CN109971729A - 一种新型酶组合物 - Google Patents
一种新型酶组合物 Download PDFInfo
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- CN109971729A CN109971729A CN201910322504.8A CN201910322504A CN109971729A CN 109971729 A CN109971729 A CN 109971729A CN 201910322504 A CN201910322504 A CN 201910322504A CN 109971729 A CN109971729 A CN 109971729A
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- ala
- leu
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Abstract
本发明涉及一种N端缺失60至120个氨基酸的酪氨酸羟化酶变体,以及一种药物组合物,其包括N端缺失60至120个氨基酸的酪氨酸羟化酶变体和芳香族L‑氨基酸脱羧酶;本发明还涉及包括所述酪氨酸羟化酶变体或所述药物组合物的核苷酸构建体、载体质粒、细胞、病毒,以及所述病毒在制备治疗退行性疾病例如帕金森病药物中的用途。
Description
技术领域
本发明涉及一种药物组合物,其包括酪氨酸羟化酶变体和芳香族L-氨基酸脱羧酶,和其核苷酸构建体、载体质粒、细胞、病毒,以及所述病毒在制备治疗退行性疾病例如帕金森病药物中的用途。属于基因工程技术领域。
背景技术
帕金森病(Parkinson′s Disease,PD)是一类严重的神经退行性疾病,以震颤、僵硬和运动障碍为主要症状。病理上主要表现为位于大脑黑质区(substantia nigra,SN)的多巴胺(dopamine)能神经元的进行性退化。上述病变将造成纹状体(Striatum)区域的多巴胺能神经元的投射减少及此区域多巴胺浓度的降低。因此,增加纹状体区域多巴胺能传递的药理学方法是治疗PD的有效手段。多巴胺替代疗法,即口服左旋多巴(L-Dopa),是目前最主要的药物疗法。虽然此疗法在短期内显著改善了PD患者的生活质量,但多巴胺替代疗法的有效性会随着时间逐渐降低,在超过5到10年后,所有患者的病情会最终进展到口服左旋多巴难以治疗的地步。
酶替代疗法(enzyme replacement therapies)的目的是补偿由于黑质区域多巴胺能神经元退化所引起的多巴胺释放的减少。上述方法原理是将编码多巴胺合成所需的酶的基因递送到纹状体的GABA能神经元中。在此条件下,GABA能神经元能够持续异位合成多巴胺,并在相应的纹状体区域释放。这种方法可以减少运动障碍的发生,并限制由基底神经节(basal ganglia)外多巴胺水平升高所引起的副作用。然而,多巴胺浓度升高会负反馈调节酪氨酸羟化酶(tyrosine hydroxylase,TH)的活性,从而限制其异位合成多巴胺的能力。
因此,寻找疗效更佳的酶替代疗法对于治疗帕金森病至关重要。
发明内容
本发明提供了一种酪氨酸羟化酶(又简称TH)变体,其中,所述酪氨酸羟化酶变体包括如SEQ ID NO:1所示的氨基酸序列的N端缺失60至120个氨基酸的人酪氨酸羟化酶,优选所述酪氨酸羟化酶变体包括如SEQ ID NO:1所示的氨基酸序列的N端缺失80至100个氨基酸的人酪氨酸羟化酶,更优选为,如SEQ ID NO:1所示的氨基酸序列的N端缺失80至90个氨基酸的人酪氨酸羟化酶,例如如SEQ ID NO:1所示的氨基酸序列的N端缺失80、81、82、83、84、85、86、87、88、89、90、91、92、92、94、95、96、97、98、99、或100个氨基酸的人酪氨酸羟化酶。
在一个实施例中,所述酪氨酸羟化酶变体包括如SEQ ID NO:2所示的蛋白或与SEQID NO:1所示的氨基酸序列具有80%序列同一性的酪氨酸羟化酶衍生物,例如80%、90%、95%、99%以上同一性,其中,所述衍生物为由SEQ ID NO:1所示氨基酸序列经过一个或少数几个例如2、3、4、5、6、7、8、9、10个氨基酸残基的取代、缺失或添加而形成的且具有氨基酸序列如SEQ ID NO:1所示的蛋白功能的酪氨酸羟化酶变体,其活性为如SEQ ID NO:1所示蛋白的50%以上,例如60%、70%、80%、85%、90%、95%、99%以上。所述酪氨酸羟化酶变体可选择性包含标签蛋白,所述标签蛋白包括但不限于HA、Myc、Flag。
在另一方面,本发明还提供了一种组合物,包括如前所述酪氨酸羟化酶变体。
在一个实施例中,所述的组合物还包括芳香族L-氨基酸脱羧酶,优选全长的芳香族L-氨基酸脱羧酶,其包含如SEQ ID NO:4-9中任一序列所示的蛋白或与SEQ ID NO:4-9任一序列所示的氨基酸序列具有80%序列同一性的芳香族L-氨基酸脱羧酶衍生物,例如80%、90%、95%、99%以上同一性,其中,所述衍生物为由SEQ ID NO:4-9所示氨基酸序列经过一个或少数几个例如2、3、4、5、6、7、8、9、10个氨基酸残基的取代、缺失或添加而形成的且具有氨基酸序列如SEQ ID NO:4-9所示的蛋白功能的芳香族L-氨基酸脱羧酶衍生物,其活性为如SEQ ID NO:4-9所示蛋白的50%以上,例如60%、70%、80%、85%、90%、95%、99%以上。所述芳香族L-氨基酸脱羧酶可选择性包含标签蛋白。所述芳香族L-氨基酸脱羧酶还可选择性在序列N端或C端包含标签蛋白,更优选地,所述标签蛋白包括但不限于HA、Myc、Flag。
在一个具体实施例中,所述芳香族L-氨基酸脱羧酶的氨基酸序列如SEQ ID NO:10所示。
在一个具体实施例中,所述芳香族L-氨基酸脱羧酶蛋白(又简称AADC)可以是来自DDC基因的天然存在的异形体或变体中的任何一种。现有技术中已经鉴别出编码不同AADC异形体的多种交替剪接的转录物变体。具体地,DDC基因产生7种转录物变体,它们编码6种不同的蛋白异形体。DDC基因转录物变体1和2都编码AADC异形体1。在优选的实施方式中,所述全长芳香族L-氨基酸脱羧酶AADC是AADC异形体1(NCBI参照序列:NP_000781.1),其编码多核苷酸序列是DDC基因转录物变体1或2的编码区序列。本领域技术人员根据现有技术可合理预期这些天然存在的异形体均可以适用于本发明中,达到相同的效果,例如SEQ IDNO:4-9中任一序列所示的氨基酸序列的AADC。
另一方面,本发明还提供了一种核苷酸构建体,其包含编码如前所述的酪氨酸羟化酶变体的多核苷酸或如前所述的药物组合物的核苷酸序列。
在一个实施例中,所述酪氨酸羟化酶变体的多核苷酸序列如SEQ ID NO:12或13或与其具有80%以上,优选80%、90%、95%、99%以上同一性的序列所示,和/或所述芳香族L-氨基酸脱羧酶的多核苷酸序列如SEQ ID NO:14-21中任一个或与其具有80%以上,优选80%、90%、95%、99%以上同一性的序列所示。
在一个具体实施例中,所述酪氨酸羟化酶的多核苷酸序列为由SEQ ID NO:12或13所示核苷酸序列经过一个或少数几个例如2、3、4、5、6、7、8、9、10个核苷酸残基的取代、缺失或添加而形成的核苷酸序列且具有如SEQ ID NO:12或13所示功能的变体,其序列与SEQ IDNO:12或13具有90%以上,例如95%、99%以上的序列同一性或生物活性。
在一个具体实施例中,所述芳香族L-氨基酸脱羧酶的多核苷酸序列为由SEQ IDNO:14-21所示核苷酸序列经过一个或少数几个例如2、3、4、5、6、7、8、9、10个核苷酸残基的取代、缺失或添加而形成的核苷酸序列且具有如SEQ ID NO:14-21所示功能的变体,其序列与SEQ ID NO:14-21具有90%以上,例如95%、99%以上的序列同一性或生物活性。
本发明提供了一种载体质粒,其包含如前所述的核苷酸构建体。
在一个实施例中,酪氨酸羟化酶变体为人源酪氨酸羟化酶变体;芳香族L-氨基酸脱羧酶为人源芳香族L-氨基酸脱羧酶。
在一个实施例中,组合物中酪氨酸羟化酶变体的核苷酸序列和芳香族L-氨基酸脱羧酶的核苷酸序列可被构建于同一载体质粒中,也可构建于不同载体质粒中,其中所述载体质粒选自单纯孢疹病毒载体、腺病毒载体、腺相关病毒载体,对于中枢神经系统(CNS)而言,有效的表达载体包括但不限于病毒载体HSV、Ad或者AAV,优选腺相关病毒AAV。在具体的实施方式中,所述AAV的血清型为AAV9。在具体的实施方式中,所述AAV转基因的长度小于5000bp,例如大约4550bp,AAV中包括ITR、启动子,WPRE和polyA。
本领域技术人员可以认识到,外源基因的表达需要适当的启动子,包括但不限于物种特异性的、可诱导的、组织特异性的或细胞周期特异性的启动子。基因表达调控的精确特性一般来说都会包含一个引导RNA转录起始的启动子,所述启动子可以是组成性的也可以是可诱导的。启动子可以是所有细胞类型都表达的,例如CMV;也可以是细胞类型特异的。对于中枢神经系统来说,神经元特异的启动子包括但不限于神经丝(neurofilament)、突触蛋白(synapsin)和血清素受体(serotonin receptor);胶质细胞特异的启动子包括但不限于胶质细胞原纤维酸性蛋白(glial fibrillary acidic protein,GFAP)、S100和谷氨酰胺合成酶(glutamine synthase)。在本发明的具体实施方式中,使用人源的突触蛋白(synapsin)作为本发明的多核苷酸在载体质粒中编码的启动子,上述多核苷酸编码的蛋白将特异性地表达于神经元中。本领域技术人员可合理预期其他神经元特异的启动子也具备相应的作用。
在一个具体实施例中,所述载体包括以下三个部分(5’到3’):
1).编码N端缺失90个氨基酸的TH的多核苷酸序列;
2).具有肽段自剪切功能的T2A序列;和
3).编码全长AADC的多核苷酸序列。
在一个具体实施例中,编码N端缺失90个氨基酸的TH的多核苷酸序列和编码全长AADC的多核苷酸序列也可以分别在不同载体中。
在一个具体实施例中,当所述编码N端缺失90个氨基酸的TH和编码全长AADC的多核苷酸序列在同一载体中,两者之间加入具有肽段自剪切功能的T2A序列,从而构建出可以同时生产两个蛋白的单顺反子。
在另一具体实施方式中,所述编码N端缺失90个氨基酸的TH和编码全长AADC的多核苷酸序列之间被加入内部核糖体进入位点(internal ribosome entry site,IRES)。当IRES存在于一条mRNA的终止密码子的下游,它可以导致核糖体的重新加入,从而起始第二个开放阅读框(Open Reading Frame,ORF)的翻译。
另一方面,本发明提供了一种细胞,其被如前所述的载体质粒转染后制备而成。
本发明提供了一种病毒,其包含如前所述的核苷酸构建体作为其基因组。
另一方面,本发明提供了一种药物组合物,包含如前所述的病毒和药物学可接受的载体。
又一方面,本发明提供了一种利用如前所述的酪氨酸羟化酶变体、如前所述的药物组合物、如前所述的核苷酸构建体、如前所述的载体质粒、如前所述的细胞、如前所述的病毒、如前所述的组合物治疗受试者神经退行性疾病的方法。
在一个实施例中,将包括酪氨酸羟化酶变体和芳香族L-氨基酸脱羧酶的核苷酸构建体的病毒施用于受试者大脑纹状体中,并将酪氨酸羟化酶变体和芳香族L-氨基酸脱羧酶的核苷酸表达,进而引起多巴胺在纹状体区域的异位合成,最终有效恢复患有帕金森疾病的受试者的运动表型。
其中,所述纹状体为尾状核-壳核(caudate-putamen,CP)区域。
在一个实施例中,本发明公开了如前所述的酪氨酸羟化酶变体、如前所述的药物组合物、如前所述的核苷酸构建体、如前所述的载体质粒、如前所述的细胞、如前所述的病毒、如前所述的组合物在制备用于治疗受试者神经退行性疾病药物中的用途。
其中,所述神经退行性疾病为帕金森病。
其中,所述受试者为哺乳动物,优选为人类、大鼠、小鼠。
发明的有益效果
本发明的有益效果在于使用本发明提供的治疗方法,多巴胺异位合成的酶组合物可以引起细胞释放的多巴胺浓度显著增高,且明显高于其他的组合方式,进而利用AAV载体递送以上外源基因,实现了编码目标酶组合物的基因在大脑纹状体区域的有效表达,从而使PD的疾病表型得到显著改善,说明AAV为表达载体的酶组合物具有基因治疗的重大应用价值。
附图说明
图1示出了本发明用于表达人源酪氨酸羟化酶变体和人源芳香族L-氨基酸脱羧酶的AAV载体图谱。
图2示出了通过高效液相色谱实验测量的一系列N端缺失的TH与全长AADC的酶组合物表达在293细胞系中促进多巴胺从头合成的定量统计图。其中GFP为阴性对照,WT表示双酶组合物中的TH为野生型全长TH,Isob表示TH的另一个蛋白异构体,40表示N端缺失40个氨基酸的TH,60表示N端缺失60个氨基酸的TH,80表示N端缺失80个氨基酸的TH,90表示N端缺失90个氨基酸的TH,100表示N端缺失100个氨基酸的TH,120表示N端缺失120个氨基酸的TH,150表示N端缺失150个氨基酸的TH,164表示N端缺失164个氨基酸的TH,190表示N端缺失190个氨基酸的TH。图2中统计方法用的是单因素方差分析。“*”表示p<0.05,“****”表示p<0.0001,“ns”表示没有显著性差异。
图3示出了制备成功的PD模型小鼠的大脑切片的TH染色情况。图的右侧为6-OHDA损伤侧,左侧为对照侧。比例尺为1mm。
图4示出了总体的实施流程(图4a)以及人源酪氨酸羟化酶变体和人源芳香族L-氨基酸脱羧酶对于PD模型小鼠由阿扑吗啡诱导的运动不协调表型的恢复情况(图4b)。图4b中统计方法用的是t检验。其中“###”表示在病毒注射后4周,相比于对照组(GFP),注射表达人源酪氨酸羟化酶变体和人源芳香族L-氨基酸脱羧酶(TH90del/AADC)病毒的实验组的运动不协调表型得到显著改善,p<0.001;“****”则表示实验组在注射该病毒后,运动不协调表型得到显著改善,p<0.0001。
具体实施方式
下面通过具体实施方式及实验数据对本发明做进一步说明。尽管为了清楚的目的,在下文中使用了专用术语,但这些术语并不意味着定义或限制本发明的范围。
本文所用的术语“PD动物模型”是指,能模拟与PD病理一致的关键表型(位于大脑黑质区多巴胺神经元的退行)的动物模型。在具体的实施方式中,本发明所用的PD动物模型是利用毒性药物(例如6-羟多巴胺,6-OHDA)杀死大脑单侧中脑腹侧被盖区(Ventraltegmental area,VTA)或黑质区的多巴胺神经元的品系名称为C57BL/6的小鼠。然而,本领域技术人员还应明白PD动物模型的构建是为人类PD的治疗提供指导依据和方法论。因此,进化上与人类亲缘关系更接近的非人灵长类的PD模型在理论上同样能帮助临床转化目标的实现。本具体实施例中使用的小鼠模型仅仅是为了说明本发明的酶组合物具有改善PD运动障碍的功能,并不意味着其只在小鼠动物上有效,本领域技术人员根据现有技术的理解,能够合理预期本发明的酶组合物具有改善其他物种例如人类等的PD运动障碍的能力。
本文所用的术语“异位合成”或“从头合成”是指,在原本不合成某化合物的细胞、组织或器官中通过某种技术手段开始合成此种化合物。在具体的实施方式中,本发明所用的酶组合物可以在原本不合成多巴胺的纹状体MSN神经元中行使功能,促进此脑区多巴胺的合成与分泌,从而起到缓解PD疾病相关表型的作用。
本文所用的术语“载体”、“表达载体”或者“病毒载体”是指,运输、转导和在靶细胞表达被包含的外源目的基因(例如本发明所述的多核苷酸)的分子工具,所述工具提供合适的在靶细胞中起始转录的核苷酸序列,即启动子。本领域技术人员明白,在基因治疗领域中,利用病毒载体将外源目的基因导入靶细胞并表达是优选的实施方式。在具体的实施方式中,本发明基于AAV载体实现酶组合物的表达和多巴胺的异位合成。然而,鉴于本发明的教导以及现有技术,本领域技术人员还应明白本发明所用的AAV载体还应包括所述载体的变化形式,所述变化形式包括但不限于不影响AAV载体基本功能的序列改变,或者AAV血清型的改变。
本发明所用术语“酶组合物”、“药物组合物”可互换,包括N端缺失大于60和小于120个氨基酸例如缺失80、90或100个氨基酸的TH和AADC。其中缺失90个氨基酸序列的TH的氨基酸序列如SEQ ID NO:2所示,AADC可以为全长的AADC,其氨基酸序列如SEQ ID NO:4所示。鉴于本发明的教导以及现有技术,本领域技术人员还应明白本发明所用的N端缺失90个氨基酸的TH或全长AADC还应包括所述酶的变异形式,所述变异形式具有与所述N端缺失90个氨基酸的TH或全长AADC相同或相似的功能,但其氨基酸序列允许有少量差异。这些变异形式包括但不限于:一个或多个(例如1-5个)氨基酸的缺失、插入和/或取代,以及在C末端和/或N末端添加一个或多个(通常为20个以内,较佳地为10个以内,更佳地为5个以内)氨基酸。例如,本领域技术人员熟知,用性能相近或相似的氨基酸进行取代,例如,异亮氨酸与亮氨酸相互取代时,不会改变所得蛋白质的功能。再例如,在C末端和/或N末端添加一个或数个氨基酸,例如为便于分离或检测而添加的标签通常不会改变所得蛋白质的功能。在具体的实施方式中,本发明所用的“酶组合物”可以为N末端添加了HA标签的N端缺失90个氨基酸的TH和C末端添加了myc标签的全长AADC。
本领域技术人员明白,本发明的“N端缺失90个氨基酸的TH”或“全长AADC”还包括所述具体“N端缺失90个氨基酸的TH”或“全长AADC”的片段、衍生物和类似物,所用术语“片段”、“衍生物”和“类似物”是指基本上保持所述“N端缺失90个氨基酸的TH”或“全长AADC”的生物学功能或活性的多肽。本发明的多肽片段、衍生物或类似物可以是(i)有一个或多个保守或非保守性氨基酸残基(优选保守性氨基酸残基)被取代的多肽,或(ii)在一个或多个氨基酸残基中具有取代基团的多肽,或(iii)成熟多肽与另一个化合物(比如延长多肽半衰期的化合物,例如聚乙二醇)融合所形成的多肽,或(iv)附加的氨基酸序列融合到此多肽序列而形成的多肽(如前导序列或分泌序列或用来纯化此多肽的序列或蛋白原序列,或融合蛋白)。根据本文的定义这些片段、衍生物和类似物属于本领域熟练技术人员公知的范围。
所述“N端缺失90个氨基酸的TH”或“全长AADC”的任何一种生物活性片段都可以应用于本发明。在本文中,“N端缺失90个氨基酸的TH”或“全长AADC”的生物活性片段是指所述“N端缺失90个氨基酸的TH”或“全长AADC”的片段,但其仍然能保持“N端缺失90个氨基酸的TH”或“全长AADC”的全部或部分功能。通常情况下,所述的生物活性片段至少保持“N端缺失90个氨基酸的TH”或“全长AADC”50%的活性。在更优选的条件下,所述活性片段能够保持“N端缺失90个氨基酸的TH”或“全长AADC”的60%、70%、80%、90%、95%、99%、或100%的活性。例如在本发明中,“N端缺失80个氨基酸的TH”保持了“N端缺失90个氨基酸的TH”100%的活性,“N端缺失100个氨基酸的TH”保持了“N端缺失90个氨基酸的TH”80%的活性,“N端缺失190个氨基酸的TH”保持了“N端缺失90个氨基酸的TH”60%的活性。
本发明中的术语“多核苷酸”可以是DNA形式或RNA形式。DNA形式包括cDNA、基因组DNA或人工合成的DNA。DNA可以是单链的或是双链的。编码成熟多肽的编码区序列可以与所述具体“N端缺失90个氨基酸的TH”或“全长AADC”的编码区序列相同或者是其简并的变异体。“简并的变异体”在本发明中是指编码具有所述“N端缺失90个氨基酸的TH”或“全长AADC”的氨基酸序列的蛋白质,但与所述“N端缺失90个氨基酸的TH”或“全长AADC”的编码序列有差别的核苷酸序列。
本发明中术语“标签蛋白”和“蛋白标签”可互换,是指利用DNA体外重组技术,与目的蛋白一起融合表达的一种多肽或者蛋白,以便于蛋白表达、检测、示踪、纯化。标签蛋白包括但不限于His6、Flag、GST、MBP、HA、GFP、Myc。
如本文所用,术语“受试者”包括任何人或非人动物。术语“非人动物”包括所有脊椎动物,例如哺乳动物和非哺乳动物,例如非人灵长类动物、绵羊、狗、猫、马、牛、鸡、大鼠、小鼠、两栖动物、爬行动物等。除非另有说明,否则术语“患者”或“受试者”可互换使用。
术语“治疗”和“治疗方法”是指治疗性和预防性措施。需要治疗的人可能包括已经患有特定疾病的个体以及最终可能患有该疾病的个体。
下述实施例中的实验方法,如无特殊说明,均为常规方法。
具体实施例:
实验和材料
1.酶组合物的AAV表达载体构建
表达所述酶组合物的多核苷酸序列及AAV载体(Addgene:26972)经过核苷酸内切酶BamHI和EcoRI在37℃酶切1小时后得到相应的粘性末端。经割胶回收目的片段后,利用T4连接酶16℃连接过夜。转化后挑选单克隆培养,并抽提质粒。所述质粒经Sanger测序验证正确。
2.293细胞系培养及体外转染
293细胞系的培养基为加入GlutaMAX和双抗(penicillin和Streptomycin)的DMEM,培养环境为37℃、5%CO2的细胞培养箱。293细胞密度达到6孔板面积约80%时进行脂质体转染,所用试剂为lipofectamine 3000reagent。每孔细胞转染3μg相应质粒。继续培养48小时后进行后续实验。
3.高效液相色谱(high-performance liquid chromatography,HPLC)
吸干293细胞的培养基后,用温暖的PBS洗一次细胞,之后在PBS(1mL)中培养1小时。收集PBS后,3000rpm、4℃离心10分钟,取上清与浓度为0.6M的HClO4按1∶1混合,使得HClO4终浓度为0.3M。充分混匀后,20000rpm、4℃离心15分钟,取上清进行HPLC检测。HPLC系统装配有ESA Coulochem III电化学检测器。儿茶酚胺用Eclipse Plus C18的柱子(3.5μm,2.1×150mm)进行分离。柱子用流速为0.2mL/分钟的流动相进行平衡,之后进行电化学检测并计算多巴胺浓度。
4.立体定位注射
向大脑单侧的黑质/中脑腹侧被盖区(Substantia Nigra/Ventral TegmentalArea,SN/VTA)注射6-OHDA以制备PD模型小鼠。利用立体定位注射仪向小鼠大脑单侧SN/VTA注射500nL浓度为8mg/mL的6-OHDA。6-OHDA作为一种毒性药物会选择性杀死多巴胺能神经元。注射位点为AP-3.6,ML-0.5和DV-4.3,注射速度为50nL/分钟。
在验证目标酶组合物对于PD模型小鼠表型恢复的实验中,发明人将包装目标双酶组合物表达载体的血清型为AAV9的病毒颗粒(滴度:1.95×1013vg/mL)注射进小鼠大脑纹状体尾状核-壳核(caudate-putamen,CP)进行表达。包装GFP的病毒颗粒(滴度:7.78×1012vg/mL)作为对照。根据小鼠大脑立体定位图谱选择三个合适的注射位点:AP 0.5,ML-2.0和DV-3.0,AP 0.5,ML-2.0和DV-3.6以及AP-0.6,ML-2.7和DV-3.3。每个位点的注射量为500nL,注射速度为50nL/分钟。
5.阿扑吗啡旋转测试
测试前对小鼠颈部皮下注射阿扑吗啡(apomorphine),注射量以小鼠体重计算(10mg/kg),并在直径为10cm的圆筒中进行旋转测试。结果表示为小鼠每分钟向6-OHDA损伤侧对侧旋转的净圈数((对侧旋转圈数-同侧旋转圈数)/记录时间)。记录时间为60分钟。
6.免疫组化
将小鼠用4%的PFA通过心脏灌流后,取大脑在4%的PFA中固定一周。之后分别用15%和30%的蔗糖溶液进行梯度脱水。利用冰冻切片获取包含所要分析的脑区(SN/VTA和CP)的大脑切片,厚度为40μm。经过0.3%的TritonX-100透化和5%的BSA封闭之后,在4℃孵育一抗(anti-TH)过夜。最后用与一抗源性相对应的带有荧光基团(吸收波长488nm)的二抗室温孵育2小时。脑片用Olympus VS120高通量荧光成像系统进行拍摄。
7.实验中涉及的序列信息
实施例1.构建表达目标双酶组合物的AAV载体
如图1所示构建表达目标双酶组合物(N端缺失90个氨基酸的TH和全长AADC的组合物)的AAV载体,以synapsin启动子来调控下游基因的表达。表达此双酶组合物的多核苷酸序列包括以下三个部分(5’到3’):
1).编码N端添加HA标签的N端缺失90个氨基酸的TH的多核苷酸序列,其是如SEQID NO:13所示的核苷酸序列;
2).具有肽段自剪切功能的T2A序列,其是如SEQ ID NO:28所示的核苷酸序列;和
3).编码C端添加myc标签的全长AADC的多核苷酸序列,其是如SEQ ID NO:21所示的核苷酸序列。
所述多核苷酸序列通过核苷酸内切酶BamHI和EcoRI被克隆到AAV载体(Addgene:26972)中。
作为对照,发明人同时构建以synapsin为启动子,表达GFP的AAV载体(GFP);为了在体外293细胞系中更好地表达,从而方便比较一系列N端缺失型TH与全长AADC的组合物在293细胞系中从头合成多巴胺的能力,发明人同时构建以ubiquitin为启动子,表达全长TH与全长AADC的组合物、TH另一异构体与全长AADC的组合物、N端缺失40个氨基酸的TH与全长AADC的组合物、N端缺失60个氨基酸的TH与全长AADC的组合物、N端缺失80个氨基酸的TH与全长AADC的组合物、N端缺失90个氨基酸的TH与全长AADC的组合物、N端缺失100个氨基酸的TH与全长AADC的组合物、N端缺失120个氨基酸的TH与全长AADC的组合物、N端缺失150个氨基酸的TH与全长AADC的组合物、N端缺失164个氨基酸的TH与全长AADC的组合物、N端缺失190个氨基酸的TH与全长AADC的组合物。一系列N端缺失型TH的N端均添加HA标签,全长AADC的C端添加myc标签。以ubiquitin为启动子,表达GFP的载体作为对照。
实施例2.在体外培养的细胞系中验证酶组合物的功能
为了寻找最高效地从头合成多巴胺的双酶组合物,发明人将上文描述的编码一系列N端缺失型TH与全长AADC双酶组合物的载体通过脂质体(lipofectamine 3000reagent)转染的方法分别导入体外培养的293细胞系中。表达GFP的载体作为阴性对照也被转染到293细胞系中。于37℃、5%CO2细胞培养箱内培养48小时后,更换细胞的培养基为PBS。继续培养1小时后分别收集PBS和细胞样本。
通过高效液相色谱(high-performance liquid chromatography,HPLC)检测上述各PBS样品中的多巴胺,即293细胞分泌的多巴胺的浓度。结果显示,表达GFP的细胞样品中没有检测到多巴胺信号,而表达一系列N端缺失型TH与全长AADC双酶组合物的293细胞样品中均检测到多巴胺信号(见图2)。这说明虽然293细胞系自身不能合成和分泌多巴胺,但当同时导入有功能的TH和AADC后,细胞便开始合成和分泌多巴胺。这证明发明人所设计的各种双酶组合物均可以发挥其正常功能,即催化多巴胺的从头合成。
结果还显示,表达N端缺失90个氨基酸的TH与全长AADC的组合物(90)的293细胞样品中多巴胺的浓度显著高于表达全长TH与全长AADC的组合物(WT)、TH的另一异构体与全长AADC的组合物(Isob)、N端缺失40个氨基酸的TH与全长AADC的组合物(40)、N端缺失60个氨基酸的TH与全长AADC的组合物(60)、N端缺失100个氨基酸的TH与全长AADC的组合物(100)、N端缺失120个氨基酸的TH与全长AADC的组合物(120)、N端缺失150个氨基酸的TH与全长AADC的组合物(150)、N端缺失164个氨基酸的TH与全长AADC的组合物(164)、N端缺失190个氨基酸的TH与全长AADC的组合物(190)的293细胞样品,而与表达N端缺失80个氨基酸的TH与全长AADC的组合物(80)的293细胞样品相比没有显著差异(见图2)。这不仅证明了上文提到的结论,即多巴胺浓度升高会负反馈调节TH的活性,从而限制其异位合成多巴胺的能力,而这一困境可以通过利用一个组成性激活的N端缺失型TH的版本得到解决。更重要的是,发明人通过比较找出了此组成性激活的N端缺失型TH的最佳版本,即N端缺失90个氨基酸的TH。本发明提供的目标双酶组合物即为N端缺失90个氨基酸的TH和全长AADC的组合物。结果表明此目标双酶组合物相较于其他各种N端缺失型TH与全长AADC的组合物都有更佳的从头合成多巴胺的能力。综上所述,本发明提供的目标双酶组合物可以发挥最佳的从头合成多巴胺的功能。虽然此前已知N端缺失型TH处于组成性激活状态,但本发明提供了最佳的组成性激活的TH版本。
实施例3.制备PD模型小鼠
选择8周龄的C57BL/6品系小鼠制备PD模型。根据小鼠大脑立体定位图谱,利用立体定位注射仪向小鼠大脑单侧的黑质/中脑腹侧被盖区(Substantia Nigra/VentralTegmental Area,SN/VTA)注射500nL的浓度为8mg/mL的6-OHDA(6-羟基多巴胺)。6-OHDA作为一种毒性药物会选择性杀死多巴胺能神经元。2周后对上述小鼠颈部皮下注射阿扑吗啡(apomorphine),注射量以小鼠体重计算(10mg/kg),并进行旋转测试。选择出现了运动不协调表型的,即向6-OHDA注射侧的对侧旋转的小鼠进行后续实验。
对出现运动不协调表型的小鼠大脑进行冷冻切片和免疫组化的分析,发现在PD模型小鼠注射6-OHDA同侧的SN/VTA或纹状体CP区域均检测不到TH阳性信号,而作为其对照的相应对侧区域则可以检测到TH阳性信号(见图3)。这一结果表明6-OHDA对于SN/VTA区域投射到CP的多巴胺能神经元造成了有效损伤。
综上所述,PD小鼠模型制备成功,可以进行后续的恢复实验。
实施例4.验证目标双酶组合物对于PD模型小鼠表型的改善
将表达N端缺失90个氨基酸的TH和全长AADC的组合物(TH90del/AADC)的载体(见图1)包装在血清型为AAV9病毒颗粒(滴度:1.95×1013vg/mL)中,用于小鼠的在体表达。包装GFP的病毒颗粒(滴度:7.78×1012vg/mL)作为对照。
取实施例3中成功制备的PD模型小鼠按照如图4a所示流程进行表型改善的实验。根据小鼠大脑立体定位图谱选择三个合适的纹状体的注射位点。利用立体定位注射仪将包装有TH90del/AADC或者GFP的AAV注射到上述三个纹状体位点,每个位点注射500nL。注射后4周,对上述小鼠颈部皮下注射阿扑吗啡(apomorphine),注射量以小鼠体重计算(10mg/kg),并进行旋转测试。结果显示,注射表达目标双酶组合物TH90del/AADC病毒的PD模型小鼠在注射后4周的阿扑吗啡诱导的运动不协调测试中,每分钟向6-OHDA损伤侧对侧旋转的净圈数((对侧旋转圈数-同侧旋转圈数)/记录时间)显著低于注射前,且显著低于注射对照病毒(GFP)的PD模型小鼠(见图4b)。上述结果证明本发明提供的目标双酶组合物(TH90del/AADC)可以在体有效地发挥功能,增加纹状体CP区域的多巴胺浓度,从而显著改善PD模型小鼠的阿扑吗啡诱导的运动不协调表型,因此具有潜在的PD治疗效果。
尽管实施例中使用的酶或组合物为人源蛋白,但人源和小鼠源TH蛋白同源性为83%,人源和小鼠源AADC蛋白同源性为89%。因此,根据本发明公开的内容,本领域技术人员应该可以合理预期人源或鼠源的双酶组合物在人临床或鼠模型上均应具有良好的治疗效果。
以上,发明人对基于本发明的实施方式进行了说明,但本发明不限定于此,本领域的技术人员应该明白,在本发明的主旨范围内能够以进行变形和变更的方式实施,这样的变形和变更的方式,理应属于本发明的保护范围。
SEQUENCE LISTING
<110> 上海信致医药科技有限公司
<120> 一种新型酶组合物
<130> AJ5480PI1901
<160> 28
<170> PatentIn version 3.3
<210> 1
<211> 528
<212> PRT
<213> 智人(Homo sapiens)
<400> 1
Met Pro Thr Pro Asp Ala Thr Thr Pro Gln Ala Lys Gly Phe Arg Arg
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Ala Val Ser Glu Leu Asp Ala Lys Gln Ala Glu Ala Ile Met Val Arg
20 25 30
Gly Gln Gly Ala Pro Gly Pro Ser Leu Thr Gly Ser Pro Trp Pro Gly
35 40 45
Thr Ala Ala Pro Ala Ala Ser Tyr Thr Pro Thr Pro Arg Ser Pro Arg
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Phe Ile Gly Arg Arg Gln Ser Leu Ile Glu Asp Ala Arg Lys Glu Arg
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Glu Ala Ala Val Ala Ala Ala Ala Ala Ala Val Pro Ser Glu Pro Gly
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Asp Pro Leu Glu Ala Val Ala Phe Glu Glu Lys Glu Gly Lys Ala Val
100 105 110
Leu Asn Leu Leu Phe Ser Pro Arg Ala Thr Lys Pro Ser Ala Leu Ser
115 120 125
Arg Ala Val Lys Val Phe Glu Thr Phe Glu Ala Lys Ile His His Leu
130 135 140
Glu Thr Arg Pro Ala Gln Arg Pro Arg Ala Gly Gly Pro His Leu Glu
145 150 155 160
Tyr Phe Val Arg Leu Glu Val Arg Arg Gly Asp Leu Ala Ala Leu Leu
165 170 175
Ser Gly Val Arg Gln Val Ser Glu Asp Val Arg Ser Pro Ala Gly Pro
180 185 190
Lys Val Pro Trp Phe Pro Arg Lys Val Ser Glu Leu Asp Lys Cys His
195 200 205
His Leu Val Thr Lys Phe Asp Pro Asp Leu Asp Leu Asp His Pro Gly
210 215 220
Phe Ser Asp Gln Val Tyr Arg Gln Arg Arg Lys Leu Ile Ala Glu Ile
225 230 235 240
Ala Phe Gln Tyr Arg His Gly Asp Pro Ile Pro Arg Val Glu Tyr Thr
245 250 255
Ala Glu Glu Ile Ala Thr Trp Lys Glu Val Tyr Thr Thr Leu Lys Gly
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Leu Tyr Ala Thr His Ala Cys Gly Glu His Leu Glu Ala Phe Ala Leu
275 280 285
Leu Glu Arg Phe Ser Gly Tyr Arg Glu Asp Asn Ile Pro Gln Leu Glu
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Asp Val Ser Arg Phe Leu Lys Glu Arg Thr Gly Phe Gln Leu Arg Pro
305 310 315 320
Val Ala Gly Leu Leu Ser Ala Arg Asp Phe Leu Ala Ser Leu Ala Phe
325 330 335
Arg Val Phe Gln Cys Thr Gln Tyr Ile Arg His Ala Ser Ser Pro Met
340 345 350
His Ser Pro Glu Pro Asp Cys Cys His Glu Leu Leu Gly His Val Pro
355 360 365
Met Leu Ala Asp Arg Thr Phe Ala Gln Phe Ser Gln Asp Ile Gly Leu
370 375 380
Ala Ser Leu Gly Ala Ser Asp Glu Glu Ile Glu Lys Leu Ser Thr Leu
385 390 395 400
Tyr Trp Phe Thr Val Glu Phe Gly Leu Cys Lys Gln Asn Gly Glu Val
405 410 415
Lys Ala Tyr Gly Ala Gly Leu Leu Ser Ser Tyr Gly Glu Leu Leu His
420 425 430
Cys Leu Ser Glu Glu Pro Glu Ile Arg Ala Phe Asp Pro Glu Ala Ala
435 440 445
Ala Val Gln Pro Tyr Gln Asp Gln Thr Tyr Gln Ser Val Tyr Phe Val
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Ser Glu Ser Phe Ser Asp Ala Lys Asp Lys Leu Arg Ser Tyr Ala Ser
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Arg Ile Gln Arg Pro Phe Ser Val Lys Phe Asp Pro Tyr Thr Leu Ala
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Ile Asp Val Leu Asp Ser Pro Gln Ala Val Arg Arg Ser Leu Glu Gly
500 505 510
Val Gln Asp Glu Leu Asp Thr Leu Ala His Ala Leu Ser Ala Ile Gly
515 520 525
<210> 2
<211> 437
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<222> ()..()
<223> TH截短90个氨基酸的氨基酸序列
<400> 2
Pro Ser Glu Pro Gly Asp Pro Leu Glu Ala Val Ala Phe Glu Glu Lys
1 5 10 15
Glu Gly Lys Ala Val Leu Asn Leu Leu Phe Ser Pro Arg Ala Thr Lys
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Pro Ser Ala Leu Ser Arg Ala Val Lys Val Phe Glu Thr Phe Glu Ala
35 40 45
Lys Ile His His Leu Glu Thr Arg Pro Ala Gln Arg Pro Arg Ala Gly
50 55 60
Gly Pro His Leu Glu Tyr Phe Val Arg Leu Glu Val Arg Arg Gly Asp
65 70 75 80
Leu Ala Ala Leu Leu Ser Gly Val Arg Gln Val Ser Glu Asp Val Arg
85 90 95
Ser Pro Ala Gly Pro Lys Val Pro Trp Phe Pro Arg Lys Val Ser Glu
100 105 110
Leu Asp Lys Cys His His Leu Val Thr Lys Phe Asp Pro Asp Leu Asp
115 120 125
Leu Asp His Pro Gly Phe Ser Asp Gln Val Tyr Arg Gln Arg Arg Lys
130 135 140
Leu Ile Ala Glu Ile Ala Phe Gln Tyr Arg His Gly Asp Pro Ile Pro
145 150 155 160
Arg Val Glu Tyr Thr Ala Glu Glu Ile Ala Thr Trp Lys Glu Val Tyr
165 170 175
Thr Thr Leu Lys Gly Leu Tyr Ala Thr His Ala Cys Gly Glu His Leu
180 185 190
Glu Ala Phe Ala Leu Leu Glu Arg Phe Ser Gly Tyr Arg Glu Asp Asn
195 200 205
Ile Pro Gln Leu Glu Asp Val Ser Arg Phe Leu Lys Glu Arg Thr Gly
210 215 220
Phe Gln Leu Arg Pro Val Ala Gly Leu Leu Ser Ala Arg Asp Phe Leu
225 230 235 240
Ala Ser Leu Ala Phe Arg Val Phe Gln Cys Thr Gln Tyr Ile Arg His
245 250 255
Ala Ser Ser Pro Met His Ser Pro Glu Pro Asp Cys Cys His Glu Leu
260 265 270
Leu Gly His Val Pro Met Leu Ala Asp Arg Thr Phe Ala Gln Phe Ser
275 280 285
Gln Asp Ile Gly Leu Ala Ser Leu Gly Ala Ser Asp Glu Glu Ile Glu
290 295 300
Lys Leu Ser Thr Leu Tyr Trp Phe Thr Val Glu Phe Gly Leu Cys Lys
305 310 315 320
Gln Asn Gly Glu Val Lys Ala Tyr Gly Ala Gly Leu Leu Ser Ser Tyr
325 330 335
Gly Glu Leu Leu His Cys Leu Ser Glu Glu Pro Glu Ile Arg Ala Phe
340 345 350
Asp Pro Glu Ala Ala Ala Val Gln Pro Tyr Gln Asp Gln Thr Tyr Gln
355 360 365
Ser Val Tyr Phe Val Ser Glu Ser Phe Ser Asp Ala Lys Asp Lys Leu
370 375 380
Arg Ser Tyr Ala Ser Arg Ile Gln Arg Pro Phe Ser Val Lys Phe Asp
385 390 395 400
Pro Tyr Thr Leu Ala Ile Asp Val Leu Asp Ser Pro Gln Ala Val Arg
405 410 415
Arg Ser Leu Glu Gly Val Gln Asp Glu Leu Asp Thr Leu Ala His Ala
420 425 430
Leu Ser Ala Ile Gly
435
<210> 3
<211> 456
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<222> ()..()
<223> 含有HA标签的TH截短90个氨基酸的氨基酸序列
<400> 3
Met Tyr Pro Tyr Asp Val Pro Asp Tyr Ala Tyr Pro Tyr Asp Val Pro
1 5 10 15
Asp Tyr Ala Pro Ser Glu Pro Gly Asp Pro Leu Glu Ala Val Ala Phe
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Glu Glu Lys Glu Gly Lys Ala Val Leu Asn Leu Leu Phe Ser Pro Arg
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Ala Thr Lys Pro Ser Ala Leu Ser Arg Ala Val Lys Val Phe Glu Thr
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Phe Glu Ala Lys Ile His His Leu Glu Thr Arg Pro Ala Gln Arg Pro
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Arg Ala Gly Gly Pro His Leu Glu Tyr Phe Val Arg Leu Glu Val Arg
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Arg Gly Asp Leu Ala Ala Leu Leu Ser Gly Val Arg Gln Val Ser Glu
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Asp Val Arg Ser Pro Ala Gly Pro Lys Val Pro Trp Phe Pro Arg Lys
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Val Ser Glu Leu Asp Lys Cys His His Leu Val Thr Lys Phe Asp Pro
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Asp Leu Asp Leu Asp His Pro Gly Phe Ser Asp Gln Val Tyr Arg Gln
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Arg Arg Lys Leu Ile Ala Glu Ile Ala Phe Gln Tyr Arg His Gly Asp
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Pro Ile Pro Arg Val Glu Tyr Thr Ala Glu Glu Ile Ala Thr Trp Lys
180 185 190
Glu Val Tyr Thr Thr Leu Lys Gly Leu Tyr Ala Thr His Ala Cys Gly
195 200 205
Glu His Leu Glu Ala Phe Ala Leu Leu Glu Arg Phe Ser Gly Tyr Arg
210 215 220
Glu Asp Asn Ile Pro Gln Leu Glu Asp Val Ser Arg Phe Leu Lys Glu
225 230 235 240
Arg Thr Gly Phe Gln Leu Arg Pro Val Ala Gly Leu Leu Ser Ala Arg
245 250 255
Asp Phe Leu Ala Ser Leu Ala Phe Arg Val Phe Gln Cys Thr Gln Tyr
260 265 270
Ile Arg His Ala Ser Ser Pro Met His Ser Pro Glu Pro Asp Cys Cys
275 280 285
His Glu Leu Leu Gly His Val Pro Met Leu Ala Asp Arg Thr Phe Ala
290 295 300
Gln Phe Ser Gln Asp Ile Gly Leu Ala Ser Leu Gly Ala Ser Asp Glu
305 310 315 320
Glu Ile Glu Lys Leu Ser Thr Leu Tyr Trp Phe Thr Val Glu Phe Gly
325 330 335
Leu Cys Lys Gln Asn Gly Glu Val Lys Ala Tyr Gly Ala Gly Leu Leu
340 345 350
Ser Ser Tyr Gly Glu Leu Leu His Cys Leu Ser Glu Glu Pro Glu Ile
355 360 365
Arg Ala Phe Asp Pro Glu Ala Ala Ala Val Gln Pro Tyr Gln Asp Gln
370 375 380
Thr Tyr Gln Ser Val Tyr Phe Val Ser Glu Ser Phe Ser Asp Ala Lys
385 390 395 400
Asp Lys Leu Arg Ser Tyr Ala Ser Arg Ile Gln Arg Pro Phe Ser Val
405 410 415
Lys Phe Asp Pro Tyr Thr Leu Ala Ile Asp Val Leu Asp Ser Pro Gln
420 425 430
Ala Val Arg Arg Ser Leu Glu Gly Val Gln Asp Glu Leu Asp Thr Leu
435 440 445
Ala His Ala Leu Ser Ala Ile Gly
450 455
<210> 4
<211> 480
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<222> ()..()
<223> 天然存在的AADC Isoform 1全长的氨基酸序列
<400> 4
Met Asn Ala Ser Glu Phe Arg Arg Arg Gly Lys Glu Met Val Asp Tyr
1 5 10 15
Val Ala Asn Tyr Met Glu Gly Ile Glu Gly Arg Gln Val Tyr Pro Asp
20 25 30
Val Glu Pro Gly Tyr Leu Arg Pro Leu Ile Pro Ala Ala Ala Pro Gln
35 40 45
Glu Pro Asp Thr Phe Glu Asp Ile Ile Asn Asp Val Glu Lys Ile Ile
50 55 60
Met Pro Gly Val Thr His Trp His Ser Pro Tyr Phe Phe Ala Tyr Phe
65 70 75 80
Pro Thr Ala Ser Ser Tyr Pro Ala Met Leu Ala Asp Met Leu Cys Gly
85 90 95
Ala Ile Gly Cys Ile Gly Phe Ser Trp Ala Ala Ser Pro Ala Cys Thr
100 105 110
Glu Leu Glu Thr Val Met Met Asp Trp Leu Gly Lys Met Leu Glu Leu
115 120 125
Pro Lys Ala Phe Leu Asn Glu Lys Ala Gly Glu Gly Gly Gly Val Ile
130 135 140
Gln Gly Ser Ala Ser Glu Ala Thr Leu Val Ala Leu Leu Ala Ala Arg
145 150 155 160
Thr Lys Val Ile His Arg Leu Gln Ala Ala Ser Pro Glu Leu Thr Gln
165 170 175
Ala Ala Ile Met Glu Lys Leu Val Ala Tyr Ser Ser Asp Gln Ala His
180 185 190
Ser Ser Val Glu Arg Ala Gly Leu Ile Gly Gly Val Lys Leu Lys Ala
195 200 205
Ile Pro Ser Asp Gly Asn Phe Ala Met Arg Ala Ser Ala Leu Gln Glu
210 215 220
Ala Leu Glu Arg Asp Lys Ala Ala Gly Leu Ile Pro Phe Phe Met Val
225 230 235 240
Ala Thr Leu Gly Thr Thr Thr Cys Cys Ser Phe Asp Asn Leu Leu Glu
245 250 255
Val Gly Pro Ile Cys Asn Lys Glu Asp Ile Trp Leu His Val Asp Ala
260 265 270
Ala Tyr Ala Gly Ser Ala Phe Ile Cys Pro Glu Phe Arg His Leu Leu
275 280 285
Asn Gly Val Glu Phe Ala Asp Ser Phe Asn Phe Asn Pro His Lys Trp
290 295 300
Leu Leu Val Asn Phe Asp Cys Ser Ala Met Trp Val Lys Lys Arg Thr
305 310 315 320
Asp Leu Thr Gly Ala Phe Arg Leu Asp Pro Thr Tyr Leu Lys His Ser
325 330 335
His Gln Asp Ser Gly Leu Ile Thr Asp Tyr Arg His Trp Gln Ile Pro
340 345 350
Leu Gly Arg Arg Phe Arg Ser Leu Lys Met Trp Phe Val Phe Arg Met
355 360 365
Tyr Gly Val Lys Gly Leu Gln Ala Tyr Ile Arg Lys His Val Gln Leu
370 375 380
Ser His Glu Phe Glu Ser Leu Val Arg Gln Asp Pro Arg Phe Glu Ile
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Cys Val Glu Val Ile Leu Gly Leu Val Cys Phe Arg Leu Lys Gly Ser
405 410 415
Asn Lys Val Asn Glu Ala Leu Leu Gln Arg Ile Asn Ser Ala Lys Lys
420 425 430
Ile His Leu Val Pro Cys His Leu Arg Asp Lys Phe Val Leu Arg Phe
435 440 445
Ala Ile Cys Ser Arg Thr Val Glu Ser Ala His Val Gln Arg Ala Trp
450 455 460
Glu His Ile Lys Glu Leu Ala Ala Asp Val Leu Arg Ala Glu Arg Glu
465 470 475 480
<210> 5
<211> 442
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<222> ()..()
<223> 天然存在的AADC Isoform 2全长的氨基酸序列
<400> 5
Met Asn Ala Ser Glu Phe Arg Arg Arg Gly Lys Glu Met Val Asp Tyr
1 5 10 15
Val Ala Asn Tyr Met Glu Gly Ile Glu Gly Arg Gln Val Tyr Pro Asp
20 25 30
Val Glu Pro Gly Tyr Leu Arg Pro Leu Ile Pro Ala Ala Ala Pro Gln
35 40 45
Glu Pro Asp Thr Phe Glu Asp Ile Ile Asn Asp Val Glu Lys Ile Ile
50 55 60
Met Pro Gly Ala Ala Ser Pro Ala Cys Thr Glu Leu Glu Thr Val Met
65 70 75 80
Met Asp Trp Leu Gly Lys Met Leu Glu Leu Pro Lys Ala Phe Leu Asn
85 90 95
Glu Lys Ala Gly Glu Gly Gly Gly Val Ile Gln Gly Ser Ala Ser Glu
100 105 110
Ala Thr Leu Val Ala Leu Leu Ala Ala Arg Thr Lys Val Ile His Arg
115 120 125
Leu Gln Ala Ala Ser Pro Glu Leu Thr Gln Ala Ala Ile Met Glu Lys
130 135 140
Leu Val Ala Tyr Ser Ser Asp Gln Ala His Ser Ser Val Glu Arg Ala
145 150 155 160
Gly Leu Ile Gly Gly Val Lys Leu Lys Ala Ile Pro Ser Asp Gly Asn
165 170 175
Phe Ala Met Arg Ala Ser Ala Leu Gln Glu Ala Leu Glu Arg Asp Lys
180 185 190
Ala Ala Gly Leu Ile Pro Phe Phe Met Val Ala Thr Leu Gly Thr Thr
195 200 205
Thr Cys Cys Ser Phe Asp Asn Leu Leu Glu Val Gly Pro Ile Cys Asn
210 215 220
Lys Glu Asp Ile Trp Leu His Val Asp Ala Ala Tyr Ala Gly Ser Ala
225 230 235 240
Phe Ile Cys Pro Glu Phe Arg His Leu Leu Asn Gly Val Glu Phe Ala
245 250 255
Asp Ser Phe Asn Phe Asn Pro His Lys Trp Leu Leu Val Asn Phe Asp
260 265 270
Cys Ser Ala Met Trp Val Lys Lys Arg Thr Asp Leu Thr Gly Ala Phe
275 280 285
Arg Leu Asp Pro Thr Tyr Leu Lys His Ser His Gln Asp Ser Gly Leu
290 295 300
Ile Thr Asp Tyr Arg His Trp Gln Ile Pro Leu Gly Arg Arg Phe Arg
305 310 315 320
Ser Leu Lys Met Trp Phe Val Phe Arg Met Tyr Gly Val Lys Gly Leu
325 330 335
Gln Ala Tyr Ile Arg Lys His Val Gln Leu Ser His Glu Phe Glu Ser
340 345 350
Leu Val Arg Gln Asp Pro Arg Phe Glu Ile Cys Val Glu Val Ile Leu
355 360 365
Gly Leu Val Cys Phe Arg Leu Lys Gly Ser Asn Lys Val Asn Glu Ala
370 375 380
Leu Leu Gln Arg Ile Asn Ser Ala Lys Lys Ile His Leu Val Pro Cys
385 390 395 400
His Leu Arg Asp Lys Phe Val Leu Arg Phe Ala Ile Cys Ser Arg Thr
405 410 415
Val Glu Ser Ala His Val Gln Arg Ala Trp Glu His Ile Lys Glu Leu
420 425 430
Ala Ala Asp Val Leu Arg Ala Glu Arg Glu
435 440
<210> 6
<211> 432
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<222> ()..()
<223> 天然存在的AADC Isoform 3全长的氨基酸序列
<400> 6
Met Asn Ala Ser Glu Phe Arg Arg Arg Gly Lys Glu Met Val Asp Tyr
1 5 10 15
Val Ala Asn Tyr Met Glu Gly Ile Glu Gly Arg Gln Val Tyr Pro Asp
20 25 30
Val Glu Pro Gly Tyr Leu Arg Pro Leu Ile Pro Ala Ala Ala Pro Gln
35 40 45
Glu Pro Asp Thr Phe Glu Asp Ile Ile Asn Asp Val Glu Lys Ile Ile
50 55 60
Met Pro Gly Val Thr His Trp His Ser Pro Tyr Phe Phe Ala Tyr Phe
65 70 75 80
Pro Thr Ala Ser Ser Tyr Pro Ala Met Leu Ala Asp Met Leu Cys Gly
85 90 95
Ala Ile Gly Cys Ile Gly Phe Ser Trp Ala Ala Ser Pro Ala Cys Thr
100 105 110
Glu Leu Glu Thr Val Met Met Asp Trp Leu Gly Lys Met Leu Glu Leu
115 120 125
Pro Lys Ala Phe Leu Asn Glu Lys Ala Gly Glu Gly Gly Gly Val Ile
130 135 140
Gln Gly Ser Ala Ser Glu Ala Thr Leu Val Ala Leu Leu Ala Ala Arg
145 150 155 160
Thr Lys Val Ile His Arg Leu Gln Ala Ala Ser Pro Glu Leu Thr Gln
165 170 175
Ala Ala Ile Met Glu Lys Leu Val Ala Tyr Ser Ser Asp Gln Met Val
180 185 190
Ala Thr Leu Gly Thr Thr Thr Cys Cys Ser Phe Asp Asn Leu Leu Glu
195 200 205
Val Gly Pro Ile Cys Asn Lys Glu Asp Ile Trp Leu His Val Asp Ala
210 215 220
Ala Tyr Ala Gly Ser Ala Phe Ile Cys Pro Glu Phe Arg His Leu Leu
225 230 235 240
Asn Gly Val Glu Phe Ala Asp Ser Phe Asn Phe Asn Pro His Lys Trp
245 250 255
Leu Leu Val Asn Phe Asp Cys Ser Ala Met Trp Val Lys Lys Arg Thr
260 265 270
Asp Leu Thr Gly Ala Phe Arg Leu Asp Pro Thr Tyr Leu Lys His Ser
275 280 285
His Gln Asp Ser Gly Leu Ile Thr Asp Tyr Arg His Trp Gln Ile Pro
290 295 300
Leu Gly Arg Arg Phe Arg Ser Leu Lys Met Trp Phe Val Phe Arg Met
305 310 315 320
Tyr Gly Val Lys Gly Leu Gln Ala Tyr Ile Arg Lys His Val Gln Leu
325 330 335
Ser His Glu Phe Glu Ser Leu Val Arg Gln Asp Pro Arg Phe Glu Ile
340 345 350
Cys Val Glu Val Ile Leu Gly Leu Val Cys Phe Arg Leu Lys Gly Ser
355 360 365
Asn Lys Val Asn Glu Ala Leu Leu Gln Arg Ile Asn Ser Ala Lys Lys
370 375 380
Ile His Leu Val Pro Cys His Leu Arg Asp Lys Phe Val Leu Arg Phe
385 390 395 400
Ala Ile Cys Ser Arg Thr Val Glu Ser Ala His Val Gln Arg Ala Trp
405 410 415
Glu His Ile Lys Glu Leu Ala Ala Asp Val Leu Arg Ala Glu Arg Glu
420 425 430
<210> 7
<211> 402
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<222> ()..()
<223> 天然存在的AADC Isoform 4全长的氨基酸序列
<400> 7
Met Asn Ala Ser Glu Phe Arg Arg Arg Gly Lys Glu Met Val Asp Tyr
1 5 10 15
Val Ala Asn Tyr Met Glu Gly Ile Glu Gly Arg Gln Val Tyr Pro Asp
20 25 30
Val Glu Pro Gly Tyr Leu Arg Pro Leu Ile Pro Ala Ala Ala Pro Gln
35 40 45
Glu Pro Asp Thr Phe Glu Asp Ile Ile Asn Asp Val Glu Lys Ile Ile
50 55 60
Met Pro Gly Gly Ser Ala Ser Glu Ala Thr Leu Val Ala Leu Leu Ala
65 70 75 80
Ala Arg Thr Lys Val Ile His Arg Leu Gln Ala Ala Ser Pro Glu Leu
85 90 95
Thr Gln Ala Ala Ile Met Glu Lys Leu Val Ala Tyr Ser Ser Asp Gln
100 105 110
Ala His Ser Ser Val Glu Arg Ala Gly Leu Ile Gly Gly Val Lys Leu
115 120 125
Lys Ala Ile Pro Ser Asp Gly Asn Phe Ala Met Arg Ala Ser Ala Leu
130 135 140
Gln Glu Ala Leu Glu Arg Asp Lys Ala Ala Gly Leu Ile Pro Phe Phe
145 150 155 160
Met Val Ala Thr Leu Gly Thr Thr Thr Cys Cys Ser Phe Asp Asn Leu
165 170 175
Leu Glu Val Gly Pro Ile Cys Asn Lys Glu Asp Ile Trp Leu His Val
180 185 190
Asp Ala Ala Tyr Ala Gly Ser Ala Phe Ile Cys Pro Glu Phe Arg His
195 200 205
Leu Leu Asn Gly Val Glu Phe Ala Asp Ser Phe Asn Phe Asn Pro His
210 215 220
Lys Trp Leu Leu Val Asn Phe Asp Cys Ser Ala Met Trp Val Lys Lys
225 230 235 240
Arg Thr Asp Leu Thr Gly Ala Phe Arg Leu Asp Pro Thr Tyr Leu Lys
245 250 255
His Ser His Gln Asp Ser Gly Leu Ile Thr Asp Tyr Arg His Trp Gln
260 265 270
Ile Pro Leu Gly Arg Arg Phe Arg Ser Leu Lys Met Trp Phe Val Phe
275 280 285
Arg Met Tyr Gly Val Lys Gly Leu Gln Ala Tyr Ile Arg Lys His Val
290 295 300
Gln Leu Ser His Glu Phe Glu Ser Leu Val Arg Gln Asp Pro Arg Phe
305 310 315 320
Glu Ile Cys Val Glu Val Ile Leu Gly Leu Val Cys Phe Arg Leu Lys
325 330 335
Gly Ser Asn Lys Val Asn Glu Ala Leu Leu Gln Arg Ile Asn Ser Ala
340 345 350
Lys Lys Ile His Leu Val Pro Cys His Leu Arg Asp Lys Phe Val Leu
355 360 365
Arg Phe Ala Ile Cys Ser Arg Thr Val Glu Ser Ala His Val Gln Arg
370 375 380
Ala Trp Glu His Ile Lys Glu Leu Ala Ala Asp Val Leu Arg Ala Glu
385 390 395 400
Arg Glu
<210> 8
<211> 387
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<222> ()..()
<223> 天然存在的AADC Isoform 5全长的氨基酸序列
<400> 8
Met Asn Ala Ser Glu Phe Arg Arg Arg Gly Lys Glu Met Val Asp Tyr
1 5 10 15
Val Ala Asn Tyr Met Glu Gly Ile Glu Gly Arg Gln Val Tyr Pro Asp
20 25 30
Val Glu Pro Gly Tyr Leu Arg Pro Leu Ile Pro Ala Ala Ala Pro Gln
35 40 45
Glu Pro Asp Thr Phe Glu Asp Ile Ile Asn Asp Val Glu Lys Ile Ile
50 55 60
Met Pro Gly Val Thr His Trp His Ser Pro Tyr Phe Phe Ala Tyr Phe
65 70 75 80
Pro Thr Ala Ser Ser Tyr Pro Ala Met Leu Ala Asp Met Leu Cys Gly
85 90 95
Ala Ile Gly Cys Ile Gly Phe Ser Trp Ala Ala Ser Pro Ala Cys Thr
100 105 110
Glu Leu Glu Thr Val Met Met Asp Trp Leu Gly Lys Met Leu Glu Leu
115 120 125
Pro Lys Ala Phe Leu Asn Glu Lys Ala Gly Glu Gly Gly Gly Val Ile
130 135 140
Gln Met Val Ala Thr Leu Gly Thr Thr Thr Cys Cys Ser Phe Asp Asn
145 150 155 160
Leu Leu Glu Val Gly Pro Ile Cys Asn Lys Glu Asp Ile Trp Leu His
165 170 175
Val Asp Ala Ala Tyr Ala Gly Ser Ala Phe Ile Cys Pro Glu Phe Arg
180 185 190
His Leu Leu Asn Gly Val Glu Phe Ala Asp Ser Phe Asn Phe Asn Pro
195 200 205
His Lys Trp Leu Leu Val Asn Phe Asp Cys Ser Ala Met Trp Val Lys
210 215 220
Lys Arg Thr Asp Leu Thr Gly Ala Phe Arg Leu Asp Pro Thr Tyr Leu
225 230 235 240
Lys His Ser His Gln Asp Ser Gly Leu Ile Thr Asp Tyr Arg His Trp
245 250 255
Gln Ile Pro Leu Gly Arg Arg Phe Arg Ser Leu Lys Met Trp Phe Val
260 265 270
Phe Arg Met Tyr Gly Val Lys Gly Leu Gln Ala Tyr Ile Arg Lys His
275 280 285
Val Gln Leu Ser His Glu Phe Glu Ser Leu Val Arg Gln Asp Pro Arg
290 295 300
Phe Glu Ile Cys Val Glu Val Ile Leu Gly Leu Val Cys Phe Arg Leu
305 310 315 320
Lys Gly Ser Asn Lys Val Asn Glu Ala Leu Leu Gln Arg Ile Asn Ser
325 330 335
Ala Lys Lys Ile His Leu Val Pro Cys His Leu Arg Asp Lys Phe Val
340 345 350
Leu Arg Phe Ala Ile Cys Ser Arg Thr Val Glu Ser Ala His Val Gln
355 360 365
Arg Ala Trp Glu His Ile Lys Glu Leu Ala Ala Asp Val Leu Arg Ala
370 375 380
Glu Arg Glu
385
<210> 9
<211> 338
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<222> ()..()
<223> 天然存在的AADC Isoform 6全长的氨基酸序列
<400> 9
Met Asn Ala Ser Glu Phe Arg Arg Arg Gly Lys Glu Met Val Asp Tyr
1 5 10 15
Val Ala Asn Tyr Met Glu Gly Ile Glu Gly Arg Gln Val Tyr Pro Asp
20 25 30
Val Glu Pro Gly Tyr Leu Arg Pro Leu Ile Pro Ala Ala Ala Pro Gln
35 40 45
Glu Pro Asp Thr Phe Glu Asp Ile Ile Asn Asp Val Glu Lys Ile Ile
50 55 60
Met Pro Gly Val Thr His Trp His Ser Pro Tyr Phe Phe Ala Tyr Phe
65 70 75 80
Pro Thr Ala Ser Ser Tyr Pro Ala Met Leu Ala Asp Met Leu Cys Gly
85 90 95
Ala Ile Gly Cys Ile Gly Phe Ser Trp Ala Ala Ser Pro Ala Cys Thr
100 105 110
Glu Leu Glu Thr Val Met Met Asp Trp Leu Gly Lys Met Leu Glu Leu
115 120 125
Pro Lys Ala Phe Leu Asn Glu Lys Ala Gly Glu Gly Gly Gly Val Ile
130 135 140
Gln Gly Ser Ala Ser Glu Ala Thr Leu Val Ala Leu Leu Ala Ala Arg
145 150 155 160
Thr Lys Val Ile His Arg Leu Gln Ala Ala Ser Pro Glu Leu Thr Gln
165 170 175
Ala Ala Ile Met Glu Lys Leu Val Ala Tyr Ser Ser Asp Gln Ala His
180 185 190
Ser Ser Val Glu Arg Ala Gly Leu Ile Gly Gly Val Lys Leu Lys Ala
195 200 205
Ile Pro Ser Asp Gly Asn Phe Ala Met Arg Ala Ser Ala Leu Gln Glu
210 215 220
Ala Leu Glu Arg Asp Lys Ala Ala Gly Leu Ile Pro Phe Phe Met Val
225 230 235 240
Ala Thr Leu Gly Thr Thr Thr Cys Cys Ser Phe Asp Asn Leu Leu Glu
245 250 255
Val Gly Pro Ile Cys Asn Lys Glu Asp Ile Trp Leu His Val Asp Ala
260 265 270
Ala Tyr Ala Gly Ser Ala Phe Ile Cys Pro Glu Phe Arg His Leu Leu
275 280 285
Asn Gly Val Glu Phe Ala Asp Ser Phe Asn Phe Asn Pro His Lys Trp
290 295 300
Leu Leu Val Asn Phe Asp Cys Ser Ala Met Trp Ser Arg Gln Pro Val
305 310 315 320
Arg Met Leu Arg Leu Lys Lys Thr Cys Leu Val Ser Ala Val Val Arg
325 330 335
Arg Ser
<210> 10
<211> 489
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<222> ()..()
<223> C端加入myc标签的AADC全长的氨基酸序列
<400> 10
Asn Ala Ser Glu Phe Arg Arg Arg Gly Lys Glu Met Val Asp Tyr Val
1 5 10 15
Ala Asn Tyr Met Glu Gly Ile Glu Gly Arg Gln Val Tyr Pro Asp Val
20 25 30
Glu Pro Gly Tyr Leu Arg Pro Leu Ile Pro Ala Ala Ala Pro Gln Glu
35 40 45
Pro Asp Thr Phe Glu Asp Ile Ile Asn Asp Val Glu Lys Ile Ile Met
50 55 60
Pro Gly Val Thr His Trp His Ser Pro Tyr Phe Phe Ala Tyr Phe Pro
65 70 75 80
Thr Ala Ser Ser Tyr Pro Ala Met Leu Ala Asp Met Leu Cys Gly Ala
85 90 95
Ile Gly Cys Ile Gly Phe Ser Trp Ala Ala Ser Pro Ala Cys Thr Glu
100 105 110
Leu Glu Thr Val Met Met Asp Trp Leu Gly Lys Met Leu Glu Leu Pro
115 120 125
Lys Ala Phe Leu Asn Glu Lys Ala Gly Glu Gly Gly Gly Val Ile Gln
130 135 140
Gly Ser Ala Ser Glu Ala Thr Leu Val Ala Leu Leu Ala Ala Arg Thr
145 150 155 160
Lys Val Ile His Arg Leu Gln Ala Ala Ser Pro Glu Leu Thr Gln Ala
165 170 175
Ala Ile Met Glu Lys Leu Val Ala Tyr Ser Ser Asp Gln Ala His Ser
180 185 190
Ser Val Glu Arg Ala Gly Leu Ile Gly Gly Val Lys Leu Lys Ala Ile
195 200 205
Pro Ser Asp Gly Asn Phe Ala Met Arg Ala Ser Ala Leu Gln Glu Ala
210 215 220
Leu Glu Arg Asp Lys Ala Ala Gly Leu Ile Pro Phe Phe Met Val Ala
225 230 235 240
Thr Leu Gly Thr Thr Thr Cys Cys Ser Phe Asp Asn Leu Leu Glu Val
245 250 255
Gly Pro Ile Cys Asn Lys Glu Asp Ile Trp Leu His Val Asp Ala Ala
260 265 270
Tyr Ala Gly Ser Ala Phe Ile Cys Pro Glu Phe Arg His Leu Leu Asn
275 280 285
Gly Val Glu Phe Ala Asp Ser Phe Asn Phe Asn Pro His Lys Trp Leu
290 295 300
Leu Val Asn Phe Asp Cys Ser Ala Met Trp Val Lys Lys Arg Thr Asp
305 310 315 320
Leu Thr Gly Ala Phe Arg Leu Asp Pro Thr Tyr Leu Lys His Ser His
325 330 335
Gln Asp Ser Gly Leu Ile Thr Asp Tyr Arg His Trp Gln Ile Pro Leu
340 345 350
Gly Arg Arg Phe Arg Ser Leu Lys Met Trp Phe Val Phe Arg Met Tyr
355 360 365
Gly Val Lys Gly Leu Gln Ala Tyr Ile Arg Lys His Val Gln Leu Ser
370 375 380
His Glu Phe Glu Ser Leu Val Arg Gln Asp Pro Arg Phe Glu Ile Cys
385 390 395 400
Val Glu Val Ile Leu Gly Leu Val Cys Phe Arg Leu Lys Gly Ser Asn
405 410 415
Lys Val Asn Glu Ala Leu Leu Gln Arg Ile Asn Ser Ala Lys Lys Ile
420 425 430
His Leu Val Pro Cys His Leu Arg Asp Lys Phe Val Leu Arg Phe Ala
435 440 445
Ile Cys Ser Arg Thr Val Glu Ser Ala His Val Gln Arg Ala Trp Glu
450 455 460
His Ile Lys Glu Leu Ala Ala Asp Val Leu Arg Ala Glu Arg Glu Glu
465 470 475 480
Gln Lys Leu Ile Ser Glu Glu Asp Leu
485
<210> 11
<211> 1587
<212> DNA
<213> Homo sapiens
<400> 11
atgcccaccc ccgacgccac cacgccacag gccaagggct tccgcagggc cgtgtctgag 60
ctggacgcca agcaggcaga ggccatcatg gtaagagggc agggcgcccc ggggcccagc 120
ctcacaggct ctccgtggcc tggaactgca gccccagctg catcctacac ccccacccca 180
aggtccccgc ggttcattgg gcgcaggcag agcctcatcg aggacgcccg caaggagcgg 240
gaggcggcgg tggcagcagc ggccgctgca gtcccctcgg agcccgggga ccccctggag 300
gctgtggcct ttgaggagaa ggaggggaag gccgtgctaa acctgctctt ctccccgagg 360
gccaccaagc cctcggcgct gtcccgagct gtgaaggtgt ttgagacgtt tgaagccaaa 420
atccaccatc tagagacccg gcccgcccag aggccgcgag ctgggggccc ccacctggag 480
tacttcgtgc gcctcgaggt gcgccgaggg gacctggccg ccctgctcag tggtgtgcgc 540
caggtgtcag aggacgtgcg cagccccgcg gggcccaagg tcccctggtt cccaagaaaa 600
gtgtcagagc tggacaagtg tcatcacctg gtcaccaagt tcgaccctga cctggacttg 660
gaccacccgg gcttctcgga ccaggtgtac cgccagcgca ggaagctgat tgctgagatc 720
gccttccagt acaggcacgg cgacccgatt ccccgtgtgg agtacaccgc cgaggagatt 780
gccacctgga aggaggtcta caccacgctg aagggcctct acgccacgca cgcctgcggg 840
gagcacctgg aggcctttgc tttgctggag cgcttcagcg gctaccggga agacaatatc 900
ccccagctgg aggacgtctc ccgcttcctg aaggagcgca cgggcttcca gctgcggcct 960
gtggccggcc tgctgtccgc ccgggacttc ctggccagcc tggccttccg cgtgttccag 1020
tgcacccagt atatccgcca cgcgtcctcg cccatgcact cccctgagcc ggactgctgc 1080
cacgagctgc tggggcacgt gcccatgctg gccgaccgca ccttcgcgca gttctcgcag 1140
gacattggcc tggcgtccct gggggcctcg gatgaggaaa ttgagaagct gtccacgctg 1200
tactggttca cggtggagtt cgggctgtgt aagcagaacg gggaggtgaa ggcctatggt 1260
gccgggctgc tgtcctccta cggggagctc ctgcactgcc tgtctgagga gcctgagatt 1320
cgggccttcg accctgaggc tgcggccgtg cagccctacc aagaccagac gtaccagtca 1380
gtctacttcg tgtctgagag cttcagtgac gccaaggaca agctcaggag ctatgcctca 1440
cgcatccagc gccccttctc cgtgaagttc gacccgtaca cgctggccat cgacgtgctg 1500
gacagccccc aggccgtgcg gcgctccctg gagggtgtcc aggatgagct ggacaccctt 1560
gcccatgcgc tgagtgccat tggctag 1587
<210> 12
<211> 1311
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<222> ()..()
<223> TH截短90个氨基酸的DNA序列
<400> 12
ccctcggagc ccggggaccc cctggaggct gtggcctttg aggagaagga ggggaaggcc 60
gtgctaaacc tgctcttctc cccgagggcc accaagccct cggcgctgtc ccgagctgtg 120
aaggtgtttg agacgtttga agccaaaatc caccatctag agacccggcc cgcccagagg 180
ccgcgagctg ggggccccca cctggagtac ttcgtgcgcc tcgaggtgcg ccgaggggac 240
ctggccgccc tgctcagtgg tgtgcgccag gtgtcagagg acgtgcgcag ccccgcgggg 300
cccaaggtcc cctggttccc aagaaaagtg tcagagctgg acaagtgtca tcacctggtc 360
accaagttcg accctgacct ggacttggac cacccgggct tctcggacca ggtgtaccgc 420
cagcgcagga agctgattgc tgagatcgcc ttccagtaca ggcacggcga cccgattccc 480
cgtgtggagt acaccgccga ggagattgcc acctggaagg aggtctacac cacgctgaag 540
ggcctctacg ccacgcacgc ctgcggggag cacctggagg cctttgcttt gctggagcgc 600
ttcagcggct accgggaaga caatatcccc cagctggagg acgtctcccg cttcctgaag 660
gagcgcacgg gcttccagct gcggcctgtg gccggcctgc tgtccgcccg ggacttcctg 720
gccagcctgg ccttccgcgt gttccagtgc acccagtata tccgccacgc gtcctcgccc 780
atgcactccc ctgagccgga ctgctgccac gagctgctgg ggcacgtgcc catgctggcc 840
gaccgcacct tcgcgcagtt ctcgcaggac attggcctgg cgtccctggg ggcctcggat 900
gaggaaattg agaagctgtc cacgctgtac tggttcacgg tggagttcgg gctgtgtaag 960
cagaacgggg aggtgaaggc ctatggtgcc gggctgctgt cctcctacgg ggagctcctg 1020
cactgcctgt ctgaggagcc tgagattcgg gccttcgacc ctgaggctgc ggccgtgcag 1080
ccctaccaag accagacgta ccagtcagtc tacttcgtgt ctgagagctt cagtgacgcc 1140
aaggacaagc tcaggagcta tgcctcacgc atccagcgcc ccttctccgt gaagttcgac 1200
ccgtacacgc tggccatcga cgtgctggac agcccccagg ccgtgcggcg ctccctggag 1260
ggtgtccagg atgagctgga cacccttgcc catgcgctga gtgccattgg c 1311
<210> 13
<211> 1368
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<222> ()..()
<223> 含有HA标签的TH截短90个氨基酸的DNA序列
<400> 13
atgtacccat acgatgttcc agattacgct tacccatacg atgttccaga ttacgctccc 60
tcggagcccg gggaccccct ggaggctgtg gcctttgagg agaaggaggg gaaggccgtg 120
ctaaacctgc tcttctcccc gagggccacc aagccctcgg cgctgtcccg agctgtgaag 180
gtgtttgaga cgtttgaagc caaaatccac catctagaga cccggcccgc ccagaggccg 240
cgagctgggg gcccccacct ggagtacttc gtgcgcctcg aggtgcgccg aggggacctg 300
gccgccctgc tcagtggtgt gcgccaggtg tcagaggacg tgcgcagccc cgcggggccc 360
aaggtcccct ggttcccaag aaaagtgtca gagctggaca agtgtcatca cctggtcacc 420
aagttcgacc ctgacctgga cttggaccac ccgggcttct cggaccaggt gtaccgccag 480
cgcaggaagc tgattgctga gatcgccttc cagtacaggc acggcgaccc gattccccgt 540
gtggagtaca ccgccgagga gattgccacc tggaaggagg tctacaccac gctgaagggc 600
ctctacgcca cgcacgcctg cggggagcac ctggaggcct ttgctttgct ggagcgcttc 660
agcggctacc gggaagacaa tatcccccag ctggaggacg tctcccgctt cctgaaggag 720
cgcacgggct tccagctgcg gcctgtggcc ggcctgctgt ccgcccggga cttcctggcc 780
agcctggcct tccgcgtgtt ccagtgcacc cagtatatcc gccacgcgtc ctcgcccatg 840
cactcccctg agccggactg ctgccacgag ctgctggggc acgtgcccat gctggccgac 900
cgcaccttcg cgcagttctc gcaggacatt ggcctggcgt ccctgggggc ctcggatgag 960
gaaattgaga agctgtccac gctgtactgg ttcacggtgg agttcgggct gtgtaagcag 1020
aacggggagg tgaaggccta tggtgccggg ctgctgtcct cctacgggga gctcctgcac 1080
tgcctgtctg aggagcctga gattcgggcc ttcgaccctg aggctgcggc cgtgcagccc 1140
taccaagacc agacgtacca gtcagtctac ttcgtgtctg agagcttcag tgacgccaag 1200
gacaagctca ggagctatgc ctcacgcatc cagcgcccct tctccgtgaa gttcgacccg 1260
tacacgctgg ccatcgacgt gctggacagc ccccaggccg tgcggcgctc cctggagggt 1320
gtccaggatg agctggacac ccttgcccat gcgctgagtg ccattggc 1368
<210> 14
<211> 1437
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<222> ()..()
<223> AADC Isoform 1全长的含有突变的DNA序列
<400> 14
aacgcaagtg agtttcgaag gagagggaag gagatggtgg attacgtggc caactacatg 60
gaaggcattg agggacgcca ggtctaccct gacgtggagc ccgggtacct gcggccgctg 120
atccctgccg ctgcccctca ggagccagac acgtttgagg acatcatcaa cgacgttgag 180
aagataatca tgcctggggt gacgcactgg cacagcccct acttcttcgc ctacttcccc 240
actgccagct cgtacccggc catgcttgcg gacatgctgt gcggggccat tggctgcatc 300
ggcttctcct gggcggcaag cccagcatgc acagagctgg agactgtgat gatggactgg 360
ctcgggaaga tgctggaact accaaaggca tttttgaatg agaaagctgg agaaggggga 420
ggagtgatcc agggaagtgc cagtgaagcc accctggtgg ccctgctggc cgctcggacc 480
aaagtgatcc atcggctgca ggcagcgtcc ccagagctca cacaggccgc tatcatggag 540
aagctggtgg cttactcatc cgatcaggca cactcctcag tggaaagagc tgggttaatt 600
ggtggagtga aattaaaagc catcccctca gatggcaact tcgccatgcg tgcgtctgcc 660
ctgcaggaag ccctggagag agacaaagcg gctggcctga ttcctttctt tatggttgcc 720
accctgggga ccacaacatg ctgctccttt gacaatctct tagaagtcgg tcctatctgc 780
aacaaggaag acatatggct gcacgttgat gcagcctacg caggcagtgc attcatctgc 840
cctgagttcc ggcaccttct gaatggagtg gagtttgcag attcattcaa ctttaatccc 900
cacaaatggc tattggtgaa ttttgactgt tctgccatgt gggtgaaaaa gagaacagac 960
ttaacgggag cctttagact ggaccccact tacctgaagc acagccatca ggattcaggg 1020
cttatcactg actaccggca ttggcagata ccactgggca gaagatttcg ctctttgaaa 1080
atgtggtttg tatttaggat gtatggagtc aaaggactgc aggcttatat ccgcaagcat 1140
gtccagctgt cccatgagtt tgagtcactg gtgcgccagg acccccgctt tgaaatctgt 1200
gtggaagtca ttctggggct tgtctgcttt cggctaaagg gttccaacaa agtgaatgaa 1260
gctcttctgc aaagaataaa cagtgccaaa aaaatccact tggttccatg tcacctcagg 1320
gacaagtttg tcctgcgctt tgccatctgt tctcgcacgg tggaatctgc ccatgtgcag 1380
cgggcctggg aacacatcaa agagctggcg gccgacgtgc tgcgagcaga gagggag 1437
<210> 15
<211> 1443
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<222> ()..()
<223> 天然存在的AADC Isoform 1全长的DNA序列
<400> 15
atgaacgcaa gtgaattccg aaggagaggg aaggagatgg tggattacgt ggccaactac 60
atggaaggca ttgagggacg ccaggtctac cctgacgtgg agcccgggta cctgcggccg 120
ctgatccctg ccgctgcccc tcaggagcca gacacgtttg aggacatcat caacgacgtt 180
gagaagataa tcatgcctgg ggtgacgcac tggcacagcc cctacttctt cgcctacttc 240
cccactgcca gctcgtaccc ggccatgctt gcggacatgc tgtgcggggc cattggctgc 300
atcggcttct cctgggcggc aagcccagca tgcacagagc tggagactgt gatgatggac 360
tggctcggga agatgctgga actaccaaag gcatttttga atgagaaagc tggagaaggg 420
ggaggagtga tccagggaag tgccagtgaa gccaccctgg tggccctgct ggccgctcgg 480
accaaagtga tccatcggct gcaggcagcg tccccagagc tcacacaggc cgctatcatg 540
gagaagctgg tggcttactc atccgatcag gcacactcct cagtggaaag agctgggtta 600
attggtggag tgaaattaaa agccatcccc tcagatggca acttcgccat gcgtgcgtct 660
gccctgcagg aagccctgga gagagacaaa gcggctggcc tgattccttt ctttatggtt 720
gccaccctgg ggaccacaac atgctgctcc tttgacaatc tcttagaagt cggtcctatc 780
tgcaacaagg aagacatatg gctgcacgtt gatgcagcct acgcaggcag tgcattcatc 840
tgccctgagt tccggcacct tctgaatgga gtggagtttg cagattcatt caactttaat 900
ccccacaaat ggctattggt gaattttgac tgttctgcca tgtgggtgaa aaagagaaca 960
gacttaacgg gagcctttag actggacccc acttacctga agcacagcca tcaggattca 1020
gggcttatca ctgactaccg gcattggcag ataccactgg gcagaagatt tcgctctttg 1080
aaaatgtggt ttgtatttag gatgtatgga gtcaaaggac tgcaggctta tatccgcaag 1140
catgtccagc tgtcccatga gtttgagtca ctggtgcgcc aggatccccg ctttgaaatc 1200
tgtgtggaag tcattctggg gcttgtctgc tttcggctaa agggttccaa caaagtgaat 1260
gaagctcttc tgcaaagaat aaacagtgcc aaaaaaatcc acttggttcc atgtcacctc 1320
agggacaagt ttgtcctgcg ctttgccatc tgttctcgca cggtggaatc tgcccatgtg 1380
cagcgggcct gggaacacat caaagagctg gcggccgacg tgctgcgagc agagagggag 1440
tag 1443
<210> 16
<211> 1329
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<222> ()..()
<223> 天然存在的AADC Isoform 2全长的DNA序列
<400> 16
atgaacgcaa gtgaattccg aaggagaggg aaggagatgg tggattacgt ggccaactac 60
atggaaggca ttgagggacg ccaggtctac cctgacgtgg agcccgggta cctgcggccg 120
ctgatccctg ccgctgcccc tcaggagcca gacacgtttg aggacatcat caacgacgtt 180
gagaagataa tcatgcctgg ggcggcaagc ccagcatgca cagagctgga gactgtgatg 240
atggactggc tcgggaagat gctggaacta ccaaaggcat ttttgaatga gaaagctgga 300
gaagggggag gagtgatcca gggaagtgcc agtgaagcca ccctggtggc cctgctggcc 360
gctcggacca aagtgatcca tcggctgcag gcagcgtccc cagagctcac acaggccgct 420
atcatggaga agctggtggc ttactcatcc gatcaggcac actcctcagt ggaaagagct 480
gggttaattg gtggagtgaa attaaaagcc atcccctcag atggcaactt cgccatgcgt 540
gcgtctgccc tgcaggaagc cctggagaga gacaaagcgg ctggcctgat tcctttcttt 600
atggttgcca ccctggggac cacaacatgc tgctcctttg acaatctctt agaagtcggt 660
cctatctgca acaaggaaga catatggctg cacgttgatg cagcctacgc aggcagtgca 720
ttcatctgcc ctgagttccg gcaccttctg aatggagtgg agtttgcaga ttcattcaac 780
tttaatcccc acaaatggct attggtgaat tttgactgtt ctgccatgtg ggtgaaaaag 840
agaacagact taacgggagc ctttagactg gaccccactt acctgaagca cagccatcag 900
gattcagggc ttatcactga ctaccggcat tggcagatac cactgggcag aagatttcgc 960
tctttgaaaa tgtggtttgt atttaggatg tatggagtca aaggactgca ggcttatatc 1020
cgcaagcatg tccagctgtc ccatgagttt gagtcactgg tgcgccagga tccccgcttt 1080
gaaatctgtg tggaagtcat tctggggctt gtctgctttc ggctaaaggg ttccaacaaa 1140
gtgaatgaag ctcttctgca aagaataaac agtgccaaaa aaatccactt ggttccatgt 1200
cacctcaggg acaagtttgt cctgcgcttt gccatctgtt ctcgcacggt ggaatctgcc 1260
catgtgcagc gggcctggga acacatcaaa gagctggcgg ccgacgtgct gcgagcagag 1320
agggagtag 1329
<210> 17
<211> 1299
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<222> ()..()
<223> 天然存在的AADC Isoform 3全长的DNA序列
<400> 17
atgaacgcaa gtgaattccg aaggagaggg aaggagatgg tggattacgt ggccaactac 60
atggaaggca ttgagggacg ccaggtctac cctgacgtgg agcccgggta cctgcggccg 120
ctgatccctg ccgctgcccc tcaggagcca gacacgtttg aggacatcat caacgacgtt 180
gagaagataa tcatgcctgg ggtgacgcac tggcacagcc cctacttctt cgcctacttc 240
cccactgcca gctcgtaccc ggccatgctt gcggacatgc tgtgcggggc cattggctgc 300
atcggcttct cctgggcggc aagcccagca tgcacagagc tggagactgt gatgatggac 360
tggctcggga agatgctgga actaccaaag gcatttttga atgagaaagc tggagaaggg 420
ggaggagtga tccagggaag tgccagtgaa gccaccctgg tggccctgct ggccgctcgg 480
accaaagtga tccatcggct gcaggcagcg tccccagagc tcacacaggc cgctatcatg 540
gagaagctgg tggcttactc atccgatcag atggttgcca ccctggggac cacaacatgc 600
tgctcctttg acaatctctt agaagtcggt cctatctgca acaaggaaga catatggctg 660
cacgttgatg cagcctacgc aggcagtgca ttcatctgcc ctgagttccg gcaccttctg 720
aatggagtgg agtttgcaga ttcattcaac tttaatcccc acaaatggct attggtgaat 780
tttgactgtt ctgccatgtg ggtgaaaaag agaacagact taacgggagc ctttagactg 840
gaccccactt acctgaagca cagccatcag gattcagggc ttatcactga ctaccggcat 900
tggcagatac cactgggcag aagatttcgc tctttgaaaa tgtggtttgt atttaggatg 960
tatggagtca aaggactgca ggcttatatc cgcaagcatg tccagctgtc ccatgagttt 1020
gagtcactgg tgcgccagga tccccgcttt gaaatctgtg tggaagtcat tctggggctt 1080
gtctgctttc ggctaaaggg ttccaacaaa gtgaatgaag ctcttctgca aagaataaac 1140
agtgccaaaa aaatccactt ggttccatgt cacctcaggg acaagtttgt cctgcgcttt 1200
gccatctgtt ctcgcacggt ggaatctgcc catgtgcagc gggcctggga acacatcaaa 1260
gagctggcgg ccgacgtgct gcgagcagag agggagtag 1299
<210> 18
<211> 1209
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<222> ()..()
<223> 天然存在的AADC Isoform 4全长的DNA序列
<400> 18
atgaacgcaa gtgaattccg aaggagaggg aaggagatgg tggattacgt ggccaactac 60
atggaaggca ttgagggacg ccaggtctac cctgacgtgg agcccgggta cctgcggccg 120
ctgatccctg ccgctgcccc tcaggagcca gacacgtttg aggacatcat caacgacgtt 180
gagaagataa tcatgcctgg gggaagtgcc agtgaagcca ccctggtggc cctgctggcc 240
gctcggacca aagtgatcca tcggctgcag gcagcgtccc cagagctcac acaggccgct 300
atcatggaga agctggtggc ttactcatcc gatcaggcac actcctcagt ggaaagagct 360
gggttaattg gtggagtgaa attaaaagcc atcccctcag atggcaactt cgccatgcgt 420
gcgtctgccc tgcaggaagc cctggagaga gacaaagcgg ctggcctgat tcctttcttt 480
atggttgcca ccctggggac cacaacatgc tgctcctttg acaatctctt agaagtcggt 540
cctatctgca acaaggaaga catatggctg cacgttgatg cagcctacgc aggcagtgca 600
ttcatctgcc ctgagttccg gcaccttctg aatggagtgg agtttgcaga ttcattcaac 660
tttaatcccc acaaatggct attggtgaat tttgactgtt ctgccatgtg ggtgaaaaag 720
agaacagact taacgggagc ctttagactg gaccccactt acctgaagca cagccatcag 780
gattcagggc ttatcactga ctaccggcat tggcagatac cactgggcag aagatttcgc 840
tctttgaaaa tgtggtttgt atttaggatg tatggagtca aaggactgca ggcttatatc 900
cgcaagcatg tccagctgtc ccatgagttt gagtcactgg tgcgccagga tccccgcttt 960
gaaatctgtg tggaagtcat tctggggctt gtctgctttc ggctaaaggg ttccaacaaa 1020
gtgaatgaag ctcttctgca aagaataaac agtgccaaaa aaatccactt ggttccatgt 1080
cacctcaggg acaagtttgt cctgcgcttt gccatctgtt ctcgcacggt ggaatctgcc 1140
catgtgcagc gggcctggga acacatcaaa gagctggcgg ccgacgtgct gcgagcagag 1200
agggagtag 1209
<210> 19
<211> 1164
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<222> ()..()
<223> 天然存在的AADC Isoform 5全长的DNA序列
<400> 19
atgaacgcaa gtgaattccg aaggagaggg aaggagatgg tggattacgt ggccaactac 60
atggaaggca ttgagggacg ccaggtctac cctgacgtgg agcccgggta cctgcggccg 120
ctgatccctg ccgctgcccc tcaggagcca gacacgtttg aggacatcat caacgacgtt 180
gagaagataa tcatgcctgg ggtgacgcac tggcacagcc cctacttctt cgcctacttc 240
cccactgcca gctcgtaccc ggccatgctt gcggacatgc tgtgcggggc cattggctgc 300
atcggcttct cctgggcggc aagcccagca tgcacagagc tggagactgt gatgatggac 360
tggctcggga agatgctgga actaccaaag gcatttttga atgagaaagc tggagaaggg 420
ggaggagtga tccagatggt tgccaccctg gggaccacaa catgctgctc ctttgacaat 480
ctcttagaag tcggtcctat ctgcaacaag gaagacatat ggctgcacgt tgatgcagcc 540
tacgcaggca gtgcattcat ctgccctgag ttccggcacc ttctgaatgg agtggagttt 600
gcagattcat tcaactttaa tccccacaaa tggctattgg tgaattttga ctgttctgcc 660
atgtgggtga aaaagagaac agacttaacg ggagccttta gactggaccc cacttacctg 720
aagcacagcc atcaggattc agggcttatc actgactacc ggcattggca gataccactg 780
ggcagaagat ttcgctcttt gaaaatgtgg tttgtattta ggatgtatgg agtcaaagga 840
ctgcaggctt atatccgcaa gcatgtccag ctgtcccatg agtttgagtc actggtgcgc 900
caggatcccc gctttgaaat ctgtgtggaa gtcattctgg ggcttgtctg ctttcggcta 960
aagggttcca acaaagtgaa tgaagctctt ctgcaaagaa taaacagtgc caaaaaaatc 1020
cacttggttc catgtcacct cagggacaag tttgtcctgc gctttgccat ctgttctcgc 1080
acggtggaat ctgcccatgt gcagcgggcc tgggaacaca tcaaagagct ggcggccgac 1140
gtgctgcgag cagagaggga gtag 1164
<210> 20
<211> 1017
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<222> ()..()
<223> 天然存在的AADC Isoform 6全长的DNA序列
<400> 20
atgaacgcaa gtgaattccg aaggagaggg aaggagatgg tggattacgt ggccaactac 60
atggaaggca ttgagggacg ccaggtctac cctgacgtgg agcccgggta cctgcggccg 120
ctgatccctg ccgctgcccc tcaggagcca gacacgtttg aggacatcat caacgacgtt 180
gagaagataa tcatgcctgg ggtgacgcac tggcacagcc cctacttctt cgcctacttc 240
cccactgcca gctcgtaccc ggccatgctt gcggacatgc tgtgcggggc cattggctgc 300
atcggcttct cctgggcggc aagcccagca tgcacagagc tggagactgt gatgatggac 360
tggctcggga agatgctgga actaccaaag gcatttttga atgagaaagc tggagaaggg 420
ggaggagtga tccagggaag tgccagtgaa gccaccctgg tggccctgct ggccgctcgg 480
accaaagtga tccatcggct gcaggcagcg tccccagagc tcacacaggc cgctatcatg 540
gagaagctgg tggcttactc atccgatcag gcacactcct cagtggaaag agctgggtta 600
attggtggag tgaaattaaa agccatcccc tcagatggca acttcgccat gcgtgcgtct 660
gccctgcagg aagccctgga gagagacaaa gcggctggcc tgattccttt ctttatggtt 720
gccaccctgg ggaccacaac atgctgctcc tttgacaatc tcttagaagt cggtcctatc 780
tgcaacaagg aagacatatg gctgcacgtt gatgcagcct acgcaggcag tgcattcatc 840
tgccctgagt tccggcacct tctgaatgga gtggagtttg cagattcatt caactttaat 900
ccccacaaat ggctattggt gaattttgac tgttctgcca tgtggtccag acaaccagtg 960
cgtatgttaa ggctgaagaa aacctgctta gtcagtgcgg tggtgagaag gagttga 1017
<210> 21
<211> 1467
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<222> ()..()
<223> C端加入myc标签的AADC全长的DNA序列
<400> 21
aacgcaagtg agtttcgaag gagagggaag gagatggtgg attacgtggc caactacatg 60
gaaggcattg agggacgcca ggtctaccct gacgtggagc ccgggtacct gcggccgctg 120
atccctgccg ctgcccctca ggagccagac acgtttgagg acatcatcaa cgacgttgag 180
aagataatca tgcctggggt gacgcactgg cacagcccct acttcttcgc ctacttcccc 240
actgccagct cgtacccggc catgcttgcg gacatgctgt gcggggccat tggctgcatc 300
ggcttctcct gggcggcaag cccagcatgc acagagctgg agactgtgat gatggactgg 360
ctcgggaaga tgctggaact accaaaggca tttttgaatg agaaagctgg agaaggggga 420
ggagtgatcc agggaagtgc cagtgaagcc accctggtgg ccctgctggc cgctcggacc 480
aaagtgatcc atcggctgca ggcagcgtcc ccagagctca cacaggccgc tatcatggag 540
aagctggtgg cttactcatc cgatcaggca cactcctcag tggaaagagc tgggttaatt 600
ggtggagtga aattaaaagc catcccctca gatggcaact tcgccatgcg tgcgtctgcc 660
ctgcaggaag ccctggagag agacaaagcg gctggcctga ttcctttctt tatggttgcc 720
accctgggga ccacaacatg ctgctccttt gacaatctct tagaagtcgg tcctatctgc 780
aacaaggaag acatatggct gcacgttgat gcagcctacg caggcagtgc attcatctgc 840
cctgagttcc ggcaccttct gaatggagtg gagtttgcag attcattcaa ctttaatccc 900
cacaaatggc tattggtgaa ttttgactgt tctgccatgt gggtgaaaaa gagaacagac 960
ttaacgggag cctttagact ggaccccact tacctgaagc acagccatca ggattcaggg 1020
cttatcactg actaccggca ttggcagata ccactgggca gaagatttcg ctctttgaaa 1080
atgtggtttg tatttaggat gtatggagtc aaaggactgc aggcttatat ccgcaagcat 1140
gtccagctgt cccatgagtt tgagtcactg gtgcgccagg acccccgctt tgaaatctgt 1200
gtggaagtca ttctggggct tgtctgcttt cggctaaagg gttccaacaa agtgaatgaa 1260
gctcttctgc aaagaataaa cagtgccaaa aaaatccact tggttccatg tcacctcagg 1320
gacaagtttg tcctgcgctt tgccatctgt tctcgcacgg tggaatctgc ccatgtgcag 1380
cgggcctggg aacacatcaa agagctggcg gccgacgtgc tgcgagcaga gagggaggaa 1440
caaaaactca tctcagaaga ggatctg 1467
<210> 22
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<222> ()..()
<223> HA标签的氨基酸序列
<400> 22
Tyr Pro Tyr Asp Val Pro Asp Tyr Ala
1 5
<210> 23
<211> 27
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<222> ()..()
<223> HA标签的DNA序列
<400> 23
tacccatacg atgttccaga ttacgct 27
<210> 24
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<222> ()..()
<223> Myc标签的氨基酸序列
<400> 24
Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
1 5 10
<210> 25
<211> 30
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<222> ()..()
<223> Myc标签的DNA序列
<400> 25
gaacaaaaac tcatctcaga agaggatctg 30
<210> 26
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<222> ()..()
<223> Flag标签的氨基酸序列
<400> 26
Asp Tyr Lys Asp Asp Asp Asp Lys
1 5
<210> 27
<211> 24
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<222> ()..()
<223> Flag标签的DNA序列
<400> 27
gactacaagg acgatgatga caag 24
<210> 28
<211> 54
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<222> ()..()
<223> T2A的DNA序列
<400> 28
gagggcagag gaagtctgct aacatgcggt gacgtcgagg agaatcctgg ccca 54
Claims (20)
1.一种酪氨酸羟化酶变体,其中,所述酪氨酸羟化酶变体包括如SEQ ID NO:1所示的氨基酸序列的N端缺失60至120个氨基酸的酪氨酸羟化酶。
2.如权利要求1所述的酪氨酸羟化酶变体,所述酪氨酸羟化酶变体包括如SEQ ID NO:1所示的氨基酸序列的N端缺失80至100个氨基酸的酪氨酸羟化酶。
3.如权利要求2所述的酪氨酸羟化酶变体,所述酪氨酸羟化酶变体包括如SEQ ID NO:1所示的氨基酸序列的N端缺失80至90个氨基酸的酪氨酸羟化酶。
4.如权利要求2或3所述的酪氨酸羟化酶变体,其中所述酪氨酸羟化酶变体包括如SEQID NO:2所示的蛋白或与SEQ ID NO:1所示的氨基酸序列具有80%序列同一性的酪氨酸羟化酶衍生物,优选地,所述酪氨酸羟化酶变体还可选择性在序列N端或C端添加标签蛋白,更优选地,所述标签蛋白可以为HA、Myc、Flag。
5.如权利要求4所述的酪氨酸羟化酶变体,其中所述酪氨酸羟化酶变体包括如SEQ IDNO:3所示的蛋白。
6.一种组合物,包括至少一种如权利要求1至5任一项所述酪氨酸羟化酶变体。
7.如权利要求6所述的组合物,还包括芳香族L-氨基酸脱羧酶。
8.如权利要求7所述的组合物,所述芳香族L-氨基酸脱羧酶为全长的芳香族L-氨基酸脱羧酶,其包含如SEQ ID NO:4-9中任一序列所示的蛋白或与SEQ ID NO:4-9任一序列所示的氨基酸序列具有80%序列同一性的芳香族L-氨基酸脱羧酶衍生物,优选地,所述芳香族L-氨基酸脱羧酶还可选择性在序列N端或C端添加标签蛋白,更优选地,所述标签蛋白可以为HA、Myc、Flag。
9.如权利要求8所述的组合物,所述芳香族L-氨基酸脱羧酶的序列如SEQ ID NO:10所示。
10.一种核苷酸构建体,其包含编码如权利要求1至5中任一项所述的酪氨酸羟化酶变体的多核苷酸或如权利要求6至9中任一项所述的组合物的核苷酸序列。
11.如权利要求10所述的核苷酸构建体,其中,所述酪氨酸羟化酶变体的多核苷酸序列如SEQ ID NO:12或13或与其具有80%以上同一性的序列所示,和/或所述芳香族L-氨基酸脱羧酶的多核苷酸序列如SEQ ID NO:14-21中任一个或与其具有80%以上同一性的序列所示。
12.一种载体质粒,其包含如权利要求10或11所述的核苷酸构建体。
13.如权利要求10或11所述的载体质粒,其中,所述酪氨酸羟化酶变体的核苷酸序列和所述芳香族L-氨基酸脱羧酶的核苷酸序列可被构建于同一载体质粒中,也可构建于不同载体质粒中。
14.如权利要求10或11所述的载体质粒,其中所述载体质粒选自单纯孢疹病毒载体、腺病毒载体、腺相关病毒载体。
15.一种细胞,其被如权利要求12至14中任一项所述的载体质粒转染制备而成。
16.一种病毒,其包含如权利要求15所述的核苷酸构建体作为其基因组。
17.一种药物组合物,包含如权利要求16所述的病毒和药物学可接受的载体。
18.如权利要求1至5中任一项所述的酪氨酸羟化酶变体、权利要求6至9中任一项所述的药物组合物、权利要求10或11所述的核苷酸构建体、权利要求12至14中任一项所述的载体质粒、权利要求15所述的细胞、权利要求16所述的病毒、权利要求17所述的组合物在制备用于治疗受试者神经退行性疾病药物中的用途。
19.如权利要求18所述的用途,其中,所述神经退行性疾病为帕金森病。
20.如权利要求18所述的用途,其中,所述受试者为哺乳动物,优选为人类、大鼠、小鼠。
Priority Applications (10)
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CN201910322504.8A CN109971729B (zh) | 2019-04-19 | 2019-04-19 | 一种酶组合物 |
PCT/CN2020/085366 WO2020211843A1 (en) | 2019-04-19 | 2020-04-17 | A new type of enzyme composition |
CA3136853A CA3136853A1 (en) | 2019-04-19 | 2020-04-17 | A new type of enzyme composition |
BR112021020926A BR112021020926A2 (pt) | 2019-04-19 | 2020-04-17 | Um novo tipo de composição de enzima |
JP2021562101A JP2022529701A (ja) | 2019-04-19 | 2020-04-17 | 新型の酵素組成物 |
AU2020258972A AU2020258972A1 (en) | 2019-04-19 | 2020-04-17 | A new type of enzyme composition |
US17/604,995 US20220204950A1 (en) | 2019-04-19 | 2020-04-17 | A new type of enzyme composition |
EP20791792.3A EP3956440A4 (en) | 2019-04-19 | 2020-04-17 | NOVEL ENZYME COMPOSITION |
KR1020217037831A KR20220003566A (ko) | 2019-04-19 | 2020-04-17 | 신규한 유형의 효소 조성물 |
MX2021012784A MX2021012784A (es) | 2019-04-19 | 2020-04-17 | Un nuevo tipo de composicion enzimatica. |
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CN201910322504.8A CN109971729B (zh) | 2019-04-19 | 2019-04-19 | 一种酶组合物 |
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US (1) | US20220204950A1 (zh) |
EP (1) | EP3956440A4 (zh) |
JP (1) | JP2022529701A (zh) |
KR (1) | KR20220003566A (zh) |
CN (1) | CN109971729B (zh) |
AU (1) | AU2020258972A1 (zh) |
BR (1) | BR112021020926A2 (zh) |
CA (1) | CA3136853A1 (zh) |
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WO (1) | WO2020211843A1 (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2020211843A1 (en) * | 2019-04-19 | 2020-10-22 | Belief Biomed Limited | A new type of enzyme composition |
WO2023093905A1 (zh) * | 2021-11-29 | 2023-06-01 | 上海瑞宏迪医药有限公司 | Aadc、gdnf多核苷酸及其用于治疗帕金森病 |
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CN107523581A (zh) * | 2011-10-28 | 2017-12-29 | 牛津生物医学(英国)有限公司 | 构建体 |
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EP0755454B1 (en) * | 1994-04-13 | 2008-02-13 | The Rockefeller University | Aav-mediated delivery of dna to cells of the nervous system |
CN109971729B (zh) * | 2019-04-19 | 2021-07-16 | 上海信致医药科技有限公司 | 一种酶组合物 |
-
2019
- 2019-04-19 CN CN201910322504.8A patent/CN109971729B/zh active Active
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- 2020-04-17 MX MX2021012784A patent/MX2021012784A/es unknown
- 2020-04-17 JP JP2021562101A patent/JP2022529701A/ja active Pending
- 2020-04-17 CA CA3136853A patent/CA3136853A1/en active Pending
- 2020-04-17 US US17/604,995 patent/US20220204950A1/en active Pending
- 2020-04-17 BR BR112021020926A patent/BR112021020926A2/pt unknown
- 2020-04-17 EP EP20791792.3A patent/EP3956440A4/en active Pending
- 2020-04-17 WO PCT/CN2020/085366 patent/WO2020211843A1/en active Application Filing
- 2020-04-17 KR KR1020217037831A patent/KR20220003566A/ko unknown
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2020211843A1 (en) * | 2019-04-19 | 2020-10-22 | Belief Biomed Limited | A new type of enzyme composition |
WO2023093905A1 (zh) * | 2021-11-29 | 2023-06-01 | 上海瑞宏迪医药有限公司 | Aadc、gdnf多核苷酸及其用于治疗帕金森病 |
Also Published As
Publication number | Publication date |
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WO2020211843A1 (en) | 2020-10-22 |
AU2020258972A1 (en) | 2021-12-16 |
EP3956440A1 (en) | 2022-02-23 |
KR20220003566A (ko) | 2022-01-10 |
CA3136853A1 (en) | 2020-10-22 |
MX2021012784A (es) | 2022-01-26 |
BR112021020926A2 (pt) | 2022-03-22 |
EP3956440A4 (en) | 2023-01-18 |
US20220204950A1 (en) | 2022-06-30 |
JP2022529701A (ja) | 2022-06-23 |
CN109971729B (zh) | 2021-07-16 |
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