的RGC是否可以响应视觉刺激并将视觉信息传递到大脑中的下游靶标,我们通过在重编程的混合物中添加AAV-DIO-GCamp6f在Lgr5EGFP-IRES-CreERT2小鼠中用钙指示剂GCamp6f标记再生的RGC。然后我们在病毒注射六周后暴露麻醉小鼠的SC,并使用体内功能性钙成像来测量再生的RGC轴突末端的视觉诱发钙动力学(图11a)。
当小鼠出现漂移光栅时,SC中沿轴突树枝状结构的单个RGC棒头表现出刺激诱发的钙信号(图11b),表明再生的RGC可以响应视觉刺激并将视觉信号传递到大脑。视觉响应棒头可以根据其响应模式分为不同的类别。棒头对刺激的开启和关闭以及对漂移光栅的定向和方向的反应不同(图5a-d和11c,d)。总之,这些数据表明再生的RGC能够将视觉信息传递给大脑,并且可以通过体内重编程产生功能上不同的RGC亚型。
再生的RGC与突触后神经元建立功能性突触连接。为了研究再生的RGC是否可以将神经元信号传递给大脑中的突触后神经元,我们在Lgr5EGFP-IRES-CreERT2;Rosa26-tdTomato小鼠的再生的RGC中表达了光敏感通道蛋白-2(ChR2),并使用全细胞贴片记录检测病毒注射后8-10周脑切片上SC神经元的光诱发突触后反应。
当用光刺激再生的RGC的轴突末端时,在SC神经元中检测到AMPA受体介导的兴奋性突触后电流(EPSC)。单个光脉冲诱发AMPA受体介导的具有多个峰的EPSC(图5e、h和i),表明再生的RGC轴突与SC神经元形成多输入突触并激活AMPA谷氨酸能受体。NMDA受体介导的EPSC和动作电位也在光刺激后的突触后SC神经元中检测到(图5f、g和j)。此外,SC神经元对再生的表达ChR2的RGC的反应与表达ChR2的正常RGC的反应相当(图11e,f)。总之,这些结果表明,响应于光刺激,再生的RGC轴突末端释放谷氨酸作为神经递质,并与SC神经元建立功能性突触连接。
在青光眼小鼠模型中再生功能性RGC。我们接下来询问再生的RGC是否可以在患病条件下修复视觉回路。我们特别感兴趣的是,当原始RGC及其轴突发生退化时,再生的RGC是否仍可以将轴突发送到适当的大脑靶标,并重建视网膜-大脑连接。
我们使用眼压升高诱导的青光眼模型来损伤RGC及其轴突,并优化可能导致视神经内所有RGC轴突退化和视网膜中RGC细胞体显著损失的条件(图12a-e)。然而,这种损伤状况也导致眼内压升高7天后Lgr5+无长突细胞的显著损失(图6b)。因此,我们寻找可以保护Lgr5+无长突细胞的试剂,发现Rock抑制剂瑞帕舒地尔可以有效保护Lgr5+无长突细胞(图6c)。
我们设计了一种将神经元保护与体内重编程相结合的方案,以测试新生成的RGC是否可以修复Lgr5EGFP-IRES-CreERT2;Rosa26-tdTomato小鼠中受损的视觉回路(图12f)。我们损坏了Lgr5EGFP-IRES-CreERT2;Rosa26-tdTomato小鼠的双眼,该小鼠接受他莫昔芬喂养以用tdTomato报告基因标记Lgr5+无长突细胞。损伤后,双眼每天接受一次瑞帕舒地尔治疗,7天后,左眼注射AAV-DIO-EGFP作为对照,而右眼注射表达转录因子(包括Brn3B、Sox4和Atoh7)的AAV组合以重编程Lgr5+无长突中间神经元。病毒注射后六周,处死小鼠进行分析。在注射了AAV-DIO-EGFP的左眼中,没有再生的RGC,因为在左视神经中没有检测到tdTomato+RGC轴突(图6e)。相比之下,Brn3B、Sox4和Atoh7的过表达将Lgr5+无长突细胞重编程为RGC,并且再生的RGC将tdTomato+轴突投射到对侧的视神经和各种脑视觉靶标中(图6f-k)。
再生的RGC在患病条件下与突触后脑神经元建立了功能性突触连接。在脑切片上的SC神经元中检测到光诱发的突触后反应,其中所有RGC轴突末端均来自原始RGC受损后的再生的RGC(图6l-n)。总之,这些结果表明再生的RGC可以将视网膜重新连接到大脑,并将视觉信息传递给突触后神经元,即使在患病条件下也是如此。
这些结果表明,通过对完全分化的视网膜中间神经元进行体内重编程,可以在成年哺乳动物中产生功能性RGC。通过必需转录因子的异位表达,无长突和置换的无长突中间神经元都可以精确地重编程为RGC,新生成的RGC整合到视觉回路中并将视觉信息传递到大脑。尽管在中枢神经系统(CNS)的其他区域已经实现了体内神经元身份重编程,但神经元亚型之间的成功转换仅限于出生后第一周,或者当化合物丙戊酸存在时,成年小鼠的成功转换有限。相比之下,这个实施例表明,即使没有化学刺激剂,视网膜神经元身份转换也可以在成年期实现,成功的重编程甚至触发无长突中间神经元从内核层迁移到RGC层。这些结果表明,神经元表现出出人意料的身份可塑性,可用于再生目的。
Brn3B和Sox4的组合有效地将Lgr5+无长突中间神经元和Prokr2+置换的无长突中间神经元重编程为RGC,表明这两种转录因子足以确定RGC的命运。将Atoh7加入Brn3B+Sox4组合显著提高了从Prokr2+置换的无长突细胞再生RGC的效率,尽管它没有改善Lgr5+无长突细胞重编程。这表明直接细胞谱系重编程受源细胞内在特性的影响。
再生的RGC通过将轴突长距离投射到不同的大脑视觉区域将视网膜连接到大脑,即使在原始RGC和轴突已受损的动物中也是如此。这些发现表明,成年哺乳动物的视觉系统仍然具有重新连接神经回路的非凡能力。
实施例2退化的RGC恢复活力
这个实施例表明退化的RGC也可以被转录因子重新激活以再次生长功能性轴突。
在这个实施例中,眼压的升高被用来触发PV-CreERT2;Rosa26-tdTomato小鼠中视网膜神经节细胞(RGC)的凋亡,从而导致它们的轴突退化。在该动物模型中,三种转录因子(Atoh7+Brn3B+Sox4)在存活的RGC中的表达刺激这些细胞再生(再生)轴突(图13)。同样重要的是,再生的RGC轴突投射到视神经中并到达大脑的视觉区域(图14)。
因此,结果表明,转录因子的组合不仅可以将中间神经元细胞重编程为再生的RGC,它们还可以使退化、受损、受伤或老化的RGC恢复活力。因此,当将这些转录因子施用于需要视觉修复、恢复或改善的受试者时,它们可以在中间神经元和RGC上协同工作以实现所需的治疗效果。
***
尽管已经参考所公开的实施方案描述了本公开,但是本领域技术人员将容易理解,以上详述的具体实施例和研究仅用于说明本公开。应当理解,在不背离本公开的精神的情况下可以进行各种修改。因此,本公开仅由以下权利要求限定。
序列表
<110> 上海科技大学
<120> 视网膜神经节细胞的再生
<130> P21401497WF
<150> CN202010047628.2
<151> 2020-01-16
<160> 27
<170> PatentIn version 3.5
<210> 1
<211> 409
<212> PRT
<213> 智人(Homo sapiens)
<400> 1
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1 5 10 15
Gly Glu Ser Ser Asp Ser Gly Ala Gly Leu Glu Leu Gly Ile Ala Ser
20 25 30
Ser Pro Thr Pro Gly Ser Thr Ala Ser Thr Gly Gly Lys Ala Asp Asp
35 40 45
Pro Ser Trp Cys Lys Thr Pro Ser Gly His Ile Lys Arg Pro Met Asn
50 55 60
Ala Phe Met Val Trp Ser Gln Ile Glu Arg Arg Lys Ile Met Glu Gln
65 70 75 80
Ser Pro Asp Met His Asn Ala Glu Ile Ser Lys Arg Leu Gly Lys Arg
85 90 95
Trp Lys Leu Leu Lys Asp Ser Asp Lys Ile Pro Phe Ile Arg Glu Ala
100 105 110
Glu Arg Leu Arg Leu Lys His Met Ala Asp Tyr Pro Asp Tyr Lys Tyr
115 120 125
Arg Pro Arg Lys Lys Val Lys Ser Gly Asn Ala Asn Ser Ser Ser Ser
130 135 140
Ala Ala Ala Ser Ser Lys Pro Gly Glu Lys Gly Asp Lys Val Gly Gly
145 150 155 160
Ser Gly Gly Gly Gly His Gly Gly Gly Gly Gly Gly Gly Ser Ser Asn
165 170 175
Ala Gly Gly Gly Gly Gly Gly Ala Ser Gly Gly Gly Ala Asn Ser Lys
180 185 190
Pro Ala Gln Lys Lys Ser Cys Gly Ser Lys Val Ala Gly Gly Ala Gly
195 200 205
Gly Gly Val Ser Lys Pro His Ala Lys Leu Ile Leu Ala Gly Gly Gly
210 215 220
Gly Gly Gly Lys Ala Ala Ala Ala Ala Ala Ala Ser Phe Ala Ala Glu
225 230 235 240
Gln Ala Gly Ala Ala Ala Leu Leu Pro Leu Gly Ala Ala Ala Asp His
245 250 255
His Ser Leu Tyr Lys Ala Arg Thr Pro Ser Ala Ser Ala Ser Ala Ser
260 265 270
Ser Ala Ala Ser Ala Ser Ala Ala Leu Ala Ala Pro Gly Lys His Leu
275 280 285
Ala Glu Lys Lys Val Lys Arg Val Tyr Leu Phe Gly Gly Leu Gly Thr
290 295 300
Ser Ser Ser Pro Val Gly Gly Val Gly Ala Gly Ala Asp Pro Ser Asp
305 310 315 320
Pro Leu Gly Leu Tyr Glu Glu Glu Gly Ala Gly Cys Ser Pro Asp Ala
325 330 335
Pro Ser Leu Ser Gly Arg Ser Ser Ala Ala Ser Ser Pro Ala Ala Gly
340 345 350
Arg Ser Pro Ala Asp His Arg Gly Tyr Ala Ser Leu Arg Ala Ala Ser
355 360 365
Pro Ala Pro Ser Ser Ala Pro Ser His Ala Ser Ser Ser Ala Ser Ser
370 375 380
His Ser Ser Ser Ser Ser Ser Ser Gly Ser Ser Ser Ser Asp Asp Glu
385 390 395 400
Phe Glu Asp Asp Leu Leu Asp Leu Asn Pro Ser Ser Asn Phe Glu Ser
405 410 415
Met Ser Leu Gly Ser Phe Ser Ser Ser Ser Ala Leu Asp Arg Asp Leu
420 425 430
Asp Phe Asn Phe Glu Pro Gly Ser Gly Ser His Phe Glu Phe Pro Asp
435 440 445
Tyr Cys Thr Pro Glu Val Ser Glu Met Ile Ser Gly Asp Trp Leu Glu
450 455 460
Ser Ser Ile Ser Asn Leu Val Phe Thr Tyr
465 470
<210> 6
<211> 1425
<212> DNA
<213> 智人(Homo sapiens)
<400> 6
atggtgcagc aaaccaacaa tgccgagaac acggaagcgc tgctggccgg cgagagctcg 60
gactcgggcg ccggcctcga gctgggaatc gcctcctccc ccacgcccgg ctccaccgcc 120
tccacgggcg gcaaggccga cgacccgagc tggtgcaaga ccccgagtgg gcacatcaag 180
cgacccatga acgccttcat ggtgtggtcg cagatcgagc ggcgcaagat catggagcag 240
tcgcccgaca tgcacaacgc cgagatctcc aagcggctgg gcaaacgctg gaagctgctc 300
aaagacagcg acaagatccc tttcattcga gaggcggagc ggctgcgcct caagcacatg 360
gctgactacc ccgactacaa gtaccggccc aggaagaagg tgaagtccgg caacgccaac 420
tccagctcct cggccgccgc ctcctccaag ccgggggaga agggagacaa ggtcggtggc 480
agtggcgggg gcggccatgg gggcggcggc ggcggcggga gcagcaacgc ggggggagga 540
ggcggcggtg cgagtggcgg cggcgccaac tccaaaccgg cgcagaaaaa gagctgcggc 600
tccaaagtgg cgggcggcgc gggcggtggg gttagcaaac cgcacgccaa gctcatcctg 660
gcaggcggcg gcggcggcgg gaaagcagcg gctgccgccg ccgcctcctt cgccgccgaa 720
caggcggggg ccgccgccct gctgcccctg ggcgccgccg ccgaccacca ctcgctgtac 780
aaggcgcgga ctcccagcgc ctcggcctcc gcctcctcgg cagcctcggc ctccgcagcg 840
ctcgcggccc cgggcaagca cctggcggag aagaaggtga agcgcgtcta cctgttcggc 900
ggcctgggca cgtcgtcgtc gcccgtgggc ggcgtgggcg cgggagccga ccccagcgac 960
cccctgggcc tgtacgagga ggagggcgcg ggctgctcgc ccgacgcgcc cagcctgagc 1020
ggccgcagca gcgccgcctc gtcccccgcc gccggccgct cgcccgccga ccaccgcggc 1080
tacgccagcc tgcgcgccgc ctcgcccgcc ccgtccagcg cgccctcgca cgcgtcctcc 1140
tcggcctcgt cccactcctc ctcttcctcc tcctcgggct cctcgtcctc cgacgacgag 1200
ttcgaagacg acctgctcga cctgaacccc agctcaaact ttgagagcat gtccctgggc 1260
agcttcagtt cgtcgtcggc gctcgaccgg gacctggatt ttaacttcga gcccggctcc 1320
ggctcgcact tcgagttccc ggactactgc acgcccgagg tgagcgagat gatctcggga 1380
gactggctcg agtccagcat ctccaacctg gttttcacct actga 1425
<210> 7
<211> 440
<212> PRT
<213> 普通家鼠(Mus musculus)
<400> 7
Met Val Gln Gln Thr Asn Asn Ala Glu Asn Thr Glu Ala Leu Leu Ala
1 5 10 15
Gly Glu Ser Ser Asp Ser Gly Ala Gly Leu Glu Leu Gly Ile Ala Ser
20 25 30
Ser Pro Thr Pro Gly Ser Thr Ala Ser Thr Gly Gly Lys Ala Asp Asp
35 40 45
Pro Ser Trp Cys Lys Thr Pro Ser Gly His Ile Lys Arg Pro Met Asn
50 55 60
Ala Phe Met Val Trp Ser Gln Ile Glu Arg Arg Lys Ile Met Glu Gln
65 70 75 80
Ser Pro Asp Met His Asn Ala Glu Ile Ser Lys Arg Leu Gly Lys Arg
85 90 95
Trp Lys Leu Leu Lys Asp Ser Asp Lys Ile Pro Phe Ile Gln Glu Ala
100 105 110
Glu Arg Leu Arg Leu Lys His Met Ala Asp Tyr Pro Asp Tyr Lys Tyr
115 120 125
Arg Pro Arg Lys Lys Val Lys Ser Gly Asn Ala Gly Ala Gly Ser Ala
130 135 140
Ala Thr Ala Lys Pro Gly Glu Lys Gly Asp Lys Val Ala Gly Ser Ser
145 150 155 160
Gly His Ala Gly Ser Ser His Ala Gly Gly Gly Ala Gly Gly Ser Ser
165 170 175
Lys Pro Ala Pro Lys Lys Ser Cys Gly Pro Lys Val Ala Gly Ser Ser
180 185 190
Val Gly Lys Pro His Ala Lys Leu Val Pro Ala Gly Gly Ser Lys Ala
195 200 205
Ala Ala Ser Phe Ser Pro Glu Gln Ala Ala Leu Leu Pro Leu Gly Glu
210 215 220
Pro Thr Ala Val Tyr Lys Val Arg Thr Pro Ser Ala Ala Thr Pro Ala
225 230 235 240
Ala Ser Ser Ser Pro Ser Ser Ala Leu Ala Thr Pro Ala Lys His Pro
245 250 255
Ala Asp Lys Lys Val Lys Arg Val Tyr Leu Phe Gly Ser Leu Gly Ala
260 265 270
Ser Ala Ser Pro Val Gly Gly Leu Gly Ala Ser Ala Asp Pro Ser Asp
275 280 285
Pro Leu Gly Leu Tyr Glu Asp Gly Gly Pro Gly Cys Ser Pro Asp Gly
290 295 300
Arg Ser Leu Ser Gly Arg Ser Ser Ala Ala Ser Ser Pro Ala Ala Ser
305 310 315 320
Arg Ser Pro Ala Asp His Arg Gly Tyr Ala Ser Leu Arg Ala Ala Ser
325 330 335
Pro Ala Pro Ser Ser Ala Pro Ser His Ala Ser Ser Ser Leu Ser Ser
340 345 350
Ser Ser Ser Ser Ser Ser Gly Ser Ser Ser Ser Asp Asp Glu Phe Glu
355 360 365
Asp Asp Leu Leu Asp Leu Asn Pro Ser Ser Asn Phe Glu Ser Met Ser
370 375 380
Leu Gly Ser Phe Ser Ser Ser Ser Ala Leu Asp Arg Asp Leu Asp Phe
385 390 395 400
Asn Phe Glu Pro Gly Ser Gly Ser His Phe Glu Phe Pro Asp Tyr Cys
405 410 415
Thr Pro Glu Val Ser Glu Met Ile Ser Gly Asp Trp Leu Glu Ser Ser
420 425 430
Ile Ser Asn Leu Val Phe Thr Tyr
435 440
<210> 8
<211> 1323
<212> DNA
<213> 普通家鼠(Mus musculus)
<400> 8
atggtacaac agaccaacaa cgcggagaac actgaggctc tgctggccgg ggagagctcg 60
gactcgggcg ccggcctgga gctgggcatc gcgtcctccc cgacgcctgg ctccaccgcg 120
tcgacgggcg gcaaggcgga cgaccccagc tggtgcaaga cgcccagtgg ccacatcaag 180
cggcccatga acgcctttat ggtgtggtcg cagatcgagc ggcgcaagat catggagcag 240
tcgcccgaca tgcacaacgc cgagatctcc aagcggctag gcaaacgctg gaagctgctc 300
aaggacagcg acaagattcc gttcatccag gaggcggagc ggctgcgcct caagcacatg 360
gctgactacc ctgactacaa gtaccggccg cgaaagaagg tgaagtcggg caacgcgggc 420
gcgggatcgg cggccacagc caagccaggg gagaagggcg acaaggtcgc gggcagcagc 480
ggccacgcgg gaagcagcca cgcggggggt ggcgcgggcg gcagctccaa gcccgcgccc 540
aagaagagct gtggccccaa ggtggcgggc agctcggtcg gcaagcccca cgctaagctg 600
gtcccggcgg gcggcagcaa ggcggctgca tcgttctctc cagagcaagc tgccctgctg 660
cccctggggg agcccacggc cgtctacaag gtgcggactc ccagtgcggc cactccggcc 720
gcctcctcct cgccgtccag tgcgctggcc accccagcca aacaccctgc cgacaagaaa 780
gtgaagcgcg tctacctgtt tggaagcctg ggcgcttcgg cgtctcccgt cgggggcctg 840
ggagcgagcg ccgaccccag tgatccactg gggttgtacg aagatggagg cccgggatgc 900
tcgcccgatg gccggagtct gagcggccgc agcagcgcag catcatcgcc agccgccagc 960
cgatcgcccg ctgaccaccg cggctacgcc agcctacgcg cagcctcgcc cgccccgtcc 1020
agcgcgccct cgcacgcgtc ctcctcgctc tcctcgtcct cttcctcctc ctcgggctct 1080
tcgtcgtccg acgacgagtt cgaagacgac ctgctcgacc tgaaccccag ctcaaacttt 1140
gagagcatgt ccctgggcag tttcagctcc tcatcggcgc tcgatcggga cctggatttt 1200
aacttcgaac ccggctcagg ctcccacttc gaattcccgg actattgcac gcccgaggtg 1260
agcgagatga tctcgggaga ttggctggag tccagcatct ctaacctggt cttcacctac 1320
tga 1323
<210> 9
<211> 152
<212> PRT
<213> 智人(Homo sapiens)
<400> 9
Met Lys Ser Cys Lys Pro Ser Gly Pro Pro Ala Gly Ala Arg Val Ala
1 5 10 15
Pro Pro Cys Ala Gly Gly Thr Glu Cys Ala Gly Thr Cys Ala Gly Ala
20 25 30
Gly Arg Leu Glu Ser Ala Ala Arg Arg Arg Leu Ala Ala Asn Ala Arg
35 40 45
Glu Arg Arg Arg Met Gln Gly Leu Asn Thr Ala Phe Asp Arg Leu Arg
50 55 60
Arg Val Val Pro Gln Trp Gly Gln Asp Lys Lys Leu Ser Lys Tyr Glu
65 70 75 80
Thr Leu Gln Met Ala Leu Ser Tyr Ile Met Ala Leu Thr Arg Ile Leu
85 90 95
Ala Glu Ala Glu Arg Phe Gly Ser Glu Arg Asp Trp Val Gly Leu His
100 105 110
Cys Glu His Phe Gly Arg Asp His Tyr Leu Pro Phe Pro Gly Ala Lys
115 120 125
Leu Pro Gly Glu Ser Glu Leu Tyr Ser Gln Arg Leu Phe Gly Phe Gln
130 135 140
Pro Glu Pro Phe Gln Met Ala Thr
145 150
<210> 10
<211> 459
<212> DNA
<213> 智人(Homo sapiens)
<400> 10
atgaagtcct gcaagcccag cggcccgccg gcgggagcgc gcgttgcacc cccgtgcgcg 60
ggcggcaccg agtgcgcggg cacgtgcgcc ggggccgggc ggctggagag cgcggcgcgc 120
aggcgcctgg cggccaacgc gcgcgagcgc cgccgcatgc aggggctcaa cactgccttc 180
gaccgcttac gcagggtggt tccccagtgg ggccaggata aaaagctgtc caagtacgag 240
accctgcaga tggccctgag ctacatcatg gctctgaccc ggatcctggc cgaggccgag 300
cgattcggct cggagcggga ctgggtgggt ctccactgtg agcacttcgg ccgcgaccac 360
tacctcccgt tcccgggcgc gaagctgccg ggcgagagcg agctgtacag ccagagactc 420
ttcggcttcc agcccgagcc cttccagatg gccacctag 459
<210> 11
<211> 149
<212> PRT
<213> 普通家鼠(Mus musculus)
<400> 11
Met Lys Ser Ala Cys Lys Pro His Gly Pro Pro Ala Gly Ala Arg Gly
1 5 10 15
Ala Pro Pro Cys Ala Gly Ala Ala Glu Arg Ala Val Ser Cys Ala Gly
20 25 30
Pro Gly Arg Leu Glu Ser Ala Ala Arg Arg Arg Leu Ala Ala Asn Ala
35 40 45
Arg Glu Arg Arg Arg Met Gln Gly Leu Asn Thr Ala Phe Asp Arg Leu
50 55 60
Arg Arg Val Val Pro Gln Trp Gly Gln Asp Lys Lys Leu Ser Lys Tyr
65 70 75 80
Glu Thr Leu Gln Met Ala Leu Ser Tyr Ile Ile Ala Leu Thr Arg Ile
85 90 95
Leu Ala Glu Ala Glu Arg Asp Trp Val Gly Leu Arg Cys Glu Gln Arg
100 105 110
Gly Arg Asp His Pro Tyr Leu Pro Phe Pro Gly Ala Arg Leu Gln Val
115 120 125
Asp Pro Glu Pro Tyr Gly Gln Arg Leu Phe Gly Phe Gln Pro Glu Pro
130 135 140
Phe Pro Met Ala Ser
145
<210> 12
<211> 450
<212> DNA
<213> 普通家鼠(Mus musculus)
<400> 12
atgaagtcgg cctgcaaacc ccacggccct ccggcgggag ctcgcggcgc gcccccgtgc 60
gcgggcgcag ccgagcgcgc ggtctcgtgc gcggggcccg ggcggctgga gagcgcggcg 120
cgcaggcgtc tggcggccaa cgcgcgcgag cggcgccgca tgcaggggct gaacacggcg 180
ttcgaccggc tgcgcagggt ggtgccgcag tggggccagg acaagaagct gtccaagtac 240
gagacactgc agatggcgct cagctacatc atcgcgctca cccgcatcct agccgaagcc 300
gagcgggact gggtcgggct gcgctgcgag cagcggggcc gcgatcaccc ctacctccct 360
ttcccgggtg ctaggctcca ggtagaccct gagccctatg ggcagaggct cttcggcttc 420
cagccggagc ccttccccat ggccagctaa 450
<210> 13
<211> 129
<212> PRT
<213> 普通家鼠(Mus musculus)
<400> 13
Met Lys Ser Ala Cys Lys Pro His Gly Pro Pro Ala Gly Ala Arg Gly
1 5 10 15
Ala Pro Pro Cys Ala Gly Ala Ala Glu Arg Ala Val Ser Cys Ala Gly
20 25 30
Pro Gly Arg Leu Glu Ser Ala Ala Arg Arg Arg Leu Ala Ala Asn Ala
35 40 45
Arg Glu Arg Arg Arg Met Gln Gly Leu Asn Thr Ala Phe Asp Arg Leu
50 55 60
Arg Arg Val Val Pro Gln Trp Gly Gln Asp Lys Lys Leu Ser Lys Tyr
65 70 75 80
Glu Thr Leu Gln Met Ala Leu Ser Tyr Ile Ile Ala Leu Thr Arg Ile
85 90 95
Leu Ala Glu Ala Glu Arg Asp Trp Val Gly Leu Arg Cys Glu Gln Arg
100 105 110
Gly Arg Asp His Pro Tyr Leu Pro Phe Pro Gly Ala Arg Leu Gln Val
115 120 125
Ser
<210> 14
<211> 390
<212> DNA
<213> 普通家鼠(Mus musculus)
<400> 14
atgaagtcgg cctgcaaacc ccacggccct ccggcgggag ctcgcggcgc gcccccgtgc 60
gcgggcgcag ccgagcgcgc ggtctcgtgc gcggggcccg ggcggctgga gagcgcggcg 120
cgcaggcgtc tggcggccaa cgcgcgcgag cggcgccgca tgcaggggct gaacacggcg 180
ttcgaccggc tgcgcagggt ggtgccgcag tggggccagg acaagaagct gtccaagtac 240
gagacactgc agatggcgct cagctacatc atcgcgctca cccgcatcct agccgaagcc 300
gagcgggact gggtcgggct gcgctgcgag cagcggggcc gcgatcaccc ctacctccct 360
ttcccgggtg ctaggctcca ggtttcatga 390
<210> 15
<211> 441
<212> PRT
<213> 智人(Homo sapiens)
<400> 15
Met Val Gln Gln Ala Glu Ser Leu Glu Ala Glu Ser Asn Leu Pro Arg
1 5 10 15
Glu Ala Leu Asp Thr Glu Glu Gly Glu Phe Met Ala Cys Ser Pro Val
20 25 30
Ala Leu Asp Glu Ser Asp Pro Asp Trp Cys Lys Thr Ala Ser Gly His
35 40 45
Ile Lys Arg Pro Met Asn Ala Phe Met Val Trp Ser Lys Ile Glu Arg
50 55 60
Arg Lys Ile Met Glu Gln Ser Pro Asp Met His Asn Ala Glu Ile Ser
65 70 75 80
Lys Arg Leu Gly Lys Arg Trp Lys Met Leu Lys Asp Ser Glu Lys Ile
85 90 95
Pro Phe Ile Arg Glu Ala Glu Arg Leu Arg Leu Lys His Met Ala Asp
100 105 110
Tyr Pro Asp Tyr Lys Tyr Arg Pro Arg Lys Lys Pro Lys Met Asp Pro
115 120 125
Ser Ala Lys Pro Ser Ala Ser Gln Ser Pro Glu Lys Ser Ala Ala Gly
130 135 140
Gly Gly Gly Gly Ser Ala Gly Gly Gly Ala Gly Gly Ala Lys Thr Ser
145 150 155 160
Lys Gly Ser Ser Lys Lys Cys Gly Lys Leu Lys Ala Pro Ala Ala Ala
165 170 175
Gly Ala Lys Ala Gly Ala Gly Lys Ala Ala Gln Ser Gly Asp Tyr Gly
180 185 190
Gly Ala Gly Asp Asp Tyr Val Leu Gly Ser Leu Arg Val Ser Gly Ser
195 200 205
Gly Gly Gly Gly Ala Gly Lys Thr Val Lys Cys Val Phe Leu Asp Glu
210 215 220
Asp Asp Asp Asp Asp Asp Asp Asp Asp Glu Leu Gln Leu Gln Ile Lys
225 230 235 240
Gln Glu Pro Asp Glu Glu Asp Glu Glu Pro Pro His Gln Gln Leu Leu
245 250 255
Gln Pro Pro Gly Gln Gln Pro Ser Gln Leu Leu Arg Arg Tyr Asn Val
260 265 270
Ala Lys Val Pro Ala Ser Pro Thr Leu Ser Ser Ser Ala Glu Ser Pro
275 280 285
Glu Gly Ala Ser Leu Tyr Asp Glu Val Arg Ala Gly Ala Thr Ser Gly
290 295 300
Ala Gly Gly Gly Ser Arg Leu Tyr Tyr Ser Phe Lys Asn Ile Thr Lys
305 310 315 320
Gln His Pro Pro Pro Leu Ala Gln Pro Ala Leu Ser Pro Ala Ser Ser
325 330 335
Arg Ser Val Ser Thr Ser Ser Ser Ser Ser Ser Gly Ser Ser Ser Gly
340 345 350
Ser Ser Gly Glu Asp Ala Asp Asp Leu Met Phe Asp Leu Ser Leu Asn
355 360 365
Phe Ser Gln Ser Ala His Ser Ala Ser Glu Gln Gln Leu Gly Gly Gly
370 375 380
Ala Ala Ala Gly Asn Leu Ser Leu Ser Leu Val Asp Lys Asp Leu Asp
385 390 395 400
Ser Phe Ser Glu Gly Ser Leu Gly Ser His Phe Glu Phe Pro Asp Tyr
405 410 415
Cys Thr Pro Glu Leu Ser Glu Met Ile Ala Gly Asp Trp Leu Glu Ala
420 425 430
Asn Phe Ser Asp Leu Val Phe Thr Tyr
435 440
<210> 16
<211> 1326
<212> DNA
<213> 智人(Homo sapiens)
<400> 16
atggtgcagc aggcggagag cttggaagcg gagagcaacc tgccccggga ggcgctggac 60
acggaggagg gcgaattcat ggcttgcagc ccggtggccc tggacgagag cgacccagac 120
tggtgcaaga cggcgtcggg ccacatcaag cggccgatga acgcgttcat ggtatggtcc 180
aagatcgaac gcaggaagat catggagcag tctccggaca tgcacaacgc cgagatctcc 240
aagaggctgg gcaagcgctg gaaaatgctg aaggacagcg agaagatccc gttcatccgg 300
gaggcggagc ggctgcggct caagcacatg gccgactacc ccgactacaa gtaccggccc 360
cggaaaaagc ccaaaatgga cccctcggcc aagcccagcg ccagccagag cccagagaag 420
agcgcggccg gcggcggcgg cgggagcgcg ggcggaggcg cgggcggtgc caagacctcc 480
aagggctcca gcaagaaatg cggcaagctc aaggcccccg cggccgcggg cgccaaggcg 540
ggcgcgggca aggcggccca gtccggggac tacgggggcg cgggcgacga ctacgtgctg 600
ggcagcctgc gcgtgagcgg ctcgggcggc ggcggcgcgg gcaagacggt caagtgcgtg 660
tttctggatg aggacgacga cgacgacgac gacgacgacg agctgcagct gcagatcaaa 720
caggagccgg acgaggagga cgaggaacca ccgcaccagc agctcctgca gccgccgggg 780
cagcagccgt cgcagctgct gagacgctac aacgtcgcca aagtgcccgc cagccctacg 840
ctgagcagct cggcggagtc ccccgaggga gcgagcctct acgacgaggt gcgggccggc 900
gcgacctcgg gcgccggggg cggcagccgc ctctactaca gcttcaagaa catcaccaag 960
cagcacccgc cgccgctcgc gcagcccgcg ctgtcgcccg cgtcctcgcg ctcggtgtcc 1020
acctcctcgt ccagcagcag cggcagcagc agcggcagca gcggcgagga cgccgacgac 1080
ctgatgttcg acctgagctt gaatttctct caaagcgcgc acagcgccag cgagcagcag 1140
ctggggggcg gcgcggcggc cgggaacctg tccctgtcgc tggtggataa ggatttggat 1200
tcgttcagcg agggcagcct gggctcccac ttcgagttcc ccgactactg cacgccggag 1260
ctgagcgaga tgatcgcggg ggactggctg gaggcgaact tctccgacct ggtgttcaca 1320
tattga 1326
<210> 17
<211> 395
<212> PRT
<213> 普通家鼠(Mus musculus)
<400> 17
Met Val Gln Gln Ala Glu Ser Ser Glu Ala Glu Ser Asn Leu Pro Arg
1 5 10 15
Asp Ala Leu Asp Thr Glu Glu Gly Glu Phe Met Ala Cys Ser Pro Val
20 25 30
Ala Leu Asp Glu Ser Asp Pro Asp Trp Cys Lys Thr Ala Ser Gly His
35 40 45
Ile Lys Arg Pro Met Asn Ala Phe Met Val Trp Ser Lys Ile Glu Arg
50 55 60
Arg Lys Ile Met Glu Gln Ser Pro Asp Met His Asn Ala Glu Ile Ser
65 70 75 80
Lys Arg Leu Gly Lys Arg Trp Lys Met Leu Lys Asp Ser Glu Lys Ile
85 90 95
Pro Phe Ile Arg Glu Ala Glu Arg Leu Arg Leu Lys His Met Ala Asp
100 105 110
Tyr Pro Asp Tyr Lys Tyr Arg Pro Arg Lys Lys Pro Lys Thr Asp Pro
115 120 125
Ala Ala Lys Pro Ser Ala Gly Gln Ser Pro Asp Lys Ser Ala Ala Gly
130 135 140
Ala Lys Ala Ala Lys Gly Pro Gly Lys Lys Cys Ala Lys Leu Lys Ala
145 150 155 160
Pro Ala Gly Lys Ala Gly Ala Gly Lys Ala Ala Gln Pro Gly Asp Cys
165 170 175
Ala Ala Gly Lys Ala Ala Lys Cys Val Phe Leu Asp Asp Asp Asp Glu
180 185 190
Asp Asp Asp Glu Asp Asp Glu Leu Gln Leu Arg Pro Lys Pro Asp Ala
195 200 205
Asp Asp Asp Asp Asp Glu Pro Ala His Ser His Leu Leu Pro Pro Pro
210 215 220
Thr Gln Gln Gln Pro Pro Gln Leu Leu Arg Arg Tyr Ser Val Ala Lys
225 230 235 240
Val Pro Ala Ser Pro Thr Leu Ser Ser Ala Ala Glu Ser Pro Glu Gly
245 250 255
Ala Ser Leu Tyr Asp Glu Val Arg Ala Gly Gly Arg Leu Tyr Tyr Ser
260 265 270
Phe Lys Asn Ile Thr Lys Gln Gln Pro Pro Pro Ala Pro Pro Ala Leu
275 280 285
Ser Pro Ala Ser Ser Arg Cys Val Ser Thr Ser Ser Ser Ser Gly Ser
290 295 300
Ser Ser Gly Ser Gly Ala Glu Asp Ala Asp Asp Leu Met Phe Asp Leu
305 310 315 320
Ser Leu Asn Phe Ser Gln Gly Ala His Ser Ala Cys Glu Gln Pro Leu
325 330 335
Gly Ala Gly Ala Ala Gly Asn Leu Ser Leu Ser Leu Val Asp Lys Asp
340 345 350
Leu Asp Ser Phe Ser Glu Gly Ser Leu Gly Ser His Phe Glu Phe Pro
355 360 365
Asp Tyr Cys Thr Pro Glu Leu Ser Glu Met Ile Ala Gly Asp Trp Leu
370 375 380
Glu Ala Asn Phe Ser Asp Leu Val Phe Thr Tyr
385 390 395
<210> 18
<211> 1188
<212> DNA
<213> 普通家鼠(Mus musculus)
<400> 18
atggtgcagc aggccgagag ctcggaagcc gagagcaacc tgccccggga cgcgctggac 60
accgaggagg gcgagttcat ggcgtgcagc ccggtggccc tggacgagag cgacccggac 120
tggtgcaaga cggcgtcggg ccacatcaaa cggcccatga acgccttcat ggtgtggtcc 180
aagatcgagc gcaggaagat catggagcag tcgcccgaca tgcacaacgc cgagatctcc 240
aagaggctgg gcaagcgctg gaagatgctg aaggacagcg agaagatccc gttcatcagg 300
gaggcggagc gcctgcgcct caagcacatg gctgattatc ccgactacaa gtaccggccg 360
cgcaaaaagc ccaagacgga cccagcggcc aagcccagcg cgggccagag ccccgacaag 420
agcgcggcgg gcgccaaggc agccaagggc cccggcaaga agtgcgccaa gctcaaggcg 480
cctgcgggca aggcgggcgc gggcaaggcg gcgcagccgg gggactgcgc cgcgggcaag 540
gcagccaagt gcgtcttcct ggacgacgac gatgaagacg acgacgaaga tgacgagctg 600
cagctacggc ccaagccgga cgctgacgac gacgacgacg agcccgcgca ctcgcacctg 660
ctgccgccgc cgacgcagca gcaaccccct cagctgctga ggcgctacag cgtggccaag 720
gtccccgcca gccccacgct cagcagtgcc gccgagtccc ccgagggcgc gagcctgtac 780
gacgaagtgc gcgcgggcgg ccggctctac tacagcttca agaacatcac caagcagcag 840
cctccgcccg cgcctcccgc gctgtcgccc gcgtcctccc gctgcgtgtc cacctcctca 900
tccagcggca gcagcagcgg cagcggcgcc gaggatgcag acgacctcat gttcgacctg 960
agcttgaatt tctcccaggg cgcgcacagc gcctgcgagc agccactggg cgcgggagcg 1020
gcggggaacc tgtccctgtc gctggtggat aaggacctgg attccttcag cgagggcagc 1080
ctgggttccc acttcgagtt ccccgactac tgcacgccgg agctgagcga gatgatcgcg 1140
ggggactggc tggaggcgaa cttctccgac ctggtgttca cgtattga 1188
<210> 19
<211> 349
<212> PRT
<213> 智人(Homo sapiens)
<400> 19
Met Gly Asp Met Gly Asp Pro Pro Lys Lys Lys Arg Leu Ile Ser Leu
1 5 10 15
Cys Val Gly Cys Gly Asn Gln Ile His Asp Gln Tyr Ile Leu Arg Val
20 25 30
Ser Pro Asp Leu Glu Trp His Ala Ala Cys Leu Lys Cys Ala Glu Cys
35 40 45
Asn Gln Tyr Leu Asp Glu Ser Cys Thr Cys Phe Val Arg Asp Gly Lys
50 55 60
Thr Tyr Cys Lys Arg Asp Tyr Ile Arg Leu Tyr Gly Ile Lys Cys Ala
65 70 75 80
Lys Cys Ser Ile Gly Phe Ser Lys Asn Asp Phe Val Met Arg Ala Arg
85 90 95
Ser Lys Val Tyr His Ile Glu Cys Phe Arg Cys Val Ala Cys Ser Arg
100 105 110
Gln Leu Ile Pro Gly Asp Glu Phe Ala Leu Arg Glu Asp Gly Leu Phe
115 120 125
Cys Arg Ala Asp His Asp Val Val Glu Arg Ala Ser Leu Gly Ala Gly
130 135 140
Asp Pro Leu Ser Pro Leu His Pro Ala Arg Pro Leu Gln Met Ala Ala
145 150 155 160
Glu Pro Ile Ser Ala Arg Gln Pro Ala Leu Arg Pro His Val His Lys
165 170 175
Gln Pro Glu Lys Thr Thr Arg Val Arg Thr Val Leu Asn Glu Lys Gln
180 185 190
Leu His Thr Leu Arg Thr Cys Tyr Ala Ala Asn Pro Arg Pro Asp Ala
195 200 205
Leu Met Lys Glu Gln Leu Val Glu Met Thr Gly Leu Ser Pro Arg Val
210 215 220
Ile Arg Val Trp Phe Gln Asn Lys Arg Cys Lys Asp Lys Lys Arg Ser
225 230 235 240
Ile Met Met Lys Gln Leu Gln Gln Gln Gln Pro Asn Asp Lys Thr Asn
245 250 255
Ile Gln Gly Met Thr Gly Thr Pro Met Val Ala Ala Ser Pro Glu Arg
260 265 270
His Asp Gly Gly Leu Gln Ala Asn Pro Val Glu Val Gln Ser Tyr Gln
275 280 285
Pro Pro Trp Lys Val Leu Ser Asp Phe Ala Leu Gln Ser Asp Ile Asp
290 295 300
Gln Pro Ala Phe Gln Gln Leu Val Asn Phe Ser Glu Gly Gly Pro Gly
305 310 315 320
Ser Asn Ser Thr Gly Ser Glu Val Ala Ser Met Ser Ser Gln Leu Pro
325 330 335
Asp Thr Pro Asn Ser Met Val Ala Ser Pro Ile Glu Ala
340 345
<210> 20
<211> 1050
<212> DNA
<213> 智人(Homo sapiens)
<400> 20
atgggagaca tgggagatcc accaaaaaaa aaacgtctga tttccctatg tgttggttgc 60
ggcaatcaga ttcacgatca gtatattctg agggtttctc cggatttgga atggcatgcg 120
gcatgtttga aatgtgcgga gtgtaatcag tatttggacg agagctgtac atgctttgtt 180
agggatggga aaacctactg taaaagagat tatatcaggt tgtacgggat caaatgcgcc 240
aagtgcagca tcggcttcag caagaacgac ttcgtgatgc gtgcccgctc caaggtgtat 300
cacatcgagt gtttccgctg tgtggcctgc agccgccagc tcatccctgg ggacgaattt 360
gcgcttcggg aggacggtct cttctgccga gcagaccacg atgtggtgga gagggccagt 420
ctaggcgctg gcgacccgct cagtcccctg catccagcgc ggccactgca aatggcagcg 480
gagcccatct ccgccaggca gccagccctg cggccccacg tccacaagca gccggagaag 540
accacccgcg tgcggactgt gctgaacgag aagcagctgc acaccttgcg gacctgctac 600
gccgcaaacc cgcggccaga tgcgctcatg aaggagcaac tggtagagat gacgggcctc 660
agtccccgtg tgatccgggt ctggtttcaa aacaagcggt gcaaggacaa gaagcgaagc 720
atcatgatga agcaactcca gcagcagcag cccaatgaca aaactaatat ccaggggatg 780
acaggaactc ccatggtggc tgccagtcca gagagacacg acggtggctt acaggctaac 840
ccagtggaag tacaaagtta ccagccacct tggaaagtac tgagcgactt cgccttgcag 900
agtgacatag atcagcctgc ttttcagcaa ctggtcaatt tttcagaagg aggaccgggc 960
tctaattcca ctggcagtga agtagcatca atgtcctctc aacttccaga tacacctaac 1020
agcatggtag ccagtcctat tgaggcatga 1050
<210> 21
<211> 349
<212> PRT
<213> 普通家鼠(Mus musculus)
<400> 21
Met Gly Asp Met Gly Asp Pro Pro Lys Lys Lys Arg Leu Ile Ser Leu
1 5 10 15
Cys Val Gly Cys Gly Asn Gln Ile His Asp Gln Tyr Ile Leu Arg Val
20 25 30
Ser Pro Asp Leu Glu Trp His Ala Ala Cys Leu Lys Cys Ala Glu Cys
35 40 45
Asn Gln Tyr Leu Asp Glu Ser Cys Thr Cys Phe Val Arg Asp Gly Lys
50 55 60
Thr Tyr Cys Lys Arg Asp Tyr Ile Arg Leu Tyr Gly Ile Lys Cys Ala
65 70 75 80
Lys Cys Ser Ile Gly Phe Ser Lys Asn Asp Phe Val Met Arg Ala Arg
85 90 95
Ser Lys Val Tyr His Ile Glu Cys Phe Arg Cys Val Ala Cys Ser Arg
100 105 110
Gln Leu Ile Pro Gly Asp Glu Phe Ala Leu Arg Glu Asp Gly Leu Phe
115 120 125
Cys Arg Ala Asp His Asp Val Val Glu Arg Ala Ser Leu Gly Ala Gly
130 135 140
Asp Pro Leu Ser Pro Leu His Pro Ala Arg Pro Leu Gln Met Ala Ala
145 150 155 160
Glu Pro Ile Ser Ala Arg Gln Pro Ala Leu Arg Pro His Val His Lys
165 170 175
Gln Pro Glu Lys Thr Thr Arg Val Arg Thr Val Leu Asn Glu Lys Gln
180 185 190
Leu His Thr Leu Arg Thr Cys Tyr Ala Ala Asn Pro Arg Pro Asp Ala
195 200 205
Leu Met Lys Glu Gln Leu Val Glu Met Thr Gly Leu Ser Pro Arg Val
210 215 220
Ile Arg Val Trp Phe Gln Asn Lys Arg Cys Lys Asp Lys Lys Arg Ser
225 230 235 240
Ile Met Met Lys Gln Leu Gln Gln Gln Gln Pro Asn Asp Lys Thr Asn
245 250 255
Ile Gln Gly Met Thr Gly Thr Pro Met Val Ala Ala Ser Pro Glu Arg
260 265 270
His Asp Gly Gly Leu Gln Ala Asn Pro Val Glu Val Gln Ser Tyr Gln
275 280 285
Pro Pro Trp Lys Val Leu Ser Asp Phe Ala Leu Gln Ser Asp Ile Asp
290 295 300
Gln Pro Ala Phe Gln Gln Leu Val Asn Phe Ser Glu Gly Gly Pro Gly
305 310 315 320
Ser Asn Ser Thr Gly Ser Glu Val Ala Ser Met Ser Ser Gln Leu Pro
325 330 335
Asp Thr Pro Asn Ser Met Val Ala Ser Pro Ile Glu Ala
340 345
<210> 22
<211> 1050
<212> DNA
<213> 普通家鼠(Mus musculus)
<400> 22
atgggagaca tgggcgatcc accaaaaaaa aaacgtctga tttccctgtg tgttggttgc 60
ggcaatcaaa ttcacgacca gtatattctg agggtttctc cggatttgga gtggcatgca 120
gcatgtttga aatgtgcgga gtgtaatcag tatttggacg aaagctgtac gtgctttgtt 180
agggatggga aaacctactg taaaagagat tatatcaggt tgtacgggat caaatgcgcc 240
aagtgcagca taggcttcag caagaacgac ttcgtgatgc gtgcccgctc taaggtgtac 300
cacatcgagt gtttccgctg tgtagcctgc agccgacagc tcatcccggg agacgaattc 360
gccctgcggg aggatgggct tttctgccgt gcagaccacg atgtggtgga gagagccagc 420
ctgggagctg gagaccctct cagtcccttg catccagcgc ggcctctgca aatggcagcc 480
gaacccatct cggctaggca gccagctctg cggccgcacg tccacaagca gccggagaag 540
accacccgag tgcggactgt gctcaacgag aagcagctgc acaccttgcg gacctgctat 600
gccgccaacc ctcggccaga tgcgctcatg aaggagcaac tagtggagat gacgggcctc 660
agtcccagag tcatccgagt gtggtttcaa aacaagcggt gcaaggacaa gaaacgcagc 720
atcatgatga agcagctcca gcagcagcaa cccaacgaca aaactaatat ccaggggatg 780
acaggaactc ccatggtggc tgctagtccg gagagacatg atggtggttt acaggctaac 840
ccagtagagg tgcaaagtta ccagccgccc tggaaagtac tgagtgactt cgccttgcaa 900
agcgacatag atcagcctgc ttttcagcaa ctggtcaatt tttcagaagg aggaccaggc 960
tctaattcta ctggcagtga agtagcatcg atgtcctcgc agctcccaga tacacccaac 1020
agcatggtag ccagtcctat tgaggcatga 1050
<210> 23
<211> 53
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 23
gcccacctgt agcatcatca acatgggacc ccagaacaga aacactagct ttg 53
<210> 24
<211> 448
<212> DNA
<213> 智人(Homo sapiens)
<400> 24
agtgcaagtg ggttttagga ccaggatgag gcggggtggg ggtgcctacc tgacgaccga 60
ccccgaccca ctggacaagc acccaacccc cattccccaa attgcgcatc ccctatcaga 120
gagggggagg ggaaacagga tgcggcgagg cgcgtgcgca ctgccagctt cagcaccgcg 180
gacagtgcct tcgcccccgc ctggcggcgc gcgccaccgc cgcctcagca ctgaaggcgc 240
gctgacgtca ctcgccggtc ccccgcaaac tccccttccc ggccaccttg gtcgcgtccg 300
cgccgccgcc ggcccagccg gaccgcacca cgcgaggcgc gagatagggg ggcacgggcg 360
cgaccatctg cgctgcggcg ccggcgactc agcgctgcct cagtctgcgg tgggcagcgg 420
aggagtcgtg tcgtgcctga gagcgcag 448
<210> 25
<211> 601
<212> DNA
<213> 智人(Homo sapiens)
<400> 25
gttgacattg attattgact agttattaat agtaatcaat tacggggtca ttagttcata 60
gcccatatat ggagttccgc gttacataac ttacggtaaa tggcccgcct ggctgaccgc 120
ccaacgaccc ccgcccattg acgtcaataa tgacgtatgt tcccatagta acgccaatag 180
ggactttcca ttgacgtcaa tgggtggagt atttacggta aactgcccac ttggcagtac 240
atcaagtgta tcatatgcca agtacgcccc ctattgacgt caatgacggt aaatggcccg 300
cctggcatta tgcccagtac atgaccttat gggactttcc tacttggcag tacatctacg 360
tattagtcat cgctattagc atggtgatgc ggttttggca gtacatcaat gggcgtggat 420
agcggtttga ctcacgggga tttccaagtc tccaccccat tgacgtcaat gggagtttgt 480
tttggcacca aaatcaacgg gactttccaa aatgtcgtaa caactccgcc ccattgacgc 540
aaatgggcgg taggcgtgta cggtgggagg tctatataag cagagctccg tttagtgaac 600
g 601
<210> 26
<211> 601
<212> DNA
<213> 智人(Homo sapiens)
<400> 26
gttgacattg attattgact agttattaat agtaatcaat tacggggtca ttagttcata 60
gcccatatat ggagttccgc gttacataac ttacggtaaa tggcccgcct ggctgaccgc 120
ccaacgaccc ccgcccattg acgtcaataa tgacgtatgt tcccatagta acgccaatag 180
ggactttcca ttgacgtcaa tgggtggagt atttacggta aactgcccac ttggcagtac 240
atcaagtgta tcatatgcca agtacgcccc ctattgacgt caatgacggt aaatggcccg 300
cctggcatta tgcccagtac atgaccttat gggactttcc tacttggcag tacatctacg 360
tattagtcat cgctattagc atggtgatgc ggttttggca gtacatcaat gggcgtggat 420
agcggtttga ctcacgggga tttccaagtc tccaccccat tgacgtcaat gggagtttgt 480
tttggcacca aaatcaacgg gactttccaa aatgtcgtaa caactccgcc ccattgacgc 540
aaatgggcgg taggcgtgta gggtgggagg tctatataag cagagctccg tttagtgaac 600
g 601
<210> 27
<211> 601
<212> DNA
<213> 智人(Homo sapiens)
<400> 27
gttgacattg attattgact agttattaat agtaatcaat tacggggtca ttagttcata 60
gcccatatat ggagttccgc gttacataac ttacggtaaa tggcccgcct ggctgaccgc 120
ccaacgaccc ccgcccattg acgtcaataa tgacgtatgt tcccatagta acgccaatag 180
ggactttcca ttgacgtcaa tgggtggagt atttacggta aactgcccac ttggcagtac 240
atcaagtgta tcatatgcca agtacgcccc ctattgacgt caatgacggt aaatggcccg 300
cctggcatta tgcccagtac atgaccttat gggactttcc tacttggcag tacatctacg 360
tattagtcat cgctattagc atggtgatgc ggttttggca gtacatcaat gggcgtggat 420
aggggtttga ctcacgggga tttccaagtc tccaccccat tgacgtcaat gggagtttgt 480
tttggcacca aaatcaacgg gactttccaa aatgtcgtaa caactccgcc ccattgacgc 540
aaatgggcgg taggcgtgta cggtgggagg tctatataag cagagctccg tttagtgaac 600
g 601
Claims (39)
1.制备对视觉信号有反应的哺乳动物细胞的方法,其包括增加视网膜神经元细胞中一个或多个选自由以下组成的组的基因的生物学活性:
POU 4类同源框2(Brn3B)
SRY-box转录因子4(Sox4)
Atonal BHLH转录因子7(Atoh7),
SRY-Box转录因子11(Sox11),和
ISL LIM同源框1(Ils1)。
2.根据权利要求1所述的方法,其中所述一种或多种基因包括Brn3B和Sox4。
3.根据权利要求2所述的方法,其中所述一种或多种基因进一步包括Atoh7。
4.根据权利要求1-3中任一项所述的方法,其中,所述视网膜神经元细胞是选自由无长突细胞、水平细胞和双极细胞组成的组的视网膜中间神经元细胞,或者是退化、损伤或老化的视网膜神经节细胞(RGC)。
5.根据权利要求1-4中任一项所述的方法,其中,所述视网膜神经元细胞是Lgr5+无长突细胞。
6.根据权利要求1-4中任一项所述的方法,其中,所述视网膜神经元细胞是Prokr2+置换的无长突细胞。
7.改善视网膜神经节细胞(RGC)功能的方法,包括增加RGC中一个或多个选自由Atoh7、Brn3B、Sox4、Sox11和Ils1组成的组的基因的生物学活性。
8.根据权利要求7所述的方法,其中,所述RGC是退化的、受损的、老化的或正常的视网膜神经节细胞(RGC)。
9.根据权利要求1-8中任一项所述的方法,其中增加所述一种或多种基因的生物学活性包括向所述视网膜神经元细胞中引入编码所述基因的一种或多种多核苷酸。
10.根据权利要求9所述的方法,其中所述一种或多种多核苷酸是cDNA。
11.根据权利要求10所述的方法,其中所述一种或多种多核苷酸在质粒或病毒载体中提供。
12.根据权利要求11所述的方法,其中,所述病毒载体是腺相关病毒(AAV)载体。
13.根据权利要求9所述的方法,其中所述一种或多种多核苷酸是mRNA。
14.根据权利要求1-8中任一项所述的方法,其中增加所述基因的生物学活性包括将相应的蛋白质引入视网膜神经元细胞。
15.根据权利要求1-8中任一项所述的方法,其中增加所述基因的生物学活性包括激活所述内源基因在所述视网膜神经元细胞中的表达。
16.根据权利要求1-15中任一项所述的方法,其中,所述视网膜神经元细胞存在于患有视力障碍的受试者体内。
17.根据权利要求1-15中任一项所述的方法,其中,所述视网膜神经元细胞是体外的。
18.根据权利要求17所述的方法,还包括将制备的对视觉信号有反应的哺乳动物细胞植入患有视力障碍的受试者。
19.能够增加一种或多种选自由Atoh7、Brn3B、Sox4、Sox11和Ils1组成的组的基因的生物学活性的试剂在制备治疗视力障碍或失明的药物中的用途。
20.用于治疗有需要的受试者的视力障碍或失明的方法,包括向受试者的视网膜施用能够增加一种或多种选自由Brn3B、Sox4、Atoh7、Sox11和Ils1组成的基因的生物学活性的试剂。
21.根据权利要求19所述的用途或权利要求20所述的方法,其中所述一种或多种基因包括Brn3B和Sox4。
22.根据权利要求19或20所述的用途或根据权利要求19或21所述的方法,其中所述视力障碍或失明是由退化的视网膜神经节细胞(RGC)引起的。
23.根据权利要求22所述的用途或方法,其中所述视力障碍或失明与选自由视神经病包括青光眼、遗传性视神经病和由毒素、营养缺陷和外伤引起的病症组成的组的病况相关。
24.根据权利要求22所述的用途或方法,其中所述试剂包含编码所述一种或多种基因的一种或多种多核苷酸。
25.根据权利要求20所述的方法,其中所述施用是通过玻璃体内注射。
26.核酸构建体,其包含编码Brn3B和Sox4蛋白的编码序列,以及与每个编码序列结合的启动子,其中每个启动子在视网膜神经元细胞中是有活性的。
27.根据权利要求26所述的核酸构建体,其中所述启动子中的至少一个是Pax6、Tcfap2b、Gad1、GlyT1、RBPMS或Prox1基因的启动子。
28.根据权利要求26所述的核酸构建体,其中所述启动子中的至少一个是突触蛋白1启动子。
29.根据权利要求26-28中任一项所述的核酸构建体,其还包含表达载体,所述表达载体为质粒载体或病毒载体。
30.根据权利要求29所述的核酸构建体,其中所述表达载体是AAV载体。
31.根据权利要求30所述的核酸构建体,其中所述AAV选自由AAV1、AAV2、AAV3、AAV4、AAV5、AAV6、AAV7、AAV8、AAV9、AAV10、AAV11和AAV12组成的组。
32.根据权利要求30所述的核酸构建体,其中所述AAV是血清型AAV2。
33.根据权利要求30所述的核酸构建体,其中所述AAV是AAV2.7m8或AAV7m8。
34.细胞,其由根据权利要求26-33中任一项所述的核酸构建体转染。
35.根据权利要求34所述的细胞,其是视网膜神经元细胞。
36.根据权利要求35所述的细胞,其对视觉信号有反应。
37.对视觉信号有反应的哺乳动物细胞,其通过增加视网膜神经元细胞中一个或多个选自由Brn3B、Sox4、Atoh7、Sox11和Ils1组成的组的基因的生物学活性而制备。
38.根据权利要求37所述的哺乳动物细胞,其是在体外制备的。
39.根据权利要求37或38所述的哺乳动物细胞,其是再生或恢复活力的视网膜神经节细胞(RGC)。
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