CN104114705B - 用于增加编码的治疗性蛋白表达的包含或编码组蛋白茎环和聚腺苷酸序列或聚腺苷酸化信号的核酸 - Google Patents
用于增加编码的治疗性蛋白表达的包含或编码组蛋白茎环和聚腺苷酸序列或聚腺苷酸化信号的核酸 Download PDFInfo
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Abstract
本发明涉及一种核酸序列,所述核酸序列包含或编码:编码区,所述编码区编码至少一种包含治疗性蛋白或其片段、变体或衍生物的肽或蛋白,至少一个组蛋白茎环和聚腺苷酸序列或聚腺苷酸化信号。此外,本发明提供所述核酸用于增加所编码的肽或蛋白的表达(特别是用于基因治疗)的应用。本发明还公开了其用于制备药物组合物的应用,所述药物组合物例如,用于基因治疗,特别是用于治疗需要使用治疗性肽或蛋白(优选如本文定义)的疾病。本发明还描述了利用包含或编码组蛋白茎环和聚腺苷酸序列或聚腺苷酸化信号的核酸增加包含治疗性蛋白或其片段、变体或衍生物的肽或蛋白的表达的方法。
Description
本发明涉及一种核酸序列,所述核酸序列包含或编码:编码区,所述编码区编码至少一种包含治疗性蛋白或其片段、变体或衍生物的肽或蛋白,至少一个组蛋白茎环和聚腺苷酸序列或聚腺苷酸化信号。此外,本发明提供所述核酸用于增加所编码的肽或蛋白的表达(特别是用于基因治疗)中的应用。本发明还公开了其用于制备药物组合物的应用,所述药物组合物例如,用于基因治疗,特别是用于治疗需要使用治疗性肽或蛋白(优选如本文定义)的疾病。本发明还描述了利用包含或编码组蛋白茎环和聚腺苷酸序列或聚腺苷酸化信号的核酸增加包含治疗性蛋白或其片段、变体或衍生物的肽或蛋白的表达的方法。
基因治疗意指使用核酸作为药剂来治疗疾病。其名称来源于这样的观点:核酸可以用来补充或改变个体细胞内基因的表达,作为治疗法来治疗疾病。最常见形式的基因治疗涉及使用编码功能性、治疗性蛋白的核酸,以替代突变的基因。其他形式涉及突变的直接校正,或使用编码治疗性蛋白药物的核酸来提供治疗。
基因治疗是已经在疾病的治疗和预防中得到证明的分子医学方法,并且通常表现出对日常医学实践、特别是对本文提及疾病的治疗的相当大的作用。基因治疗是基于将核酸引入到患者细胞或组织中然后处理由已经引入到细胞或组织中的核酸编码的信息,也就是说,处理所需要的多肽的(蛋白)表达。
基因治疗可以对多种遗传或获得性疾病、特别是传染病、肿瘤(例如,癌症或肿瘤疾病)、血液和血液形成器官的疾病、内分泌、营养和代谢病、神经系统的疾病、循环系统的疾病、呼吸系统的疾病、消化系统的疾病、皮肤和皮下组织的疾病、肌肉骨骼系统和结缔组织的疾病和生殖泌尿系统的疾病是有益的。
在基因治疗方法中,典型地是使用DNA,尽管在最近的开发过程中RNA也是已知的。重要的是,在所有这些基因治疗方法中,不管是使用DNA、病毒RNA还是mRNA,mRNA作用为所编码的蛋白的序列信息的信使。
通常,认为RNA是不稳定分子:RNA酶是普遍存在的,并且众所周知其是难于灭活的。此外,与DNA相比,RNA还是更化学不稳定的。因此,可能令人惊讶的是,真核细胞中mRNA的“默认状态”特征在于相对的稳定性,并且需要特定的信号来加速个体mRNAs的分解。关于这一发现的主要原因似乎是细胞内mRNA分解几乎专门由核酸外切酶催化。然而,真核mRNAs的末端是通过下述特定的末端结构及其相缔合的蛋白针对这些酶进行保护的:在5’端的m7GpppN CAP和典型地在3’端的聚腺苷酸序列。由此认为这两种末端修饰的去除是mRNA分解的速度限制。尽管稳定元件已经表征为α-珠蛋白mRNA的3’UTR,但是影响真核mRNAs的更新的RNA序列典型地通过加速脱腺苷作用而作用为分解的启动剂(在Meyer,S.,C.Temme,等人.(2004),Crit Rev Biochem Mol Biol(生物化学分子生物学重要综述)39(4):197-216.中综述)。
如上文提及的,真核mRNAs的5’端典型地在转录后修饰,以携带甲基化的CAP结构,例如,m7GpppN。除了在RNA剪接、稳定和转运中的作用,在翻译起始过程中,CAP结构显著增强40S核糖体亚基向mRNA的5’端的募集。后一种功能需要由真核起始因子复合物eIF4F来识别该CAP结构。聚腺苷酸序列另外通过增加40S亚基到mRNAs的募集而刺激翻译,这是一种需要聚腺苷酸结合蛋白(PABP)的干预的作用。PABP,最近又证明与eIF4G物理相互作用,eIF4G是CAP-结合的eIF4F复合物的一部分。因此,假设了对加帽的、聚腺苷化的mRNAs的翻译起始的闭环模型(Michel,Y.M.,D.Poncet,等人.(2000),J Biol Chem(生物化学杂志)275(41):32268-76.)。
几乎所有的真核mRNAs的末端都是通过遍在切割/聚腺苷化机制添加在其3′末端的聚腺苷酸序列。在3′末端存在聚腺苷酸序列是真核mRNAs的最显著的特征之一。在切割后,除了复制依赖性组蛋白转录物之外,大部分前mRNAs都获得聚腺苷化的尾部。在这种情形中,3’末端加工是促进mRNAs从细胞核转运到细胞质并且影响mRNAs的稳定性和翻译的核共转录过程。该3’末端的信息以由切割/聚腺苷化机制引导的两步反应发生,并且取决于在mRNA前体(前mRNAs)中存在两种序列元件:高度保守的核苷酸六聚体AAUAAA(聚腺苷酸化信号)和下游的富含G/U的序列。在第一步中,前mRNAs在这两个元件之间被切割开。在与第一步紧密偶联的第二步中,刚形成的3′端通过添加由200-250个腺苷酸组成的聚腺苷酸序列而延伸,所述聚腺苷酸序列基本上影响mRNA代谢的所有方面,包括mRNA输出、稳定性和翻译(Dominski,Z.和W.F.Marzluff(2007),Gene(基因)396(2):373-90.)。
这一法则唯一已知的例外是复制依赖性组蛋白mRNAs,其末端是组蛋白茎环而不是聚腺苷酸序列。示例性的组蛋白茎环序列记述在Lopez等人.(Dávila López,M.,&Samuelsson,T.(2008),RNA(纽约,N.Y.),14(1),1-10.doi:10.1261/rna.782308.)中。
组蛋白前mRNAs中的茎环典型地接着富含嘌呤的序列,其称为组蛋白下游元件(HDE)。这些前mRNAs在细胞核中在该茎环下游的大约5个核苷酸处由单次内切核酸水解切割而进行加工,该单次内切核酸水解切割由U7 snRNP通过U7 snRNA与HDE的碱基配对进行催化。包含组蛋白茎环结构和组蛋白下游元件(HDE)(U7 snRNP的结合位点)的3’-UTR序列通常称为组蛋白3’-加工信号(例如,参见Chodchoy,N.,N.B.Pandey,等人.(1991).MolCell Biol(分子细胞生物学)11(1):497-509.)。
由于需要将刚合成的DNA包装成染色质,组蛋白合成与细胞周期相适应地进行调节。在S期过程中增加的组蛋白类蛋白(histone proteins)合成通过组蛋白基因的转录激活以及组蛋白mRNA水平的转录后调控而实现。这可能表明,组蛋白茎环对于组蛋白表达调节的所有转录后步骤都是重要的。其是有效加工、mRNA输出到细胞质中、负载到多核糖体上和对mRNA稳定性的调节所必需的。
在上述情形中,鉴定一种32 kDa的蛋白,其在细胞核和细胞质中在组蛋白信使的3’端与组蛋白茎环相缔合。该茎环结合蛋白(SLBP)的表达水平是细胞周期调节的,并且在S期最高,此时组蛋白mRNA水平增加。SLBP是U7 snRNP对组蛋白前mRNA的有效的3’端加工所必需的。在加工完成后,SLBP保持与成熟的组蛋白mRNAs的末端的茎环缔合,并且在刺激其细胞质中翻译成组蛋白类蛋白。(Dominski,Z.和W.F.Marzluff(2007),Gene(基因)396(2):373-90)。有趣的是,SLBP的RNA结合结构域在后生动物和原生动物中都是保守的(Dávila López,M.,&Samuelsson,T.(2008),RNA(纽约,N.Y.),14(1),1-10.doi:10.1261/rna.782308),并且能够表明,其与组蛋白茎环序列的结合取决于茎环结构,并且最小的结合位点包含所述茎环的至少3个5’核苷酸和2个3’核苷酸(Pandey,N.B.,等人.(1994),Molecular and Cellular Biology(分子和细胞生物学),14(3),1709-1720和Williams,A.S.,&Marzluff,W.F.,(1995),NucleicAcids Research(核酸研究),23(4),654-662.)。
尽管组蛋白基因通常分类为“复制依赖性的”,其产生末端是组蛋白茎环的mRNA,或是“置换型的”,其相反产生携带聚腺苷酸-尾的mRNA,但是,在一些非常少见的情形中已经鉴定了其天然存在的在其3’包含组蛋白茎环和聚腺苷酸或寡(A)的mRNAs。Sanchez等人使用荧光素酶作为报道蛋白在爪蟾(Xenopus)卵子发生过程中检验了附着在组蛋白mRNA的组蛋白茎环的3’的天然存在的寡腺苷酸尾的作用,并且发现寡腺苷酸尾是在卵子发生过程中使组蛋白mRNA沉默的翻译抑制机制的活性部分,并且去除其是激活组蛋白mRNAs翻译的机制的一部分(Sanchez,R.和W.F.Marzluff(2004),Mol Cell Biol(分子细胞生物学)24(6):2513-25)。
此外,已经使用编码标记蛋白α珠蛋白的人工构建体研究了在前mRNA加工和mRNA稳定性水平上对复制依赖性组蛋白的调节的需要,这是利用与内含子较少的组蛋白基因相比珠蛋白基因含有内含子的事实。对于这一目的,产生这样的构建体,其中α珠蛋白编码序列之后接着组蛋白茎环信号(组蛋白茎环之后接着组蛋白下游元件)和聚腺苷酸化信号(Whitelaw,E.,等人.(1986).Nucleic Acids Research(核酸研究),14(17),7059-7070.;Pandey,N.B.,&Marzluff,W.F.(1987).Molecular and Cellular Biology(分子和细胞生物学),7(12),4557-4559.;Pandey,N.B.,等人.(1990).Nucleic Acids Research(核酸研究),18(11),3161-3170)。
Lüscher等人以另一种方法研究了重组组蛋白H4基因的细胞周期依赖性调节。产生这样的构建体,其中H4编码序列之后接着组蛋白茎环信号和聚腺苷酸化信号,这两种加工信号临时由半乳糖激酶编码序列隔开(Lüscher,B.等人.,(1985).Proc.Natl.Acad.Sci.USA(美国国家科学院学报),82(13),4389-4393)。
另外,Stauber等人鉴定了在组蛋白H4 mRNA水平上赋予细胞周期调节所需要的最小序列。对于这些研究,使用这样的构建体,其包含在组蛋白茎环信号(其后接着聚腺苷酸化信号)之前的选择标记黄嘌呤:鸟嘌呤磷酸核糖基转移酶(GPT)的编码序列(Stauber,C.等人.,(1986).EMBO J,5(12),3297-3303)。
检验组蛋白前mRNA加工,Wagner等人使用在组蛋白茎环信号与聚腺苷酸化信号之间放置EGFP的报道子构建体(以使EGFP仅在组蛋白前mRNA加工被破坏的情形中表达)鉴定了组蛋白前mRNAs切割所需要的因子(Wagner,E.J.等人.,(2007).Mol Cell(分子细胞)28(4),692-9)。
应该注意,聚腺苷化的mRNA的翻译通常需要使得3′聚腺苷酸序列接近5′CAP。这通过聚腺苷酸结合蛋白与真核起始因子eIF4G之间的蛋白-蛋白相互作用而调控。关于复制依赖性的组蛋白mRNAs,已经揭示了类似的机制。在这种情形中,Gallie等人表明组蛋白茎环在功能上与聚腺苷酸序列类似,原因在于其提高翻译效率并且共同依赖于5’-CAP,从而建立有效的翻译水平。他们表明组蛋白茎环足以增加报道mRNA在转染的中国仓鼠卵巢细胞中的翻译并且是必需的,但是为了最理想地行使功能,必须位于3’-端。因此,与其他mRNAs上的聚腺苷酸尾相似,这些组蛋白mRNAs的3′端似乎是在体内翻译所必需的,并且在功能上与聚腺苷酸尾相似(Gallie,D.R.,Lewis,N.J.,&Marzluff,W.F.(1996),Nucleic AcidsResearch(核酸研究),24(10),1954-1962)。
另外,可以显示,SLBP结合在细胞质组蛋白mRNA上,并且是其翻译所需要的。即使SLBP不直接与eIF4G相互作用,但是组蛋白mRNA翻译所需要的结构域与最近鉴定的蛋白SLIPl相互作用。在另一个步骤中,SLIPl与eIF4G相互作用,并且允许组蛋白mRNA循环并通过与聚腺苷化mRNAs翻译相似的机制支持组蛋白mRNA的有效的翻译。
如上文提及,基因治疗方法通常使用DNA将编码信息转运到细胞中,然后其转录成mRNA,所述mRNA携带天然存在的mRNA元件,特别是5’-CAP结构和3’聚腺苷酸序列以确保所编码的治疗性蛋白或抗原性蛋白的表达。
然而,在多种情形中,不管是使用DNA还是RNA,基于将所述核酸引入到患者细胞或组织中并且随后通过表达由这些核酸编码的需要的多肽的表达系统没有表现出合乎需要的、或者甚至是必需的可能允许有效的治疗的表达水平。
在现有技术中,迄今已经进行了不同的尝试在体外和/或体内增加编码的蛋白的表达产率,特别是使用改善的表达系统。现有技术中通常所述的增加表达的方法常规上是基于使用包含特定启动子和相应的调节元件的表达载体或盒。由于这些表达载体或盒典型地局限于特定的细胞系统,因此这些表达系统必须进行修改才能用于不同的细胞系统。然后通常将所述修改的表达载体或盒转染到细胞中并且典型地依赖于特定的细胞系进行处理。因此,优选主要产生对不依赖于对特定细胞类型特异性的启动子和调节元件、能够通过细胞中固有的系统在靶细胞中表达编码的蛋白的那些核酸分子。在这种情形中,在mRNA稳定元件和增加mRNA翻译效率的元件之间可以区分。
在其编码序列进行优化并且通常适用于这样的目的的mRNAs记述在中请WO 02/098443(CureVac GmbH)中。例如,WO 02/098443描述了以通用形式稳定并且在其编码区翻译优化的mRNAs。WO 02/098443还公开了确定序列修饰的方法。WO 02/098443另外描述了为增加序列中的鸟嘌呤/胞嘧啶(G/C)含量而取代mRNA序列中的腺嘌呤和尿嘧啶核苷酸的可能性。依据WO 02/098443,所述为增加G/C含量的取代和修改可以用于基因治疗应用,而且还可以用作遗传疫苗用于癌症或传染病的治疗。在这一情形中,WO 02/098443通常提及作为用于所述修饰的基础序列的序列,其中修饰的mRNA编码至少一种生物活性肽或多肽,所述肽或多肽在待治疗的患者中例如全然不翻译或不充分翻译的或具有错误的翻译。备选地,WO 02/098443提议编码抗原(例如,治疗性蛋白或病毒抗原)的mRNAs作为所述修饰的基础序列。
在另一种增加所编码的蛋白的表达的方法中,申请WO 2007/036366记述了长的聚腺苷酸序列(特别是长于120bp)以及β珠蛋白基因的至少两个3’非翻译区的组合对mRNA稳定性和翻译活性的阳性作用。
然而,即使所有这些近来的现有技术文献已经尝试提供非常有效的用于基因治疗方法以及另外改善的mRNA稳定性和翻译活性的工具,但是,相对于DNA疫苗和基于DNA的基因治疗方法,仍然存在基于RNA的应用稳定性通常较低的问题。因此,在本领域中仍然存在提供用于基因治疗方法或作为上文讨论的常规治疗的补充治疗法的改善的工具的需求,其允许在体内更好地提供所编码的蛋白,例如,通过进一步改善的mRNA稳定性和/或翻译活性,优选用于基因治疗。
此外,尽管本领域中的所有进展,在不含细胞的系统、细胞或生物体中有效表达所编码的肽或蛋白(重组表达)仍然是具有挑战性的问题。
因此,本发明基本目的是提供另外的和/或备选的增加所编码的蛋白的表达的方法,优选地,通过相对于现有技术中已知用于遗传或获得性疾病(特别如本文定义的)的治疗性或预防性治疗中的基因治疗的所述核酸进一步稳定mRNA和/或增加所述mRNA的翻译效率而进行。
该目的通过后附权利要求的主题来解决。具体地,按照第一方面,本发明基本目的通过本发明的核酸序列而解决,所述核酸序列包含或编码:
a)编码区,所述编码区编码至少一种包含治疗性蛋白或其片段、变体或衍生物的肽或蛋白;
b)至少一个组蛋白茎环,和
c)聚腺苷酸序列或聚腺苷酸化信号,
优选地用于增加所编码的肽或蛋白的表达。
备选地,除组蛋白茎环序列之外的任意适宜的茎环序列(来源于组蛋白基因,特别是H1,H2A,H2B,H3和H4家族的组蛋白基因)都可以由本发明用于其所有的方面和实施方案中。
在这一情形中,特别优选的是本发明第一方面所述的本发明的核酸至少部分通过DNA或RNA合成产生,优选如本文所述,或是分离的核酸。
本发明是基于本发明人的令人惊讶的发现:聚腺苷酸序列或聚腺苷酸化信号与至少一种组蛋白茎环的组合(尽管二者均代表自然中的择一机制)协同作用,原因在于该组合增加蛋白的表达,高于使用任一种单独的元件所观察到的水平数倍(manifold)。观察到聚腺苷酸与至少一种组蛋白茎环的组合的协同作用与聚腺苷酸和组蛋白茎环的顺序无关,并且与聚腺苷酸序列的长度无关。
因此,特别优选的是,本发明的核酸序列包含或编码:a)编码区,所述编码区编码至少一种包含治疗性蛋白或其片段、变体或衍生物的肽或蛋白;b)至少一个组蛋白茎环,和c)聚腺苷酸序列或聚腺苷酸化序列;优选地用于增加所编码的肽或蛋白的表达,其中所编码的蛋白优选不是组蛋白类蛋白,特别不是H4,H3,H2A和/或H2B组蛋白家族的组蛋白类蛋白或其保留组蛋白(-样)功能(即,形成核小体)的片段、衍生物或变体。此外,所编码的蛋白典型地不对应于H1组蛋白家族的组蛋白接头蛋白。本发明的核酸分子典型地不包含小鼠组蛋白基因的任何调节信号(5’和/或,特别是3’),特别不是小鼠组蛋白基因H2A的任何调节信号,并且进一步最优选不是小鼠组蛋白基因H2A614的任何调节信号。特别地,其不包含来自小鼠组蛋白基因的组蛋白茎环和/或组蛋白茎环加工信号,特别地不是小鼠组蛋白基因H2A的组蛋白茎环和/或组蛋白茎环加工信号,最优选不是小鼠组蛋白基因H2A614的组蛋白茎环和/或组蛋白茎环加工信号。
此外,本发明的核酸在其元件(a)中典型地不提供报道蛋白(例如,荧光素酶,GFP,EGFP,β-半乳糖苷酶,特别是EGFP),半乳糖激酶(galK)和/或标记或选择蛋白(例如,α-珠蛋白,半乳糖激酶和黄嘌呤:鸟嘌呤磷酸核糖基转移酶(GPT))或细菌报道蛋白,例如氯霉素乙酰转移酶(CAT)或其他细菌抗生素抗性蛋白,例如,来源于细菌neo基因的细菌抗生素抗性蛋白。
报道、标记或选择蛋白典型地理解为不是本发明所述的治疗性蛋白。报道、标记或选择蛋白或其基础基因(underlying gene)通常用作细菌、细胞培养物、动物或植物中的研究工具。它们赋予表达其的生物体(优选是异源表达)容易鉴别的特性,所述特性可以测量或允许进行选择。具体地,标记或选择蛋白表现出可选择的功能。典型地,所述选择、标记或报道蛋白在人或其他动物中不是天然存在的,而是来源于其他生物体,特别是来源于细菌或植物。因此,来源于除哺乳动物之外的物种、特别是除人之外的物种的具有选择、标记或报道功能的蛋白优选排除被理解为本发明所述的“治疗性蛋白”。特别地,选择、标记或报道蛋白允许通过例如基于荧光或其他分光光度计技术以及针对抗生素的抗性的体外测定来鉴定转化的细胞。因此,赋予转化的细胞所述特性的选择、报道或标记基因典型地不被理解为本发明所述的治疗性蛋白。
在任何情形中,报道、标记或选择蛋白通常不发挥任何治疗性作用。如果任一种单独的报道、标记或选择蛋白仍然发挥治疗性作用(除了其报道、选择或标记功能之外),则所述报道、标记或选择蛋白优选不被理解为本发明意义内的“治疗性蛋白”。
相比之下,本发明所述的治疗性蛋白(包括其片段、变体和衍生物),特别排除H1、H2A、H2B、H3和H4家族的组蛋白基因,典型地不表现出选择、标记或报道功能。如果任一单个“治疗性蛋白”仍然应该表现出选择、标记或报道功能(除了其治疗性功能之外),则所述治疗性蛋白优选不被理解为本发明意义内的“选择、标记或报道蛋白”。
最优选地理解为本发明所述的治疗性蛋白来源于哺乳动物,特别是人,并且,其不适合作为选择、标记或报道蛋白。
因此,优选的是,编码至少一种肽或蛋白的编码区(a)与至少一种组蛋白茎环的至少(b),或更广泛地,与任意适当的茎环是异源的。换言之,在本发明的情形中,“异源”意指至少一种茎环序列不是天然存在为编码本发明核酸的元件(a)的(治疗性)蛋白或肽的特定基因的(调节)序列(例如,在3’UTR)。因此,本发明核酸的(组蛋白)茎环优选来源于不同于包含本发明核酸的元件(a)的编码区的基因的基因的3’UTR。例如,如果本发明核酸是异源的,则元件(a)的编码区不编码组蛋白类蛋白或其(保留组蛋白类蛋白的功能的)片段、变体或衍生物,而是编码发挥生物学功能、优选不同于组蛋白(-样)功能的治疗性功能的任意其他的(相同物种或另一种物种的)肽或序列,例如,编码治疗性蛋白(发挥治疗性功能,例如,关于内分泌紊乱,替代缺陷性的内源蛋白,例如,缺陷性的内源哺乳动物蛋白,特别是缺陷性的内源人蛋白)。
在这一情形中,特别优选的是本发明的核酸在5’-至3’-方向上包含或编码:
a)编码区,所述编码区编码至少一种包含治疗性蛋白或其片段、变体或衍生物的肽或蛋白;
b)至少一个组蛋白茎环,任选地没有所述组蛋白茎环3’的组蛋白下游元件(HDE),
c)聚腺苷酸序列或聚腺苷酸化信号。
术语“组蛋白下游元件(HDE)”是指在天然存在的组蛋白茎环3’的约15-20个核苷酸的富含嘌呤的多核苷酸片段,其表示参与将组蛋白前mRNA加工为成熟的组蛋白mRNA的U7snRNA的结合位点。例如,在海胆(sea urchins)中,所述HDE为CAAGAAAGA(Dominski,Z.和W.F.Marzluff(2007),Gene(基因)396(2):373-90)。
此外,优选地,本发明第一方面所述的本发明的核酸不包含内含子。
在另一个特别优选的实施方案中,本发明第一方面所述的本发明的核酸序列从5’到3’包含或编码:
a)编码区,优选地所述编码区编码至少一种包含治疗性蛋白或其片段、变体或衍生物的肽或蛋白;
c)聚腺苷酸序列;和
b)至少一个组蛋白茎环。
本发明第一实施方案所述的本发明的核酸序列包含任意适当的核酸,例如,选自任意(单链或双链)DNA,优选地,但不限于此,例如,基因组DNA,质粒DNA,单链DNA分子,双链DNA分子,或可以选自例如任意PNA(肽核酸)或可以选自例如任意(单链或双链)RNA,优选信使RNA(mRNA);等等。本发明的核酸序列还可以包含病毒RNA(vRNA)。然而,本发明的核酸序列可以不是病毒RNA或者可以不包含病毒RNA。更具体地,本发明的核酸序列可以不包含病毒序列元件,例如,病毒增强子或病毒启动子(例如,没有灭活的病毒启动子或序列元件,更具体地不是通过更换策略灭活),或其他病毒序列元件,或病毒或反转录病毒核酸序列。更具体地,本发明的核酸序列可以不是反转录病毒或病毒载体或修饰的反转录病毒或病毒载体。
在任意情形中,本发明的核酸序列可以或可以不包含增强子和/或启动子序列,其可以被修饰或不被修饰或者其可以是激活的或不被激活。所述增强子或启动子可以是植物可表达的或不可表达的,和/或在真核生物中可表达或不可表达和/或在原核生物中可表达或不可表达。本发明的核酸序列可以包含或不包含编码(自我剪接)核酶的序列。
在具体的实施方案中,本发明的核酸序列可以是或可以包含自我复制的RNA(复制子)。
优选地,本发明的核酸序列是质粒DNA或RNA,特别是mRNA。
在本发明第一方面的具体的实施方案中,本发明的核酸是包含在适于体外转录的核酸中的核酸序列,特别是包含在适当的体外转录载体中的核酸序列(例如,包含用于体外转录的特定启动子(诸如T3、T7或Sp6启动子)的质粒或线性核酸序列)。
在本发明第一方面的其他特别优选的实施方案中,本发明的核酸包含在适于在表达系统中(例如,在表达载体或质粒中)、特别是在原核(例如,细菌,如大肠杆菌(E.coli),或真核(例如,哺乳动物细胞,如CHO细胞,酵母细胞或昆虫细胞或完整生物体,如植物或动物)表达系统中)转录和/或翻译的核酸中。
术语“表达系统”意指适于产生肽、蛋白或RNA,特别是mRNA(重组表达)的系统(细胞培养物或完整生物体)。
本发明第一方面所述的本发明的核酸序列包含或编码至少一个(组蛋白)茎环。茎环(不管其是组蛋白茎环还是不是组蛋白茎环)通常可以存在于单链DNA中,或者更常见地存在于RNA中。该结构还称为发夹或发夹环,并且通常由连续序列内的茎和(末端)环组成,其中所述茎由两条由在一定程度上作为间隔体的短序列隔开的相邻的完全或部分反向互补的序列形成,所述作为间隔体的短序列成为所述茎环结构的环。这两条相邻的完全或部分反向互补的序列可以定义为,例如,茎环元件茎1和茎2。当这两条相邻的完全或部分反向互补的序列,例如,茎环元件茎1和茎2,彼此形成碱基配对时,形成双链的核酸序列片段,其在其末端包含由位于连续序列上的茎环元件茎1和茎2之间的短序列形成的不配对的环,从而形成茎环。不配对的环由此典型地表示核酸不能与这些茎环元件中的任一个碱基配对的区域。形成的棒棒糖-形状的结构是多种RNA二级结构的主要结构单元。因此,茎环结构的形成依赖于产生的茎和环区域的稳定性,其中第一前提条件典型地是存在可以自身向后折叠形成配对双链的序列。配对的茎环元件的稳定性由长度、其包含的错配或凸起的数量(少量错配典型地是可耐受的,尤其是较长的双链片段)以及配对区的碱基组成决定。在本发明的情形中,3-15个碱基的环长度是可能的,但是更优选的环长度是3-10个碱基,更优选3-8个,3-7个,3-6个或甚至更优选4-5个碱基,并且最优选4个碱基。形成双链结构的茎序列典型地具有5-10个碱基的长度,更优选5-8个碱基的长度。
在本发明的情形中,组蛋白茎环典型地来源于组蛋白基因(例如,来源于组蛋白家族H1,H2A,H2B,H3,H4的基因),并且包含两条相邻的完全或部分反向互补的序列的分子内碱基配对,由此形成茎环。典型地,组蛋白3′UTR茎环是参与组蛋白mRNAs的核质转运以及在细胞质中的稳定性和翻译效率的调节的RNA元件。后生动物组蛋白基因的mRNAs缺少聚腺苷化和聚腺苷酸尾,相比之下,3′端加工在该高度保守的茎环与下游约20个核苷酸处的富含嘌呤的区域(组蛋白下游元件,或HDE)之间的位点发生。组蛋白茎环被31kDa茎环结合蛋白(SLBP-也称为组蛋白发夹结合蛋白或HBP)结合。所述组蛋白茎环结构优选由本发明与其他序列元件和结构组合使用,所述其他序列元件和结构不天然存在于(意指在未转化的活生物体/细胞中)组蛋白基因中,而是按照本发明组合以提供人造的异源核酸。因此,本发明特别是基于这样的发现:组蛋白茎环结构与其他异源序列元件的人工(非天然的)组合提供有利的作用,所述其他异源序列元件不存在于组蛋白基因中或后生动物组蛋白基因中,并且分离自编码不同于组蛋白的蛋白的基因的可操作和/或调节序列区域(影响转录和/或翻译)。因此,本发明的一个方面提供组蛋白茎环结构与不存在于后生动物组蛋白基因中的聚腺苷酸序列或表示聚腺苷酸化信号的序列(编码区的3’-端)的组合。
按照本发明的另一个优选的方面,提供组蛋白茎环结构与编码优选不存在于后生动物组蛋白基因中的治疗性蛋白的编码区的组合(编码区和组蛋白茎环序列是异源的)。如果所述治疗性蛋白天然存在于哺乳动物中,优选人中,则其是优选的。在一个更优选的实施方案中,本发明核酸的所有元件(a)、(b)和(c)彼此是异源的,并且由三种不同的来源人工组合,例如,(a)治疗性蛋白编码区来源于人基因,(b)组蛋白茎环来源于后生动物、例如哺乳动物、非人或人组蛋白基因,(c)聚腺苷酸序列或聚腺苷酸化信号来源于例如不同于组蛋白基因并且不同于编码本发明的核酸元件(a)所述的治疗性蛋白的基因的基因的非翻译区。
因此,组蛋白茎环是本文所述的茎环结构,如果优选是官能化限定的,则其表现出/保留与其天然结合配偶体茎环结合蛋白(SLBP-也称作组蛋白发夹结合蛋白或HBP)结合的特性。
按照本发明,权利要求1的组件(b)所述的组蛋白茎环序列可以不是来源于小鼠组蛋白类蛋白。更特别地,所述组蛋白茎环序列可以不是来源于小鼠组蛋白基因H2A614。此外,本发明的核酸可以不包含小鼠组蛋白茎环序列也不包含小鼠组蛋白基因H2A614。此外,即使本发明的核酸序列可以包含至少一种哺乳动物组蛋白基因,但是本发明的核酸序列可以不包含茎环加工信号,更具体地,小鼠组蛋白加工信号,并且最具体地,可以不包含小鼠茎环加工信号H2kA614。然而,所述至少一种哺乳动物组蛋白基因可以不是WO 01/12824的Seq.ID No.7。
按照本发明第一方面的一个优选的实施方案,本发明的核酸序列包含或编码至少一种组蛋白茎环序列,优选按照下式(I)或(II)中的至少一种所述:
式(I)(不具有茎边界元件的茎环序列):
式(II)(具有茎边界元件的茎环序列):
其中:
茎1或茎2边界元件N1-6 是1-6个、优选2-6个、更优选2-5个、甚至更优选3-5个、最优选4-5个或5个N的连续序列,其中每个N彼此独立地选自下述核苷酸:所述核苷酸选自A,U,T,G和C,或其核苷酸类似物;
茎1[N0-2GN3-5] 与元件茎2反向互补或部分反向互补,并且是5-7个核苷酸的连续序列;
其中N0-2是0-2个、优选0-1个、更优选1个N的连续序列,其中每个N彼此独立地选自下述核苷酸:所述核苷酸选自A,U,T,G和C或其核苷酸类似物;
其中N3-5是3-5个、优选4-5个、更优选4个N的连续序列,其中每个N彼此独立地选自下述核苷酸:所述核苷酸选自A,U,T,G和C或其核苷酸类似物,并且
其中G是鸟苷或其类似物,并且可以任选地被胞苷或其类似物替代,条件是其在茎2中的互补核苷酸胞苷被鸟苷替代;
环序列[N0-4(U/T)N0-4] 位于元件茎1和茎2之间,并且是3-5个核苷酸、更优选4个核苷酸的连续序列;
其中每个N0-4彼此独立地是0-4个、优选1-3个、更优选1-2个N的连续序列,其中每个N彼此独立地选自下述核苷酸:所述核苷酸选自A,U,T,G和C或其核苷酸类似物;并且
其中U/T表示尿苷或任选地胸苷;
茎2[N3-5CN0-2] 与元件茎1反向互补或部分反向互补,并且是5-7个核苷酸的连续序列;
其中N3-5是3-5个、优选4-5个、更优选4个N的连续序列,其中每个N彼此独立地选自下述核苷酸:所述核苷酸选自A,U,T,G和C或其核苷酸类似物;
其中N0-2是0-2个、优选0-1个、更优选1个N的连续序列,其中每个N彼此独立地选自下述核苷酸:所述核苷酸选自A,U,T,G和C或其核苷酸类似物;并且
其中C是胞苷或其类似物,并且可以任选地被鸟苷或其类似物替代,条件是其在茎1中的互补核苷酸鸟苷被胞苷替代;
其中
茎1和茎2能够彼此碱基配对形成反向互补序列,其中碱基配对可以发生在茎1与茎2之间,例如,通过核苷酸A与U/T或G与C的沃森-克里克碱基配对或通过非沃森-克里克碱基配对,例如摆动碱基配对,反向沃森-克里克碱基配对,Hoogsteen碱基配对,反向Hoogsteen碱基配对,或者能够彼此碱基配对形成部分反向互补的序列,其中,基于一个茎中的一个或多个碱基在另一个茎的反向互补序列中不具有互补碱基,不完全的碱基配对可以发生在茎1和茎2之间。
在上述情形中,摆动碱基配对典型地是两个核苷酸之间的非沃森-克里克碱基配对。在本发明的情形中,可以使用的四个主要的摆动碱基对是鸟苷-尿苷,肌苷-尿苷,肌苷-腺苷,肌苷-胞苷(G-U/T,I-U/T,I-A和I-C)和腺苷-胞苷(A-C)。
因此,在本发明的情形中,摆动碱基是这样的碱基,其与上述另一个碱基形成摆动碱基对。因此,非沃森-克里克碱基配对,例如,摆动碱基配对,可以发生在本发明所述的组蛋白茎环结构的茎中。
在上述情形中,部分反向互补序列在由茎1与茎2的碱基配对形成的茎环序列的茎结构中包含最多2个、优选仅一个错配。换言之,茎1和茎2优选能够在茎1和茎2的整个序列上彼此(完全)碱基配对(100%可能正确的沃森-克里克或非沃森-克里克碱基配对),由此形成反向互补序列,其中每个碱基具有其正确的沃森-克里克或非沃森-克里克碱基悬垂物作为互补结合配偶体。备选地,茎1和茎2优选能够在茎1和茎2的整个序列上彼此部分碱基配对,其中100%可能正确的沃森-克里克或非沃森-克里克碱基配对中的至少约70%,75%,80%,85%,90%或95%被正确的沃森-克里克或非沃森-克里克碱基配对占据,并且其余碱基的至多约30%,25%,20%,15%,10%或5%是不配对的。
按照本发明第一方面的优选的实施方案,本文定义的本发明的核酸序列的所述至少一个组蛋白茎环序列(具有茎边界元件)包含约15-约45个核苷酸的长度,优选约15至约40个核苷酸的长度,优选约15至约35个核苷酸的长度,优选约15至约30个核苷酸的长度,并且甚至更优选约20至约30个核苷酸的长度,并且最优选约24至约28个核苷酸的长度。
按照本发明第一方面的进一步优选的实施方案,本文定义的本发明的核酸序列的所述至少一个组蛋白茎环序列(不具有茎边界元件)包含约10至约30个核苷酸的长度,优选约10至约20个核苷酸的长度,优选约12至约20个核苷酸的长度,优选约14至约20个核苷酸的长度,并且甚至更优选约16至约17个核苷酸的长度,并且最优选约16个核苷酸的长度。
按照本发明第一方面的进一步优选的实施方案,按照本发明第一方面所述的本发明的核酸序列可以包含或编码至少一种按照下列具体的式(Ia)或(IIa)中的至少一个所述的组蛋白茎环序列:
式(Ia)(不具有茎边界元件的茎环序列):
式(IIa)(具有茎边界元件的茎环序列):
其中:
N,C,G,T和U 如上文定义。
按照第一方面的另一个更特别优选的实施方案,本发明的核酸序列可以包含或编码至少一种按照下述具体的式(Ib)或(IIb)中的至少一个所述的组蛋白茎环序列:
式(Ib)(不具有茎边界元件的茎环序列):
式(IIb)(具有茎边界元件的茎环序列):
其中:N,C,G,T和U 如上文定义。
按照本发明第一方面的甚至更优选的实施方案,本发明第一方面所述的本发明的核酸序列可以包含或编码至少一种按照下述具体的式(Ic)-(Ih)或(IIc)-(IIh)中的至少一个所述的组蛋白茎环序列,备选地以其茎环结构并且作为表示按照实施例1产生的组蛋白茎环序列的线性序列显不:
式(Ic):(不具有茎边界元件的后生动物和原生动物组蛋白茎环共有序列):
式(IIc):(具有茎边界元件的后生动物和原生动物组蛋白茎环共有序列):
式(Id):(不具有茎边界元件)
式(IId):(具有茎边界元件)
式(Ie):(不具有茎边界元件的原生动物组蛋白茎环共有序列)
式(IIe):(具有茎边界元件的原生动物组蛋白茎环共有序列)
式(If):(不具有茎边界元件的后生动物组蛋白茎环共有序列)
式(IIf):(具有茎边界元件的后生动物组蛋白茎环共有序列)
式(Ig):(不具有茎边界元件的脊椎动物组蛋白茎环共有序列)
式(IIg):(具有茎边界元件的脊椎动物组蛋白茎环共有序列)
式(Ih):(不具有茎边界元件的人组蛋白茎环共有序列(智人(Homo sapiens)))
式(IIh):(具有茎边界元件的人组蛋白茎环共有序列(智人))
其中在上述式(Ic)-(Ih)或(IIc)-(IIh)中的每一个式中:
N,C,G,A,T和U如上文定义;
每个U可以被T替代;
茎元件1和2中的每个(高度)保守的G或C可以被其互补核苷酸碱基C或G替代,条件是其在对应的茎中的互补核苷酸平行地被其互补核苷酸替代;和/或
G,A,T,U,C,R,Y,M,K,S,W,H,B,V,D和N是如下表中定义的核苷酸:
缩写 | 核苷酸碱基 | 备注 |
G | G | 鸟嘌呤 |
A | A | 腺嘌呤 |
T | T | 胸腺嘧啶 |
U | U | 尿嘧啶 |
C | C | 胞嘧啶 |
R | G或A | 嘌呤 |
Y | T/U或C | 嘧啶 |
M | A或C | 氨基 |
K | G或T/U | 酮 |
S | G或C | 强(3个氢键) |
W | A或T/U | 弱(2个氢键) |
H | A或C或T/U | 不是G |
B | G或T/U或C | 不是A |
V | G或C或A | 不是T/U |
D | G或A或T/U | 不是C |
N | G或C或T/U或A | 任意碱基 |
* | 存在或不存在 | 碱基可以存在或不存在 |
在这一情形中,特别优选的是,按照本发明的式(I)或(Ia)-(Ih)或(II)或(IIa)-(IIh)中的至少一个式所述的组蛋白茎环序列选自天然存在的组蛋白茎环序列,更特别优选地选自原生动物或后生动物组蛋白茎环序列,并且甚至更特别优选地选自脊椎动物,最优选的选自哺乳动物组蛋白茎环序列,尤其是选自人组蛋白茎环序列。
按照第一方面的特别优选的实施方案,按照本发明的式(I)或(Ia)-(Ih)或(II)或(IIa)-(IIh)中的至少一个式所述的组蛋白茎环序列是这样的组蛋白茎环序列,所述组蛋白茎环序列在每个核苷酸位置包含图1-5所示的后生动物和原始动物(图1)、原生动物(图2)、后生动物(图3)、脊椎动物(图4)和人(图5)中天然存在的组蛋白茎环序列的最常见的核苷酸,或最常见的或第二最常见的核苷酸。在这一情形中,特别优选的是,所有核苷酸中至少80%、优选至少85%或最优选至少90%对应于天然存在的组蛋白茎环序列的最常见的核苷酸。
在第一方面的另一个具体的实施方案中,按照本发明的具体的式(I)或(Ia)-(Ih)中的至少一个式所述的组蛋白茎环序列选自下述表示按照实施例1产生的组蛋白茎环序列的组蛋白茎环序列(不具有茎边界元件):
VGYYYYHHTHRVVRCB(按照式(Ic)的SEQ ID NO:13)
SGYYYTTYTMARRRCS(按照式(Ic)的SEQ ID NO:14)
SGYYCTTTTMAGRRCS(按照式(Ic)的SEQ ID NO:15)
DGNNNBNNTHVNNNCH(按照式(Ie)的SEQ ID NO:16)
RGNNNYHBTHRDNNCY(按照式(Ie)的SEQ ID NO:17)
RGNDBYHYTHRDHNCY(按照式(Ie)的SEQ ID NO:18)
VGYYYTYHTHRVRRCB(按照式(If)的SEQ ID NO:19)
SGYYCTTYTMAGRRCS(按照式(If)的SEQ ID NO:20)
SGYYCTTTTMAGRRCS(按照式(If)的SEQ ID NO:21)
GGYYCTTYTHAGRRCC(按照式(Ig)的SEQ ID NO:22)
GGCYCTTYTMAGRGCC(按照式(Ig)的SEQ ID NO:23)
GGCTCTTTTMAGRGCC(按照式(Ig)的SEQ ID NO:24)
DGHYCTDYTHASRRCC(按照式(Ih)的SEQ ID NO:25)
GGCYCTTTTHAGRGCC(按照式(Ih)的SEQ ID NO:26)
GGCYCTTTTMAGRGCC(按照式(Ih)的SEQ ID NO:27)
此外,在这一情形中,下述按照具体的式(II)或(IIa)-(IIh)中的一个式所述的按照实施例1产生的组蛋白茎环序列(具有茎边界元件)是特别优选的:
H*H*HHVVGYYYYHHTHRVVRCBVHH*N*N*(按照式(IIc)的SEQ ID NO:28)
M*H*MHMSGYYYTTYTMARRRCSMCH*H*H*(按照式(IIc)的SEQ ID NO:29)
M*M*MMMSGYYCTTTMAGRRCSACH*M*H*(按照式(IIc)的SEQ ID NO:30)
N*N*NNNDGNNNBNNTHVNNNCHNHN*N*N*(按照式(IIe)的SEQ IDNO:31)
N*N*HHNRGNNNYHBTHRDNNCYDHH*N*N*(按照式(IIe)的SEQ ID NO:32)
N*H*HHVRGNDBYHYTHRDHNCYRHH*H*H*(按照式(IIe)的SEQ ID NO:33)
H*H*MHMVGYYYTYHTHRVRRCBVMH*H*N*(按照式(IIf)的SEQ ID NO:34)
M*M*MMMSGYYCTTYTMAGRRCSMCH*H*H*(按照式(IIf)的SEQ IDNO:35)
M*M*MMMSGYYCTTTTMAGRRCSACH*M*H*(按照式(IIf)的SEQ ID NO:36)
H*H*MAMGGYYCTTYTHAGRRCCVHN*N*M*(按照式(IIg)的SEQ ID NO:37)
H*H*AAMGGCYCTTYTMAGRGCCVCH*H*M*(按照式(IIg)的SEQ ID NO:38)
M*M*AAMGGCTCTTTTMAGRGCCMCY*M*M*(按照式(IIg)的SEQ ID NO:39)
N*H*AAHDGHYCTDYTHASRRCCVHB*N*H*(按照式(IIh)的SEQ ID NO:40)
H*H*AAMGGCYCTTTTHAGRGCCVMY*N*M*(按照式(IIh)的SEQ ID NO:41)
H*M*AAAGGCYCTTTTMAGRGCCRMY*H*M*(按照式(IIh)的SEQ ID NO:42)
按照本发明第一方面进一步优选的实施方案,本发明的核酸序列包含或编码至少一种与按照具体的式(I)或(Ia)-(Ih)或(II)或(IIa)-(IIh)中至少一个式所述的组蛋白茎环序列中不到100%保守的核苷酸或与天然存在的组蛋白茎环序列显示出至少约80%、优选至少约85%、更优选至少约90%、或甚至更优选至少约95%的序列同一性的组蛋白茎环序列。
在一个优选的实施方案中,所述组蛋白茎环序列不包含环序列5’-UUUC-3’。更具体地,所述组蛋白茎环序列分别不包含茎1序列5’-GGCUCU-3’和/或茎2序列5’-AGAGCC-3’。在另一个优选的实施方案中,所述茎环序列不包含环序列5’-CCUGCCC-3’或环序列5’-UGAAU-3’。更具体地,所述茎环不包含茎1序列5’-CCUGAGC-3’或分别不包含茎1序列5’-ACCUUUCUCCA-3’和/或茎2序列5’-GCUCAGG-3’或5’-UGGAGAAAGGU-3’。此外,只要本发明不具体限制为组蛋白茎环序列,则茎环序列优选不是来源于哺乳动物胰岛素受体3’-非翻译区。此外,优选地,本发明的核酸可以不包含组蛋白茎环加工信号,特别是不包含来源于小鼠组蛋白基因H2A614基因(H2kA614)的那些。
按照本发明第一方面所述的本发明的核酸序列可以任选地包含或编码聚腺苷酸序列。当存在时,所述聚腺苷酸序列包含约25至约400个腺苷核苷酸的序列,优选约30,或更优选约50至约400个腺苷核苷酸的序列,更优选约50至约300个腺苷核苷酸的序列,甚至更优选约50至约250个腺苷核苷酸的序列,最优选约60至约250个腺苷核苷酸的序列。在这一情形中,术语“约”是指其后数值的±10%的偏差。因此,所述聚腺苷酸序列包含至少25个或多于25个,更优选地至少30个,更优选地至少50个腺苷核苷酸。因此,所述聚腺苷酸序列典型地不包含少于20个腺苷核苷酸。更具体地,其不包含10个和/或少于10个腺苷核苷酸。
优选地,本发明所述的核酸不包含由下述组成的组的组件中的一个或两个或至少一个或几乎一个或全部:编码核酶(优选自我剪接核酶)的序列,病毒核酸序列,组蛋白茎环加工信号,特别是来源于小鼠组蛋白H2A614基因的组蛋白茎环加工序列,Neo基因,灭活的启动子序列和灭活的增强子序列。甚至更优选地,本发明所述的核酸不包含核酶,优选不包含自我剪接的核酶,并且不包含由下述组成的组中的一种:Neo基因,灭活的启动子序列,灭活的增强子序列,组蛋白茎环加工信号,特别是来源于小鼠组蛋白H2A614基因的组蛋白茎环加工序列。因此,在一种优选模式中,所述核酸可以既不包含核酶(优选自我剪接核酶)也不包含Neo或者备选地既不包含核酶(优选自我剪接核酶)也不包含任何抗性基因(例如,通常用于选择)。在另一种优选的模式中,本发明的核酸可以既不包含核酶(优选自我剪接核酶)也不包含组蛋白茎环加工信号,特别是来源于小鼠组蛋白H2A614基因的组蛋白茎环加工序列。
备选地,按照本发明的第一方面,本发明的核酸序列任选地包含聚腺苷酸化信号,所述聚腺苷酸化信号在本文中定义为通过特定的蛋白因子(例如,切割和聚腺苷酸化特异性因子(CPSF),切割刺激因子(CstF),切割因子I和II(CF I和CF II),聚腺苷酸聚合酶(PAP))向(转录的)mRNA传送多腺苷酸化的信号。在这一情形中,优选包含NN(U/T)ANA共有序列的共有聚腺苷酸化信号。在特别优选的方面中,所述聚腺苷酸化信号包含下述序列中的一种:AA(U/T)AAA或A(U/T)(U/T)AAA(其中尿苷通常存在于RNA中,并且胸苷通常存在于DNA中)。在一些实施方案中,用于本发明的核酸的聚腺苷酸化信号不对应于U3 snRNA,U5,来自人基因G-CSF的聚腺苷化加工信号,或SV40聚腺苷酸化信号序列。特别地,上述聚腺苷酸化信号不与任意抗生素抗性基因(或任意其他报道、标记或选择基因)组合,特别是不与抗性neo基因(新霉素磷酸转移酶)(作为本发明核酸的元件(a)所述的编码区的基因)组合。并且,上述聚腺苷酸化信号(其典型的不存在于本发明的核酸中)中的任一种优选不与本发明核酸中的组蛋白茎环或来自小鼠组蛋白基因H2A614的组蛋白茎环加工序列组合。
按照本发明第一方面所述的本发明的核酸序列另外编码这样的蛋白或肽,所述蛋白或肽包含治疗性蛋白或其片段、变体或衍生物。
本文定义的治疗性蛋白是有益于任何遗传或获得性疾病的治疗或改善个体的状况的肽或蛋白。具体地,除其他功能外,治疗性蛋白在产生可以修饰并修复遗传错误、破坏癌细胞或病原体感染的细胞、治疗免疫系统病症、治疗代谢或内分泌病症的治疗剂方面起很大的作用。例如,红细胞生成素(EPO)(一种蛋白激素)可以用于治疗患有红细胞缺陷(erythrocyte deficiency)的患者,其是肾脏并发症的常见原因。此外,治疗性蛋白涵盖佐剂蛋白、治疗性抗体,以及例如用于绝经期妇女的治疗中的激素替代疗法。在最新的方法中,利用患者的体细胞来使其重新编程为多能干细胞,所述多能干细胞替代有争议的干细胞疗法。此外,用于使体细胞重新编程或用于使干细胞分化的这些蛋白在本文中定义为治疗性蛋白。此外,治疗性蛋白可以用于其他目的,例如,伤口愈合、组织再生、血管发生等。
因此,治疗性蛋白可以用于多种目的,包括多种疾病的治疗,所述疾病如例如,传染病、肿瘤(例如,癌症或肿瘤疾病)、血液和血液形成器官的疾病、内分泌、营养和代谢病、神经系统的疾病、循环系统的疾病、呼吸系统的疾病、消化系统的疾病、皮肤和皮下组织的疾病、肌肉骨骼系统和结缔组织的疾病和生殖泌尿系统的疾病,不管其是遗传的还是获得性的。
在这一情形中,可以用于包括代谢或内分泌病症的治疗的特别优选的治疗性蛋白选自:酸性鞘磷脂酶(尼曼-皮克病(Niemann-Pick disease)),Adipotide(肥胖(obesity)),Agalsidase-β(人半乳糖苷酶A(human galactosidase A)法布里病(Fabrydisease;防止可能导致肾脏和心血管并发症的脂肪累积)),Alglucosidase(庞贝病(Pompedisease)糖原贮积症II型(glycogen storage disease type II)),α-半乳糖苷酶A(α-GALA,Agalsidaseα)(法布里病),α-葡糖苷酶(糖原贮积症(Glycogen storage disease,GSD),Morbus Pompe),α-L-艾杜糖苷酸酶(黏多糖贮积症(mucopolysaccharidoses,MPS),胡尔勒综合征(Hurler syndrome),沙伊综合征(Scheie syndrome)),α-N-乙酰葡糖苷酶(桑菲利波综合征(Sanfilippo syndrome)),双调蛋白(癌症,代谢紊乱(metabolic disorder)),血管生成素((Ang1,Ang2,Ang3,Ang4,ANGPTL2,ANGPTL3,ANGPTL4,ANGPTL5,ANGPTL6,ANGPTL7)(血管发生,稳定血管),β动物纤维素(代谢紊乱(metabolic disorder)),β-葡糖醛酸糖苷酶(斯赖综合征(Sly syndrome)),骨形态发生蛋白BMPs(BMP1,BMP2,BMP3,BMP4,BMP5,BMP6,BMP7,BMP8a,BMP8b,BMP10,BMP15)(再生性作用,骨骼相关的病症,慢性肾病(chronic kidney disease,CKD)),CLN6蛋白(CLN6疾病-非典型性晚期婴儿期,晚期发作的变体,青少年早期,神经元蜡样脂脂褐质沉积症(Neuronal Ceroid Lipofuscinoses,NCL)),表皮生长因子(EGF)(伤口愈合,调节细胞生长、增殖和分化),Epigen(代谢紊乱),表皮调节素(代谢紊乱),成纤维细胞生长因子(FGF,FGF-1,FGF-2,FGF-3,FGF-4,FGF-5,FGF-6,FGF-7,FGF-8,FGF-9,FGF-10,FGF-11,FGF-12,FGF-13,FGF-14,FGF-16,FGF-17,FGF-17,FGF-18,FGF-19,FGF-20,FGF-21,FGF-22,FGF-23)(伤口愈合,血管发生,内分泌紊乱,组织再生),Galsulphase(黏多糖贮积症IV(Mucopolysaccharidosis VI)),葛瑞林(Ghrelin)(肠易激综合征(irritable bowel syndrome,IBS),肥胖,普拉德-威利综合征(Prader-Willi syndrome),II型糖尿病(type II diabetes mellitus)),葡糖脑苷脂酶(戈谢病(Gaucher′s disease)),GM-CSF(再生作用,产生白血细胞,癌症),肝素-结合EGF-样生长因子(HB-EGF)(伤口愈合,心脏肥大(cardiac hypertrophy)和心脏发育与功能),肝细胞生长因子HGF(再生作用,伤口愈合),Hepcidin(铁代谢紊乱(iron metabolism disorders),β-地中海贫血(Beta-thalassemia)),人白蛋白(减少的白蛋白产生(低蛋白血症(hypoproteinaemia)),增加的白蛋白损失(肾病综合征(nephrotic syndrome)),低血容量症(hypovolaemia),高胆红素血症(hyperbilirubinaemia)),艾度硫酸酯酶(Idursulphase)(艾杜糖醛酸-2-硫酸酯酶)(黏多糖贮积症II(MucopolysaccharidosisII)(亨特综合征(Hunter syndrome))),整联蛋白αVβ3,αVβ5和α5β1(结合基质大分子和蛋白酶,血管发生),艾杜糖醛酸硫酸酯酶(亨特综合征(Hunter syndrome)),拉罗尼酶(Laronidase)(胡尔勒和胡尔勒-沙伊形式的黏多糖贮积症I(Hurler and Hurler-Scheieforms of mucopolysaccharidosis I)),N-乙酰半乳糖胺-4-硫酸酯酶(rhASB;galsulfase,芳基硫酸酯酶A(ARSA),芳基硫酸酯酶B(ARSB))(芳基硫酸酯酶B缺陷,马洛托-拉梅综合征(Maroteaux-Lamy syndrome),黏多糖贮积症VI(mucopolysaccharidosisVI)),N-乙酰葡糖胺-6-硫酸酯酶(桑菲利波综合征(Sanfilippo syndrome)),神经生长因子(NGF,脑源性神经营养因子(BDNF),神经营养因子-3(NT-3),和神经营养因子4/5(NT-4/5)(再生作用,心血管病(cardiovascular diseases),冠状动脉动脉粥样硬化(coronaryatherosclerosis),肥胖,2型糖尿病,代谢综合征,急性冠状动脉综合征(acute coronarysyndromes),痴呆(dementia),抑郁(depression),精神分裂症(schizophrenia),孤独症(autism),雷特综合征(Rett syndrome),神经性厌食症(anorexia nervosa),神经性贪食症(bulimia nervosa),伤口愈合,皮肤溃疡(skin ulcers),角膜溃疡(corneal ulcers),阿尔茨海默病(Alzheimer′s disease)),神经调节蛋白(NRG1,NRG2,NRG3,NRG4)(代谢紊乱,精神分裂症),神经毡蛋白(NRP-1,NRP-2)(血管发生,轴突导向,细胞存活,迁移),肥胖抑制素(Obestatin)(肠易激综合征(irritable bowel syndrome,IBS),肥胖,普拉德-威利综合征(Prader-Willi syndrome),II型糖尿病),血小板衍生生长因子(PDGF(PDFF-A,PDGF-B,PDGF-C,PDGF-D)(再生作用,伤口愈合,血管发生中的紊乱(disorder inangiogenesis),动脉硬化(Arteriosclerosis),纤维化(Fibrosis),癌症),TGFβ受体(内皮因子,TGF-β1受体,TGF-β2受体,TGF-β3受体)(肾纤维化(renal fibrosis),肾病(kidneydisease),糖尿病(diabetes),终末期肾病(ultimately end-stage renal disease,ESRD),血管发生),血小板生成素(THPO)(巨核细胞生长和发育因子(Megakaryocytegrowth and development factor,MGDF))(血小板病症(platelets disorders),献血用血小板(platelets for donation),骨髓抑制性化疗后血小板计数的恢复),转化生长因子(TGF(TGF-a,TGF-β(TGFβ1,TGFβ2和TGFβ3)))(再生作用,伤口愈合,免疫性,癌症,心脏疾病,糖尿病,马方综合征(Marfan syndrome),Loeys-Dietz综合征(Loeys-Dietzsyndrome)),VEGF(VEGF-A,VEGF-B,VEGF-C,VEGF-D,VEGF-E,VEGF-F und PIGF)(再生作用,血管发生,伤口愈合,癌症,渗透性),奈西立肽(Nesiritide)(急性代偿失调性充血性心力衰竭(Acute decompensated congestive heart failure)),胰蛋白酶(褥疮溃疡(Decubitus ulcer),静脉曲张性溃疡(varicose ulcer),焦痂清创(debridementofeschar),裂开性伤口(dehiscent wound),晒伤(sunburn),胎粪性肠梗阻(meconiumileus)),促肾上腺皮质激素(adrenocorticotrophic hormone,ACTH)(艾迪生病(″Addison′s disease),小细胞癌(Small cell carcinoma),肾上腺脑白质营养不良(Adrenoleukodystrophy),先天性肾上腺增生(Congenital adrenal hyperplasia),库欣综合征(Cushing′s syndrome),纳尔逊综合征(Nelson′s syndrome),婴儿痉挛(Infantilespasms)),心房钠尿肽(Atrial-natriuretic peptide,ANP)(内分泌紊乱(endocrinedisorders)),胆囊收缩素(Cholecystokinin)(不同的),低胃泌素血症(hypogastrinemia),瘦蛋白(糖尿病,高甘油三酯血症(hypertriglyceridemia),肥胖),催产素(刺激人乳喂养,分娩的不进展(non-progression ofparturition)),生长抑素(类癌综合征(carcinoid syndrome)、急性静脉曲张破裂出血(acute variceal bleeding)和肢端肥大症(acromegaly),肝肾多囊性病(polycystic diseases of the liver andkidney),肢端肥大症和由神经内分泌瘤(neuroendocrine tumors)引起的症状的对症治疗),加压素(Vasopressin)(抗利尿激素)(尿崩症(diabetes insipidus)),降钙素(Calcitonin)(绝经后骨质疏松(Postmenopausal osteoporosis),高钙血症(Hypercalcaemia),佩吉特病(Paget′s disease),骨转移(Bone metastases),幻肢痛(Phantom limb pain),椎管狭窄(Spinal Stenosis)),Exenatide(对二甲双胍(metformin)和磺脲(sulphonylurea)治疗有耐药性的2型糖尿病),生长激素(Growthhormone,GH),生长素(somatotropin)(由于GH不足(GH deficiency)或慢性肾功能不全(chronic renal insufficiency)、普拉德-威利综合征(Prader-Willi syndrome)、特纳综合征(Turner syndrome)、艾滋消耗(AIDS wasting)或使用抗病毒疗法的恶病质(cachexia)导致的生长不足(Growth failure)),胰岛素(糖尿病,糖尿病酮症酸中毒(diabetic ketoacidosis),高钾血症(hyperkalaemia)),胰岛素样生长因子1 IGF-1(具有GH基因缺失或严重的原发性IGFl不足(severe primary IGF1 deficiency)的儿童生长不足,神经变性疾病(neurodegenerative disease),心血管疾病(cardiovasculardiseases),心力衰竭(heart failure)),Mecasermin rinfabate,IGF-1类似物(具有GH基因缺失或严重的原发性IGF1不足的儿童生长不足,神经变性疾病,心血管疾病,心力衰竭),美卡舍明(Mecasermin),IGF-1类似物(有GH基因缺失或严重的原发性IGF1不足的儿童生长不足,神经变性疾病,心血管疾病,心力衰竭),培维索孟(Pegvisomant)(肢端肥大症),普兰林肽(Pramlintide)(糖尿病,与胰岛素组合),特立帕肽(Teriparatide)(人甲状旁腺素残基1-34)(严重的骨质疏松症(Severe osteoporosis)),贝卡普勒明(Becaplermin)(糖尿病性溃疡(diabetic ulcers)辅助性清创术(Debridement)),Dibotermin-α(骨形态发生蛋白2)(脊柱融合手术(Spinal fusion surgery),骨损伤修复(bone injury repair)),醋酸组氨瑞林(Histrelin acetate)(促性腺素释放激素(gonadotropin releasing hormone;GnRH))(早熟青春期(Precocious puberty)),奥曲肽(Octreotide)(肢端肥大症,VIP-分泌腺瘤(VIP-secreting adenoma)和转移性类癌肿瘤(metastatic carcinoid tumours)的症状缓和),和帕利夫明(Palifermin)(角质形成细胞生长因子(keratinocyte growthfactor;KGF))(经历化疗的患者中的严重的口粘膜炎(Severe oral mucositis),伤口愈合)。
(括号中是在治疗中使用治疗性蛋白的具体的疾病)。这些和其他的蛋白应该理解为是治疗性的,原因在于其旨在通过以充分的量替代其功能蛋白的缺陷性内源产生而治疗受试者。因此,所述治疗性蛋白典型地是哺乳动物蛋白,特别是人蛋白。
为了治疗血液病症、循环系统的疾病、呼吸系统的疾病、癌症或肿瘤疾病、传染病或免疫缺陷,可以使用下述治疗性蛋白:阿替普酶(Alteplase)(组织型纤溶酶原激活物(tissue plasminogen activator;tPA))(肺栓塞(Pulmonary embolism),心肌梗死(myocardial infarction),急性局部缺血性卒中(acute ischaemic stroke),中央静脉通路装置的阻塞(occlusion of central venous access devices)),阿尼普酶(Anistreplase)(溶栓(Thrombolysis)),抗凝血酶III(AT-III)(遗传性AT-III不足(Hereditary AT-III deficiency),血栓栓塞(Thromboembolism)),比伐卢定(Bivalirudin)(冠状动脉血管成形术(coronary angioplasty)和肝素诱发的血小板减少症(heparin-induced thrombocytopaenia)中减少的血液凝结危险),达贝泊汀α(Darbepoetin-alpha)(治疗患有慢性肾功能不全(chronic renal insufficiency)和慢性肾衰竭(肾功能不全)(+/-透析)的患者的贫血症(anaemia)),屈曲克凝α(Drotrecogin-alpha)(活化的蛋白C)(具有高死亡危险的严重败血症(Severe sepsis)),促红细胞生成素,依泊汀α(Epoetin-alpha),促血红细胞生长素,红细胞生成素(erthropoyetin)(慢性疾病的贫血症,myleodysplasia,由于肾衰竭或化疗导致的贫血,术前准备),因子IX(血友病B(Haemophilia B)),因子VIIa(患有血友病A或B的患者中的出血和因子VIII或因子IX的抑制剂),因子VIII(血友病A(HaemophiliaA)),来匹卢定(Lepirudin)(肝素诱发的血小板减少症(Heparin-induced thrombocytopaenia)),蛋白质C浓缩剂(静脉血栓形成(Venousthrombosis),暴发性紫癜(Purpura fulminans)),瑞替普酶(Reteplase)(tPA的缺失突变蛋白)(急性心肌梗死(acute myocardial infarction)的管理,心室功能的改善),链激酶(急性进展性透壁性心肌梗死(Acute evolving transmural myocardial infarction),肺栓塞(pulmonary embolism),深静脉血栓形成(deep vein thrombosis),动脉血栓形成(arterial thrombosis)或栓塞(embolism),动静脉插管闭塞(occlusion ofarteriovenous cannula)),替奈普酶(Tenecteplase)(急性心肌梗死),尿激酶(肺栓塞),血管抑素(癌症),抗-CD22免疫毒素(复发的CD33+急性髓性白血病(Relapsed CD33+acutemyeloid leukaemia)),地尼白介素-毒素连接物(Denileukin diftitox)(皮肤T细胞淋巴瘤(Cutaneous T-cell lymphoma,CTCL)),Immunocyanin(膀胱和前列腺癌(bladder andprostate cancer)),MPS(Metallopanstimulin)(癌症),Aflibercept(非小细胞肺癌(Non-small cell lung cancer,NSCLC),转移性结直肠癌(metastatic colorectal cancer,mCRC),激素难治性转移性前列腺癌(hormone-refractory metastatic prostatecancer),湿性黄斑变性(wet macular degeneration)),内皮抑素(Endostatin)(癌症,炎性疾病,如类风湿性关节炎(rheumatoid arthritis)以及克罗恩病(Crohn’s disease),糖尿病视网膜病变(diabetic retinopathy),银屑病(psoriasis)和子宫内膜异位症(endometriosis)),胶原酶(慢性皮肤溃疡(chronic dermal ulcers)和严重烧伤区域(severely burned areas)的清创术,迪皮特朗挛缩(Dupuytren′s contracture),佩罗尼病(Peyronie′s disease)),人脱氧核糖核酸酶I,链道酶(dornase)(囊性纤维化(Cysticfibrosis);减少所选的患有FVC的患者中的呼吸道感染,大于预测的40%),透明质酸酶(用作佐剂以增加注射的药物的吸收和分散,特别是眼科手术中的麻醉剂和特定的成像剂的吸收和分散),木瓜蛋白酶(坏死组织的清创或急性和慢性损伤中腐肉的软化,诸如压力性溃疡(pressure ulcers),曲张性和糖尿病性溃疡(varicose and diabetic ulcers),烧伤(burns),术后伤口(postoperative wounds),藏毛囊肿伤口(pilonidal cyst wounds),痈(carbuncles),以及其他伤口),L-天冬酰胺酶(急性淋巴性白血病(Acute lymphocyticleukaemia),其需要外源性天冬酰胺进行增殖),Peg-天冬酰胺酶(急性淋巴性白血病,其需要外源性天冬酰胺进行增殖),拉布立酶(Rasburicase)(患有白血病(1eukaemia)、淋巴瘤(lymphoma)和实体瘤的正在进行引起肿瘤溶解综合征(tumour lysis syndrome)的抗癌疗法的儿科患者),人慢性促性腺素(Human chorionic gonadotropin,HCG)(辅助的生殖),人促卵泡激素(follicle-stimulating hormone,FSH)(辅助的生殖),促黄体素-α(Lutropin-alpha)(具有促黄体激素不足的不育(Infertility with luteinizing hormonedeficiency)),催乳素(低泌乳素血症(Hypoprolactinemia),血清催乳素不足(serumprolactin deficiency),妇女卵巢功能不全(ovarian dysfunction in women),焦虑(anxiety),动脉生成性勃起功能障碍(arteriogenic erectile dysfunction),早泄(premature ejaculation),精子减少症(oligozoospermia),精子活力不足(asthenospermia),精囊功能不良(hypofunction of seminal vesicles),男性的雄激素缺乏症(hypoandrogenism)),α-1-蛋白酶抑制剂(先天性抗胰蛋白酶缺乏(Congenitalamitrypsin deficiency)),乳糖酶(由于乳糖消化不能(inability to digest lactose)引起的胀气(Gas)、胃气胀(bloating)、痛性痉挛(cramps)和腹泻(diarrhoea)),胰酶(脂肪酶,淀粉酶,蛋白酶(protease))(囊性纤维化,慢性胰腺炎(chronic pancreatitis),胰腺功能不全(pancreatic insufficiency),Billroth II胃分流术后(post-Billroth IIgastric bypass surgery),胰管阻塞(pancreatic duct obstruction),脂肪泻(steatorrhoea),消化不良(poor digestion),胀气(gas),胃气胀(bloating)),腺苷脱氨酶(牛培加酶(pegademase bovine,PEG-ADA))(由于腺苷脱氨酶不足导致的严重组合性免疫缺陷疾病(Severe combined immunodeficiency disease)),阿巴他塞(Abatacept)(类风湿性关节炎(Rheumatoid arthritis)(尤其是当耐受TNFa抑制时)),阿来法塞(Alefacept)(斑块状银屑病(Plaque Psoriasis)),阿那白滞素(Anakinra)(类风湿性关节炎),依那西普(Etanercept)(类风湿性关节炎,多关节病程幼年型类风湿关节炎(polyarticular-course juvenile rheumatoid arthritis),银屑病关节炎(psoriaticarthritis),强直性脊柱炎(ankylosing spondylitis),斑块状银屑病,强直性脊柱炎),白细胞介素-1(IL-1)受体拮抗剂,阿那白滞素(Anakinra)(与类风湿关节炎相关的炎症和软骨降解(cartilage degradation)),胸腺素(Thymulin)(神经变性病(neurodegenerativediseases),风湿病(rheumatism),神经性厌食症(anorexia nervosa)),TNF-α拮抗剂(自身免疫病症,诸如类风湿性关节炎,强直性脊柱炎,克罗恩病,银屑病,化脓性汗腺炎(hidradenitis suppurativa),难治性哮喘(refractory asthma)),恩夫韦肽(Enfuvirtide)(HIV-1感染)和胸腺素α1(乙型和丙型肝炎(Hepatitis B and C))。
(括号中是在治疗中使用所述治疗性蛋白的具体的疾病)
此外,术语治疗性蛋白也包括佐剂或免疫刺激性蛋白。在这一情形中,佐剂或免疫刺激蛋白可以用来诱导、改变或改善个体中的免疫应答,以治疗特定的疾病或改善该个体的状况。
在这一情形中,佐剂蛋白可以选自哺乳动物佐剂蛋白,特别是人佐剂蛋白,其典型的包括能够(在哺乳动物中)引发先天性免疫应答(例如,作为外源性TLR配体与TLR的结合的反应)的任意人蛋白或肽。更优选地,人佐剂蛋白选自由下述蛋白组成的组:所述蛋白是模式识别受体的信号传导网络的组分和配体,包括:TLR,NLR和RLH,包括TLR1,TLR2,TLR3,TLR4,TLR5,TLR6,TLR7,TLR8,TLR9,TLR10,TLRI1;NOD1,NOD2,NOD3,NOD4,NOD5,NALP1,NALP2,NALP3,NALP4,NALP5,NALP6,NALP6,NALP7,NALP7,NALP8,NALP9,NALP10,NALP11,NALP12,NALP13,NALP14,1IPAF,NAIP,CIITA,RIG-I,MDA5和LGP2,TLR信号传导的信号转导剂,包括衔接子蛋白,包括例如,Trif和Cardif;小-GTP酶信号传导的组分(RhoA,Ras,Rac1,Cdc42,Rab等),PIP信号传导的组分(PI3K,Src-激酶等),MyD88-依赖性信号传导的组分(MyD88,IRAK1,IRAK2,IRAK4,TIRAP,TRAF6等),MyD88-非依赖性信号传导的组分(TICAM1,TICAM2,TRAF6,TBK1,IRF3,TAK1,IRAK1等);活化的激酶,包括,例如,Akt,MEKK1,MKK1,MKK3,MKK4,MKK6,MKK7,ERK1,ERK2,GSK3,PKC激酶,PKD激酶,GSK3激酶,JNK,p38MAPK,TAK1,IKK,和TAK1;活化的转录因子,包括,例如,NF-κB,c-Fos,c-Jun,c-Myc,CREB,AP-1,Elk-1,ATF2,IRF-3,IRF-7。
此外,哺乳动物佐剂蛋白,特别是人佐剂蛋白可以选自由下述组成的组:热休克蛋白,诸如HSP10,HSP60,HSP65,HSP70,HSP75和HSP90,gp96,纤维蛋白原,纤连蛋白的TypIII重复额外结构域A;或补体系统的成分,包括C1q,MBL,C1r,C1s,C2b,Bb,D,MASP-1,MASP-2,C4b,C3b,C5a,C3a,C4a,C5b,C6,C7,C8,C9,CR1,CR2,CR3,CR4,C1qR,C1INH,C4bp,MCP,DAF,H,I,P和CD59,或诱导的靶基因,包括,例如,β-防卫素,细胞表面蛋白;或人佐剂蛋白,包括trif,flt-3配体,Gp96或纤连蛋白等,或上述佐剂蛋白中任一种的任意物种同系物。
此外,哺乳动物佐剂蛋白,特别是人佐剂蛋白可以包括诱导或增强先天性免疫应答的细胞因子,包括IL-1α,IL1β,IL-2,IL-6,IL-7,IL-8,IL-9,IL-12,IL-13,IL-15,IL-16,IL-17,IL-18,IL-21,IL-23,TNFα,IFNα,IFNβ,IFNγ,GM-CSF,G-CSF,M-CSF;趋化因子,包括IL-8,IP-10,MCP-1,MIP-1α,RANTES,嗜酸性粒细胞趋化因子(Eotaxin),CCL21;由巨噬细胞释放的细胞因子,包括IL-1,IL-6,IL-8,IL-12和TNF-a;以及IL-1R1和IL-1α。
用于治疗血液病症、循环系统的疾病、呼吸系统的疾病、癌症或肿瘤疾病、传染病或免疫缺陷的治疗性蛋白或佐剂蛋白典型地是哺乳动物来源的蛋白,优选人来源的蛋白,这取决于要治疗的动物。例如,人优选用人来源的治疗性蛋白进行治疗。
病原性佐剂蛋白,典型地包括能够(在哺乳动物中)引发先天性免疫应答的任意病原性佐剂蛋白,更优选地选自来源于细菌、原生动物、病毒或真菌等的病原性佐剂蛋白,例如,细菌(佐剂)蛋白,原生动物(佐剂)蛋白(例如,刚地弓形虫(Toxoplasma gondii)的肌动蛋白抑制蛋白样蛋白(profilin-like protein)),病毒(佐剂)蛋白或真菌(佐剂)蛋白等。
特别地,细菌(佐剂)蛋白可以选自由下述组成的组:细菌热休克蛋白或伴侣蛋白,包括Hsp60,Hsp70,Hsp90,Hsp100;来自革兰氏阴性细菌的OmpA(外膜蛋白);细菌孔蛋白,包括OmpF;细菌毒素,包括来自百日咳博德特氏菌(Bordetella pertussts)的百日咳毒素(PT),来自百日咳博德特氏菌的百日咳腺苷酸环化酶毒素CyaA和CyaC,来自百日咳毒素的PT-9K/129G突变体,来自百日咳博德特氏菌的百日咳腺苷酸环化酶毒素CyaA和CyaC,破伤风毒素,霍乱毒素(CT),霍乱毒素B-亚基,来自霍乱毒素的CTK63突变体,来自CT的CTE112K突变体,大肠杆菌(Escherichia coli)热不稳定性肠毒素(LT),来自热不稳定性肠毒素的B亚基(LTB),具有减少的毒性的大肠杆菌热不稳定性肠毒素突变体,包括LTK63,LTR72;苯酚可溶性调控蛋白;来自幽门螺杆菌(Helicobacter pylori)的嗜中性粒细胞活化蛋白(HP-NAP);表面活性蛋白D;来自布氏疏螺旋体(Borrelia burgdorferi)的外表面蛋白A脂蛋白,来自结核分枝杆菌(Mycobacterium tuberculosis)的Ag38(38 kDa抗原);来自细菌菌毛的蛋白;霍乱弧菌(Vibrio cholerae)的肠毒素CT,来自革兰氏阴性细菌的菌毛的菌毛蛋白,和表面活性蛋白A;等,或上述细菌(佐剂)蛋白中任一种的任意物种同系物。
细菌(佐剂)蛋白还可以包括细菌鞭毛蛋白。在本发明的情形中,细菌鞭毛蛋白可以选自来自下述生物体的鞭毛蛋白:所述生物体包括,但不限于,土壤杆菌属(Agrobacterium),产液菌属(Aquifex),固氮螺菌属(Azospirillum),芽孢杆菌属(Bacillus),巴尔通氏体属(Bartonella),博德特氏菌属(Bordetella),疏螺旋体属(Borrelia),伯克霍尔德氏菌属(Burkholderia),弯曲杆菌属(Campylobacter),柄杆菌属(Caulobacte),梭菌属(Clostridium),埃希氏菌属(Escherichia),螺杆菌属(Helicobacter),毛螺菌属(Lachnospiraceae),军团病杆菌属(Legionella),利斯特菌属(Listeria),变形菌属(Proteus),假单胞菌属(Pseudomonas),根瘤菌属(Rhizobium),红杆菌属(Rhodobacter),Roseburia,沙门菌属(Salmonella),小蛇菌属(Serpulina),沙雷氏菌属(Serratia),志贺菌属(Shigella),密螺旋体属(Treponema),弧菌属(Vibrio),沃林氏菌属(Wolinella),耶尔森氏菌属(Yersinia),更优选地来自下述物种的鞭毛蛋白,所述物种包括但不限于,根癌土壤杆菌(Agrobacterium tumefaciens),嗜火产液菌(Aquifexpyrophilus),巴西固氮螺菌(Azospirillum brasilense),枯草芽孢杆菌(Bacillussubtilis),苏云金芽孢杆菌(Bacillusthuringiensis),杆状巴尔通氏体(Bartonellabacilliformis),支气管炎博德特氏菌(Bordetella bronchiseptica),布氏疏螺旋体(Borrelia burgdorferi),洋葱伯克霍尔德氏菌(Burkholderia cepacia),空肠弯曲杆菌(Campylobacter jejuni),新月柄杆菌(Caulobacter crescentus),肉毒梭菌菌株Bennett克隆1(Clostridium botulinum strain Bennett clone l),大肠杆菌(Escherichiacoli),幽门螺杆菌(Helicobacter pylori),毛螺菌属细菌(Lachnospiraceaebacterium),嗜肺军团病杆菌(Legionella pneumophila),单核细胞增生利斯特菌(Listeria monocytogenes),奇异变形菌(Proteus mirabilis),铜绿假单胞菌(Pseudomonas aeroguinosa),丁香假单胞菌(Pseudomonas syringae),苜蓿根瘤菌(Rhizobium meliloti),类球红细菌(Rhodobacter sphaeroides),Roseburia cecicola,Roseburis hominis,鼠伤寒沙门菌(Salmonella typhimurium),乍得沙门氏菌(Salmonella bongori),伤寒沙门菌(Salmonella typhi),猪霍乱沙门氏菌(Salmonellaenteritidis),猪痢疾小蛇菌(Serpulina hyodysenteriae),粘质沙雷氏菌(Serratiamarcescens),鲍氏志贺氏菌(Shigella boydii),溃蚀密螺旋体(Treponemaphagedenis),解藻朊酸弧菌(Vibrio alglnolytlcus),霍乱弧菌(Vibrio cholerae),副溶血弧菌(Vibrio parahaemolyticus),产琥珀酸沃林氏菌(Wolinella succinogenes)和小肠结肠炎耶尔森氏菌(Yersinia enterocolitica)。
原生动物(佐剂)蛋白是病原性佐剂蛋白的另一种实例。在这一情形中,原生动物(佐剂)蛋白可以选自表现出佐剂特征的任意原生动物蛋白,更优选地,选自由下述组成的组,但不限于此:来自克鲁斯锥虫(Trypanosoma cruzi)的Tc52,来自Trypanosoma gondii的PFTG,原生动物热休克蛋白,来自利什曼原虫属物种(Leishmania spp.)的LeIF,来自刚地弓形虫(Toxoplasma gondii)的肌动蛋白抑制蛋白样蛋白,等等。
病毒(佐剂)蛋白是病原性佐剂蛋白的另一种实例。在这一情形中,病毒(佐剂)蛋白可以选自表现出佐剂特征的任意病毒蛋白,更优选地,选自由下述组成的组,但不限于此:呼吸道合胞病毒(Respiratory Syncytial Virus)融合糖蛋白(F-蛋白),来自MMT病毒的包膜蛋白,小鼠白血病病毒蛋白,野生型麻疹病毒(measles virus)的血凝素蛋白等。
真菌(佐剂)蛋白也是病原性佐剂蛋白的另一种实例。在本发明的情形中,真菌(佐剂)蛋白可以选自表现出佐剂特征的任意真菌蛋白,更优选地选自由真菌免疫调节性蛋白(FIP;LZ-8)等组成的组。
最后,佐剂蛋白还可以选自由钥孔血蓝蛋白(KLH)、OspA等组成的组。
在另一个实施方案中,治疗性蛋白可以用于激素替代疗法,特别是用于绝经妇女的疗法。这些治疗性蛋白优选地选自雌激素、孕酮或黄体酮,并且有时选自睾酮。
此外,治疗性蛋白可以用于将体细胞重新编程为多能或全能干细胞。为了这一目的,记载了数种因子,特别是Oct-3/4,Sox基因家族(Sox1,Sox2,Sox3和Sox15),Klf家族(Klf1,Klf2,Klf4和Klf5),Myc家族(c-myc,L-myc和N-myc),Nanog和LIN28。
如上文提及,治疗性抗体在本文中也被定义为治疗性蛋白。这些治疗性抗体优选选自用于包括癌症或肿瘤疾病的治疗的抗体,例如,131I-托西莫单抗(131I-tositumomab)(滤泡型淋巴瘤(Follicular lymphoma),B细胞淋巴瘤(B cell lymphomas),白血病(leukemias)),3F8(神经母细胞瘤(Neuroblastoma)),8H9,阿巴扶单抗(Abagovomab)(卵巢癌(Ovarian cancer)),阿德术单抗(Adecatumumab)(前列腺癌和乳腺癌),Afutuzumab(淋巴瘤(Lymphoma)),Alacizumab pegol,阿仑珠单抗(Alemtuzumab)(B细胞慢性淋巴细胞性白血病,T细胞淋巴瘤(B-cell chronic lymphocytic leukaemia,T-cell-Lymphoma)),Amatuximab,AME-133v(滤泡型淋巴瘤,癌症),AMG 102(晚期肾细胞癌(Advanced RenalCell Carcinoma)),麻安莫单抗(Anatumomab mafenatox)(非小细胞肺癌(Non-small celllung carcinoma)),阿泊珠单抗(Apolizumab)(实体瘤,白血病,非霍奇金淋巴瘤(Non-Hodgkin-Lymphoma),淋巴瘤),巴土昔单抗(Bavituximab)(癌症,病毒感染),贝妥莫单抗(Bectumomab)(非霍奇金淋巴瘤),贝利木单抗(Belimumab)(非霍奇金淋巴瘤),贝伐珠单抗(Bevacizumab)(结肠癌(Colon Cancer),乳腺癌(Breast Cancer),脑和中枢神经系统肿瘤(Brain and Central Nervous System Tumors),肺癌(Lung Cancer),肝细胞癌(Hepatocellular Carcinoma,Kidney Cancer),乳腺癌,胰腺癌(Pancreatic Cancer),膀胱癌(Bladder Cancer),肉瘤(Sarcoma),黑色素瘤(Melanoma),食管癌(EsophagealCancer);胃癌(Stomach Cancer),转移性肾细胞癌(Metastatic Renal Cell Carcinoma);肾癌(Kidney Cancer),胶质母细胞瘤(Glioblastoma),肝癌(Liver Cancer),增生型糖尿病性视网膜病变(Proliferative Diabetic Retinopathy),黄斑变性(MacularDegeneration)),比伐单抗-DMl(Bivatuzumab mertansine)(鳞状细胞癌(Squamous cellcarcinoma)),Blinatumomab,Brentuximab vedotin(血液癌(Hematologic cancers)),Cantuzumab(结肠癌,胃癌,胰腺癌,NSCLC),美坎珠单抗(Cantuzumab mertansine)(结直肠癌),Cantuzumab ravtansine(癌症),卡罗单抗喷地肽(Capromab pendetide)(前列腺癌),Carlumab,卡妥索单抗(Catumaxomab)(卵巢癌,输卵管肿瘤(Fallopian Tube Neoplasms),腹膜肿瘤(Peritoneal Neoplasms)),西妥昔单抗(Cetuximab)(转移性结直肠癌(Metastatic colorectal cancer)和头颈癌(head and neck cancer)),Citatuzumabbogatox(卵巢癌和其他实体瘤),Cixutumumab(实体瘤),Clivatuzumab tetraxetan(胰腺癌),CNTO 328(B细胞非霍奇金淋巴瘤(B-Cell Non-Hodgkin′s Lymphoma),多发性骨髓瘤(Multiple Myeloma),卡斯太拉尼病(Castleman′s Disease),卵巢癌),CNTO 95(黑色素瘤),Conatumumab,Dacetuzumab(血液癌症),Dalotuzumab,地舒单抗(Denosumab)(骨髓瘤(Myeloma),骨骼巨细胞瘤(Giant Cell Tumor of Bone),乳腺癌,前列腺癌,骨质疏松(Osteoporosis)),地莫单抗(Detumomab)(淋巴瘤),Drozitumab,Ecromeximab(恶性黑色素瘤(Malignant melanoma)),依决洛单抗(Edrecolomab)(结直肠癌(Colorectalcarcinoma)),Elotuzumab(多发性骨髓瘤(Multiple myeloma)),Elsilimomab,Enavatuzumab,Ensituximab,依帕珠单抗(Epratuzumab)(自身免疫病(Autoimmunediseases),系统性红斑狼疮(Systemic Lupus Erythematosus),非霍奇金淋巴瘤,白血病),Ertumaxomab(乳腺癌),Ertumaxomab(乳腺癌),Etaracizumab(黑色素瘤,前列腺癌,卵巢癌),Farletuzumab(卵巢癌),FBTA05(慢性淋巴细胞性白血病(Chronic lymphocyticleukaemia)),Ficlatuzumab(癌症),Figitumumab(肾上腺皮质癌(Adrenocorticalcarcinoma),非小细胞肺癌),Flanvotumab(黑色素瘤),Galiximab(B细胞淋巴瘤),Galiximab(非霍奇金淋巴瘤),Ganitumab,GCl008(晚期肾细胞癌;恶性黑色素瘤,肺纤维化(Pulmonary Fibrosis)),吉妥珠单抗(Gemtuzumab)(白血病(Leukemia)),吉妥珠单抗奥佐米星(Gemtuzumab ozogamicin)(急性髓性白血病(Acute myelogenous leukemia)),Girentuximab(透明细胞肾细胞癌(Clear cell renal cell carcinoma)),Glembatumumabvedotin(黑色素瘤,乳腺癌),GS6624(特发性肺纤维化(Idiopathic pulmonary fibrosis)和实体瘤(solid tumors)),HuC242-DM4(结肠癌,胃癌,胰腺癌),HuHMFGl(乳腺癌),HuN901-DM1(黑色素瘤),替伊莫单抗(Ibritumomab)(复发的或难治性低级滤泡或转化的B细胞非霍奇金淋巴瘤(NHL)(Relapsed or refractory low-grade,follicular,ortransformed B-cell non-Hodgkin′s lymphoma(NHL))),Icrucumab,ID09C3(非霍奇金淋巴瘤),Indatuximab ravtansine,伊珠单抗奥佐米星(Inotuzumab ozogamicin),Intetumumab(实体瘤(前列腺癌黑色素瘤)),Ipilimumab(肉瘤,黑色素瘤,肺癌(Lungcancer),(卵巢癌,白血病,淋巴瘤,脑和中枢神经系统肿瘤,睾丸癌(Testicular Cancer),前列腺癌,胰腺癌,乳腺癌),Iratumumab(霍奇金淋巴瘤(Hodgkin′s lymphoma)),Labetuzumab(结直肠癌),雷克萨单抗(Lexatumumab),林妥珠单抗(Lintuzumab),Lorvotuzumab mertansine,Lucatumumab(多发性骨髓瘤,非霍奇金淋巴瘤,霍奇金淋巴瘤),鲁昔单抗(Lumiliximab)(慢性淋巴细胞性白血病(Chronic lymphocyticleukemia)),Mapatumumab(结肠癌,骨髓瘤),Matuzumab(肺癌,宫颈癌(Cervical Cancer),食管癌(Esophageal Cancer)),MDX-060(霍奇金淋巴瘤,淋巴瘤),MEDI 522(实体瘤,白血病,淋巴瘤,小肠癌(Small Intestine Cancer),黑色素瘤),米妥莫单抗(Mitumomab)(小细胞肺癌),Mogamulizumab,MORab-003(卵巢癌,输卵管癌(Fallopian Tube Cancer),腹膜癌(Peritoneal Cancer)),MORab-009(胰腺癌,间皮瘤(Mesothelioma),卵巢癌,非小细胞肺癌,输卵管癌,腹腔癌),Moxetumomab pasudotox,MTl03(非霍奇金淋巴瘤),他那可单抗(Nacolomab tafenatox)(结直肠癌),他那莫单抗(Naptumomab estafenatox)(非小细胞肺癌,肾细胞癌),Narnatumab,Necitumumab(非小细胞肺癌),尼妥珠单抗(Nimotuzumab)(鳞状细胞癌,头颈癌,鼻咽癌(nasopharyngeal cancer),胶质瘤(glioma)),尼妥珠单抗(鳞状细胞癌,胶质瘤,实体瘤,肺癌),Olaratumab,Onartuzumab(癌症),Oportuzumab monatox,Oregovomab(卵巢癌),Oregovomab(卵巢癌,输卵管癌,腹腔癌),PAM4(胰腺癌),帕尼单抗(Panitumumab)(结肠癌,肺癌,乳腺癌;膀胱癌;卵巢癌),Patritumab,Pemtumomab,帕妥珠单抗(Pertuzumab)(乳腺癌,卵巢癌,肺癌,前列腺癌),普立昔单抗(Pritumumab)(脑癌),Racotumomab,Radretumab,雷莫芦单抗(Ramucirumab)(实体瘤),Rilotumumab(实体瘤),利妥昔单抗(Rituximab)(荨麻疹(Urticaria),类风湿性关节炎,溃疡性结肠炎(UlcerativeColitis),慢性病灶性脑炎(Chronic Focal Encephalitis),非霍奇金淋巴瘤,淋巴瘤,慢性淋巴细胞性白血病),Robatumumab,Samalizumab,SGN-30(霍奇金淋巴瘤,淋巴瘤),SGN-40(非霍奇金淋巴瘤,骨髓瘤,白血病,慢性淋巴细胞性白血病),西罗珠单抗(Sibrotuzumab),Siltuximab,Tabalumab(B-细胞癌),Tacatuzumab tetraxetan,帕他普莫单抗(Taplitumomab paptox),Tenatumomab,Teprotumumab(血液肿瘤),TGN1412(慢性淋巴细胞性白血病,风湿性关节炎),Ticilimumab(=tremelimumab),Tigatuzumab,TNX-650(霍奇金淋巴瘤),托西莫单抗(Tositumomab)(滤泡型淋巴瘤,B细胞淋巴瘤,白血病,骨髓瘤),曲妥珠单抗(Trastuzumab)(乳腺癌,子宫内膜癌症,实体瘤),TRBS07(黑色素瘤),Tremelimumab,TRU-016(慢性淋巴细胞性白血病),TRU-016(非霍奇金淋巴瘤),Tucotuzumab celmoleukin,Ublituximab,Urelumab,维妥珠单抗(Veltuzumab)(非霍奇金淋巴瘤),维妥珠单抗(IMMU--106)(非霍奇金淋巴瘤),Volociximab(肾细胞癌,胰腺癌,黑色素瘤),伏妥莫单抗(Votumumab)(结肠直肠肿瘤(Colorectal tumors)),WX-G250(肾细胞癌),Zalutumumab(头颈癌,鳞状细胞癌),和他珠单抗(Zanolimumab)(T-细胞淋巴瘤);
用于包括治疗免疫病症的抗体,例如,依法利珠单抗(Efalizumab)(银屑病(Psoriasis)),依帕珠单抗(Epratuzumab)(自身免疫病,系统性红斑狼疮,非霍奇金淋巴瘤,白血病),Etrolizumab(炎性肠病(inflammatory bowel disease)),Fontolizumab(克罗恩病),Ixekizumab(自身免疫病),美泊利单抗(Mepolizumab)(高嗜酸粒细胞综合征(Hypereosinophilie-Syndrom),哮喘,嗜酸细胞性胃肠炎(EosinophilicGastroenteritis),丘-施综合征(Churg-Strauss Syndrome),嗜酸细胞性食管炎(Eosinophilic Esophagitis)),Milatuzumab(多发性骨髓瘤和其他血液恶性病),汇集的免疫球蛋白(Pooled immunoglobulins)(原发性免疫缺陷(Primaryimmunodeficiencies)),普立昔单抗(Priliximab)(克罗恩病,多发性硬化病(multiplesclerosis)),利妥昔单抗(Rituximab)(荨麻疹,类风湿性关节炎,溃疡性结肠炎,慢性病灶性脑炎,非霍奇金淋巴瘤,淋巴瘤,慢性淋巴细胞性白血病),Rontalizumab(系统性红斑狼疮),卢利珠单抗(Ruplizumab)(风湿性疾病(rheumatic diseases)),Sarilumab(类风湿性关节炎,强直性脊柱炎),维多珠单抗(Vedolizumab)(克罗恩病,溃疡性结肠炎),Visilizumab(克罗恩病,溃疡性结肠炎),Reslizumab(呼吸道、皮肤和胃肠道的炎症),阿达木单抗(Adalimumab)(类风湿性关节炎,克罗恩病,强直性脊柱炎,银屑病关节炎(Psoriatic arthritis)),Aselizumab(严重受伤的患者),Atinumab(治疗神经系统),Atlizumab(类风湿性关节炎,系统性青少年特发性关节炎(systemic juvenileidiopathic arthritis)),贝利术单抗(Bertilimumab)(严重变应性病症),Besilesomab(炎性损伤和转移),BMS-945429,ALD518(癌症和类风湿性关节炎),Briakinumab(银屑病,类风湿性关节炎,炎性肠病,多发性硬化),Brodalumab(炎性病),卡那单抗(Canakinumab)(类风湿性关节炎),卡那单抗(cryopyrin-相关周期热综合征(cryopyrin-associatedperiodic syndromes,CAPS),类风湿性关节炎,慢性阻塞性肺病(chronic obstructivepulmonary disease)),培舍珠单抗(Certolizumab pegol)(克罗恩病),厄利珠单抗(Erlizumab)(心脏病发作(heart attack),卒中(stroke),创伤性休克(traumaticshock)),Fezakinumab(类风湿性关节炎,银屑病),戈利木单抗(Golimumab)(类风湿性关节炎,银屑病关节炎,强直性脊柱炎),Gomiliximab(变应性哮喘(allergic asthma)),英夫利昔单抗(Infliximab)(类风湿性关节炎,克罗恩病,强直性脊柱炎,银屑病关节炎,斑块状银屑病,强直性脊椎炎(Morbus Bechterew),溃疡性结肠炎(Colitis ulcerosa)),Mavrilimumab(类风湿性关节炎),那他珠单抗(Natalizumab)(多发性硬化),Ocrelizumab(多发性硬化,类风湿性关节炎,红斑狼疮(lupus erythematosus),血液癌症),奥度莫单抗(Odulimomab)(预防器官移植排斥,免疫疾病),奥法木单抗(Ofatumumab)(慢性淋巴细胞性白血病,滤泡型非霍奇金淋巴瘤(follicular non-Hodgkin’s lymphoma),B细胞淋巴瘤,类风湿性关节炎,复发性缓和型多发性硬化(relapsing remitting multiple sclerosis),淋巴瘤,B-细胞慢性淋巴细胞性白血病),Ozoralizumab(炎症),Pexelizumab(减少心脏手术的副作用),罗维珠单抗(Rovelizumab)(出血性休克(haemorrhagic shock)),SBI-087(类风湿性关节炎),SBI-087(系统性红斑狼疮),Secukinumab(葡萄膜炎(uveitis),类风湿性关节炎银屑病),Sirukumab(类风湿性关节炎),他利珠单抗(Talizumab)(变态反应(allergic reaction)),托珠单抗(Tocilizumab)(类风湿性关节炎,系统性青少年特发性关节炎(systemic juvenile idiopathic arthritis),卡斯太拉尼病(Castleman′sdisease)),Toralizumab(类风湿性关节炎,狼疮性肾炎(lupus nephritis)),TRU-015(类风湿性关节炎),TRU-016(自身免疫病和炎症),优特克单抗(Ustekinumab)(多发性硬化,银屑病,银屑病关节炎),优特克单抗(IL-12/IL-23阻断剂)(斑块状银屑病,银屑病关节炎,多发性硬化,肉瘤样病(sarcoidosis),后者相对于(the latter versus)),维帕莫单抗(Vepalimomab)(炎症),阿佐莫单抗(Zolimomab aritox)(系统性红斑狼疮,移植物抗宿主病(graft-versus-host disease)),Sifalimumab(SLE,皮肌炎(dermatomyositis),多肌炎(polymyositis)),鲁昔单抗(Lumiliximab)(变态反应(Allergies)),和Rho(D)免疫球蛋白(Rho(D)Immune Globulin)(恒河猴病(Rhesus disease));或选自用于治疗传染病的抗体,例如,阿非莫单抗(Afelimomab)(败血症(sepsis)),CR6261(传染病/A型流感(influenzaA)),埃巴单抗(Edobacomab)(由革兰氏阴性细菌引起的败血症),Efungumab(侵入性念珠菌属感染(invasive Candida infection)),艾韦单抗(Exbivirumab)(乙型肝炎),非维珠单抗(Felvizumab)(呼吸道合胞病毒感染(respiratory syncytial virus infection)),Foravirumab(狂犬病(rabies)(预防)),Ibalizumab(HIV感染),Libivirumab(乙型肝炎),Motavizumab(呼吸道合胞病毒(预防)),奈巴库单抗(Nebacumab)(败血症),妥韦单抗(Tuvirumab)(慢性乙型肝炎),乌珠单抗(Urtoxazumab)(由大肠杆菌引起的腹泻),巴土昔单抗(Bavituximab)(多种病毒感染),Pagibaximab(败血症(例如,葡萄球菌属(Staphylococcus))),帕利珠单抗(Palivizumab)(预防高危儿科患者中的呼吸道合胞病毒感染),Panobacumab(铜绿假单胞菌(Pseudomonas aeruginosa)感染),PRO 140(HIV感染),瑞非韦鲁(Rafivirumab)(狂犬病(预防)),Raxibacumab(炭疽(anthrax)(预防和治疗)),瑞加韦单抗(Regavirumab)(巨细胞病毒感染),司韦单抗(Sevirumab)(巨细胞病毒感染),Suvizumab(病毒感染),和替非珠单抗(Tefibazumab)(金黄色葡萄球菌(Staphylococcusaureus)感染);
用于包括治疗血液病症的抗体,例如,阿昔单抗(Abciximab)(经皮冠状动脉干预),阿托木单抗(Atorolimumab)(新生儿溶血疾病(hemolytic disease ofthenewborn)),依库珠单抗(Eculizumab)(突发性夜间血红蛋白尿(Paroxysmal nocturnalhaemoglobinuria)),美泊利单抗(Mepolizumab)(高嗜酸粒细胞综合征(Hypereosinophilie-Syndrom),哮喘,嗜酸细胞性胃肠炎,丘-施综合征,嗜酸细胞性食管炎),以及Milatuzumab(多发性骨髓瘤和其他血液恶性病);
用于包括免疫调节的抗体,例如,抗胸腺细胞球蛋白(Antithymocyte globulin)(急性肾移植排斥(Acute kidney transplant rejection),再生障碍性贫血(aplasticanaemia)),巴利昔单抗(Basiliximab)(在接受包括环孢菌素(cyclosporine)和皮质类固醇(corticosteroids)的免疫抑制方案的肾移植患者中预防同种异体移植物排斥),西地珠单抗(Cedelizumab)(防止器官移植排斥,治疗自身免疫病),达利珠单抗(Daclizumab)(预防接受肾移植的患者中的急性同种异体移植物排斥,多发性硬化),Gavilimomab(移植物抗宿主病),伊诺莫单抗(Inolimomab)(移植物抗宿主病),莫罗莫那-CD3(Muromonab-CD3)(防止器官移植排斥),莫罗莫那-CD3(急性肾同种异体移植物排斥(Acute renal allograftrejection)或类固醇抗性心脏或肝脏同种异体移植物排斥(steroid-resistant cardiacor hepatic allograft rejection)),奥度莫单抗(Odulimomab)(防止器官移植排斥,免疫学疾病),以及Siplizumab(银屑病,移植物抗宿主病(预防));
用于治疗糖尿病的抗体,例如,Gevokizumab(糖尿病),Otelixizumab(1型糖尿病)和Teplizumab(1型糖尿病);
用于治疗阿尔茨海默病的抗体,例如,Bapineuzumab,Crenezumab,Gantenerumab,Ponezumab,R1450,和Solanezumab;
用于治疗哮喘的抗体,例如,Benralizumab,Enokizumab,Keliximab,Lebrikizumab,奥马珠单抗(Omalizumab),Oxelumab,Pascolizumab和Tralokinumab;
以及用于治疗多种病症的抗体,例如,Blosozumab(骨质疏松症),CaroRx(龋齿(Tooth decay)),Fresolimumab(特发性肺纤维化,局灶性节段性肾小球硬化症(focalsegmental glomerulosclerosis),癌症),Fulranumab(疼痛),Romosozumab(骨质疏松症),司他莫单抗(Stamulumab)(肌营养不良症(muscular dystrophy)),Tanezumab(疼痛)和雷珠单抗(Ranibizumab)(新生血管年龄相关的黄斑变性(Neovascular age-relatedmacular degeneration))。
本发明第一方面所述的本发明的核酸的编码区可以作为单顺反子、双顺反子或甚至多顺反子核酸而存在,即为携带一种、两种或更多种蛋白或肽的编码序列的核酸。在双顺反子或甚至多顺反子核酸中的所述编码序列可以被至少一个内部核糖体进入位点(IRES)序列(例如,如本文所述)或被信号肽隔开,所述信号肽诱导所产生的包含数个蛋白或肽的多肽的切割。
按照本发明的第一方面,本发明的核酸序列包含编码区,所述编码区编码包含治疗性蛋白或其片段、变体或衍生物的肽或蛋白。优选地,所编码的治疗性抗原不是组蛋白类蛋白。在本发明的情形中,所述组蛋白类蛋白典型地是在真核细胞核中发现的强碱性蛋白,其包装并且使DNA按秩序成为称为核小体的结构单位。组蛋白类蛋白是染色质的主要蛋白成分,作为DNA围绕其缠绕的轴,并且在基因调节中起作用。如果没有组蛋白,染色体中未缠绕的DNA将非常长(在人DNA中,长度与宽度的比率大于10,000,000)。例如,每个人体细胞具有约1.8米长的DNA,但是缠绕在组蛋白上,其具有约90毫米长的染色质,当在有丝分裂过程中复制并压缩时,其产生约120微米的染色体。更优选地,在本发明的情形中,所述组蛋白类蛋白典型地定义为选自下述五种主要种类的组蛋白中的一种的高度保守的蛋白:H1/H5,H2A,H2B,H3和H4″,优选选自哺乳动物组蛋白,更优选选自人组蛋白或组蛋白类蛋白。所述组蛋白或组蛋白类蛋白典型地分成两个超级种类:定义为核心组蛋白,包括组蛋白H2A,H2B,H3和H4;和定义为接头组蛋白,包括组蛋白H1和H5。
在这一情形中,接头组蛋白,优选地排除在待审的发明的保护范围之外,优选哺乳动物接头组蛋白,更优选人接头组蛋白,典型地选自H1,包括H1F,特别包括H1F0,H1FNT,H1FOO,H1FX和H1H1,特别包括HIST1H1A,HIST1H1B,HIST1H1C,HIST1H1D,HIST1H1E,HIST1H1T;并且
此外,核心组蛋白,优选地排除在待审的发明的保护范围之外,优选哺乳动物核心组蛋白,更优选人核心组蛋白,典型地选自H2A,包括H2AF,特别包括H2AFB1,H2AFB2,H2AFB3,H2AFJ,H2AFV,H2AFX,H2AFY,H2AFY2,H2AFZ,和H2A1,特别包括HIST1H2AA,HIST1H2AB,HIST1H2AC,HIST1H2AD,HIST1H2AE,HIST1H2AG,HIST1H2AI,HIST1H2AJ,HIST1H2AK,HIST1H2AL,HIST1H2AM,和H2A2,特别包括HIST2H2AA3,HIST2H2AC;H2B,包括H2BF,特别包括H2BFM,H2BFO,H2BFS,H2BFWT H2B1,特别包括HIST1H2BA,HIST1H2BB,HIST1H2BC,HIST1H2BD,HIST1H2BE,HIST1H2BF,HIST1H2BG,HIST1H2BH,HIST1 H2BI,HIST1H2BJ,HIST1H2BK,HIST1H2BL,HIST1H2BM,HIST1H2BN,HIST1H2BO,和H2B2,特别包括HIST2H2BE;H3,包括H3A1,特别包括HIST1H3A,HIST1H3B,HIST1H3C,HIST1H3D,HIST1H3E,HIST1H3F,HIST1H3G,HIST1H3H,HIST1H3I,HIST1H3J,和H3A2,特别包括HIST2H3C,和H3A3,特别包括HIST3H3;H4,包括H41,特别包括HIST1H4A,HIST1H4B,HIST1H4C,HIST1H4D,HIST1H4E,HIST1H4F,HIST1H4G,HIST1H4H,HIST1H4I,HIST1H4J,HIST1H4K,HIST1H4L,和H44,特别包括HIST4H4,和H5。
按照本发明的第一方面,本发明的核酸包含编码区,所述编码区编码包含治疗性蛋白或其片段、变体或衍生物的肽或蛋白。优选地,所编码的治疗性蛋白不是报道蛋白(例如,荧光素酶,绿色荧光蛋白(GFP),增强的绿色荧光蛋白(EGFP),β-半乳糖苷酶),并且不是标记或选择蛋白(例如,d-珠蛋白,半乳糖激酶和黄嘌呤:鸟嘌呤磷酸核糖基转移酶(GPT))。优选地,本发明的核酸序列不包含(细菌)抗生素抗性基因,特别是不包含neo基因序列(新霉素抗性基因)或CAT基因序列(氯霉素乙酰转移酶,氯霉素抗性基因)。
上文定义的本发明的核酸包含或编码:a)编码区,所述编码区编码包含治疗性蛋白或其片段、变体或衍生物的肽或蛋白;b)至少一个组蛋白茎环,和c)聚腺苷酸序列或聚腺苷酸化序列;优选地用于增加所编码的肽或蛋白的表达,其中所编码的肽或蛋白优选不是组蛋白类蛋白,不是报道蛋白和/或不是标记或选择蛋白,如上文定义。本发明的核酸的元件b)至c)可以以任意顺序存在于本发明的核酸中,即,元件a),b)和c)可以从5’至3’方向以a),b)和c)或a),c)和b)的顺序存在于本发明的核酸序列中,其中也可以包含本文所述的其他元件,诸如5’-CAP结构,聚(C)序列,稳定序列,IRES序列等。本发明的核酸的元件a)至c)中的每一个,特别是在双顺反子或多顺反子构建体中的a)和/或元件b)和c)中的每一个,更优选元件b)在本发明的核酸中也可以重复至少一次,优选两次或更多次。例如,本发明的核酸可以例如以下述顺序显示其序列元件a),b)和任选的c):
5’-编码区-组蛋白茎环-聚腺苷酸序列-3’;或
5’-编码区-组蛋白茎环-聚腺苷酸化信号-3’;或
5’-编码区-聚腺苷酸序列-组蛋白茎环-3’;或
5’-编码区-聚腺苷酸化信号-组蛋白茎环-3’;或
5’-编码区-编码区-组蛋白茎环-聚腺苷酸化信号-3’;或
5’-编码区-组蛋白茎环-组蛋白茎环-聚腺苷酸序列-3’;或
5’-编码区-组蛋白茎环-组蛋白茎环-聚腺苷酸化信号-3’;等。
在这一情形中,特别优选的是本发明的核酸序列包含或编码:a)编码区,所述编码区编码包含治疗性蛋白或其片段、变体或衍生物的肽或蛋白;b)至少一个组蛋白茎环,和c)聚腺苷酸序列或聚腺苷酸化序列;优选地用于增加所编码的肽或蛋白的表达,其中所编码的蛋白优选不是组蛋白类蛋白,不是报道蛋白(例如,荧光素酶,GFP,EGFP,β-半乳糖苷酶,特别是EGFP)和/或不是标记或选择蛋白(例如,α-珠蛋白,半乳糖激酶和黄嘌呤:鸟嘌呤磷酸核糖基转移酶(GPT))。
在第一方面的进一步优选的实施方案中,本文定义的本发明的核酸序列还可以以修饰的核酸的形式存在。
在这一情形中,本文定义的本发明的核酸序列可以被修饰,以提供“稳定的核酸”,优选稳定的RNA,更优选基本上耐受体内降解(例如,通过核酸外切酶或核酸内切酶降解)的RNA。例如,稳定的核酸可以通过改变本发明的核酸序列的编码区的G/C含量,通过引入核苷酸类似物(例如,具有主链修饰、糖修饰或碱基修饰的核苷酸)或通过在本发明核酸序列的3’-和/或5’-非翻译区引入稳定序列而获得。
如上文提及,本文定义的本发明的核酸序列可以包含核苷酸类似物/修饰,例如,主链修饰,糖修饰或碱基修饰。与本发明相联系的主链修饰是这样的修饰,即,本文定义的本发明的核酸序列中所包含的核苷酸的主链的磷酸被化学修饰。与本发明相联系的糖修饰是本文定义的本发明的核酸序列的核苷酸的糖的化学修饰。此外,与本发明相联系的碱基修饰是本发明的核酸序列的核酸分子的核苷酸的碱基结构部分的化学修饰。在这一情形中,核苷酸类似物或修饰优选选自适于转录和/或翻译的核苷酸类似物。
在本发明第一方面的特别优选的实施方案中,本文定义的核苷酸类似物/修饰选自下述碱基修饰:所述碱基修饰另外增加所编码的蛋白的表达,并且优选地选自:2-氨基-6-氯嘌呤核苷-5′-三磷酸,2-氨基腺苷-5′-三磷酸,2-硫代胞苷-5′-三磷酸,2-硫代尿苷-5′-三磷酸,4-硫代尿苷-5′-三磷酸,5-氨基烯丙基胞苷-5′-三磷酸,5-氨基烯丙基尿苷-5′-三磷酸,5-溴胞苷-5′-三磷酸,5-溴尿苷-5′-三磷酸,5-碘胞苷-5′-三磷酸,5-碘尿苷-5′-三磷酸,5-甲基胞苷-5′-三磷酸,5-甲基尿苷-5′-三磷酸,6-氮胞苷-5′-三磷酸,6-氮尿苷-5′-三磷酸,6-氯嘌呤核苷-5′-三磷酸,7-脱氮腺苷-5′-三磷酸,7-脱氮鸟苷-5′-三磷酸,8-氮杂腺苷-5′-三磷酸,8-叠氮腺苷-5′-三磷酸,苯并咪唑-核苷-5′-三磷酸,N1-甲基腺苷-5′-三磷酸,N1-甲基鸟苷-5′-三磷酸,N6-甲基腺苷-5′-三磷酸,O6-甲基鸟苷-5′-三磷酸,假尿苷-5′-三磷酸,或嘌呤霉素-5′-三磷酸,黄苷-5′-三磷酸。对于核苷酸,特别优选的是选自由下述组成的碱基修饰的核苷酸的组的碱基修饰:5-甲基胞苷-5′-三磷酸,7-脱氮鸟苷-5′-三磷酸,5-溴胞苷-5′-三磷酸和假尿苷-5′-三磷酸。
按照另一个实施方案,本文定义的本发明的核酸序列可以包含脂质修饰。所述脂质-修饰的核酸典型地包含本文定义的核酸。本文定义的本发明的核酸序列的所述脂质-修饰的核酸分子典型地进一步包含与所述核酸分子共价连接的至少一个接头,和与各个接头共价连接的至少一个脂质。备选地,所述脂质-修饰的核酸分子包含如本文定义的至少一种核酸分子和与所述核酸分子共价连接(不用接头)的至少一个(双功能)脂质。根据第三备选方案,所述脂质-修饰的核酸分子包含如本文定义的核酸分子,与所述核酸分子共价连接的至少一个接头和与各个接头共价连接的至少一个脂质,以及还有与所述核酸分子共价连接(不用接头)的至少一个(双功能)脂质。在这一情形中,特别优选的是,脂质修饰存在于线性的本发明的核酸序列的末端。
按照本发明第一方面另一个优选的实施方案,本文定义的本发明的核酸序列,特别是如果提供为(m)RNA,由此可以通过添加所谓的“5′CAP”结构而针对RNA酶的降解而稳定。
按照本发明第一方面进一步优选的实施方案,本文定义的本发明的核酸序列可以由至少10个胞苷的序列、优选至少20个胞苷、更优选至少30个胞苷的序列(所谓的“聚(C)序列”)修饰。特别地,本发明的核酸序列可以包含或编码典型地约10-200个胞苷核苷酸、优选约10-100个胞苷核苷酸、更优选约10-70个胞苷核苷酸或甚至更优选约20-50个或甚至20-30个胞苷核苷酸的聚(C)序列。该聚(C)序列优选位于包含在本发明第一方面所述的本发明的核酸中的编码区的3’。
在本发明的一个特别优选的实施方案中,与其特定的野生型编码区(即,未修饰的编码区)的G/C含量相比,本文定义的本发明的核酸序列的编码区(编码至少一种包含治疗性蛋白或其片段、变体或衍生物的肽或蛋白)的G/C含量被改变,特别地被增加。与特定野生型编码区编码的氨基酸序列相比,该编码区所编码的氨基酸序列优选没有改变。
本文定义的本发明的核酸序列编码区的G/C-含量的改变是基于这样的事实,即,要被翻译的任意mRNA区的序列对于该mRNA的有效翻译是重要的。因此,各种核苷酸的组成和序列是重要的。特别地,与具有增加的A(腺苷)/U(尿嘧啶)含量的mRNA序列相比,具有增加的G(鸟苷)/C(胞嘧啶)含量的mRNA序列更稳定。因此,按照本发明,与其野生型编码序列相比,所述编码区的密码子是改变的,但是保留翻译的氨基酸序列,以使其包含增加量的G/C核苷酸。关于几种密码子编码同一种氨基酸(所谓的遗传密码的简并性)的事实,可以确定对稳定性最有利的密码子(所谓的替代密码子使用(alternative codon usage))。
与其野生型编码区相比,取决于本文定义的本发明的核酸序列的编码区所编码的氨基酸,对于所述核酸序列,例如编码区的修饰存在多种可能性。在由仅含有G或C核苷酸的密码子编码的氨基酸的情形中,不需要对该密码子的修饰。因此,由于不存在A或U,关于Pro(CCC或CCG),Arg(CGC或CGG),Ala(GCC或GCG)和Gly(GGC或GGG)的密码子不需要修饰。
相比之下,含有A和/或U核苷酸的密码子可以通过编码相同的氨基酸但是不含有A和/或U的其他密码子的替代而进行修饰。这些的实例如下:
Pro的密码子可以由CCU或CCA修饰为CCC或CCG;
Arg的密码子可以由CGU或CGA或AGA或AGG修饰为CGC或CGG;
Ala的密码子可以由GCU或GCA修饰为GCC或GCG;
Gly的密码子可以由GGU或GGA修饰为GGC或GGG。
在其他情形中,尽管不能从密码子中消除A或U核苷酸,但是其可以通过使用含有较低A和/或U核苷酸含量的密码子来减少A和U的含量。这些的实例如下:
Phe的密码子可以由UUU修饰为UUC;
Leu的密码子可以由UUA,UUG,CUU或CUA修饰为CUC或CUG;
Ser的密码子可以由UCU或UCA或AGU修饰为UCC,UCG或AGC;
Tyr的密码子可以由UAU修饰为UAC;
Cys的密码子可以由UGU修饰为UGC;
His的密码子可以由CAU修饰为CAC;
Gln的密码子可以由CAA修饰为CAG;
Ile的密码子可以由AUU或AUA修饰为AUC;
Thr的密码子可以由ACU或ACA修饰为ACC或ACG;
Asn的密码子可以由AAU修饰为AAC;
Lys的密码子可以由AAA修饰为AAG;
Val的密码子可以由GUU或GUA修饰为GUC或GUG;
Asp的密码子可以由GAU修饰为GAC;
Glu的密码子可以由GAA修饰为GAG;
终止密码子UAA可以修饰为UAG或UGA。
另一方面,在Met(AUG)和Trp(UGG)密码子的情形中,没有序列修饰的可能性。
上文列出的置换可以单独或以所有可能的组合使用,从而与其特定的野生型编码区(即,原始序列)相比,增加本文定义的本发明的核酸序列的编码区的G/C含量。因此,例如,关于野生型序列中存在的Thr的所有的密码子都可以修饰为ACC(或ACG)。
在上述情形中,显示了mRNA中存在的密码子。因此,在相应的编码特定mRNA的DNA中,mRNA中存在的尿苷也可以存在为胸苷。
优选地,与野生型编码区的G/C含量相比,本文定义的本发明的核酸序列的编码区的G/C含量增加至少7%,更优选增加至少15%,特别优选地增加至少20%。根据具体的实施方案,在编码至少一种包含治疗性蛋白或其片段、变体或衍生物的肽或蛋白的编码区中至少5%,10%,20%,30%,40%,50%,60%,更优选至少70%,甚至更优选至少80%且最优选至少90%,95%或甚至100%的可取代的密码子被取代,由此增加所述编码区的G/C含量。
在这一情形中,特别优选的是,与野生型编码区相比,将本文定义的本发明的核酸序列的编码区的G/C含量增加至最大(即,100%可取代的密码子)。
按照本发明,本文定义的本发明的核酸序列的编码至少一种包含治疗性抗原或其片段、变体或衍生物的肽或蛋白的编码区的进一步优选的修饰是基于这样的发现,即,翻译效率还取决于tRNAs在细胞中存在的不同频率。因此,如果在本文定义的本发明的核酸序列的编码区中存在增加程度的所谓的“稀少密码子”,与其中存在编码相对“常见的”tRNAs的密码子的情形相比,相应的修饰的核酸序列以显著更少的程度翻译。
在这一情形中,与相对应的野生型编码区相比,本发明的核酸序列的编码区优选被修饰,以使编码在细胞中相对稀少的tRNA的野生型序列的至少一个密码子交换为编码在细胞中相对常见且与所述相对稀少的tRNA携带相同的氨基酸的tRNA的密码子。通过这种修饰,本文定义的本发明的核酸序列的编码区被修饰,以插入关于常见的tRNAs是可用的密码子。换言之,按照本发明,通过这种修饰,编码在细胞中相对稀少的tRNA的野生型编码区的所有密码子可以交换为编码在细胞中相对常见且在每种情形中与所述相对稀少的tRNA携带相同的氨基酸的tRNA的密码子。
哪些tRNAs在细胞中相对常见,相比之下,哪些tRNAs相对稀少,对于本领域技术人员是已知的;例如,参考Akashi,Curr.Opin.Genet.Dev.(现代遗传发育观点)2001,11(6):660-666。特别优选为特定氨基酸使用最常见的tRNA的密码子,例如,Gly密码子,其利用在(人)细胞中最常见的tRNA。
按照本发明,特别优选的是,在不改变由核酸序列的编码区所编码的肽或蛋白的氨基酸序列的前提下,将本文定义的本发明的核酸序列的编码区中增加的(特别是最大化的)序列G/C含量与“常见”密码子联系起来。这种优选的实施方案允许提供特别有效翻译的和稳定的(修饰的)本文定义的本发明的核酸序列。
按照本发明第一方面的另一个优选的实施方案,本文定义的本发明的核酸序列优选另外具有至少一个5′和/或3′稳定序列。这些在5’和/或3’非翻译区的稳定序列具有增加核酸、特别是胞质中的mRNA的半衰期的作用。这些稳定序列可以与在病毒、细菌和真核生物中存在的天然存在的序列具有100%的序列同一性,但是也可以是部分或完全合成的。可以提及(α-)珠蛋白基因(例如,来自智人(Homo sapiens)或光滑爪蟾(Xenopus laevis))的非翻译序列(UTR)作为可以在本发明中用于稳定的核酸的稳定序列的实例。稳定序列的另一个实例具有通式:(C/U)CCANxCCC(U/A)PyxUC(C/U)CC(SEQ ID NO:55),其包含在编码(α-)珠蛋白、(I)型-胶原蛋白、15-脂氧合酶或编码酪氨酸羟化酶的非常稳定的RNAs的3’-UTRs中(参见Holcik等人,Proc.Natl.Acad.Sci.USA(美国国家科学院学报)1997,94:2410-2414)。所述稳定序列当然能够单独使用或与另一种组合使用并且还与本领域技术人员已知的其他稳定序列组合使用。在这一情形中,特别优选的是,α珠蛋白基因的3’UTR序列位于包含在本发明第一方面所述的本发明的核酸序列的编码至少一种包含治疗性蛋白或其片段、变体或衍生物的肽或蛋白的编码区的3’。
碱基的置换、添加或消除优选地用本文定义的本发明的核酸序列使用用于制备所述核酸序列的DNA基质通过公知的定点诱变技术或使用寡核苷酸连接策略进行(参见,例如,Maniatis等人.,Molecular Cloning:A Laboratory Manual(分子克隆:实验室手册),Cold Spring Harbor Laboratory Press,第3版,Cold Spring Harbor,NY,2001)。
上述任一种修饰可以适用于本文定义的本发明的核酸序列,并且适用于用在本发明的情形中的任一种核酸,并且,如果适当的或必要的,可以彼此以任意组合来组合,条件是,这些修饰的组合在各个核酸中彼此不干扰。因此,本领域技术人员能够作出选择。
按照本发明使用的本文定义的核酸序列可以使用本领域已知的任意方法制备,包括合成法,诸如例如,固相合成,以及体外方法,诸如体外转录反应或体内反应,诸如DNA质粒在细菌中的体内繁殖。
在这样的方法中,为了制备本文定义的本发明的核酸序列,特别是当所述核酸是mRNA的形式时,可以在体外转录相对应的DNA分子。该DNA基质优选地包含合适的启动子,例如T7或SP6启动子,以用于体外转录,其后跟随着关于待制备的核酸分子(例如mRNA)的需要的核苷酸序列和体外转录的终止信号。形成至少一种目的RNA基质的DNA分子可以通过发酵增殖和随后分离为可以在细菌内复制的质粒的一部分来制备。可以作为适合于本发明提及的质粒是例如质粒pT7Ts(GenBank编号U26404;Lai等人,Development(发育)1995,121:2349-2360),系列,例如(GenBank编号X65300;来自Promega)和pSP64(GenBank编号X65327);还参考:Mezei和Storts,Purification of PCR Products(PCR产物的纯化),在:Griffin和Griffin(编),PCR Technology:Current Innovation(PCR技术:当前改革)中,CRC Press(CRC出版社),Boca Raton,FL,2001中。
本文定义的本发明的核酸序列以及由该核酸序列编码的蛋白或肽可以包含这些序列的片段或变体。所述片段或变体可以典型地包含这样的序列,所述序列在核酸水平或氨基酸水平上与上文提及的核酸中的一种,或与由本发明的核酸序列编码的蛋白或肽或序列中的一种具有至少5%,10%,20%,30%,40%,50%,60%,优选至少70%,更优选至少80%,同等地更优选至少85%,甚至更优选至少90%和最优选至少95%或甚至97%,98%或99%的序列同一性,至完整的野生型序列。
在本发明的情形中,蛋白或肽的“片段”(例如,由本文定义的本发明的核酸序列编码)可以包含本文定义的蛋白或肽的序列,关于其氨基酸序列(或其编码核酸分子),与原始(天然)蛋白的氨基酸序列(或其编码核酸分子)相比,其是N端、C端和/或序列内部截短/变短的。因此,所述截短可以在氨基酸水平或相应地在核酸水平上发生。因此,关于本文定义的所述片段的序列同一性可以优选地指本文定义的完整的蛋白或肽或所述蛋白或肽的完整的(编码)核酸。同样地,在本发明的情形中核酸的“片段”可以包含本文定义的核酸的序列,关于其核酸分子,与原始(天然)核酸分子相比,其是5’-,3’-和/或序列内部截短/变短的。因此,关于本文定义的片段的序列同一性可以优选指本文定义的完整的核酸,并且优选的序列同一性水平典型地如本文所示。与全长天然野生型肽或蛋白相比,片段具有相同的生物学功能或特异性的活性或者至少保留所述天然全长蛋白至少50%、更优选至少70%、甚至更优选至少90%的活性(如在适当的功能测定中测量,例如,评估所述治疗性蛋白的片段的酶活性或其结合活性的测定),例如其特异性抗原性或治疗性特性。因此,在优选的实施方案中,所述“片段”是全长(天然存在的)野生型治疗性蛋白的一部分,其发挥本文所示的治疗性特性。
此外,蛋白的结构域,如胞外结构域、胞内结构域或跨膜结构域以及蛋白的缩短或截短版本,也可以理解为包含/对应蛋白的片段。
在本发明的情形中定义的蛋白或肽的“变体”可以由本文定义的本发明的核酸序列编码。由此,可以产生具有与原始序列在一个或多个(2,3,4,5,6,7个以上)突变,诸如一个或多个置换的、插入的和/或缺失的氨基酸处不同的氨基酸序列的蛋白或肽。“变体”关于全长天然野生型蛋白序列的优选的序列同一性水平典型地如本文所示。优选地,与全长天然肽或蛋白相比,变体具有相同的生物学功能或特异性的活性或者至少保留所述天然全长蛋白至少50%、更优选至少70%、甚至更优选至少90%的活性(如在适当的功能测定中测量,例如,评估治疗性蛋白的变体的酶活性或其结合活性的测定),例如其特异性治疗性特性。因此,在优选的实施方案中,“变体”是治疗性蛋白的变体,其发挥本文所示的程度的治疗性特性。
在本发明的情形中定义的蛋白或肽的“变体”(例如,由本文定义的核酸编码)与其天然的(即,未突变的)生理学序列相比可以包含保守氨基酸取代。这些氨基酸序列及其编码核苷酸序列特别都在本文定义的术语变体的涵盖下。其中来源于同一类的氨基酸彼此交换的取代称为保守取代。具体地,这些是具有脂族侧链、带正电荷或负电荷的侧链、在侧链中有芳香基团的氨基酸,或是这样的氨基酸,即所述氨基酸的侧链可以参与氢键,例如,具有羟基官能的侧链。这意味着,例如,具有极性侧链的氨基酸被具有相似极性侧链的另一种氨基酸替代,或者例如,以疏水侧链为特征的氨基酸被另一种具有类似的疏水侧链的氨基酸取代(例如,丝氨酸(苏氨酸)被苏氨酸(丝氨酸)取代,或亮氨酸(异亮氨酸)被异亮氨酸(亮氨酸)取代)。特别地,插入和取代可能在不引起三维结构改变或不影响结合区的那些序列位置。例如,使用CD光谱(圆二色谱)可以容易地确定插入或缺失对三维结构的改变(Urry,1985,Absorption,Circular Dichroism and ORD ofPolypeptides(多肽的吸光度、圆二色性和ORD),在:Modern Physical Methods in Biochemistry(生物化学中的现代物理方法),Neuberger等人,(编),Elsevier,Amsterdam)中。
此外,本文定义的可以由本文定义的本发明的核酸序列编码的蛋白或肽的变体还可以包含那些序列,其中所述核酸的核苷酸按照遗传密码的简并性交换而不导致蛋白或肽相应的氨基酸序列改变,即,所述氨基酸序列或其至少部分在上述意义内的一个或多个突变处与原始序列没有区别。
为了确定两个序列相同的百分数,所述序列例如,本文定义的核酸序列或氨基酸序列,优选由本文定义的本发明的核酸序列编码的氨基酸序列或氨基酸序列本身,可以比对所述序列,以随后彼此比较。因此,例如,第一序列的位置可以与第二序列的相应位置进行比较。如果第一序列中的位置被与第二序列中某位置相同的成分占据,则这两个序列在该位置是相同的。如果这不是这样的情形,则所述序列在该位置是不同的。如果与第一序列相比,在第二序列中存在插入,则可以在第一序列中插入缺口以允许进一步的比对。如果与第一序列相比,在第二序列中存在缺失,则可以在第二序列中插入缺口以允许进一步的比对。然后,两个序列相同的百分数是相同位置的数目除以位置总数(包括仅在一个序列中占据的那些位置)的函数。两个序列相同的百分数可以使用数学算法确定。可以使用的一种优选的但非限制性的数学算法的实例是Karlin等人,(1993),PNAS USA,90:5873-5877或Altschul等人,(1997),Nucleic Acids Res.(核酸研究),25:3389-3402的算法。这样的算法整合在BLAST程序中。通过该程序能够鉴定与本发明的序列在某种程度上相同的序列。
本文定义的本发明的核酸序列可以编码肽或蛋白的衍生物。所述肽或蛋白的衍生物是来源于另一种分子(如所述肽或蛋白)的分子。“衍生物”典型地包含天然野生型肽或蛋白的全长序列以及另外的序列特征,例如,在N端或在C端,其可以对天然全长肽/蛋白表现出另外的功能。同样地,与全长天然肽或蛋白相比,所述衍生物具有相同的生物学功能或特异性的活性或者至少保留天然野生型全长蛋白至少50%,更优选至少70%,甚至更优选至少90%(如在适当的功能测定中测量,参见上文,例如,结合或酶活性测定)的活性,例如,其特异性的治疗性特性。由此,蛋白或肽的“衍生物”还包括包含与独特的肽/蛋白融合的用于本发明的肽或蛋白或天然全长蛋白(或其变体/片段)的(嵌合的)融合肽/蛋白,例如,为所述融合肽/蛋白赋予两种以上的生物学功能。例如,融合体可以包含标记,诸如例如,表位,例如,FLAG表位或V5表位或HA表位。例如,所述表位是FLAG表位。例如,这样的标记用于纯化所述融合蛋白。
在这一情形中,蛋白或肽的“变体”可以与所述蛋白或肽的10,20,30,50,75或100个氨基酸的片段具有至少70%,75%,80%,85%,90%,95%,98%或99%的氨基酸同一性。类似地,核酸序列的“变体”,或具体地,“片段”,可以与所述核酸序列的10,20,30,50,75或100个核苷酸的片段具有至少70%,75%,80%,85%,90%,95%,98%或99%的核苷酸同一性;然而,典型地是与天然存在的全长序列相比。典型地,在“片段”的情形中,对于(所述片段)在全长蛋白的一部分上的长度(反映与所述片段相同的长度)确定该片段的序列同一性,所述长度表现出最高水平的序列同一性。
在本发明第一方面的另一个优选的实施方案中,本发明的核酸序列与载体、转染或复合试剂缔合,以增加本发明的核酸序列的转染效率和/或免疫刺激性特性。在这一情形中,适于增加转染效率的特别优选的试剂是阳离子或聚阳离子化合物,包括鱼精蛋白,核仁蛋白,精胺或亚精胺,或其它阳离子肽或蛋白质,诸如聚-L-赖氨酸(PLL),聚-精氨酸,碱性多肽,细胞渗透肽(CPPs),包括HIV结合肽,HIV-1 Tat(HIV),Tat-衍生的肽,穿膜肽,VP22衍生的或类似的肽,HSV VP22(单纯疱疹(Herpes simplex)),MAP,KALA或蛋白转导结构域(PTDs),PpT620,富含脯氨酸的肽,富含精氨酸的肽,富含赖氨酸的肽,一种或多种MPG-肽,Pep-1,L-寡聚体,降钙素肽,触角足衍生肽(特别地来自果蝇触角足(Drosophilaantennapedia)),pAntp,pIsl,FGF,乳铁蛋白,Transportan,Buforin-2,Bac715-24,SynB,SynB(1),pVEC,hCT-衍生的肽,SAP或组蛋白。另外,优选的阳离子或聚阳离子蛋白或肽可以选自具有下述总式的蛋白或肽:(Arg)1;(Lys)m;(His)n;(Om)o;(Xaa)x,其中l+m+n+o+x=8-15,并且l,m,n或o彼此独立地可以是选自0,1,2,3,4,5,6,7,8,9,10,11,12,13,14或15的任意数字,条件是Arg,Lys,His和Orn的总含量占该寡肽全部氨基酸的至少50%;并且Xaa可以是选自除Arg、Lys、His或Orn之外的天然(=天然存在的)或非天然氨基酸中的任一种氨基酸;x是选自0,1,2,3或4的任意数字,条件是,Xaa的总含量不超过该寡肽全部氨基酸的50%。在这一情形中,特别优选的阳离子肽是,例如,Arg7,Arg8,Arg9,H3R9,R9H3,H3R9H3,YSSR9SSY,(RKH)4,Y(RKH)2R等。可以用作转染剂的特别优选的阳离子或聚阳离子化合物可以包括阳离子多糖,例如,壳聚糖,1,5-二甲基-1,5-二氮十一亚甲基聚甲溴化物(polybrene),阳离子聚合物,例如,聚乙烯亚胺(PEI),阳离子脂质,例如,DOTMA:[1-(2,3-二油酰氧基)丙基)]-N,N,N-三甲基氯化铵,DMRIE,二-C14-脒,DOTIM,SAINT,DC-Chol,BGTC,CTAP,DOPC,DODAP,DOPE:二油基磷脂酰乙醇胺,DOSPA,DODAB,DOIC,DMEPC,DOGS:Dioctadecylamidoglicylspermin,DIMRI:二肉豆蔻酰-氧丙基二甲基羟乙基溴化铵,DOTAP:二油基氧基-3-(三甲基铵基)丙烷,DC-6-14:O,O-双十四酰基-N-(α-三甲基铵基乙酰基)二乙醇胺氯化物,CLIP1:外消旋-[(2,3-双十八基氧基丙基)(2-羟乙基)]-二甲基氯化铵,CLIP6:外消旋-[2(2,3-双十六基氧基丙基-氧基甲氧基)乙基]三甲基铵,CLIP9:外消旋-[2(2,3-双十六基氧基丙基-氧基琥珀酰基氧基)乙基]-三甲基铵,oligofectamine,或阳离子或聚阳离子聚合物,例如,修饰的聚氨基酸,诸如β-氨基酸-聚合物或反向聚酰胺(reversed polyamides)等,改性的聚乙烯,诸如PVP(聚(N-乙基-4-乙烯基吡啶溴化物))等,改性的丙烯酸酯,诸如pDMAEMA(聚(二甲基氨基乙基丙烯酸甲酯))等,改性的氨基胺(Amidoamines),诸如pAMAM(聚(氨基胺))等,改性的聚β氨基酯(PBAE),诸如二胺末端修饰的1,4丁二醇双丙烯酸酯-共-5-氨基-1-戊醇聚合物等,树枝状聚合物(dendrimers),诸如聚丙胺树枝状聚合物或基于pAMAM的树枝状聚合物等,聚亚胺,诸如PEI:聚(乙烯亚胺),聚(丙烯亚胺)等,聚烯丙基胺,基于糖骨架的聚合物,诸如基于环糊精的聚合物,基于葡聚糖的聚合物,壳聚糖等,基于甲硅烷骨架的聚合物,诸如PMOXA-PDMS共聚物等,由一个或多个阳离子嵌段(例如选自上文提及的阳离子聚合物)的组合和一个或多个亲水或疏水嵌段(例如,聚乙二醇)的组合组成的嵌段聚合物等。
在这一情形中,特别优选的是本发明的核酸至少部分与阳离子或聚阳离子化合物、优选阳离子蛋白或肽复合。部分意指只有一部分本发明的核酸与阳离子或聚阳离子化合物复合,并且其余的本发明的核酸是未复合的形式(“游离的”)。优选地,复合的核酸:游离的核酸的比率选自约5∶1(w/w)至约1∶10(w/w)的范围,更优选约4∶1(w/w)至约1∶8(w/w)的范围,甚至更优选约3∶1(w/w)至约1∶5(w/w)或1∶3(w/w)的范围,最优选复合的核酸:游离的核酸的比率选自约1∶1(w/w)的比率。
优选地,本发明的核酸序列以裸露形式或复合形式提供,所述复合形式例如通过不论何种化学结构的聚阳离子化合物、优选聚阳离子(多)肽或合成的聚阳离子化合物复合。优选地,所述核酸序列不与包装细胞一起提供。
在另一个方面,本发明提供组合物或试剂盒或部件的试剂盒,其包含多种或多于一个,优选2-10个,更优选2-5个,最优选2-4个本文定义的本发明的核酸序列。这些本发明的组合物包含多于一种本发明的核酸序列,优选地编码不同的肽或蛋白,所述肽或蛋白优选地包含不同的治疗性蛋白或其片段、变体或衍生物。
按照另一个方面,本发明还提供用于增加所编码的肽或蛋白的表达的方法,所述方法包括下述步骤:例如,a)提供本文定义的本发明的核酸序列或包含多个(意指典型地多于1、2、3、4、5、6或多于10个核酸,例如,2-10个,优选2-5个核酸)本文定义的本发明的核酸序列的本发明的组合物,b)将本文定义的本发明的核酸序列或包含多种本文定义的本发明的核酸序列的本发明的组合物用于或施用于表达系统,例如,不含细胞的表达系统、细胞(例如,表达宿主细胞或体细胞)、组织或生物体。所述方法可以用于实验室、用于研究、用于诊断、用于肽或蛋白的商业生产和/或用于治疗目的。在这一情形中,典型地在制备本文定义的本发明的核酸序列或包含多种本文定义的本发明的核酸序列的本发明的组合物后,典型地以例如裸露或复合形式或作为本文所述的药物组合物,优选通过转染或通过使用本文所述的任一种施用模式应用于或施用于不含细胞的表达系统、细胞(例如,表达宿主细胞或体细胞)、组织或生物体。所述方法可以在体外、体内或离体进行。所述方法可以进一步在治疗特定疾病(优选如本文所定义)的情形中进行。
在这一情形中,体外在本文中定义为将本文定义的本发明的核酸或包含多种本文定义的本发明的核酸序列的本发明的组合物转染或转导到在生物体外的培养物中的细胞中;体内在本文中定义为通过将本发明的核酸或本发明的组合物应用到完整生物体或个体上而将本发明的核酸或包含多个(意指典型地多于1、2、3、4、5、6或多于10个核酸,例如,2-10个,优选2-5个核酸)本发明的核酸序列的本发明的组合物转染或转导到细胞中,离体在本文中定义为将本发明的核酸或包含多种本发明的核酸序列的本发明的组合物转染或转导到生物体或个体之外的细胞中并且随后将所转染的细胞应用到所述生物体或个体。
同样地,按照另一个方面,本发明还提供本文定义的本发明的核酸序列或包含多种本文定义的本发明的核酸序列的本发明的组合物用于增加所编码的肽或蛋白的表达(特别是在基因治疗中)的应用,优选用于诊断或治疗目的的应用,例如,通过将本文定义的本发明的核酸序列或包含多种本文定义的本发明的核酸序列的本发明的组合物应用或施用到例如不含细胞的表达系统、细胞(例如,表达宿主细胞或体细胞)、组织或生物体中。所述应用可以用于实验室、用于研究、用于诊断、用于肽或蛋白的商业生产和/或用于治疗目的,优选用于基因治疗。在这一情形中,典型地在制备本文定义的本发明的核酸序列或包含多种本文定义的本发明的核酸序列的本发明的组合物之后,典型地,优选以裸露形式或复合形式或作为本文所述的药物组合物,优选通过转染或通过使用本文所述的任一种施用模式应用于或施用于不含细胞的表达系统、细胞(例如,表达宿主细胞或体细胞)、组织或生物体。所述应用可以在体外、体内或离体进行。所述应用可以进一步在治疗特定疾病(优选如本文所定义)的情形中进行。
在另一个方面,本发明还涉及本发明的表达系统,所述表达系统包含本发明第一方面所述的本发明的核酸序列或表达载体或质粒。在这一情形中,所述表达系统可以是不含细胞的表达系统(例如,体外转录/翻译系统)、细胞表达系统(例如,哺乳动物细胞,如CHO细胞,昆虫细胞,酵母细胞,细菌细胞,如大肠杆菌(E.coli))或用于表达肽或蛋白的生物体(例如植物或动物,如母牛)。
另外,按照另一个方面,本发明还涉及本文定义的本发明的核酸或包含多种本文定义的本发明的核酸序列的本发明的组合物用于制备增加编码的肽或蛋白的表达(特别是用于基因治疗,例如,用于治疗优选如本文定义的疾病)的药物组合物的应用,例如,将本文定义的本发明的核酸或包含多种本文定义的本发明的核酸序列的本发明的组合物应用于或施用于细胞(例如,表达宿主细胞或体细胞)、组织或生物体,优选以裸露形式或复合形式或作为本文所述的药物组合物应用或施用,更优选使用本文所述的任一种施用模式应用或施用。
因此,在一个特别优选的方面,本发明还提供药物组合物,其包含本文定义的本发明的核酸或包含多种本文定义的本发明的核酸序列的本发明的组合物以及任选地药用载体和/或赋形剂(vehicle)。
本发明的药物组合物包含至少一种本文定义的本发明的核酸作为第一成分。
本发明的药物组合物可以任选地包含至少一种另外的药物活性组分作为第二成分。在这种联系下,药物活性组分是具有治愈、减轻或预防本文提及的特定的适应证或疾病的治疗作用的化合物。所述化合物包括,不暗示任何限制,肽或蛋白,优选如本文定义,核酸,优选如本文定义,(治疗活性的)低分子量有机或无机化合物(分子量小于5000,优选小于1000),糖,抗原或抗体,优选如本文定义,现有技术已知的治疗剂,抗原性细胞,抗原性细胞片段,细胞级分;细胞壁成分(例如,多糖),修饰的、减毒的或去活性的(例如,化学去活性或通过辐照)病原体(病毒、细菌等),佐剂,优选如本文定义,等等。
此外,本发明的药物组合物可以包含药用载体和/或赋形剂。在本发明的情形中,药用载体典型地包括本发明的药物组合物的液体或非液体基础。如果本发明的药物组合物以液体形式提供,则所述载体典型地是不含致热原的水;等渗的盐水或缓冲的(水性)溶液,例如,磷酸、柠檬酸等缓冲的溶液。参考特定的参比介质,注射缓冲液可以是高渗的、等渗的或低渗的,即,参考特定的参比介质,缓冲液可以具有更高、相等的或更低的盐含量,其中,优选可以使用前述盐的所述浓度,其不引起由于渗透性或其他浓度作用导致的细胞损害。参比介质是,例如,在“体内”方法中存在的液体,诸如血液、淋巴、细胞质液体,或其他体液,或例如可以在“体外”方法中用作参比介质的液体,诸如常规的缓冲液或液体。所述常规的缓冲液或液体是技术人员已知的。Ringer-乳酸盐溶液是特别优选的液体基础。
然而,一种或多种相容的固体或液体填充剂或稀释剂或包封化合物也可以用于本发明的药物组合物,其适于施用给待治疗的患者。术语“相容的”用在本文中意指本发明的药物组合物的这些组成成分能够与本文定义的本发明的核酸以这样的方式混合,所述方式是指不发生将基本上减少本发明的药物组合物在典型应用条件下的药物有效性的相互作用。
按照一个具体的实施方案,本发明的药物组合物可以包含佐剂。在该情形中,佐剂可以理解为适于起始或增加先天性免疫系统的免疫应答(即,非特异性免疫应答)的任意化合物。换言之,当施用时,本发明的药物组合物优选地引发由任选地包含在其中的佐剂引起的先天性免疫应答。优选地,所述佐剂可以选自技术人员已知并且适于本情形的的任一种佐剂,即,支持在哺乳动物中诱导先天性免疫应答,例如,上文定义的佐剂蛋白或下文定义的佐剂。
对于本发明的核酸序列,适于储存和递送的特别优选的佐剂是上文定义的阳离子或聚阳离子化合物作为赋形剂、转染剂或复合剂。
可以包含在本发明的药物组合物中的其他添加剂是乳化剂,诸如例如,;湿润剂,诸如例如,十二烷基硫酸钠;着色剂;赋味剂,药用载体;片剂形成剂;稳定剂;抗氧化剂;防腐剂。
本发明的药物组合物还可以另外包含任一种其他化合物,所述化合物已知由于其与人Toll样受体TLR1,TLR2,TLR3,TLR4,TLR5,TLR6,TLR7,TLR8,TLR9,TLR10的结合亲和性(作为配体),或由于其与鼠Toll样受体TLR1,TLR2,TLR3,TLR4,TLR5,TLR6,TLR7,TLR8,TLR9,TLR10,TLRI1,TLR12或TLR13的结合亲和性(作为配体)而具有免疫刺激性。
本发明的药物组合物可以口服、肠胃外、通过吸入喷雾、局部、直肠、鼻腔、口腔、阴道或经由植入型储库(implanted reservoir)施用。术语肠胃外用于本文中时包括皮下、静脉内、肌内、关节内、滑膜内、胸骨内、鞘内、肝内、病灶内、颅内、经皮、皮内、肺内、腹膜内、心内、动脉内和舌下注射或输注技术。
优选地,本发明的药物组合物可以通过肠胃外注射,更优选通过皮下、静脉内、肌内、关节内、滑膜内、胸骨内、鞘内、肝内、病灶内、颅内、经皮、皮内、肺内、腹膜内、心内、动脉内和舌下注射或经由输注技术施用。特别优选的是皮内和肌内注射。本发明的药物组合物的无菌可注射形式可以是水性或油质混悬液。这些混悬液可以根据本领域中已知的技术,使用适合的分散剂或湿润剂和悬浮剂来配制。
本文定义的本发明的药物组合物还可以以任何口服可接受的剂型,包括但不限于,胶囊剂、片剂、水性混悬液或溶液口服施用。
本发明的药物组合物还可以局部施用,特别是当治疗靶标包括容易通过局部施用接近的区域或器官,例如包括皮肤或任何其他可接近的上皮组织的疾病时。合适的局部制剂对于这些区域或器官的每一个容易地制备。为了局部施用,本发明的药物组合物可以以合适的膏剂来配制,所述膏剂包含悬浮或溶解在一种或多种载体中的本文定义的本发明的核酸。
本发明的药物组合物典型地包含“安全且有效量”的本发明的药物组合物的组分,特别是本文定义的本发明的核酸序列。用于本文中时,“安全且有效量”意指足以显著诱导如本文中定义的疾病或病症的正向改善的本文定义的本发明的核酸序列的量。然而,同时,“安全且有效量”足够小到避免严重的副作用,并且允许合理的优势和风险之间的关系。这些限制的确定典型地属于合理的医学判断范围之内。
本发明还提供本文定义的本发明的核酸序列、包含多种本文定义的本发明的核酸序列的本发明的组合物、包含本文定义的本发明的核酸序列的本发明的药物组合物或包含其的试剂盒的一些应用和用途。
按照一个具体的方面,本发明涉及本文定义的本发明的核酸序列或包含多种本文定义的本发明的核酸序列的本发明的组合物作为药物、用于包括基因治疗、优选用于治疗本文定义的疾病的第一医学用途。
按照另一个方面,本发明涉及本文定义的本发明的核酸序列或包含多种本文定义的本发明的核酸序列的本发明的组合物用于治疗本文定义的疾病的第二医学用途,优选涉及本文定义的本发明的核酸序列、包含多种本文定义的本发明的核酸序列的本发明的组合物、包含其的药物组合物、或包含其的试剂盒在制备用于预防、治疗和/或减轻本文定义的疾病的药物中的用途。优选地,所述药物组合物用于施用给有此需要的患者而用于这一目的。
优选地,本文提及的疾病优选地选自传染病、肿瘤(例如,癌症或肿瘤疾病)、血液或血液形成器官的疾病、内分泌、营养和代谢病、神经系统的疾病、循环系统的疾病、呼吸系统的疾病、消化系统的疾病、皮肤和皮下组织的疾病、肌肉骨骼系统和结缔组织的疾病和生殖泌尿系统的疾病。
在这一情形中,特别优选的是选自下述的遗传病:lp36缺失综合征(1p36deletion syndrome);18p缺失综合征;21-羟化酶缺乏;45,X(特纳综合征(Turnersyndrome));47,XX,+21(唐氏综合征(Down syndrome));47,XXX(三X染色体综合征(tripleX syndrome));47,XXY(克兰费尔特综合征(Klinefelter syndrome));47,XY,+21(唐氏综合征);47,XYY综合征;5-ALA脱水酶缺乏卟啉病(5-ALA dehydratase-deficientporphyria)(ALA脱水酶不足);5-氨基酮戊酸脱水酶缺乏卟啉病(5-aminolaevulinicdehydratase deficiency porphyria)(ALA脱水酶缺乏);5p缺失综合征(猫叫样哭泣(Cridu chat))5p-综合征(猫叫样哭泣);A-T(运动失调性毛细血管扩张症(ataxia-telangiectasia));AAT(α-1抗胰蛋白酶缺乏(alpha-1antitrypsin deficiency));输精管缺如(Absence of vas deferens)(先天性双侧输精管缺如(congenital bilateralabsence ofvas deferens));输精管缺如(Absent vasa)(先天性双侧输精管缺如);铜蓝蛋白缺乏症(aceruloplasminemia);ACG2(II型软骨成长不全(achondrogenesis type II));ACH(软骨发育不全(achondroplasia));II型软骨成长不全;软骨发育不全;酸性β-葡萄糖苷酶缺乏(Acid beta-glucosidase deficiency)(1型戈谢病(Gaucher disease type1));尖头并指(趾)(Acrocephalosyndactyly,Apert)(Apert综合征);V型尖头并指(趾)(acrocephalosyndactyly,type V)(斐弗综合征(Pfeiffer syndrome));尖头(Acrocephaly)(Apert综合征);急性脑型戈谢病(Acute cerebral Gaucher′s disease)(2型戈谢病(Gaucher disease type 2));急性间歇性卟啉病(acute intermittentporphyria);ACY2缺乏(卡纳万病(Canavan disease));AD(阿尔茨海默病(Alzheimer′sdisease));Adelaide型颅缝早闭(Adelaide-type craniosynostosis)(Muenke 综合征);腺瘤性结肠息肉病(Adenomatous Polyposis Coli)(家族性腺瘤性息肉病(familialadenomatous polyposis));结肠腺瘤性息肉病(Adenomatous Polyposis of the Colon)(家族性腺瘤性息肉病);ADP(ALA脱水酶缺乏);腺苷酸琥珀酸裂解酶缺乏(adenylosuccinate lyase deficiency);肾上腺病症(Adrenal gland disorders)(21-羟化酶缺乏症);肾上腺生殖综合征(Adrenogenital syndrome)(21-羟化酶缺乏症);肾上腺脑白质营养不良(Adrenoleukodystrophy);AIP(急性间歇性卟啉病(acute intermittentporphyria));AIS(雄激素不敏感综合征(androgen insensitivity syndrome));AKU(尿黑酸尿(alkaptonuria));ALA脱水酶卟啉症(ALA脱水酶缺乏);ALA-D卟啉症(ALA-Dporphyria)(ALA脱水酶缺乏);ALA脱水酶缺乏;尿黑酸症(Alcaptonuria)(尿黑酸尿);亚历山大病(Alexander disease);尿黑酸尿;尿黑酸黄褐病(Alkaptonuric ochronosis)(尿黑酸尿);α-1抗胰蛋白酶缺乏;α-1蛋白酶抑制剂(α-1抗胰蛋白酶缺乏);α-1相关的气肿(alpha-1 related emphysema)(α-1抗胰蛋白酶缺乏);α-半乳糖苷酶A缺乏(法布里病(Fabry disease));ALS(肌萎缩侧索硬化(amyotrophic lateral sclerosis));阿尔斯特伦综合征(Alstrom syndrome);ALX(亚历山大病);阿尔茨海默病;釉质形成不全(Amelogenesis Imperfecta);氨基乙酰丙酸脱水酶缺乏(Amino levulinic aciddehydratase deficiency)(ALA脱水酶缺乏);酰化氨基酸水解酶2缺乏(卡纳万病(Canavandisease));肌萎缩侧索硬化;安德森-法布里病(Anderson-Fabry disease)(法布里病);雄激素不敏感综合征;贫血(Anemia);遗传性成高铁红细胞贫血(Anemia,hereditarysideroblastic)(X-连锁的成高铁红细胞贫血(X-linked sideroblastic anemia));性别连锁的低色性成高铁红细胞贫血(Anemia,sex-linked hypochromic sideroblastic)(X-连锁的成高铁红细胞贫血);家族性脾脏贫血(Anemia,splenic,familial)(戈谢病);安吉尔曼综合征(Angelman syndrome);弥漫性躯体性血管角化瘤(Angiokeratoma CorporisDiffusum)(法布里病);弥散性血管角质瘤(Angiokeratoma diffuse)(法布里病);视网膜血管瘤病(Angiomatosis retinae)(脑视网膜血管瘤病(von Hippel-Lindau disease));ANHl(X-连锁的成高铁红细胞贫血);Leiden型APC抗性(因子V莱顿血栓形成倾向(factor VLeiden thrombophilia));阿佩尔综合征(Apert syndrome);AR缺乏(雄激素不敏感综合征);AR-CMT2 ee(2型进行性神经性腓骨肌萎缩症(Charcot-Mare-Tooth disease,type2));蜘蛛脚样指(Arachnodactyly)(马方综合征(Marfan syndrome));ARNSHL(非症候性耳聋#常染色体隐性(Nonsyndromic deafness#autosomal recessive));遗传性进行性关节-眼病(Arthro-ophthalmopathy,hereditary progressive)(斯蒂克勒综合征#COL2A1(Stickler syndrome#COL2A1));先天性多发性关节松弛(Arthrochalasis multiplexcongenita)(埃勒斯-当洛综合征#关节松弛型(Ehlers-Danlos syndrome#arthrochalasiatype));AS(安吉尔曼综合征);Asp缺乏(卡纳万病);Aspa缺乏(卡纳万病);天冬氨酸酰酶缺乏(卡纳万病);运动失调性毛细血管扩张症(ataxia-telangiectasia);孤独症-痴呆症-共济失调-有目的的手使用损失综合征(Autism-Dementia-Ataxia-Loss of PurposefulHand Use syndrome)(雷特综合征(Rett syndrome));常染色体显性青少年ALS(autosomaldominant juvenile ALS)(4型肌萎缩侧索硬化(amyotrophic lateral sclerosis,type4));常染色体显性opitz G/BBB综合征(22q11.2缺失综合征);常染色体隐性形式的3型青少年ALS(autosomal recessive form of juvenile ALS type 3)(肌萎缩侧索硬化#2型);常染色体隐性非症候性听力丧失(Autosomal recessive nonsyndromic hearing loss)(非症候性耳聋#常染色体隐性(Nonsyndromic deafness#autosomal recessive);常染色体隐形感觉神经性听力受损和甲状腺肿(Autosomal Recessive Sensorineural HearingImpairment and Goiter)(彭德莱综合征(Pendred syndrome));AxD(亚历山大病);阿耶萨综合征(Ayerza syndrome)(原发性肺动脉高压(primary pulmonary hypertension));己糖胺酶GM2神经节苷脂贮积症B变型(B variant of the Hexosaminidase GM2gangliosidosis)(桑德霍夫病(Sandhoff disease));BANF(神经纤维瘤病(neurofibromatosis 2));Beare-Stevenson cutis gyrata综合征(Beare-Stevensoncutis gyrata syndrome);良性阵发性腹膜炎(Benign paroxysmal peritonitis)(家族性地中海热(Mediterranean fever,familial));体质性贫血综合征(Benjamin syndrome);β地中海贫血(beta thalassemia);BH4缺乏(四氢生物喋呤缺乏(tetrahydrobiopterindeficiency));双侧听神经纤维瘤病(Bilateral Acoustic Neurofibromatosis)(神经纤维瘤病2);生物素酶缺乏(biotinidase deficiency);膀胱癌(bladder cancer);出血障碍(Bleeding disorders)(因子V莱顿血栓形成倾向);布洛克-苏兹贝格综合征(Bloch-Sulzberger syndrome)(色素失调症(incontinentia pigmenti));布卢姆综合征(Bloomsyndrome);骨骼疾病(Bone diseases);骨髓疾病(Bone marrow diseases)(X-连锁的成高铁红细胞贫血);Bonnevie-Ullrich综合征(Bonnevie-Ullrich syndrome)(特纳综合征);布尔尼维利病(Bourneville disease)(结节性硬化症(tuberous sclerosis));Bourneville斑痣性错构瘤病(Bourneville phakomatosis)(结节性硬化症);脑病(朊病毒病(prion disease));乳腺癌;Birt-Hogg-Dubé综合征;脆骨病(Brittle bone disease)(成骨不全(osteogenesis imperfecta));宽指综合征(Broad Thumb-Hallux syndrome)(鲁宾斯坦-泰比综合征(Rubinstein-Taybi syndrome));青铜色糖尿病(BronzeDiabetes)(血色素沉着病(hemochromatosis));青铜色肝硬变(Bronzed cirrhosis)(血色素沉着病);X-连锁的延髓肌萎缩(Bulbospinal muscular atrophy,X-linked)(肯尼迪病(Kennedy disease));Burger-Grutz综合征(家族性脂蛋白脂肪酶缺乏(lipoproteinlipase deficiency,familial));CADASIL;CGD慢性肉芽肿病症(CGD ChronicGranulomatous Disorder);屈肢骨发育不全(Camptomelic dysplasia);卡纳万病;癌症;家族性癌症综合征(Cancer Family syndrome)(遗传性非息肉性结直肠癌(hereditarynonpolyposis colorectal Cancer);乳癌(Cancer of breast)(乳腺癌);膀胱癌症(Cancer of the bladder)(膀胱癌);羧化酶缺乏(Carboxylase Deficiency),多发性晚期发作(Multiple,Late-Onset)(生物素酶缺乏(biotinidase deficiency));心肌症(Cardiomyopathy)(努南综合征(Noonan syndrome));猫叫综合征(Cat cry syndrome)(猫叫样哭泣);CAVD(先天性双侧输精管缺如(congenital bilateral absence of vasdeferens));Caylor心面综合征(Caylor cardiofacial syndrome)(22q11.2缺失综合征);CBAVD(先天性双侧输精管缺如);乳糜泻(Celiac Disease);CEP(先天性红细胞生成性卟啉病(congenital erythropoietic porphyria));神经酰胺三己糖酶缺乏(Ceramidetrihexosidase deficiency)(法布里病);家族性小脑视网膜血管瘤(CerebelloretinalAngiomatosis,familial)(脑视网膜血管瘤病(von Hippel-Lindau disease));具有皮质下梗死和脑白质的大脑动脉病(Cerebral arteriopathy with subcortical infarctsand leukoencephalopathy,CADASIL);具有皮质下梗死和脑白质的大脑常染色体显性动脉病(Cerebral autosomal dominant ateriopathy with subcortical infarcts andleukoencephalopathy,CADASIL);脑硬化症(Cerebral sclerosis)(结节性硬化症);脑萎缩性血氨过高(Cerebroatrophic Hyperammonemia)(雷特综合征);脑苷脂沉积综合征(Cerebroside Lipidosis syndrome)(戈谢病);CF(囊性纤维化(cystic fibrosis));CH(先天性甲状腺功能减退症(congenital hypothyroidism));沙尔科病(Charcot disease)(肌萎缩侧索硬化);进行性神经性腓骨肌萎缩症(Charcot-Marie-Tooth disease);软骨营养不良(Chondrodystrophia)(软骨发育不全);软骨营养不良综合征(Chondrodystrophysyndrome)(软骨发育不全);伴有感觉神经性耳聋的软骨营养不良(Chondrodystrophywith sensorineural deafness)(otospondylomegaepiphyseal dysplasia);软骨发育不全(Chondrogenesis imperfecta)(II型软骨成长不全(achondrogenesis,type II));舞蹈徐动症-自残-高尿酸血综合征(Choreoatheto sis self-mutilation hyperuricemiasyndrome)(莱施-奈恩综合征(Lesch-Nyhan syndrome));经典型半乳糖血症(ClassicGalactosemia)(半乳糖血症(galactosemia));经典型埃勒斯-当洛综合征(ClassicalEhlers-Danlos syndrome)(埃勒斯-当洛综合征#经典型(Ehlers-Danlos syndrome#classical type));经典型酮尿症(Classical Phenylketonuria)(酮尿症(phenylketonuria));唇腭裂(Cleft lip and palate)(斯蒂克勒综合征(Sticklersyndrome));伴有致死性侏儒症的分叶状颅(Cloverleaf skull with thanatophoricdwarfism)(致死性发育不全#2型(Thanatophoric dysplasia#type 2));CL S(科-洛综合征(Coffin-Lowry syndrome));CMT(进行性神经性腓骨肌萎缩症(Charcot-Marie-Toothdisease));科凯恩综合征(Cockayne syndrome);科-洛综合征;II型和XI型胶原病(collagenopathy,types II and XI);家族性非息肉性结肠癌(Colon Cancer,familialNonpolyposis)(遗传性非息肉性结直肠癌(hereditary nonpolyposis Colorectalcancer));家族性结肠癌(Colon cancer,familial)(家族性腺瘤性息肉病(familialadenomatous polyposis));结直肠癌;完全HPRT缺乏(Complete HPRT deficiency)(莱施-奈恩综合征(Lesch-Nyhan syndrome));完全的次黄嘌呤鸟嘌呤磷酸核糖转移酶缺乏症(Complete hypoxanthine-guanine phosphoribosy transferase deficiency)(莱施-奈恩综合征);压迫性神经障碍(Compression neuropathy)(伴有易患压迫性麻痹的遗传性神经病变(hereditary neuropathy with liability to pressure palsies));先天性肾上腺增生(Congenital adrenal hyperplasia)(21-羟化酶缺乏);先天性双侧输精管缺如(先天性输精管缺如(Congenital absence of the vas deferens));先天性红细胞生成性卟啉病(Congenital erythropoietic porphyria);先天性心脏病(Congenital heartdisease);先天性低髓鞘形成(Congenital hypomyelination)(进行性神经性腓骨肌萎缩症#1型/进行性神经性腓骨肌萎缩症#4型);先天性甲状腺功能减退症;先天性高铁血红蛋白血症(Congenital methemoglobinemia)(高铁血红蛋白血症(Methemoglobinemia)#先天性高铁血红蛋白血症(Congenital methaemoglobinaemia));先天性骨硬化病(Congenitalosteosclerosis)(软骨发育不全);先天性成高铁红细胞贫血(Congenital sideroblasticanaemia)(X-连锁的成高铁红细胞贫血);结缔组织病(Connective tissue disease);先天性异常面容综合征(Conotruncal anomaly face syndrome)(22q11.2缺失综合征);库利贫血(Cooley′s Anemia)(β地中海贫血);铜贮积症(Copper storage disease)(威尔逊病(Wilson disease));铜转运疾病(Copper transport disease)(门克斯病(Menkesdisease));遗传性粪卟啉症(Coproporphyria,hereditary)(hereditarycoproporphyria);粪卟啉原氧化酶缺乏症(Coproporphyrinogen oxidase deficiency)(遗传性粪卟啉症);考登综合征(Cowden syndrome);CPO缺乏症(遗传性粪卟啉症);CPRO缺乏症(遗传性粪卟啉症);CPX缺乏症(遗传性粪卟啉症);颅面关节变形(Craniofacialdysarthrosis)(克鲁宗综合征(Crouzon syndrome));颅面骨骨发育不良(CraniofacialDysostosis)(克鲁宗综合征);呆小病(Cretinism)(先天性甲状腺功能减退症);克-雅病(Creutzfeldt-Jakob disease)(朊病毒病(prion disease));猫叫样哭泣(克罗恩病,fibrostenosing);克鲁宗综合征;伴有黑棘皮症的克鲁宗综合征(Crouzon syndrome withacanthosis nigricans)(Crouzonodermoskeletal综合征);Crouzonodermoskeletal综合征;CS(科凯恩综合征(Cockayne syndrome))(考登综合征);库-巴-斯综合征(Curschmann-Batten-Steinert syndrome)(营养不良性肌强直(myotonic dystrophy));Beare-Stevenson cuffs gyrata综合征(cuffs gyrata syndrome of Beare-Stevenson)(Beare-Stevenson cuffs gyrata syndrome);突变染色体紊乱(Disorder MutationChromosome);D-甘油酸脱氢酶缺乏症(D-glycerate dehydrogenase deficiency)(原发性高草酸尿(hyperoxaluria,primary));斑驳的干骺端综合征(Dappled metaphysissyndrome)(Strudwick型脊椎干骺端发育不全(spondyloepimetaphyseal dysplasia,Strudwick type));阿尔茨海默型DAT-痴呆症(DAT-Dementia Alzheimer′s type)(阿尔茨海默病);遗传性高钙尿症(Genetic hypercalciuria)(登特病(Dent′s disease));DBMD(迪谢内和贝克尔型肌营养不良症(muscular dystrophy,Duchenne and Becker types));伴有甲状腺肿的耳聋(Deafness with goiter)(彭德莱综合征(Pendred syndrome));耳聋-色素性视网膜炎综合征(Deafness-retinitis pigmentosa syndrome)(厄舍尔综合征(Usher syndrome));苯丙氨酸羟化酶缺乏病(Deficiency disease,PhenylalanineHydroxylase)(苯丙酮尿(phenylketonuria));神经变性疾病(Degenerative nervediseases);德格罗契综合征1(de Grouchy syndrome 1)(德格罗契综合征(De GrouchySyndrome));德热里纳-索塔斯综合征(Dejerine-Sottas syndrome)(进行性神经性腓骨肌萎缩症);δ-氨基乙酰丙酸脱水酶缺乏性卟啉症(Delta-aminolevulinate dehydratasedeficiency porphyria)(ALA脱水酶缺乏);痴呆(Dementia)(CADASIL);脱髓鞘发生性脑白质营养不良(demyelinogenic leukodystrophy)(亚历山大病);皮肤脆裂型埃勒斯-当洛综合征(Dermatosparactic type of Ehlers-Danlos syndrome)(埃勒斯-当洛综合征#皮肤脆裂型(dermatosparaxis type));皮肤脆裂(Dermatosparaxis)(埃勒斯-当洛综合征#皮肤脆裂型);发育障碍(developmental disabilities);dHMN(肌萎缩侧索硬化#4型);DHM-V(V型远端脊髓性肌萎缩(distal spinal muscular atrophy,type V));DHTR缺乏(雄激素不敏感综合征);弥漫性球体硬化(Diffuse Globoid Body Sclerosis)(克拉伯病(Krabbedisease));DiGeorge综合征(DiGeorge syndrome);双氢睾酮受体缺乏(Dihydrotestosterone receptor deficiency)(雄激素不敏感综合征);V型远端脊髓性肌萎缩;DMl((营养不良性肌强直Myotonic dystrophy)#1型);DM2(营养不良性肌强直#2型);唐氏综合征;DSMAV(V型远端脊髓性肌萎缩);DSN(进行性神经性腓骨肌萎缩症#4型);DSS(进行性神经性腓骨肌萎缩症,4型);迪谢内/贝克尔肌营养不良症(Duchenne/Beckermuscular dystrophy)(迪谢内和贝克尔型肌营养不良症(muscular dystrophy,Duchenneand Becker types));软骨发育不全性侏儒症(Dwarf,achondroplastic)(软骨发育不全);致死性侏儒症(Dwarf,thanatophoric)(致死性发育不全(thanatophoric dysplasia));侏儒症(Dwarfism);侏儒症-视网膜萎缩-耳聋综合征(Dwarfism-retinal atrophy-deafnesssyndrome)(科凯恩综合征);脱髓鞘发生性脑白质营养不良(dysmyelinogenicleukodystrophy)(亚历山大病);营养不良性肌强直(Dystrophia myotonica)(myotonicdystrophy);视网膜色素营养不良-成骨不全综合征(dystrophia retinae pigmentosa-dysostosis syndrome)(厄舍尔综合征);早发型家族性阿尔茨海默病(Early-Onsetfamilial alzheimer disease,EOFAD)(阿尔茨海默病);EDS(埃勒斯-当洛综合征);埃勒斯-当洛综合征;艾克曼-洛布斯坦病(Ekman-Lobstein disease)(成骨不全(osteogenesisimperfecta));压迫性神经障碍(Entrapment neuropathy)(伴有易患压迫性麻痹的遗传性神经病变);结节性脑硬化(Epiloia)(结节性硬化症(tuberous sclerosis));EPP(红细胞生成性原卟啉病(erythropoietic protoporphyria));成红细胞性贫血(Erythroblasticanemia)(β地中海贫血);红细胞生成性原卟啉症(Erythrohepatic protoporphyria)(红细胞生成性原卟啉病(erythropoietic protoporphyria));红细胞5-氨基酮戊酸合成酶缺乏症(Erythroid5-aminolevulinate synthetase deficiency)(X-连锁的成高铁红细胞贫血);红细胞生成性卟啉病(Erythropoietic porphyria)(先天性红细胞生成性卟啉病(congenital erythropoietic porphyria));红细胞生成性原卟啉病(Erythropoieticprotoporphyria);红细胞生成性尿卟啉症(Erythropoietic uroporphyria)(先天性红细胞生成性卟啉病);眼癌(Eye cancer)(视网膜母细胞瘤FA-弗里德赖希共济失调(retinoblastoma FA-Friedreich ataxia));法布里病;面部损伤和疾病(Facialinjuries and disorders);因子V莱顿血栓形成(Factor V Leiden thrombophilia);FALS(肌萎缩侧索硬化);家族性听神经瘤(familial acoustic neuroma)(II型神经纤维瘤病(neurofibromatosis type II));家族性腺瘤性息肉病(familial adenomatouspolyposis);家族性阿尔茨海默病(familial Alzheimer disease,FAD)(阿尔茨海默病);家族性肌萎缩侧索硬化(familial amyotrophic lateral sclerosis)(肌萎缩侧索硬化);家族性自主神经异常(familial dysautonomia);家族性脂诱导的高甘油三酯血症(familial fat-induced hypertriglyceridemia)(家族性脂蛋白脂肪酶缺乏(lipoprotein lipase deficiency,familial));家族性血色病(familialhemochromatosis)(血色素沉着病);家族性LPL缺乏(familial LPL deficiency)(家族性脂蛋白脂肪酶缺乏);家族性非息肉性结肠癌(familial nonpolyposis colon cancer)(遗传性非息肉性结直肠癌(hereditary nonpolyposis colorectal cancer));家族性发作性多浆膜炎(familial paroxysmal polyserositis)(家族性地中海热(Mediterraneanfever,familial));家族性PCT(迟发性皮肤卟啉病(porphyria cutanea tarda));家族性压力敏感的神经病变(familial pressure sensitive neuropathy)(伴有易患压迫性麻痹的遗传性神经病变);家族性原发性肺动脉高压(familial primary pulmonaryhypertension,FPPH)(原发性肺动脉高压(primary pulmonary hypertension));家族性特纳综合征(Familial Turner syndrome)(努南综合征);家族性血管脑白质病(familialvascular leukoencephalopathy,CADASIL);FAP(家族性腺瘤性息肉病(familialadenomatous polyposis));FD(家族性自主神经功能异常(familial dysautonomia));女性假特纳综合征(Female pseudo-Turner syndrome)(努南综合征);亚铁螫合酶缺乏症(Ferrochelatase deficiency)(红细胞生成性原卟啉病);膜铁转运蛋白(ferroportindisease)(血色素沉着#4型);发烧(Fever)(家族性地中海热(Mediterranean fever,familial));FG综合征;FGFR3-相关的冠状缝早闭(FGFR3-associated coronalsynostosis)(Muenke综合征);星形胶质细胞的纤维蛋白样变性(Fibrinoid degenerationof astrocytes)(亚历山大病);胰腺纤维囊性病(Fibrocystic disease of thepancreas)(囊性纤维化);FMF(家族性地中海热);苯丙酮尿症(Folling disease)(苯丙酮尿(phenylketonuria));fra(X)综合征(脆性X染色体综合征(fragile X syndrome));脆性X染色体综合征;脆骨症(Fragilitas ossium)(成骨不全);FRAXA综合征(脆性X染色体综合征);FRDA(弗里德赖希共济失调症);弗里德赖希共济失调(Friedreich ataxia)(Friedreich′s ataxia);弗里德赖希共济失调(Friedreich′s ataxia);FXS(脆性X染色体综合征);G6PD缺乏症;半乳糖激酶缺乏症(Galactokinase deficiency disease)(半乳糖血症(galactosemia));半乳糖-1-磷酸尿苷转移酶缺乏病(Galactose-1-phosphateuridyl-transferase deficiency disease)(半乳糖血症);半乳糖血症;半乳糖神经酰胺酶缺乏病(Galactosylceramidase deficiency disease)(克拉伯病(Krabbe disease));半乳糖酰基鞘氨醇脂沉积症(Galactosylceramide lipidosis)(克拉伯病);半乳糖基脑苷酶缺乏病(galactosylcerebrosidase deficiency)(克拉伯病);半乳糖鞘氨醇脂肪沉积(galactosylsphingosine lipidosis)(克拉伯病);GALC缺乏症(克拉伯病);GALT缺乏症(半乳糖血症);戈谢病;戈谢样病(Gaucher-like disease)(假-戈谢病(pseudo-Gaucherdisease));GBA缺乏症(1型戈谢病(Gaucher disease type 1));GD(戈谢病);遗传性脑部疾病(Genetic brain disorders);遗传性肺气肿(genetic emphysema)(α-1抗胰蛋白酶缺乏);遗传性血色素沉积症(genetic hemochromatosis)(血色素沉积症(hemochromatosis));新生儿巨细胞性肝炎(Giant cell hepatitis,neonatal)(新生儿血色病(Neonatal hemochromatosis));GLA缺乏(法布里病);视网膜胶质母细胞瘤(Glioblastoma,retinal)(视网膜母细胞瘤(retinoblastoma));视网膜胶质瘤(Glioma,retinal)(视网膜母细胞瘤);球样细胞脑白质营养不良(globoid cell leukodystrophy,GCL,GLD)(克拉伯病);球样细胞脑白质病(globoid cell leukoencephalopathy)(克拉伯病);葡糖脑苷脂酶缺乏(Glucocerebrosidase deficiency)(戈谢病);葡糖脑苷沉积病(Glucocerebrosidosis)(戈谢病);葡糖基脑苷脂沉积病(Glucosyl cerebrosidelipidosis)(戈谢病);葡糖苷酰鞘氨醇酶缺乏(Glucosylceramidase deficiency)(戈谢病);葡糖神经酰胺β葡萄糖苷酶缺乏(Glucosylceramide beta-glucosidase deficiency)(戈谢病);葡萄糖酰鞘氨醇脂沉积症(Glucosylceramide lipidosis)(戈谢病);甘油酸尿(Glyceric aciduria)(原发性高草酸尿(hyperoxaluria,primary));甘氨酸脑病(Glycineencephalopathy)(非酮性高甘氨酸血症(Nonketotic hyperglycinemia));羟基乙酸尿症(Glycolic aciduria)(原发性高草酸尿);1型GM2神经节苷脂贮积症(GM2gangliosidosis,type 1)(泰-萨克斯病(Tay-Sachs disease));甲状腺肿-耳聋综合征(Goiter-deafness syndrome)(彭德莱综合征);格雷费-厄舍尔综合征(Graefe-Ushersyndrome)(厄舍尔综合征);格伦伯莱德-斯特兰伯格综合征(Gronblad-Strandbergsyndrome)(弹性假黄瘤(pseudoxanthoma elasticum));Guenther卟啉症(Guentherporphyria)(先天性红细胞生成性卟啉病);Gunther disease(京塞病)(先天性红细胞生成性卟啉病);血色病(Haemochromatosis)(血色素沉着病(hemochromatosis));Hallgren综合征(厄舍尔综合征);丑角样鱼鳞病(Harlequin Ichthyosis);Hb S病(镰状细胞性贫血(sickle cell anemia));HCH(软骨发育不良(hypochondroplasia));HCP(遗传性粪卟啉症(hereditary coproporphyria));头部和脑部畸形(Head and brain malformations);听力障碍和耳聋(Hearing disorders and deafness);儿童听力问题(Hearing problems inchildren);HEF2A(血色素沉着病#2型);HEF2B(血色素沉着病#2型);血卟啉病(Hematoporphyria)(卟啉症);血红素合成酶缺乏症(Heme synthetase deficiency)(红细胞生成性原卟啉病);血色素沉着症(Hemochromatoses)(血色素沉着病(hemochromatosis));血色素沉着病;血红蛋白M病(hemoglobin M disease)(高铁血红蛋白血症#β珠蛋白型(methemoglobinemia#beta-globin type));血红蛋白S病(HemoglobinS disease)(镰状细胞性贫血);血友病(hemophilia);HEP(肝红细胞生成型卟啉症(hepatoerythropoietic porphyria));肝AGT不足(原发性高草酸尿);肝红细胞生成型卟啉症(hepatoerythropoietic porphyria);肝豆状核变性综合征(Hepatolenticulardegeneration syndrome)(Wilson病);遗传性关节-眼病(Hereditary arthro-ophthalmopathy)(斯蒂克勒综合征);遗传性粪卟啉症;遗传性异位沉积症(Hereditarydystopic lipidosis)(法布里病);遗传性血色素沉着病(HHC)(血色素沉着病);遗传性包涵体肌病(Hereditary Inclusion Body Myopathy)(骨骼肌再生(skeletal muscleregeneration));遗传性铁负荷贫血(Hereditary iron-loading anemia)(X-连锁的成高铁红细胞贫血);遗传性运动感觉性神经病(Hereditary motor and sensory neuropathy)(进行性神经性腓骨肌萎缩症);遗传性运动神经元病(Hereditary motor neuronopathy)(脊髓性肌萎缩(spinal muscular atrophy));V型遗传性运动神经元病(Hereditarymotor neuronopathy,type V)(V型远端脊髓性肌萎缩);遗传性多发性外生骨疣(Hereditary Multiple Exostoses);遗传性非息肉性结直肠癌(Hereditarynonpolyposis colorectal cancer);遗传性周期性发热综合征(Hereditary periodicfever syndrome)(家族性地中海热);遗传性结肠息肉病(Hereditary Polyposis Coli)(家族性腺瘤性息肉病(familial adenomatous polyposis));家族性腺瘤性息肉病(α-1抗胰蛋白酶缺乏);针对活化的蛋白质C的遗传性抗性(Hereditary resistance toactivated protein C)(因子V莱顿血栓形成倾向);III型遗传性感觉和自主神经病变(Hereditary sensory and autonomic neuropathy type III)(家族性自主神经机能异常(familial dysautonomia));遗传性痉挛性截瘫(Hereditary spastic paraplegia)(婴幼儿发病上升的遗传性痉挛性瘫痪(infantile-onset ascending hereditary spasticparalysis));遗传性脊髓性共济失调(Hereditary spinal ataxia)(弗里德赖希共济失调);遗传性脊髓硬化(Hereditary spinal sclerosis)(弗里德赖希共济失调);Herrick′s贫血(镰状细胞性贫血);杂合子OSMED(Heterozygous OSMED)(Weissenbacher-Zweymüller综合征(Weissenbacher-Zweymüller syndrome));杂合子耳-脊髓-大骨骺发育异常(Heterozygous otospondylomegaepiphyseal dysplasia)(Weissenbacher-Zweymüller综合征);HexA缺乏(泰-萨克斯病);己糖胺酶A缺乏(Hexosaminidase A deficiency)(泰-萨克斯病);己糖胺酶α亚基缺失(Hexosaminidase alpha-subunit deficiency)(变体B)(泰-萨克斯病);HFE-相关的血色素沉着病(血色素沉着病);HGPS(早衰(Progeria));希佩尔-林道病(Hippel-Lindau disease)(脑视网膜血管瘤病);HLAH(血色素沉着病);HMNV(V型远端脊髓性肌萎缩);HMSN(进行性神经性腓骨肌萎缩症);HNPCC(遗传性非息肉性结直肠癌);HNPP(伴有易患压迫性麻痹的遗传性神经病变);同型胱氨酸尿症(homocystinuria);尿黑酸氧化酶缺乏症(Homogentisic acid oxidase deficiency)(尿黑酸尿(alkaptonuria));尿黑酸尿(Homogentisic acidura)(alkaptonuria);纯合子性迟发性皮肤卟啉症(Homozygous porphyria cutanea tarda)(肝红细胞生成型卟啉症(hepatoerythropoietic porphyria));HPl(原发性高草酸尿);HP2(原发性高草酸尿);HPA(高苯丙氨酸血症(hyperphenylalaninemia));HPRT-次黄嘌呤鸟嘌呤磷酸核糖转移酶缺乏症(Hypoxanthine-guanine phosphoribosyltransferase deficiency)(莱施-奈恩综合征);III型HSAN(家族性自主神经异常);HSAN3(家族性自主神经异常);HSN-III(家族性自主神经异常);人皮肤脆裂(Human dermatosparaxis)(埃勒斯-当洛综合征#皮肤脆裂型(Ehlers-Danlos syndrome#dermatosparaxis type));亨廷顿病(Huntington′sdisease);哈钦森-吉利福德早衰综合征(Hutchinson-Gilford progeria syndrome)(早衰);雄激素增多症(Hyperandrogenism),非典型性由于21-羟化酶缺乏导致的疾病(nonclassic type,due to 21-hydroxylase deficiency)(21羟化酶缺乏症);家族性高乳糜微粒血症(Hyperchylomicronemia,familial)(家族性脂蛋白脂肪酶缺乏(lipoproteinlipase deficiency,familial));伴有酮酸中毒和白血球减少症的高甘氨酸血症(hyperglycinemia with ketoacidosis and leukopenia)(丙酸血症(propionicacidemia));I型高脂蛋白血症(Hyperlipoproteinemia type I)家族性脂蛋白脂肪酶缺乏);原发性高草酸尿(hyperoxaluria,primary);高苯丙氨酸血症(hyperphenylalaninaemia)(hyperphenylalaninemia);高苯丙氨酸血症;季肋部发育不全(Hypochondrodysplasia)(软骨发育不良);软骨形成不足(hypochondrogenesis);软骨发育不良;低色素性贫血(Hypochromic anemia)(X-连锁的成高铁红细胞贫血);先天性低铜血(Hypocupremia,congenital);门克斯综合征(Menkes syndrome));次黄嘌呤磷酸核糖转移酶(HPRT)缺乏(hypoxanthine phosphoribosyltransferse(HPRT)deficiency)(莱施-奈恩综合征);IAHSP(婴幼儿发病上升的遗传性痉挛性瘫痪(infantile-onset ascendinghereditary spastic paralysis));特发性血色素沉着(idiopathic hemochromatosis)(3型血色素沉着(hemochromatosis,type3));特发性新生儿血色病(Idiopathic neonatalhemochromatosis)(新生儿血色素沉着(hemochromatosis,neonatal));特发性肺动脉高压(Idiopathic pulmonary hypertension)(原发性肺动脉高压(primary pulmonaryhypertension));免疫系统疾病(Immune system disorders)(X-连锁的严重联合免疫缺陷(X-linked severe combined immunodeficiency));色素失调症(IncontinentiaPigmenti);婴儿脑戈谢病(Infantile cerebral Gaucher′s disease)(2型戈谢病);婴儿戈谢病(Infantile Gaucher disease)(2型戈谢病);婴幼儿发病上升的遗传性痉挛性瘫痪;不育症(Infertility);遗传性肺气肿(inherited emphysema)(α-1抗胰蛋白酶缺乏);遗传的人传播性海绵状脑病(Inherited human transmissible spongiformencephalopathies)(朊病毒病);遗传的压力麻痹倾向(inherited tendency to pressurepalsies)(伴有易患压迫性麻痹的遗传性神经病变);Insley-Astley综合征(Insley-Astley syndrome)(耳-脊髓-大骨骺发育异常(otospondylomegaepiphysealdysplasia));间歇性急性卟啉综合征(Intermittent acute porphyria syndrome)(急性间歇性卟啉症(acute intermittent porphyria));肠息肉病-皮肤色素沉着综合征(Intestinal polyposis-cutaneous pigmentation syndrome)(波伊茨-耶格综合征(Peutz-Jeghers syndrome));IP(色素失调症);铁贮积症(Iron storage disorder)(血色素沉着病);Isodicentric 15(idicl 5);孤立性耳聋(Isolated deafness)(非综合征状耳聋(nonsyndromic deafness));Jackson-Weiss综合征(Jackson-Weiss syndrome);JH(血色病#2型);Joubert综合征(Joubert syndrome);JPLS(青少年原发性侧索硬化症(Juvenile Primary Lateral Sclerosis));青少年肌萎缩性侧索硬化症(juvenileamyotrophic lateral sclerosis)(肌萎缩侧索硬化#2型);青少年痛风、舞蹈手足徐动症、智力低下综合征(Juvenile gout,choreoathetosis,mental retardation syndrome)(莱施-奈恩综合征);青少年高尿酸血症综合征(juvenile hyperuricemia syndrome)(莱施-奈恩综合征);JWS(Jackson-Weiss综合征);KD(X-连锁的脊髓-延髓肌萎缩(X-linkedspinal-bulbar muscle atrophy));肯尼迪病(Kennedy disease)(X-连锁的脊髓-延髓肌萎缩);肯尼迪脊髓和延髓肌萎缩症(Kennedy spinal and bulbar muscular atrophy)(X-连锁的脊髓-延髓肌萎缩);角苷脂组织细胞增多症(Kerasin histiocytosis)(戈谢病);Kerasin lipoidosis(戈谢病);角苷脂贮积症(Kerasin thesaurismosis)(戈谢病);酮症甘氨酸血症(ketotic glycinemia)(丙酸血症);酮症高甘氨酸血症(ketotichyperglycinemia)(丙酸血症);肾病(Kidney diseases)(原发性高草酸尿);克兰费尔特综合征(Klinefelter syndrome);克兰费尔特综合征(Klinefelter′s syndrome);Kniest发育不良(Kniest dysplasia);克拉伯病;腔隙性痴呆(Lacunar dementia)(CADASIL);Langer-Saldino软骨成长不全(Langer-Saldino achondrogenesis)(II型软骨成长不全(achondrogenesis,type II));Langer-Saldino发育不良(Langer-Saldino dysplasia)(II型软骨成长不全);迟发型阿尔茨海默病(Late-onset Alzheimer disease)(阿尔茨海默病#2型);迟发型家族性阿尔茨海默病(Late-onset familial Alzheimer disease)(AD2)(阿尔茨海默病#2型);迟发型克拉伯病(late-onset Krabbe disease,LOKD)(克拉伯病);学习障碍(Learning Disorders)(学习无能(Learning disability));口周着色斑病(Lentiginosis,perioral)(波伊茨-耶格综合征);莱施-奈恩综合征;脑白质营养不良症(Leukodystrophies);伴有罗森索尔纤维的脑白质营养不良症(leukodystrophy withRosenthal fibers)(亚历山大病);海绵状脑白质营养不良症(Leukodystrophy,spongiform)(卡纳万病);LFS(李弗劳明综合征(Li-Fraumeni syndrome));李弗劳明综合征;脂肪酶D缺乏(Lipase D deficiency)(家族性脂蛋白脂肪酶缺乏);LIPD缺乏(家族性脂蛋白脂肪酶缺乏);脑苷脂贮积症(Lipidosis,cerebroside)(戈谢病);婴儿神经节苷脂贮积症(Lipidosis,ganglioside,infantile)(泰-萨克斯病);类脂性组织细胞增生症(Lipoid histiocytosis)(角苷脂型)(戈谢病);家族性脂蛋白脂肪酶缺乏;肝病(Liverdiseases)(半乳糖血症);卢·盖里格病(Lou Gehrig disease)(肌萎缩侧索硬化);毛细血管扩张性共济失调综合征(Louis-Bar syndrome)(ataxia-telangiectasia(ataxia-telangiectasia));林奇综合征(Lynch syndrome)(遗传性非息肉性结直肠癌);赖氨酰羟化酶缺乏(Lysyl-hydroxylase deficiency)(埃勒斯-当洛综合征#脊柱后凸侧弯型(kyphoscoliosis type));马-约病(Machado-Joseph disease)(脊髓小脑性共济失调#3型(Spinocerebellar ataxia#type 3));男性乳腺癌(乳腺癌);男性生殖疾病(Male genitaldisorders);男性特纳综合征(Male Turner syndrome)(努南综合征);乳腺恶性肿瘤(Malignant neoplasm ofbreast)(乳腺癌);乳腺恶性瘤(malignant tumor of breast)(乳腺癌);膀胱恶性肿瘤(Malignant tumor ofurinary bladder)(膀胱癌);乳腺癌(Mammary cancer)(乳腺癌);马方综合征15;标记X综合征(Marker X syndrome)(脆性X染色体综合征);Martin-Bell综合征(Martin-Bell syndrome)(脆性X染色体综合征);麦-奥综合征(McCune-Albright syndrome);麦克劳德综合征(McLeod syndrome);MEDNIK;地中海贫血(Mediterranean Anemia)(β地中海贫血);家族性地中海热(Mediterranean fever,familial);巨型骨骺侏儒症(Mega-epiphyseal dwarfism)(耳-脊髓-大骨骺发育异常);Menkea综合征(Menkea syndrome)(门克斯综合征(Menkes syndrome));门克斯综合征;伴有骨软骨异常的智力低下(Mental retardation with osteocartilaginousabnormalities)(科-洛综合征);代谢紊乱(Metabolic disorders);II性间向性侏儒(Metatropic dwarfism,type II)(Kniest发育不全);II型间向性发育不良(Metatropicdysplasia type II)(Kniest发育不良);高铁血红蛋白血症#β珠蛋白型(Methemoglobinemia#beta-globin type);甲基丙二酸血症(methylmalonic acidemia);MFS(马方综合征);MHAM(考登综合征);MK(门克斯综合征);Micro综合征(Microsyndrome);小头畸形(Microcephaly);MMA(甲基丙二酸血症);MNK(门克斯综合征(Menkessyndrome));lp36单体综合征(Monosomy lp36syndrome)(1p36缺失综合征);X单体(monosomy X)(特纳综合征);运动神经元病(Motor neuron disease),肌萎缩侧索硬化(amyotrophic lateral sclerosis);运动障碍(Movement disorders);Mowat-Wilson综合征(Mowat-Wilson syndrome);粘多糖贮积症(Mucopolysaccharidosis)(MPS I);粘液粘稠病(Mucoviscidosis)(囊性纤维化);Muenke综合征;多发梗塞性痴呆(Multi-Infarctdementia)(CADASIL);多发性羧化酶缺乏(Multiple carboxylase deficiency),迟发性(生物素酶缺乏症);多发性错构瘤综合征(Multiple hamartoma syndrome)(考登综合征);多发性神经纤维瘤病(Multiple neurofibromatosis)(神经纤维瘤病);肌营养不良症(Muscular dystrophy);迪谢内和贝克尔型肌营养不良症(Muscular dystrophy,Duchenneand Becker type);萎缩性肌强直(营养不良性肌强直);失养性肌强直病(Myotoniadystrophica)(营养不良性肌强直);营养不良性肌强直;先天性粘液水肿(Myxedema,congenital)(先天性甲状腺功能减退症);Nance-Insley综合征(Nance-Insley syndrome)(耳-脊髓-大骨骺发育异常);Nance-Sweeney软骨发育不全(Nance-Sweeneychondrodysplasia)(耳-脊髓-大骨骺发育异常);NBIAl(泛酸激酶相关的神经变性病(pantothenate kinase-associated neurodegeneration));Neill-Dingwall综合征(Neill-Dingwall syndrome)(科凯恩综合征);视网膜神经母细胞瘤(Neuroblastoma,retinal)(视网膜母细胞瘤(retinoblastoma));伴有脑铁累积的1型神经变性病(Neurodegeneration with brain iron accumulation type 1)(泛酸激酶相关的神经变性病);I型神经纤维瘤病(Neurofibromatosis type I);II型神经纤维瘤病(Neurofibromatosis type II);神经病(Neurologic diseases);神经肌肉疾病(Neuromuscular disorders);V型远端遗传性运动神经元病(neuronopathy,distalhereditary motor,typeV)(V型远端脊髓性肌萎缩#V型);伴有锥状体特征的远端遗传性运动神经元病(neuronopathy,distal hereditary motor,with pyramidal features)(肌萎缩侧索硬化#4型);NF(神经纤维瘤病);尼曼-皮克(Niemann-Pick)(尼曼-皮克病);诺克综合征(Noack syndrome)(斐弗综合征);非酮性高甘氨酸血症(Nonketotichyperglycinemia)(甘氨酸脑病(Glycine encephalopathy));非神经性戈谢病(Non-neuronopathic Gaucher disease)(1型戈谢病);非苯丙酮尿性高苯丙氨酸血症(Non-phenylketonuric hyperphenylalaninemia)(四氢生物喋呤缺乏(tetrahydrobiopterindeficiency));非综合性耳聋(nonsyndromic deafness);努南综合征;Norrbottnian戈谢病(Norrbottnian Gaucher disease)(3型戈谢病);褐黄病(Ochronosis)(尿黑酸尿);褐黄病性关节炎(Ochronotic arthritis)(尿黑酸尿);OI(成骨不全(osteogenesisimperfecta));OSMED(耳-脊髓-大骨骺发育异常(otospondylomegaepiphysealdysplasia));成骨不全;脆骨症(Osteopsathyrosis)(成骨不全);先天性骨硬化(Osteosclerosis congenita)(软骨发育不全(achondroplasia));耳-脊髓-大骨骺发育异常(Oto-spondylo-megaepiphyseal dysplasia)(otospondylomegaepiphysealdysplasia);耳-脊髓-大骨骺发育异常;草酸盐沉着症(Oxalosis)(原发性高草酸尿(hyperoxaluria,primary));原发性草酸尿(Oxaluria,primary)(原发性高草酸尿);泛酸激酶相关的神经变性(pantothenate kinase-associated neurodegeneration);帕塔综合征(Patau Syndrome)(13三体(Trisomy 13));PBGD缺乏(急性间歇性卟啉病(acuteintermittent porphyria));PCC缺乏(丙酸血症(propionic acidemia));PCT(迟发性皮肤卟啉病(porphyria cutanea tarda));PDM(2型营养不良性肌强直(Myotonic dystrophy#type 2));彭德莱综合征(Pendred syndrome);周期性疾病(Periodic disease)(家族性地中海热);周期性腹膜炎(Periodic peritonitis)(家族性地中海热);口周着色斑病综合征(Periorificial lentiginosis syndrome)(波伊茨-耶格综合征);;周围神经疾病(Peripheral nerve disorders)(家族性自主神经功能异(familial dysautonomia));周围神经纤维瘤病(Peripheral neurofibromatosis)(神经纤维瘤病1);腓肌萎缩(Peronealmuscular atrophy)(进行性神经性腓骨肌萎缩症);过氧化物酶体丙氨酸:乙醛酸氨基转移酶缺乏症(peroxisomal alanine:glyoxylate aminotransferase deficiency(原发性高草酸尿(hyperoxaluria,primary));波伊茨-耶格综合征;斐弗综合征(Pfeiffersyndrome);苯丙氨酸羟化酶缺乏病(Phenylalanine hydroxylase deficiency disease)(苯丙酮尿(phenylketonuria));苯丙酮尿;嗜铬细胞瘤(Pheochromocytoma)(脑视网膜血管瘤病(von Hippel-Lindau disease));伴有胎儿软骨发育不良的皮埃尔罗班综合征(Pierre Robin syndrome with fetal chondrodysplasia)(Weissenbacher-Zweymüller综合征(Weissenbacher-Zweymüller syndrome));色素性肝硬变(Pigmentary cirrhosis)(血色素沉着病);PJS(波伊茨-耶格综合征);PKAN(泛酸激酶相关的神经变性);PKU苯丙酮尿);Plumboporphyria(ALA缺乏卟啉病(ALA deficiency porphyria));PMA(进行性神经性腓骨肌萎缩症);多骨纤维发育不良(polyostotic fibrous dysplasia)(McCune-Albright综合征(McCune-Albright syndrome));结肠息肉病(polyposis coli)(家族性腺瘤性息肉病(familial adenomatous polyposis));错构瘤性肠息肉(polyposis,hamartomatousintestinal)(波伊茨-耶格综合征);肠息肉II(polyposis,intestinal,II)(波伊茨-耶格综合征);息肉和斑点综合征(polyps-and-spots syndrome)(波伊茨-耶格综合征);卟啉胆素原合酶缺乏(Porphobilinogen synthase deficiency)(ALA缺乏卟啉病);卟啉病(porphyria);卟啉病症(porphyrin disorder)(卟啉病);PPH(原发性肺动脉高压);PPOX缺乏(PPOX deficiency)(多样性卟啉病(variegate porphyria));普-拉-威综合征(Prader-Labhart-Willi syndrome)(普拉德-威利综合征(Prader-Willi syndrome));普拉德-威利综合征;早老性和老年性痴呆(presenile and senile dementia)(阿尔茨海默病);原发性血色病(primary hemochromatosis)(血色素沉着病);原发性高尿酸血症综合征(primaryhyperuricemia syndrome)(莱施-奈恩综合征);原发性肺动脉高压;原发性老年性退行性痴呆(primary senile degenerative dementia)(阿尔茨海默病);朊病毒病;突变型前胶原型EDS VII(procollagen type EDS VII,mutant)(埃勒斯-当洛综合征#关节松弛型(arthrochalasia type));早衰(progeria)(早年衰老综合症(Hutchinson GilfordProgeria Syndrome));早衰样综合征(Progeria-like syndrome)(科凯恩综合征);类早老症侏儒(progeroid nanism)(科凯恩综合征);慢性遗传性进展性舞蹈症(progressivechorea,chronic hereditary)(亨廷顿)(亨廷顿病(Huntington′s disease));进行性肌萎缩(progressive muscular atrophy)(脊髓性肌萎缩(spinal muscular atrophy));具有正常巩膜的进行性变形性成骨不全(progressively deforming osteogenesisimperfecta with normal sclerae)(成骨不全#III型);PROMM(营养不良性肌强直#2型);丙酸血症;丙酰辅酶A羧化酶缺乏症(propionyl-CoA carboxylase deficiency)(丙酸血症);蛋白C缺乏症;蛋白S缺乏症(protein S deficiency);原卟啉病(protoporphyria)(红细胞生成性原卟啉病(erythropoietic protoporphyria));原卟啉原氧化酶缺乏(protoporphyrinogen oxidase deficiency)(多样性卟啉病);近端营养不良性肌强直(proximal myotonic dystrophy)(营养不良性肌强直#2型);近端营养不良性肌强直(营养不良性肌强直#2型);假戈谢病;假-Ullrich-特纳综合征(pseudo-Ullrich-Turnersyndrome)(努南综合征);弹性假黄瘤(pseudoxanthoma elasticum);鞘氨醇半乳糖苷脂质沉积(psychosine lipidosis)(克拉伯病);肺动脉高压(pulmonary arterialhypertension)(原发性肺动脉高压);肺动脉高压(原发性肺动脉高压);PWS(普拉德-威利综合征);PXE-弹性假黄瘤(弹性假黄瘤);Rb(视网膜母细胞瘤);神经雷克林霍曾病(Recklinghausen disease,nerve)(神经纤维瘤病1);复发性多浆膜炎(Recurrentpolyserositis)(家族性地中海热);视网膜疾病(Retinal disorders);色素性视网膜炎-耳聋综合征(Retinitis pigmentosa-deafness syndrome)(厄舍尔综合征);视网膜母细胞瘤;雷特综合征;3型RFALS(肌萎缩侧索硬化#2型);Ricker综合征(Ricker syndrome)(营养不良性肌强直#2型);赖利-戴综合征(Riley-Day syndrome)(家族性自主神经功能异常);鲁息-莱维综合征(Roussy-Levy syndrome)(进行性神经性腓骨肌萎缩症);RSTS(鲁宾斯坦-泰比综合征);RTS(Rett syndrome)(鲁宾斯坦-泰比综合征);RTT(Rett syndrome);鲁宾斯坦-泰比综合征;Sack-Barabas综合征(Sack-Barabas syndrome)(血管型埃勒斯-当洛综合征);SADDAN;李弗劳明家族性肉瘤综合征(sarcoma family syndrome of Li andFraumeni)(李弗劳明综合征(Li-Fraumeni syndrome));肉瘤、乳腺癌、白血病和肾上腺(SBLA)综合征(sarcoma,breast,leukemia,and adrenal gland(SBLA)syndrome)(李弗劳明综合征);SBLA综合征(李弗劳明综合征);SBMA(X-连锁的脊髓-延髓肌萎缩);SCD(镰状细胞性贫血);双侧听神经鞘瘤(Schwannoma,acoustic,bilateral)(经纤维瘤病2);SCIDX1(X-连锁的重症联合免疫缺陷(X-linked severe combined immunodeficiency));结节性硬化(sclerosis tuberosa)(结节性硬化症(tuberous sclerosis));SDAT(阿尔茨海默病);先天性SED(SED congenita)(先天性脊椎骺发育不全(spondyloepiphysealdysplasia congenita));SED Strudwick(Strudwick型脊椎干骺端发育不全(spondyloepimetaphyseal dysplasia,Strudwick type));SEDc(先天性脊椎骺发育不全(spondyloepiphyseal dysplasia congenita));Strudwick型SEMD(SEMD,Strudwicktype)(Strudwick型脊椎干骺端发育不全);老年性痴呆(senile dementia)(阿尔茨海默病#2型);伴有发育迟缓和黑棘皮症的严重软骨发育不全(severe achondroplasia withdevelopmental delay and acamhosis nigricans,SADDAN);斯普林泽综合征(Shprintzensyndrome)(22q11.2缺失综合征);镰状细胞性贫血;骨骼-皮肤-脑综合征(skeleton-skin-brain syndrome,SADDAN);皮肤色素沉着症(Skin pigmentation disorders);SMA(脊髓性肌萎缩(spinal muscular atrophy));Strudwick型SMED(SMED,Strudwick type)(Strudwick型脊椎干骺端发育不全);I型SMED(Strudwick型脊椎干骺端发育不全);SmithLemli Opitz综合征(Smith Lemli Opitz Syndrome);南非遗传性卟啉病(South-Africangenetic porphyria)(多样性卟啉病);婴幼儿发病上升的痉挛性瘫痪(spasticparalysis,infantile onset ascending)(婴幼儿发病上升的遗传性痉挛性瘫痪(infantile-onset ascending hereditary spastic paralysis));语言和沟通障碍(Speech and communication disorders);泰-萨克斯神经鞘脂贮积症(sphingolipidosis,Tay-Sachs)(泰-萨克斯病);脊髓-延髓肌萎缩(spinal-bulbarmuscular atrophy);脊髓性肌萎缩;V型远端脊髓性肌萎缩(spinal muscular atrophy,distal type V)(远端脊髓性肌萎缩#V型);具有上肢优势的脊髓性肌萎缩(spinalmuscular atrophy,distal,with upper limb predominance)(远端脊髓性肌萎缩#V型);脊髓小脑性共济失调;Strudwick型脊椎干骺端发育不全;先天性脊椎骺发育不全;脊椎骺发育不全(胶原病(collagenopathy),II和XI型);Strudwick型先天性脊椎干骺端发育不良(spondylometaepiphyseal dysplasia congenita,Strudwick type)(Strudwick型脊椎干骺端发育不全);脊椎干骺端发育不良(spondylometaphyseal dysplasia)(SMD)(Strudwick型脊椎干骺端发育不全);Strudwick型脊椎干骺端发育不良(Strudwick型脊椎干骺端发育不全);中枢神经系统海绵状变性(spongy degeneration of central nervoussystem)(卡纳万病);脑海绵状变性(spongy degeneration ofthe brain)(卡纳万病);婴儿白质海绵样变性(spongy degeneration of white matter in infancy)(卡纳万病);偶发性原发性肺动脉高压(sporadic primary pulmonary hypertension)(原发性肺动脉高压);SSB综合征(SADDAN);钢发综合征(steely hair syndrome)(门克斯综合征);Steinert病(Steinert disease)(营养不良性肌强直);Steinert营养不良性肌强直综合征(Steinert myotonic dystrophy syndrome)(营养不良性肌强直);斯蒂克勒综合征(Stickler syndrome);卒中(CADASIL);Strudwick综合征(Strudwick型脊椎干骺端发育不全);亚急性神经元病性戈谢病(subacute neuronopathic Gaucher disease)(3型戈谢病);瑞典遗传性卟啉病(Swedish genetic porphyria)(急性间歇性卟啉病(acuteintermittent porphyria));瑞典型卟啉症(Swedish porphyria)(瑞典型卟啉症);瑞士奶酪软骨发育不良(Swiss cheese cartilage)(Kniest发育不良(Kniest dysplasia));泰-萨克斯病;TD-致死性侏儒症(thanatophoric dwarfism)(致死性发育不全(thanatophoricdysplasia));具有直股骨和颅底的TD(TD with straight femurs and cloverleafskull)(致死性发育不全#2型);小脑-眼皮肤毛细血管扩张(Telangiectasia,cerebello-oculocutaneous)(运动失调性毛细血管扩张症(ataxia-telangiectasia));睾丸女性化综合征(Testicular feminization syndrome)(雄激素不敏感综合征);四氢生物喋呤缺乏;TFM-睾丸女性化综合征(雄激素不敏感综合征);中间型地中海贫血(thalassemiaintermedia)(β地中海贫血);重型地中海贫血(Thalassemia Major)(beta thalassemia);致死性发育不良(thanatophoric dysplasia);伴有糖尿病和感觉神经性耳聋的硫胺素响应巨幼细胞性贫血(thiamine-responsive megaloblastic anemia with diabetesmellitus and sensorineural deafness);缺乏活化的蛋白C的辅因子引起的莱顿型血栓形成倾向(Thrombophilia due to deficiency of cofactor for activated protein C,Leiden type)(因子V莱顿血栓形成倾向);甲状腺病(Thyroid disease);Tomaculous神经病(Tomaculous neuropathy)(伴有易患压迫性麻痹的遗传性神经病变);总HPRT缺乏(Total HPRT deficiency)(莱施-奈恩综合征);总的次黄嘌呤-鸟嘌呤磷酸核糖转移酶缺乏Total hypoxanthine-guanine phosphoribosyl transferase deficiency)(莱施-奈恩综合征);图雷特综合征(Tourette′s Syndrome);传播性痴呆(Transmissible dementias)(朊病毒病);传播性海绵状脑病(Transmissible spongiform encephalopathies)(朊病毒病);Treacher Collins 综合征(Treacher Collins syndrome);三叠系脆骨症(Triasfragilitis ossium)(成骨不全#I型);三X染色体综合征(triple X syndrome);三体X综合征(Triplo X syndrome)(三X染色体综合征);21号染色体三体(Trisomy 21)(唐氏综合症);X染色体三体性(Trisomy X)(三X染色体综合征);特鲁瓦西耶-阿诺特-乔福地综合征(Troisier-Hanot-Chauffard syndrome)(血色素沉着病);TS(特纳综合征);TSD(泰-萨克斯病);TSEs(朊病毒病);结节状硬化(tuberose sclerosis)(结节性硬化症(tuberoussclerosis));结节性硬化症;特纳综合征;具有X染色体的女性特纳综合征(Turnersyndrome in female with X chromosome)(努南综合征);核型正常的特纳表型(Turner′sphenotype,karyotype normal)(努南综合征);特纳综合征(Turner′s syndrome)(Turnersyndrome);特纳样综合征(Turner-like syndrome)(努南综合征);2型戈谢病(戈谢病2型);3型戈谢病(戈谢病3型);UDP-半乳糖-4-差向异构酶缺乏病(UDP-galactose-4-epimerase deficiency disease)(半乳糖血症);UDP葡萄糖4-差向异构酶缺乏病(UDPglucose 4-epimerase deficiency disease)(半乳糖血症);UDP-葡萄糖己糖-1-磷酸尿苷基转移酶缺乏(UDP glucose hexose-1-phosphate uridylyltransferasedeficiency)(半乳糖血症);Ullrich-努南综合征(Ullrich-Noonan syndrome)(努南综合征);Ullrich-特纳综合征(Ullrich-Turner syndrome)(特纳综合征);未分化性耳聋(Undifferentiated deafness)(非综合性耳聋(nonsyndromic deafness));UPS缺乏(UPSdeficiency)(急性间歇性卟啉病);膀胱癌(Urinary bladder cancer)(bladder cancer);UROD缺乏(UROD deficiency)(迟发性皮肤卟啉症);尿卟啉原脱羧酶缺乏(Uroporphyrinogen decarboxylase deficiency)(迟发性皮肤卟啉症);尿卟啉原合酶缺乏(Uroporphyrinogen synthase deficiency)(急性间歇性卟啉病);UROS缺乏(UROSdeficiency)(先天性红细胞生成性卟啉病);厄舍尔综合征;UTP己糖-1-磷酸尿苷基转移酶缺乏(UTP hexose-1-phosphate uridylyltransferase deficiency)(半乳糖血症);范-贝二氏综合征(Van Bogaert-Bertrand syndrome)(卡纳万病);范德赫夫综合征(Van derHoeve syndrome)(成骨不全#I型);多样性卟啉病;软腭-心-面综合征(Velocardiofacialsyndrome)(22q11.2缺失综合征);VHL综合征(脑视网膜血管瘤病);视力损伤和失明(Vision impairment and blindness)(综合征(Alstrom syndrome));Von Bogaert-Bertrand病(Von Bogaert-Bertrand disease)(卡纳万病);脑视网膜血管瘤病;VonRecklenhausen-Applebaum病(Von Recklenhausen-Applebaum disease)(血色素沉着病);von Recklinghausen病(von Recklinghausen disease)(神经纤维瘤病1);VP(多样性卟啉病);夫罗利克病(Vrolik disease)(成骨不全);Waardenburg综合征(Waardenburgsyndrome);Warburg Sjo Fledelius综合征(Warburg Sjo Fledelius Syndrome)(微小综合征(Micro syndrome));WD(威尔逊病(Wilson disease));Weissenbacher-Zweymüller综合征(Weissenbacher-Zweymüller syndrome);威尔逊病;威尔逊病(Wilson′s disease)(Wilson disease);Wolf-Hirschhorn综合征(Wolf-Hirschhorn syndrome);WolffPeriodic病(Wolff Periodic disease)(家族性地中海热);WZS(Weissenbacher-Zweym/iller综合征);着色性干皮病(Xeroderma Pigmentosum);X连锁的精神发育迟滞和大睾丸(X-linked mental retardation and macroorchidism)(脆性X染色体综合征(fragile Xsyndrome));X连锁的原发性高尿酸血症(X-linked primary hyperuricemia)(莱施-奈恩综合征);X-连锁的严重联合免疫缺陷(X-linked severe combined immunodeficiency);X-连锁的成高铁红细胞贫血;X-连锁的脊髓-延髓肌萎缩(X-linked spinal-bulbarmuscle atrophy)(肯尼迪病);X-连锁的尿酸脲酶缺陷(X-linked uric aciduria enzymedefect)(莱施-奈恩综合征);X-SCID(X-连锁的严重联合免疫缺陷);XLSA(X-连锁的成高铁红细胞贫血);XSCID(X-连锁的严重联合免疫缺陷);XXX综合征(三X染色体综合征);XXXX综合征(48,XXXX);XXXXX综合征(49,XXXXX);XXY综合征(Klinefelter综合征(Klinefeltersyndrome));XXY三体(XXY trisomy)(Klinefelter综合征);XYY核型(XYY karyotype)(47,XYY综合征);XYY综合征(47,XYY综合征);和YY综合征(47,XYY综合征)。
在进一步优选的方面,本文定义的本发明的核酸序列或包含多种本文定义的本发明的核酸序列的本发明的组合物可以用于制备药物组合物,特别是用于本文定义的目的,优选用于治疗本文定义的疾病的基因疗法中的药物组合物。
本发明的药物组合物可以进一步用于基因疗法,特别是治疗优选如本文定义的疾病或病症的基因疗法中。
按照最后的方面,本发明还提供试剂盒,特别是部件的试剂盒。所述试剂盒,特别是部件的试剂盒,典型地包含单独的至少一种本文定义的本发明的核酸序列、包含本发明的核酸序列的本发明的药物组合物或疫苗或与本文定义的其他组分组合作为组分。所述至少一种本文定义的本发明的核酸序列任选地与本文定义的其他组分组合,其中所述至少一种本发明的核酸与包含一种或多种其他组分的试剂盒的至少一个其他部件分开提供(试剂盒的第一部件)。例如,本发明的药物组合物可以存在于试剂盒的不同部件中。例如,一个实例,试剂盒的至少一个部件可以包含至少一种本文定义的本发明的核酸序列,并且所述试剂盒的至少一个其他部件包含至少一种本文定义的其他组分,例如,所述试剂盒的至少一个其他部件可以包含至少一种药物组合物或其部分,例如,所述试剂盒的至少一个部件可以包含本文定义的本发明的核酸序列,所述试剂盒的至少一个其他部件包括至少一种本文定义的其他组分,所述试剂盒的至少一个其他部件包括本发明的药物组合物中的至少一种组分或者包括作为整体的本发明的药物组合,并且所述试剂盒的至少一个其他部件,例如,包含至少一种药物载体或赋形剂等。如果所述试剂盒或部件的试剂盒包含多种本发明的核酸序列,所述试剂盒的一个组件可以包含仅一种、几种或全部该试剂盒所包含的本发明的核酸序列。在备选的实施方案中,每一种本发明的核酸序列可以包含在试剂盒的不同/分开的组件中,以使每个组件形成所述试剂盒的一部分。此外,多于一种核酸可以包含在作为试剂盒的一部分的第一组件中,而一种或多种其他(第二、第三等)组件(提供试剂盒的一个或多个其他部分)可以包含一种或多于一种本发明的核酸,其可以与第一组件相同或部分相同或不同。所述试剂盒或部件的试剂盒还可以包含技术说明书,其具有关于本发明的核酸序列、本发明的药物组合物的施用和剂量的信息或关于任意其组件或部件(例如,如果所述试剂盒制备为部件的试剂盒)的信息。
综上所述,本发明提供包含或编码下述的核酸序列:
a)编码区,所述编码区编码至少一种肽或蛋白;
b)至少一种组蛋白茎环,和
c)聚腺苷酸序列或聚腺苷酸化信号;
其中所述肽或蛋白包含治疗性蛋白或其片段、变体或衍生物,其可以是这样的治疗性蛋白,
优选用于治疗代谢或内分泌紊乱、用于治疗血液病症、循环系统的疾病、呼吸系统的疾病、癌症或肿瘤疾病、传染病或免疫缺陷、用于激素替代疗法或用于使体细胞重新编程的治疗性蛋白,
或选自下述的治疗性蛋白:佐剂或免疫刺激性蛋白,人佐剂蛋白,细菌(佐剂)蛋白,原生动物(佐剂)蛋白,病毒(佐剂)蛋白,真菌(佐剂)蛋白,
或是抗体,优选选自下述的抗体:用于治疗癌症或肿瘤疾病的抗体,用于治疗免疫病症的抗体,用于治疗传染病的抗体,用于治疗传染病的抗体,用于治疗血液病症的抗体,用于免疫调节的抗体,用于治疗糖尿病的抗体,用于治疗阿尔茨海默病的抗体,用于治疗哮喘的抗体或用于治疗多种病症的抗体。
本发明还提供所述核酸序列在本文定义的基因疗法中的应用。本发明还提供包含所述核酸序列的试剂盒或部件的试剂盒。此外,本发明提供包含所述核酸序列的药物组合物。此外,本发明提供用于增加所编码的肽或蛋白的表达的方法,所述方法包括提供所述核酸序列或包含所述核酸序列的组合物并且将所述核酸序列或其他组合物应用至或施用至不含细胞的表达系统、细胞、组织或生物体中的步骤。
优选地,本发明提供包含或编码下述的核酸序列:
a)编码区,所述编码区编码至少一种肽或蛋白;
b)至少一种组蛋白茎环,和
c)聚腺苷酸序列或聚腺苷酸化信号;
其中所述肽或蛋白包含治疗性蛋白或其片段、变体或衍生物,其可以是这样的治疗性蛋白,所述治疗性蛋白
用于治疗代谢或内分泌紊乱,
用于治疗血液病症,循环系统的疾病,呼吸系统的疾病,癌症或肿瘤疾病,传染病或免疫缺陷,
用于激素替代疗法或
用于使体细胞重新编程。
本发明还提供所述核酸序列在本文定义的基因疗法中的应用。本发明还提供包含所述核酸序列的试剂盒或部件的试剂盒。此外,本发明提供包含所述核酸序列的药物组合物。此外,本发明提供用于增加所编码的肽或蛋白的表达的方法,所述方法包括提供所述核酸序列或包含所述核酸序列的组合物并且将所述核酸序列或其他组合物应用至或施用至不含细胞的表达系统、细胞、组织或生物体中的步骤。
更优选地,本发明提供包含或编码下述的核酸序列:
a)编码区,所述编码区编码至少一种肽或蛋白;
b)至少一种组蛋白茎环,和
c)聚腺苷酸序列或聚腺苷酸化信号;
其中所述肽或蛋白包含治疗性蛋白或其片段、变体或衍生物,优选这样的治疗性蛋白,其选自佐剂或免疫刺激性蛋白,更优选地选自人佐剂蛋白,细菌(佐剂)蛋白,原生动物(佐剂)蛋白,病毒(佐剂)蛋白,真菌(佐剂)蛋白。
本发明还提供所述核酸序列在本文定义的基因疗法中的应用。本发明还提供包含所述核酸序列的试剂盒或部件的试剂盒。此外,本发明提供包含所述核酸序列的药物组合物。此外,本发明提供用于增加所编码的肽或蛋白的表达的方法,所述方法包括提供所述核酸序列或包含所述核酸序列的组合物并且将所述核酸序列或其他组合物应用至或施用至不含细胞的表达系统、细胞、组织或生物体中的步骤。
更优选地,本发明提供包含或编码下述的核酸序列:
a)编码区,所述编码区编码至少一种肽或蛋白;
b)至少一种组蛋白茎环,和
c)聚腺苷酸序列或聚腺苷酸化信号;
其中所述肽或蛋白包含治疗性蛋白或其片段、变体或衍生物,优选下述的治疗性蛋白或其片段、变体或衍生物:治疗性抗体,更优选选自用于治疗癌症或肿瘤疾病的抗体,用于治疗免疫病症的抗体,用于治疗传染病的抗体,用于治疗传染病的抗体,用于治疗血液病症的抗体,用于免疫调节的抗体,用于治疗糖尿病的抗体,用于治疗阿尔茨海默病的抗体,用于治疗哮喘的抗体或用于治疗多种病症的抗体。
本发明还提供所述核酸序列在本文定义的基因疗法中的应用。本发明还提供包含所述核酸序列的试剂盒或部件的试剂盒。此外,本发明提供包含所述核酸序列的药物组合物。此外,本发明提供用于增加所编码的肽或蛋白的表达的方法,所述方法包括提供所述核酸序列或包含所述核酸序列的组合物并且将所述核酸序列或其他组合物应用至或施用至不含细胞的表达系统、细胞、组织或生物体中的步骤。
优选地,本发明提供包含或编码下述的核酸序列:
a)编码区,所述编码区编码至少一种肽或蛋白;
b)至少一种组蛋白茎环,和
c)聚腺苷酸序列或聚腺苷酸化信号;
其中所述肽或蛋白包含治疗性蛋白或其片段、变体或衍生物,优选用于治疗代谢或内分泌紊乱的治疗性蛋白,
更优选选自下述的肽或蛋白:酸性鞘磷脂酶,Adipotide,Agalsidase-β,Alglucosidase,α-半乳糖苷酶A,α-葡糖苷酶,α-L-艾杜糖苷酸酶,α-N-乙酰葡糖苷酶,双调蛋白,血管生成素(Ang1,Ang2,Ang3,Ang4,ANGPTL2,ANGPTL3,ANGPTL4,ANGPTL5,ANGPTL6,ANGPTL7),β动物纤维素,β-葡糖醛酸糖苷酶,骨形态发生蛋白BMPs(BMP1,BMP2,BMP3,BMP4,BMP5,BMP6,BMP7,BMP8a,BMP8b,BMP10,BMP15),CLN6蛋白,表皮生长因子(EGF),Epigen,表皮调节素,成纤维细胞生长因子(FGF,FGF-1,FGF-2,FGF-3,FGF-4,FGF-5,FGF-6,FGF-7,FGF-8,FGF-9,FGF-10,FGF-11,FGF-12,FGF-13,FGF-14,FGF-16,FGF-17,FGF-17,FGF-18,FGF-19,FGF-20,FGF-21,FGF-22,FGF-23),Galsulphase,葛瑞林,葡糖脑苷脂酶,GM-CSF,肝素-结合EGF-样生长因子(HB-EGF),肝细胞生长因子HGF,Hepcidin,人白蛋白,增加的白蛋白损失,艾度硫酸酯酶(艾杜糖醛酸-2-硫酸酯酶),整联蛋白αVβ3,αVβ5和α5β1,艾杜糖醛酸硫酸酯酶,拉罗尼酶,N-乙酰半乳糖胺-4-硫酸酯酶(rhASB;galsulfase,芳基硫酸酯酶A(ARSA),芳基硫酸酯酶B(ARSB)),N-乙酰葡糖胺-6-硫酸酯酶,神经生长因子(NGF,脑源性神经营养因子(BDNF),神经营养因子-3(NT-3),和神经营养因子4/5(NT-4/5),神经调节蛋白(NRG1,NRG2,NRG3,NRG4),神经毡蛋白(NRP-1,NRP-2),肥胖抑制素,血小板衍生生长因子(PDGF(PDFF-A,PDGF-B,PDGF-C,PDGF-D),TGFβ受体(内皮因子,TGF-β1受体,TGF-β2受体,TGF-β3受体),血小板生成素(THPO)(巨核细胞生长和发育因子(MGDF)),转化生长因子(TGF(TGF-a,TGF-β(TGFβ1,TGFβ2,和TGFβ3))),VEGF(VEGF-A,VEGF-B,VEGF-C,VEGF-D,VEGF-E,VEGF-F und PIGF),奈西立肽,胰蛋白酶,促肾上腺皮质激素(ACTH),心房钠尿肽(ANP),胆囊收缩素,胃泌素,瘦蛋白,催产素,生长抑素,加压素(抗利尿激素),降钙素,Exenatide,生长激素(GH),生长素,胰岛素,胰岛素样生长因子1 IGF-1,Mecasermin rinfabate,IGF-1类似物,美卡舍明,IGF-1类似物,培维索孟,普兰林肽,特立帕肽(人甲状旁腺素残基1-34),贝卡普勒明,Dibotermin-α(骨形态发生蛋白2),醋酸组氨瑞林(促性腺素释放激素;GnRH),奥曲肽,和帕利夫明(角质形成细胞生长因子;KGF)。
本发明还提供所述核酸序列在本文定义的基因疗法中的应用。本发明还提供包含所述核酸序列的试剂盒或部件的试剂盒。此外,本发明提供包含所述核酸序列的药物组合物。此外,本发明提供用于增加所编码的肽或蛋白的表达的方法,所述方法包括提供所述核酸序列或包含所述核酸序列的组合物并且将所述核酸序列或其他组合物应用至或施用至不含细胞的表达系统、细胞、组织或生物体中的步骤。
优选地,本发明提供包含或编码下述的核酸序列:
a)编码区,所述编码区编码至少一种肽或蛋白;
b)至少一种组蛋白茎环,和
c)聚腺苷酸序列或聚腺苷酸化信号;
其中所述肽或蛋白包含治疗性蛋白或其片段、变体或衍生物,优选用于治疗血液病症、循环系统的疾病、呼吸系统的疾病、癌症或肿瘤疾病、传染病或免疫缺陷的治疗性蛋白,更优选选自下述的肽或蛋白:阿替普酶(组织型纤溶酶原激活物;tPA),阿尼普酶,抗凝血酶III(AT-III),比伐卢定,达贝泊汀α,屈曲克凝α(活化的蛋白C,促红细胞生成素,依泊汀α,促血红细胞生长素,红细胞生成素,因子IX,因子VIIa,因子VIII,来匹卢定,蛋白质C浓缩剂,瑞替普酶(tPA的缺失突变蛋白),链激酶,替奈普酶,尿激酶,血管抑素,抗-CD22免疫毒素,地尼白介素-毒素连接物,Immunocyanin,MPS(Metallopanstimulin),Aflibercept,内皮抑素,胶原酶,人脱氧核糖核酸酶I,链道酶,透明质酸酶,木瓜蛋白酶,L-天冬酰胺酶,Peg-天冬酰胺酶,拉布立酶,人慢性促性腺素(HCG),人促卵泡激素(FSH),促黄体素-α,催乳素,α-1-蛋白酶抑制剂,乳糖酶,胰酶(脂肪酶,淀粉酶,蛋白酶),腺苷脱氨酶(牛培加酶,PEG-ADA),阿巴他塞,阿来法塞,阿那白滞素,Etanercept,白血病介素-1(IL-1)受体拮抗剂,阿那白滞素,胸腺素,TNF-α拮抗剂,恩夫韦肽,和胸腺素α1。
本发明还提供所述核酸序列在本文定义的基因疗法中的应用。本发明还提供包含所述核酸序列的试剂盒或部件的试剂盒。此外,本发明提供包含所述核酸序列的药物组合物。此外,本发明提供用于增加所编码的肽或蛋白的表达的方法,所述方法包括提供所述核酸序列或包含所述核酸序列的组合物并且将所述核酸序列或其他组合物应用至或施用至不含细胞的表达系统、细胞、组织或生物体中的步骤。
优选地,本发明提供包含或编码下述的核酸序列:
a)编码区,所述编码区编码至少一种肽或蛋白;
b)至少一种组蛋白茎环,和
c)聚腺苷酸序列或聚腺苷酸化信号;
其中所述肽或蛋白包含治疗性蛋白或其片段、变体或衍生物,优选用于激素替代疗法的治疗性蛋白,更优选选自雌激素、孕酮或黄体酮,以及睾酮的肽或蛋白。
本发明还提供所述核酸序列在本文定义的基因疗法中的应用。本发明还提供包含所述核酸序列的试剂盒或部件的试剂盒。此外,本发明提供包含所述核酸序列的药物组合物。此外,本发明提供用于增加所编码的肽或蛋白的表达的方法,所述方法包括提供所述核酸序列或包含所述核酸序列的组合物并且将所述核酸序列或其他组合物应用至或施用至不含细胞的表达系统、细胞、组织或生物体中的步骤。
优选地,本发明提供包含或编码下述的核酸序列:
a)编码区,所述编码区编码至少一种肽或蛋白;
b)至少一种组蛋白茎环,和
c)聚腺苷酸序列或聚腺苷酸化信号;
其中所述肽或蛋白包含治疗性蛋白或其片段、变体或衍生物,优选用于使体细胞重新变成为多能或全能干细胞的治疗性蛋白,更优选选自Oct-3/4,Sox基因家族(Sox1,Sox2,Sox3和Sox15),Klf家族(Klf1,Klf2,Klf4和Klf5),Myc家族(c-myc,L-myc和N-myc),Nanog以及LIN28的肽或蛋白。
本发明还提供所述核酸序列在本文定义的基因疗法中的应用。本发明还提供包含所述核酸序列的试剂盒或部件的试剂盒。此外,本发明提供包含所述核酸序列的药物组合物。此外,本发明提供用于增加所编码的肽或蛋白的表达的方法,所述方法包括提供所述核酸序列或包含所述核酸序列的组合物并且将所述核酸序列或其他组合物应用至或施用至不含细胞的表达系统、细胞、组织或生物体中的步骤。
优选地,本发明提供包含或编码下述的核酸序列:
a)编码区,所述编码区编码至少一种肽或蛋白;
b)至少一种组蛋白茎环,和
c)聚腺苷酸序列或聚腺苷酸化信号;
其中所述肽或蛋白包含治疗性蛋白或其片段、变体或衍生物,优选选自佐剂或免疫刺激性蛋白、人佐剂蛋白、细菌(佐剂)蛋白、原生动物(佐剂)蛋白、病毒(佐剂)蛋白、真菌(佐剂)蛋白的治疗性蛋白。
本发明还提供所述核酸序列在本文定义的基因疗法中的应用。本发明还提供包含所述核酸序列的试剂盒或部件的试剂盒。此外,本发明提供包含所述核酸序列的药物组合物。此外,本发明提供用于增加所编码的肽或蛋白的表达的方法,所述方法包括提供所述核酸序列或包含所述核酸序列的组合物并且将所述核酸序列或其他组合物应用至或施用至不含细胞的表达系统、细胞、组织或生物体中的步骤。
优选地,本发明提供包含或编码下述的核酸序列:
a)编码区,所述编码区编码至少一种肽或蛋白;
b)至少一种组蛋白茎环,和
c)聚腺苷酸序列或聚腺苷酸化信号;
其中所述肽或蛋白包含治疗性蛋白或其片段、变体或衍生物,优选选自佐剂或免疫刺激性蛋白、人佐剂蛋白、细菌(佐剂)蛋白、原生动物(佐剂)蛋白、病毒(佐剂)蛋白、真菌(佐剂)蛋白的治疗性蛋白,更优选选自人佐剂蛋白,最优选选自模式识别受体TLR1,TLR2,TLR3,TLR4,TLR5,TLR6,TLR7,TLR8,TLR9,TLR10,TLR11;NOD1,NOD2,NOD3,NOD4,NOD5,NALPI,NALP2,NALP3,NALP4,NALP5,NALP6,NALP6,NALP7,NALP7,NALP8,NALP9,NALP10,NALP11,NALP12,NALP13,NALP14,1IPAF,NAIP,CIITA,RIG-I,MDA5和LGP2,TLR信号传导的信号转导剂,包括衔接子蛋白,包括例如,Trif和Cardif;小-GTP酶信号传导的组分(RhoA,Ras,Rac1,Cdc42,Rab等),PIP信号传导的组分(PI3K,Src-激酶等),MyD88-依赖性信号传导的组分(MyD88,IRAK1,IRAK2,IRAK4,TIRAP,TRAF6等),MyD88-非依赖性信号传导的组分(TICAM1,TICAM2,TRAF6,TBK1,IRF3,TAK1,IRAK1等);活化的激酶,包括,例如,Akt,MEKK1,MKK1,MKK3,MKK4,MKK6,MKK7,ERK1,ERK2,GSK3,PKC激酶,PKD激酶,GSK3激酶,JNK,p38MAPK,TAK1,IKK和TAK1;活化的转录因子,包括,例如,NF-κB,c-Fos,c-Jun,c-Myc,CREB,AP-1,Elk-1,ATF2,IRF-3,IRF-7,热休克蛋白,诸如HSP10,HSP60,HSP65,HSP70,HSP75和HSP90,gp96,纤维蛋白原,纤连蛋白的TypIII重复额外结构域A;或补体系统的成分,包括C1q,MBL,C1r,C1s,C2b,Bb,D,MASP-1,MASP-2,C4b,C3b,C5a,C3a,C4a,C5b,C6,C7,C8,C9,CR1,CR2,CR3,CR4,C1qR,C1INH,C4bp,MCP,DAF,H,I,P和CD59,或诱导的靶基因,包括,例如,β-防卫素,细胞表面蛋白;或人佐剂蛋白,包括trif,flt-3配体,Gp96配体,诱导或增强先天性免疫应答的细胞因子,包括IL-1α,IL1β,IL-2,IL-6,IL-7,IL-8,IL-9,IL-12,IL-13,IL-15,IL-16,IL-17,IL-18,IL-21,IL-23,TNFα,IFNα,IFNβ,IFNγ,GM-CSF,G-CSF,M-CSF;趋化因子,包括IL-8,IP-10,MCP-1,MIP-1α,RANTES,嗜酸性粒细胞趋化因子,CCL21;由巨噬细胞释放的细胞因子,包括IL-1,IL-6,IL-8,IL-12和TNF-α;以及IL-1R1和IL-1α。
本发明还提供所述核酸序列在本文定义的基因疗法中的应用。本发明还提供包含所述核酸序列的试剂盒或部件的试剂盒。此外,本发明提供包含所述核酸序列的药物组合物。此外,本发明提供用于增加所编码的肽或蛋白的表达的方法,所述方法包括提供所述核酸序列或包含所述核酸序列的组合物并且将所述核酸序列或其他组合物应用至或施用至不含细胞的表达系统、细胞、组织或生物体中的步骤。
优选地,本发明提供包含或编码下述的核酸序列:
a)编码区,所述编码区编码至少一种肽或蛋白;
b)至少一种组蛋白茎环,和
c)聚腺苷酸序列或聚腺苷酸化信号;
其中所述肽或蛋白包含治疗性蛋白或其片段、变体或衍生物,优选选自佐剂或免疫刺激性蛋白、人佐剂蛋白、细菌(佐剂)蛋白、原生动物(佐剂)蛋白、病毒(佐剂)蛋白、真菌(佐剂)蛋白的治疗性蛋白,更优选选自细菌(佐剂)蛋白,最优选选自细菌热休克蛋白或伴侣蛋白,包括Hsp60,Hsp70,Hsp90,Hsp100;来自革兰氏阴性细菌的OmpA(外膜蛋白);细菌孔蛋白,包括OmpF;细菌毒素,包括来自百日咳博德特氏菌(Bordetella pertussis)的百日咳毒素(PT),p来自百日咳博德特氏菌的百日咳腺苷酸环化酶毒素CyaA和CyaC,来自百日咳毒素的PT-9K/129G突变体,来自百日咳博德特氏菌的百日咳腺苷酸环化酶毒素CyaA和CyaC,破伤风毒素,霍乱毒素(CT),霍乱毒素B-亚基,来自霍乱毒素的CTK63突变体,来自CT的CTE112K突变体,大肠杆菌热不稳定性肠毒素(LT),来自热不稳定性肠毒素的B亚基(LTB),具有减少的毒性的大肠杆菌热不稳定性肠毒素突变体,包括LTK63,LTR72;苯酚可溶性调控蛋白;来自幽门螺杆菌的嗜中性粒细胞活化蛋白(HP-NAP);表面活性蛋白D;来自布氏疏螺旋体的外表面蛋白A脂蛋白,来自结核分枝杆菌的Ag38(38 kDa抗原);来自细菌菌毛的蛋白;霍乱弧菌的肠毒素CT,来自革兰氏阴性细菌的菌毛的菌毛蛋白,和表面活性蛋白A以及细菌鞭毛蛋白。
本发明还提供所述核酸序列在本文定义的基因疗法中的应用。本发明还提供包含所述核酸序列的试剂盒或部件的试剂盒。此外,本发明提供包含所述核酸序列的药物组合物。此外,本发明提供用于增加所编码的肽或蛋白的表达的方法,所述方法包括提供所述核酸序列或包含所述核酸序列的组合物并且将所述核酸序列或其他组合物应用至或施用至不含细胞的表达系统、细胞、组织或生物体中的步骤。
优选地,本发明提供包含或编码下述的核酸序列:
a)编码区,所述编码区编码至少一种肽或蛋白;
b)至少一种组蛋白茎环,和
c)聚腺苷酸序列或聚腺苷酸化信号;
其中所述肽或蛋白包含治疗性蛋白或其片段、变体或衍生物,优选选白佐剂或免疫刺激性蛋白、人佐剂蛋白、细菌(佐剂)蛋白、原生动物(佐剂)蛋白、病毒(佐剂)蛋白、真菌(佐剂)蛋白的治疗性蛋白,更优选选自原生动物(佐剂)蛋白,最优选选自来自克鲁斯锥虫(Trypanosoma cruzi)的Tc52,来自Trypanosoma gondii的PFTG,原生动物热休克蛋白,来自利什曼原虫属物种的LeIF,来自刚地弓形虫的肌动蛋白抑制蛋白样蛋白。
本发明还提供所述核酸序列在本文定义的基因疗法中的应用。本发明还提供包含所述核酸序列的试剂盒或部件的试剂盒。此外,本发明提供包含所述核酸序列的药物组合物。此外,本发明提供用于增加所编码的肽或蛋白的表达的方法,所述方法包括提供所述核酸序列或包含所述核酸序列的组合物并且将所述核酸序列或其他组合物应用至或施用至不含细胞的表达系统、细胞、组织或生物体中的步骤。
优选地,本发明提供包含或编码下述的核酸序列:
a)编码区,所述编码区编码至少一种肽或蛋白;
b)至少一种组蛋白茎环,和
c)聚腺苷酸序列或聚腺苷酸化信号;
其中所述肽或蛋白包含治疗性蛋白或其片段、变体或衍生物,优选选自佐剂或免疫刺激性蛋白、人佐剂蛋白、细菌(佐剂)蛋白、原生动物(佐剂)蛋白、病毒(佐剂)蛋白、真菌(佐剂)蛋白的治疗性蛋白,更优选选自病毒(佐剂)蛋白,最优选选自呼吸道合胞病毒融合糖蛋白(F-蛋白)、来自MMT病毒的包膜蛋白、小鼠白血病病毒蛋白、野生型麻疹病毒的血凝素蛋白。
本发明还提供所述核酸序列在本文定义的基因疗法中的应用。本发明还提供包含所述核酸序列的试剂盒或部件的试剂盒。此外,本发明提供包含所述核酸序列的药物组合物。此外,本发明提供用于增加所编码的肽或蛋白的表达的方法,所述方法包括提供所述核酸序列或包含所述核酸序列的组合物并且将所述核酸序列或其他组合物应用至或施用至不含细胞的表达系统、细胞、组织或生物体中的步骤。
优选地,本发明提供包含或编码下述的核酸序列:
a)编码区,所述编码区编码至少一种肽或蛋白;
b)至少一种组蛋白茎环,和
c)聚腺苷酸序列或聚腺苷酸化信号;
其中所述肽或蛋白包含治疗性蛋白或其片段、变体或衍生物,优选选自佐剂或免疫刺激性蛋白、人佐剂蛋白、细菌(佐剂)蛋白、原生动物(佐剂)蛋白、病毒(佐剂)蛋白、真菌(佐剂)蛋白的治疗性蛋白,更优选选自真菌(佐剂)蛋白,最优选选自真菌免疫调节蛋白(FIP;LZ-8);和钥孔血蓝蛋白(KLH)、OspA。
本发明还提供所述核酸序列在本文定义的基因疗法中的应用。本发明还提供包含所述核酸序列的试剂盒或部件的试剂盒。此外,本发明提供包含所述核酸序列的药物组合物。此外,本发明提供用于增加所编码的肽或蛋白的表达的方法,所述方法包括提供所述核酸序列或包含所述核酸序列的组合物并且将所述核酸序列或其他组合物应用至或施用至不含细胞的表达系统、细胞、组织或生物体中的步骤。
优选地,本发明提供包含或编码下述的核酸序列:
a)编码区,所述编码区编码至少一种肽或蛋白;
b)至少一种组蛋白茎环,和
c)聚腺苷酸序列或聚腺苷酸化信号;
其中所述肽或蛋白包含治疗性蛋白或其片段、变体或衍生物,优选选自用于治疗癌症或肿瘤疾病的抗体的治疗性抗体,优选是131I-托西莫单抗,3F8,8H9,阿巴扶单抗,阿德木单抗,Afutuzumab,Alacizumab pegol,阿仑珠单抗,Amatuximab,AME-133v,AMG 102,麻安莫单抗,阿泊珠单抗,巴土昔单抗,贝妥莫单抗,贝利木单抗,贝伐珠单抗,比伐单抗-DM1,Blinatumomab,Brentuximab vedotin,Cantuzumab,美坎珠单抗,Cantuzumabravtansine,卡罗单抗喷地肽,Carlumab,卡妥索单抗,西妥昔单抗,Citatuzumab bogatox,Cixutumumab,Clivatuzumab tetraxetan,CNTO328,CNTO 95,Conatumumab,Dacetuzumab,Dalotuzumab,地舒单抗,Detumomab,Drozitumab,Ecromeximab,依决洛单抗,Elotuzumab,Elsilimomab,Enavatuzumab,Ensituximab,依帕珠单抗,Ertumaxomab,Ertumaxomab,Etaracizumab,Farletuzumab,FBTA05,Ficlatuzumab,Figitumumab,Flanvotumab,Galiximab,Galiximab,Ganitumab,GC1008,吉妥珠单抗,吉妥珠单抗奥佐米星,Girentuximab,Glembatumumab vedotin,GS6624,HuC242-DM4,HuHMFGl,HuN901-DMl,替伊莫单抗,Icrucumab,ID09C3,Indatuximab ravtansine,伊珠单抗奥佐米星,Intetumumab,Ipilimumab,Iratumumab,Labetuzumab,雷克萨单抗,林妥珠单抗,Lorvotuzumabmertansine,Lucatumumab,鲁昔单抗,Mapatumumab,Matuzumab,MDX-060,MEDI 522,米妥莫单抗,Mogamulizumab,MORab-003,MORab-009,Moxetumomab pasudotox,MT103,他那可单抗,Naptumomab estafenatox,Narnatumab,Necitumumab,尼妥珠单抗,尼妥珠单抗,Olaratumab,Onartuzumab,Oportuzumab monatox,Oregovomab,Oregovomab,PAM4,帕尼单抗,Patritumab,Pemtumomab,帕妥珠单抗,普立昔单抗,Racotumomab,Radretumab,雷莫芦单抗,Rilotumumab,利妥昔单抗,Robatumumab,Samalizumab,SGN-30,SGN-40,西罗珠单抗,Siltuximab,Tabalumab,Tacatuzumab tetraxetan,帕他普莫单抗,Tenatumomab,Teprotumumab,TGNl412,Ticilimumab(=tremelimumab),Tigatuzumab,TNX-650,托西莫单抗,曲妥珠单抗,TRBS07,Tremelimumab,TRU-016,TRU-016,Tucotuzumab celmoleukin,Ublituximab,Urelumab,维妥珠单抗,维妥珠单抗(IMMU--106),Volociximab,伏妥莫单抗,WX-G250,zalutumumab和他珠单抗。
本发明还提供所述核酸序列在本文定义的基因疗法中的应用。本发明还提供包含所述核酸序列的试剂盒或部件的试剂盒。此外,本发明提供包含所述核酸序列的药物组合物。此外,本发明提供用于增加所编码的肽或蛋白的表达的方法,所述方法包括提供所述核酸序列或包含所述核酸序列的组合物并且将所述核酸序列或其他组合物应用至或施用至不含细胞的表达系统、细胞、组织或生物体中的步骤。
优选地,本发明提供包含或编码下述的核酸序列:
a)编码区,所述编码区编码至少一种肽或蛋白;
b)至少一种组蛋白茎环,和
c)聚腺苷酸序列或聚腺苷酸化信号;
其中所述肽或蛋白包含治疗性蛋白或其片段、变体或衍生物,优选选自用于治疗免疫病症的抗体的治疗性抗体,优选选自依法利珠单抗,依帕珠单抗,Etrolizumab,Fontolizumab,Ixekizumab,美泊利单抗,Milatuzumab,汇集的免疫球蛋白,普立昔单抗,利妥昔单抗,Rontalizumab,卢利珠单抗,Sarilumab,维多珠单抗,Visilizumab,Reslizumab,阿达木单抗,Aselizumab,Atinumab,Atlizumab,贝利木单抗,Besilesomab,BMS-945429,Briakinumab,Brodalumab,卡那单抗,卡那单抗,培舍珠单抗,厄利珠单抗,Fezakinumab,戈利木单抗,Gomiliximab,英夫利昔单抗,Mavrilimumab,那他珠单抗,Ocrelizumab,奥度莫单抗,奥法木单抗,Ozoralizumab,Pexelizumab,罗维珠单抗,SBI-087,SBI-087,Secukinumab,Sirukumab,他利珠单抗,托珠单抗,Toralizumab,TRU-015,TRU-016,优特克单抗,优特克单抗,维帕莫单抗,阿佐莫单抗,Sifalimumab,鲁昔单抗,和Rho(D)免疫球蛋白。
本发明还提供所述核酸序列在本文定义的基因疗法中的应用。本发明还提供包含所述核酸序列的试剂盒或部件的试剂盒。此外,本发明提供包含所述核酸序列的药物组合物。此外,本发明提供用于增加所编码的肽或蛋白的表达的方法,所述方法包括提供所述核酸序列或包含所述核酸序列的组合物并且将所述核酸序列或其他组合物应用至或施用至不含细胞的表达系统、细胞、组织或生物体中的步骤。
优选地,本发明提供包含或编码下述的核酸序列:
a)编码区,所述编码区编码至少一种肽或蛋白;
b)至少一种组蛋白茎环,和
c)聚腺苷酸序列或聚腺苷酸化信号;
其中所述肽或蛋白包含治疗性蛋白或其片段、变体或衍生物,优选选自用于治疗癌症或肿瘤疾病的抗体的治疗性抗体,优选用于治疗传染病的抗体,特别是阿非莫单抗,CR6261,埃巴单抗,Efungumab,艾韦单抗,非维珠单抗,Foravirumab,Ibalizumab,Libivirumab,Motavizumab,奈巴库单抗,Tuvirumab,乌珠单抗,巴土昔单抗,Pagibaximab,帕利珠单抗,Panobacumab,PRO 140,瑞非韦鲁,Raxibacumab,瑞加韦单抗,司韦单抗,Suvizumab,和替非珠单抗。
本发明还提供所述核酸序列在本文定义的基因疗法中的应用。本发明还提供包含所述核酸序列的试剂盒或部件的试剂盒。此外,本发明提供包含所述核酸序列的药物组合物。此外,本发明提供用于增加所编码的肽或蛋白的表达的方法,所述方法包括提供所述核酸序列或包含所述核酸序列的组合物并且将所述核酸序列或其他组合物应用至或施用至不含细胞的表达系统、细胞、组织或生物体中的步骤。
优选地,本发明提供包含或编码下述的核酸序列:
a)编码区,所述编码区编码至少一种肽或蛋白;
b)至少一种组蛋白茎环,和
c)聚腺苷酸序列或聚腺苷酸化信号;
其中所述肽或蛋白包含治疗性蛋白或其片段、变体或衍生物,优选选自用于治疗癌症或肿瘤疾病的抗体的治疗性抗体,优选用于治疗血液病症的抗体,特别是阿昔单抗,阿托木单抗,依库珠单抗,美泊利单抗和Milatuzumab。
本发明还提供所述核酸序列在本文定义的基因疗法中的应用。本发明还提供包含所述核酸序列的试剂盒或部件的试剂盒。此外,本发明提供包含所述核酸序列的药物组合物。此外,本发明提供用于增加所编码的肽或蛋白的表达的方法,所述方法包括提供所述核酸序列或包含所述核酸序列的组合物并且将所述核酸序列或其他组合物应用至或施用至不含细胞的表达系统、细胞、组织或生物体中的步骤。
优选地,本发明提供包含或编码下述的核酸序列:
a)编码区,所述编码区编码至少一种肽或蛋白;
b)至少一种组蛋白茎环,和
c)聚腺苷酸序列或聚腺苷酸化信号;
其中所述肽或蛋白包含治疗性蛋白或其片段、变体或衍生物,优选选自用于治疗癌症或肿瘤疾病的抗体的治疗性抗体,优选用于免疫调节的抗体,特别是抗胸腺细胞球蛋白,巴利昔单抗,西地珠单抗,达利珠单抗,Gavilimomab,伊诺莫单抗,莫罗莫那-CD3,莫罗莫那-CD3,奥度莫单抗和Siplizumab。
本发明还提供所述核酸序列在本文定义的基因疗法中的应用。本发明还提供包含所述核酸序列的试剂盒或部件的试剂盒。此外,本发明提供包含所述核酸序列的药物组合物。此外,本发明提供用于增加所编码的肽或蛋白的表达的方法,所述方法包括提供所述核酸序列或包含所述核酸序列的组合物并且将所述核酸序列或其他组合物应用至或施用至不含细胞的表达系统、细胞、组织或生物体中的步骤。
优选地,本发明提供包含或编码下述的核酸序列:
a)编码区,所述编码区编码至少一种肽或蛋白;
b)至少一种组蛋白茎环,和
c)聚腺苷酸序列或聚腺苷酸化信号;
其中所述肽或蛋白包含治疗性蛋白或其片段、变体或衍生物,优选选自用于治疗癌症或肿瘤疾病的抗体的治疗性抗体,优选用于治疗糖尿病的抗体,特别是Gevokizumab,Otelixizumab和Teplizumab。
本发明还提供所述核酸序列在本文定义的基因疗法中的应用。本发明还提供包含所述核酸序列的试剂盒或部件的试剂盒。此外,本发明提供包含所述核酸序列的药物组合物。此外,本发明提供用于增加所编码的肽或蛋白的表达的方法,所述方法包括提供所述核酸序列或包含所述核酸序列的组合物并且将所述核酸序列或其他组合物应用至或施用至不含细胞的表达系统、细胞、组织或生物体中的步骤。
优选地,本发明提供包含或编码下述的核酸序列:
a)编码区,所述编码区编码至少一种肽或蛋白;
b)至少一种组蛋白茎环,和
c)聚腺苷酸序列或聚腺苷酸化信号;
其中所述肽或蛋白包含治疗性蛋白或其片段、变体或衍生物,优选选自用于治疗癌症或肿瘤疾病的抗体的治疗性抗体,优选用于治疗阿尔茨海默病的抗体,特别是Bapineuzumab,Crenezumab,Gantenerumab,Ponezumab,R1450和Solanezumab。
本发明还提供所述核酸序列在本文定义的基因疗法中的应用。本发明还提供包含所述核酸序列的试剂盒或部件的试剂盒。此外,本发明提供包含所述核酸序列的药物组合物。此外,本发明提供用于增加所编码的肽或蛋白的表达的方法,所述方法包括提供所述核酸序列或包含所述核酸序列的组合物并且将所述核酸序列或其他组合物应用至或施用至不含细胞的表达系统、细胞、组织或生物体中的步骤。
优选地,本发明提供包含或编码下述的核酸序列:
a)编码区,所述编码区编码至少一种肽或蛋白;
b)至少一种组蛋白茎环,和
c)聚腺苷酸序列或聚腺苷酸化信号;
其中所述肽或蛋白包含治疗性蛋白或其片段、变体或衍生物,优选选自用于治疗癌症或肿瘤疾病的抗体的治疗性抗体,优选用于治疗哮喘的抗体,特别是Benralizumab,Enokizumab,Keliximab,Lebrikizumab,奥马珠单抗,Oxelumab,Pascolizumab和Tralokinumab。
本发明还提供所述核酸序列在本文定义的基因疗法中的应用。本发明还提供包含所述核酸序列的试剂盒或部件的试剂盒。此外,本发明提供包含所述核酸序列的药物组合物。此外,本发明提供用于增加所编码的肽或蛋白的表达的方法,所述方法包括提供所述核酸序列或包含所述核酸序列的组合物并且将所述核酸序列或其他组合物应用至或施用至不含细胞的表达系统、细胞、组织或生物体中的步骤。
优选地,本发明提供包含或编码下述的核酸序列:
a)编码区,所述编码区编码至少一种肽或蛋白;
b)至少一种组蛋白茎环,和
c)聚腺苷酸序列或聚腺苷酸化信号;
其中所述肽或蛋白包含治疗性蛋白或其片段、变体或衍生物,优选选自用于治疗癌症或肿瘤疾病的抗体的治疗性抗体,优选用于治疗多种病症的抗体,特别是Blosozumab,CaroRx,Fresolimumab,Fulranumab,Romosozumab,司他莫单抗,Tanezumab和雷珠单抗。
本发明还提供所述核酸序列在本文定义的基因疗法中的应用。本发明还提供包含所述核酸序列的试剂盒或部件的试剂盒。此外,本发明提供包含所述核酸序列的药物组合物。此外,本发明提供用于增加所编码的肽或蛋白的表达的方法,所述方法包括提供所述核酸序列或包含所述核酸序列的组合物并且将所述核酸序列或其他组合物应用至或施用至不含细胞的表达系统、细胞、组织或生物体中的步骤。
优选地,本发明提供包含或编码下述的核酸序列:
a)编码区,所述编码区编码至少一种肽或蛋白;
b)至少一种组蛋白茎环,和
c)聚腺苷酸序列或聚腺苷酸化信号;
其中所述肽或蛋白包含治疗性蛋白或其片段、变体或衍生物,其可以是这样的治疗性蛋白:
所述治疗性蛋白用于治疗代谢或内分泌紊乱,
用于治疗血液病症、循环系统疾病、呼吸系统疾病、癌症或肿瘤疾病、传染病或免疫缺陷,
用于激素替代疗法,或
用于使体细胞重新编程,
更优选选自下述的治疗性蛋白:酸性鞘磷脂酶,Adipotide,Agalsidase-β,Alglucosidase,α-半乳糖苷酶A,α-葡糖苷酶,α-L-艾杜糖苷酸酶,α-N-乙酰葡糖苷酶,双调蛋白,血管生成素(Ang1,Ang2,Ang3,Ang4,ANGPTL2,ANGPTL3,ANGPTL4,ANGPTL5,ANGPTL6,ANGPTL7),β动物纤维素,β-葡糖醛酸糖苷酶,骨形态发生蛋白BMPs(BMP1,BMP2,BMP3,BMP4,BMP5,BMP6,BMP7,BMP8a,BMP8b,BMP10,BMP15),CLN6蛋白,表皮生长因子(EGF),Epigen,表皮调节素,成纤维细胞生长因子(FGF,FGF-1,FGF-2,FGF-3,FGF-4,FGF-5,FGF-6,FGF-7,FGF-8,FGF-9,FGF-10,FGF-11,FGF-12,FGF-13,FGF-14,FGF-16,FGF-17,FGF-17,FGF-18,FGF-19,FGF-20,FGF-21,FGF-22,FGF-23),Galsulphase,葛瑞林,葡糖脑苷脂酶,GM-CSF,肝素-结合EGF-样生长因子(HB-EGF),肝细胞生长因子HGF,Hepcidin,人白蛋白,增加的白蛋白损失,艾度硫酸酯酶(艾杜糖醛酸-2-硫酸酯酶),整联蛋白αVβ3,αVβ5和α5β1,艾杜糖醛酸硫酸酯酶,拉罗尼酶,N-乙酰半乳糖胺-4-硫酸酯酶(rhASB;galsulfase,芳基硫酸酯酶A(ARSA),芳基硫酸酯酶B(ARSB)),N-乙酰葡糖胺-6-硫酸酯酶,神经生长因子(NGF,脑源性神经营养因子(BDNF),神经营养因子-3(NT-3),和神经营养因子4/5(NT-4/5),神经调节蛋白(NRG1,NRG2,NRG3,NRG4),神经毡蛋白(NRP-1,NRP-2),肥胖抑制素,血小板衍生生长因子(PDGF(PDFF-A,PDGF-B,PDGF-C,PDGF-D),TGFβ受体(内皮因子,TGF-β1受体,TGF-β2受体,TGF-β3受体),血小板生成素(THPO)(巨核细胞生长和发育因子(MGDF)),转化生长因子(TGF(TGF-a,TGF-β(TGFβ1,TGFβ2,和TGFβ3))),VEGF(VEGF-A,VEGF-B,VEGF-C,VEGF-D,VEGF-E,VEGF-F und PIGF),奈西立肽,胰蛋白酶,促肾上腺皮质激素(ACTH),心房钠尿肽(ANP),胆囊收缩素,胃泌素,瘦蛋白,催产素,生长抑素,加压素(抗利尿激素),降钙素,Exenatide,生长激素(GH),生长素,胰岛素,胰岛素样生长因子1 IGF-1,Mecasermin rinfabate,IGF-1类似物,美卡舍明,IGF-1类似物,培维索孟,普兰林肽,特立帕肽(人甲状旁腺素残基1-34),贝卡普勒明,Dibotermin-α(骨形态发生蛋白2),醋酸组氨瑞林(促性腺素释放激素;GnRH),奥曲肽,和帕利夫明(角质形成细胞生长因子;KGF),阿替普酶(组织型纤溶酶原激活物;tPA),阿尼普酶,抗凝血酶III(AT-III),比伐卢定,达贝泊汀α,屈曲克凝α(活化的蛋白C,促红细胞生成素,依泊汀α,促血红细胞生长素,红细胞生成素,因子IX,因子VIIa,因子VIII,来匹卢定,蛋白质C浓缩剂,瑞替普酶(tPA的缺失突变蛋白),链激酶,替奈普酶,尿激酶,血管抑素,抗-CD22免疫毒素,地尼白介素-毒素连接物,Immunocyanin,MPS(Metallopanstimulin),Aflibercept,内皮抑素,胶原酶,人脱氧核糖核酸酶I,链道酶,透明质酸酶,木瓜蛋白酶,L-天冬酰胺酶,Peg-天冬酰胺酶,拉布立酶,人慢性促性腺素(HCG),人促卵泡激素(FSH),促黄体素-α,催乳素,α-1-蛋白酶抑制剂,乳糖酶,胰酶(脂肪酶,淀粉酶,蛋白酶),腺苷脱氨酶(牛培加酶,PEG-ADA),阿巴他塞,阿来法塞,阿那白滞素,Etanercept,白细胞介素-1(IL-1)受体拮抗剂,阿那白滞素,胸腺素,TNF-α拮抗剂,恩夫韦肽,胸腺素α1,雌激素,孕酮或黄体酮,睾酮,Oct-3/4,Sox基因家族(Sox1,Sox2,Sox3和Sox15),Klf家族(Klf1,Klf2,Klf4和Klf5),Myc家族(c-myc,L-myc和N-myc),Nanog,和LIN28。
本发明还提供所述核酸序列在本文定义的基因疗法中的应用。本发明还提供包含所述核酸序列的试剂盒或部件的试剂盒。此外,本发明提供包含所述核酸序列的药物组合物。此外,本发明提供用于增加所编码的肽或蛋白的表达的方法,所述方法包括提供所述核酸序列或包含所述核酸序列的组合物并且将所述核酸序列或其他组合物应用至或施用至不含细胞的表达系统、细胞、组织或生物体中的步骤。
优选地,本发明提供包含或编码下述的核酸序列:
a)编码区,所述编码区编码至少一种肽或蛋白;
b)至少一种组蛋白茎环,和
c)聚腺苷酸序列或聚腺苷酸化信号;
其中所述肽或蛋白包含治疗性蛋白或其片段、变体或衍生物,优选选自佐剂或免疫刺激性蛋白、人佐剂蛋白、细菌(佐剂)蛋白、原生动物(佐剂)蛋白、病毒(佐剂)蛋白、真菌(佐剂)蛋白的治疗性蛋白,更优选选自人佐剂蛋白,最优选选自模式识别受体TLR1,TLR2,TLR3,TLR4,TLR5,TLR6,TLR7,TLR8,TLR9,TLR10,TLR11;NOD1,NOD2,NOD3,NOD4,NOD5,NALP1,NALP2,NALP3,NALP4,NALP5,NALP6,NALP6,NALP7,NALP7,NALP8,NALP9,NALP10,NALP11,NALP12,NALP13,NALP14,1IPAF,NAIP,CIITA,RIG-I,MDA5和LGP2,TLR信号传导的信号转导剂,包括衔接子蛋白,包括例如,Trif和Cardif;小-GTP酶信号传导的组分(RhoA,Ras,Rac1,Cdc42,Rab等),PIP信号传导的组分(P13K,Src-激酶等),MyD88-依赖性信号传导的组分(MyD88,IRAK1,IRAK2,IRAK4,TIRAP,TRAF6等),MyD88-非依赖性信号传导的组分(TICAM1,TICAM2,TRAF6,TBK1,IRF3,TAK1,IRAK1等);活化的激酶,包括,例如,Akt,MEKK1,MKK1,MKK3,MKK4,MKK6,MKK7,ERK1,ERK2,GSK3,PKC激酶,PKD激酶,GSK3激酶,JNK,p38MAPK,TAK1,IKK和TAK1;活化的转录因子,包括,例如,NF-κB,c-Fos,c-Jun,c-Myc,CREB,AP-1,Elk-1,ATF2,IRF-3,IRF-7,热休克蛋白,诸如HSP10,HSP60,HSP65,HSP70,HSP75和HSP90,gp96,纤维蛋白原,纤连蛋白的TypIII重复额外结构域A;或补体系统的成分,包括C1q,MBL,C1r,C1s,C2b,Bb,D,MASP-1,MASP-2,C4b,C3b,C5a,C3a,C4a,C5b,C6,C7,C8,C9,CR1,CR2,CR3,CR4,C1qR,C1INH,C4bp,MCP,DAF,H,I,P和CD59,或诱导的靶基因,包括,例如,β-防卫素,细胞表面蛋白;或人佐剂蛋白,包括trif,flt-3配体,Gp96或纤连蛋白,诱导或增强先天性免疫应答的细胞因子,包括IL-1α,IL1β,IL-2,IL-6,IL-7,IL-8,IL-9,IL-12,IL-13,IL-15,IL-16,IL-17,IL-18,IL-21,IL-23,TNFα,IFNα,IFNβ,IFNγ,GM-CSF,G-CSF,M-CSF;趋化因子,包括IL-8,IP-10,MCP-1,MIP-1α,RANTES,嗜酸性粒细胞趋化因子,CCL21;由巨噬细胞释放的细胞因子,包括IL-1,IL-6,IL-8,IL-12和TNF-α;以及IL-1R1和IL-1α,细菌热休克蛋白或伴侣蛋白,包括Hsp60,Hsp70,Hsp90,Hsp100;来自革兰氏阴性细菌的OmpA(外膜蛋白);细菌孔蛋白,包括OmpF;细菌毒素,包括来自百日咳博德特氏菌的百日咳毒素(PT),来自百日咳博德特氏菌的百日咳腺苷酸环化酶毒素CyaA和CyaC,来自百日咳毒素的PT-9K/129G突变体,来自百日咳博德特氏菌的百日咳腺苷酸环化酶毒素CyaA和CyaC,破伤风毒素,霍乱毒素(CT),霍乱毒素B-亚基,来自霍乱毒素的CTK63突变体,来自霍乱毒素的CTK63突变体,大肠杆菌热不稳定性肠毒素(LT),来自热不稳定性肠毒素的B亚基(LTB),具有减少的毒性的大肠杆菌热不稳定性肠毒素突变体,包括LTK63,LTR72;苯酚可溶性调控蛋白;来自幽门螺杆菌的嗜中性粒细胞活化蛋白(HP-NAP);表面活性蛋白D;来自布氏疏螺旋体的外表面蛋白A脂蛋白,来自结核分枝杆菌的Ag38(38 kDa抗原);来自细菌菌毛的蛋白;霍乱弧菌的肠毒素CT,来自革兰氏阴性细菌的菌毛的菌毛蛋白,和表面活性蛋白A和细菌鞭毛蛋白,来自克鲁斯锥虫的Tc52,来自Trypanosoma gondii的PFTG,原生动物热休克蛋白,来自利什曼原虫属物种的LeIF,来自刚地弓形虫的肌动蛋白抑制蛋白样蛋白,呼吸道合胞病毒融合糖蛋白(F-蛋白),来自MMT病毒的包膜蛋白,小鼠白血病病毒蛋白,野生型麻疹病毒的血凝素蛋白,真菌免疫调节性蛋白(FIP;LZ-8);和钥孔血蓝蛋白(KLH),OspA。
优选地,本发明提供包含或编码下述的核酸序列:
a)编码区,所述编码区编码至少一种肽或蛋白;
b)至少一种组蛋白茎环,和
c)聚腺苷酸序列或聚腺苷酸化信号;
其中所述肽或蛋白包含治疗性蛋白或其片段、变体或衍生物,优选选自用于治疗癌症或肿瘤疾病的抗体的治疗性抗体,优选是131I-托西莫单抗,3F8,8H9,阿巴扶单抗,阿德木单抗,Afutuzumab,Alacizumab pegol,阿仑珠单抗,Amatuximab,AME-133v,AMG 102,麻安莫单抗,阿泊珠单抗,巴土昔单抗,贝妥莫单抗,贝利木单抗,贝伐珠单抗,比伐单抗-DM1,Blinatumomab,Brentuximab vedotin,Cantuzumab,美坎珠单抗,Cantuzumabravtansine,卡罗单抗喷地肽,Carlumab,卡妥索单抗,西妥昔单抗,Citatuzumab bogatox,Cixutumumab,Clivatuzumab tetraxetan,CNTO328,CNTO 95,Conatumumab,Dacetuzumab,Dalotuzumab,地舒单抗,Detumomab,Drozitumab,Ecromeximab,依决洛单抗,Elotuzumab,Elsilimomab,Enavatuzumab,Ensituximab,依帕珠单抗,Ertumaxomab,Ertumaxomab,Etaracizumab,Farletuzumab,FBTA05,Ficlatuzumab,Figitumumab,Flanvotumab,Galiximab,Galiximab,Ganitumab,GC1008,吉妥珠单抗,吉妥珠单抗奥佐米星,Girentuximab,Glembatumumab vedotin,GS6624,HuC242-DM4,HuHMFG1,HuN901-DM1,替伊莫单抗,Icrucumab,ID09C3,Indatuximab ravtansine,伊珠单抗奥佐米星,Intetumumab,Ipilimumab,Iratumumab,Labetuzumab,雷克萨单抗,林妥珠单抗,Lorvotuzumabmertansine,Lucatumumab,鲁昔单抗,Mapatumumab,Matuzumab,MDX-060,MEDI 522,米妥莫单抗,Mogamulizumab,MORab-003,MORab-009,Moxetumomab pasudotox,MT103,他那可单抗,Naptumomab estafenatox,Narnatumab,Necitumumab,尼妥珠单抗,尼妥珠单抗,Olaratumab,Onartuzumab,Oportuzumab monatox,Oregovomab,Oregovomab,PAM4,帕尼单抗,Patritumab,Pemtumomab,帕妥珠单抗,普立昔单抗,Racotumomab,Radretumab,雷莫芦单抗,Rilotumumab,利妥昔单抗,Robatumumab,Samalizumab,SGN-30,SGN-40,西罗珠单抗,Siltuximab,Tabalumab,Tacatuzumab tetraxetan,帕他普莫单抗,Tenatumomab,Teprotumumab,TGN1412,Ticilimumab(=tremelimumab),Tigatuzumab,TNX-650,托西莫单抗,曲妥珠单抗,TRBS07,Tremelimumab,TRU-016,TRU-016,Tucotuzumab celmoleukin,Ublituximab,Urelumab,维妥珠单抗,维妥珠单抗(IMMU-106),Volociximab,伏妥莫单抗,WX-G250,Zalutumumab,他珠单抗,依法利珠单抗,依帕珠单抗,Etrolizumab,Fontolizumab,Ixekizumab,美泊利单抗,Milatuzumab,汇集的免疫球蛋白,普立昔单抗,利妥昔单抗,Rontalizumab,卢利珠单抗,Sarilumab,维多珠单抗,Visilizumab,Reslizumab,阿达术单抗,Aselizumab,Atinumab,Atlizumab,贝利木单抗,Besilesomab,BMS-945429,Briakinumab,Brodalumab,卡那单抗,卡那单抗,培舍珠单抗,厄利珠单抗,Fezakinumab,戈利木单抗,Gomiliximab,英夫利昔单抗,Mavrilimumab,那他珠单抗,Ocrelizumab,奥度莫单抗,奥法木单抗,Ozoralizumab,Pexelizumab,罗维珠单抗,SBI-087,SBI-087,Secukinumab,Sirukumab,他利珠单抗,托珠单抗,Toralizumab,TRU-015,TRU-016,优特克单抗,优特克单抗,维帕莫单抗,阿佐莫单抗,Sifalimumab,鲁昔单抗,and Rho(D)免疫球蛋白,阿非莫单抗,CR6261,埃巴单抗,Efungumab,艾韦单抗,非维珠单抗,Foravirumab,Ibalizumab,Libivirumab,Motavizumab,奈巴库单抗,Tuvirumab,乌珠单抗,巴土昔单抗,Pagibaximab,帕利珠单抗,Panobacumab,PRO 140,瑞非韦鲁,Raxibacumab,瑞加韦单抗,司韦单抗,Suvizumab,替非珠单抗,阿昔单抗,阿托木单抗,依库珠单抗,美泊利单抗,Milatuzumab,抗胸腺细胞球蛋白,巴利昔单抗,西地珠单抗,达利珠单抗,Gavilimomab,伊诺莫单抗,莫罗莫那-CD3,莫罗莫那-CD3,奥度莫单抗,Siplizumab,Gevokizumab,Otelixizumab,Teplizumab,Bapineuzumab,Crenezumab,Gantenerumab,Ponezumab,R1450,Solanezumab,Benralizumab,Enokizumab,Keliximab,Lebrikizumab,奥马珠单抗,Oxelumab,Pascolizumab,Tralokinumab,Blosozumab,CaroRx,Fresolimumab,Fulranumab,Romosozumab,司他莫单抗,Tanezumab和雷珠单抗。
本发明还提供所述核酸序列在本文定义的基因疗法中的应用。本发明还提供包含所述核酸序列的试剂盒或部件的试剂盒。此外,本发明提供包含所述核酸序列的药物组合物。此外,本发明提供用于增加所编码的肽或蛋白的表达的方法,所述方法包括提供所述核酸序列或包含所述核酸序列的组合物并且将所述核酸序列或其他组合物应用至或施用至不含细胞的表达系统、细胞、组织或生物体中的步骤。
优选地,本发明提供包含或编码下述的核酸序列:
a)编码区,所述编码区编码至少一种肽或蛋白;
b)至少一种组蛋白茎环,和
c)聚腺苷酸序列或聚腺苷酸化信号;
其中所述肽或蛋白包含治疗性蛋白或其片段、变体或衍生物,优选是蛋白激素的治疗性蛋白。
本发明还提供所述核酸序列在本文定义的基因疗法中的应用。本发明还提供包含所述核酸序列的试剂盒或部件的试剂盒。此外,本发明提供包含所述核酸序列的药物组合物。此外,本发明提供用于增加所编码的肽或蛋白的表达的方法,所述方法包括提供所述核酸序列或包含所述核酸序列的组合物并且将所述核酸序列或其他组合物应用至或施用至不含细胞的表达系统、细胞、组织或生物体中的步骤。
优选地,本发明提供包含或编码下述的核酸序列:
a)编码区,所述编码区编码至少一种肽或蛋白;
b)至少一种组蛋白茎环,和
c)聚腺苷酸序列或聚腺苷酸化信号;
其中所述肽或蛋白包含治疗性蛋白或其片段、变体或衍生物,优选是蛋白激素的治疗性蛋白。
本发明还提供所述核酸序列在本文定义的基因疗法中的应用。本发明还提供包含所述核酸序列的试剂盒或部件的试剂盒。此外,本发明提供包含所述核酸序列的药物组合物。此外,本发明提供用于增加所编码的肽或蛋白的表达的方法,所述方法包括提供所述核酸序列或包含所述核酸序列的组合物并且将所述核酸序列或其他组合物应用至或施用至不含细胞的表达系统、细胞、组织或生物体中的步骤。
在本发明中,如果没有另外指明,则各备选方案和各实施方案的不同的特征可以彼此组合。此外,如果没有特别提及,术语“包含”不应该解释为意指“由……组成”。然而,在本发明的情形中,在适用时,术语“包含”可以被术语“由……组成”替代。
附图:
下述附图意欲进一步举例说明本发明,并且不应该解释为将本发明限制于此。
图1:显示由后生动物和原生动物茎环序列产生的组蛋白茎环共有序列(由DávilaLópez,M.,&Samuelsson,T.(2008),RNA(纽约,N.Y.),14(1),1-10.doi:10.1261/rna.782308报道)。比对来自后生动物和原生动物的4001条组蛋白茎环序列,并且对该茎环序列中的每个位置显示存在的核苷酸的量。使用单字母核苷酸密码给出表示在所分析的序列中存在的所有核苷酸的所产生的共有序列。除了共有序列之外,显示表示在所分析的序列中存在的至少99%,95%和90%的核苷酸的序列。
图2:显示由原生动物茎环序列产生的组蛋白茎环共有序列的(由Dávila López,M.,&Samuelsson,T.(2008),RNA(纽约,N.Y.),14(1),1-10.doi:10.1261/rna.782308报道)。比对来自原生动物的131条组蛋白茎环序列,并且对该茎环序列中的每个位置显示存在的核苷酸的量。使用单字母核苷酸密码给出表示在所分析的序列中存在的所有核苷酸的所产生的共有序列。除了共有序列之外,显示表示在所分析的序列中存在的至少99%,95%和90%的核苷酸的序列。
图3:显示由后生动物茎环序列产生的组蛋白茎环共有序列(由Dávila López,M.,&Samuelsson,T.(2008),RNA(纽约,N.Y.),14(1),1-10.doi:10.1261/rna.782308报道)。比对来自后生动物的3870条组蛋白茎环序列,并且对该茎环序列中的每个位置显示存在的核苷酸的量。使用单字母核苷酸密码给出表示在所分析的序列中存在的所有核苷酸的所产生的共有序列。除了共有序列之外,显示表示在所分析的序列中存在的至少99%,95%和90%的核苷酸的序列。
图4:显示由脊椎动物茎环序列产生的组蛋白茎环共有序列(由Dávila López,M.,&Samuelsson,T.(2008),RNA(纽约,N.Y.),14(1),1-10.doi:10.1261/rna.782308报道)。比对来自脊椎动物的1333条组蛋白茎环序列,并且对该茎环序列中的每个位置显示存在的核苷酸的量。使用单字母核苷酸密码给出表示在所分析的序列中存在的所有核苷酸的所产生的共有序列。除了共有序列之外,显示表示在所分析的序列中存在的至少99%,95%和90%的核苷酸的序列。
图5:显示由人(智人(Homo sapiens))茎环序列产生的组蛋白茎环共有序列(由Dávila López,M.,&Samuelsson,T.(2008),RNA(纽约,N.Y.),14(1),1-10.doi:10.1261/rna.782308报道)。比对来自人的84条组蛋白茎环序列,并且对该茎环序列中的每个位置显示存在的核苷酸的量。使用单字母核苷酸密码给出表示在所分析的序列中存在的所有核苷酸的所产生的共有序列。除了共有序列之外,显示表示在所分析的序列中存在的至少99%,95%和90%的核苷酸的序列。
图6-19:显示来自体外转录的mRNAs。
给出通过体外转录得到的mRNAs的命名和序列。使用下述缩写:
ppLuc(GC): 编码北美萤火虫(Photinus pyralis)的荧光素酶的富含GC的mRNA序列
ag: α珠蛋白基因的3’非翻译区(UTR)
A64: 具有64个腺苷酸的聚腺苷酸-序列
A120: 具有120个腺苷酸的聚腺苷酸-序列
组蛋白SL: 组蛋白茎环
aCPSL: 已经针对其αCP-2KL蛋白的特异性结合从文库中选择的茎环
PolioCL: 来自脊髓灰质炎病毒(Polio virus)基因组RNA的5’三叶草形
G30: 具有30个鸟苷酸的聚(G)序列
U30: 具有30个尿苷酸的聚(U)序列
SL: 非特异性/人工茎环
N32: 32个核苷酸的非特异性序列
MmEPO(GC): 编码鼠EPO的富含GC-的mRNA序列
在所述序列中,突出显示下述元件:
编码区(ORF)(大写字母),ag(粗体),组蛋白SL(下划线),所检测的其他独特的序列(斜体)。
图6:显示ppLuc(GC)-ag(SEQ ID NO:43)的mRNA序列。
通过在紧接在α-珠蛋白3’-UTR(ag)后的限制性位点使原始载体线性化,获得缺少聚腺苷酸序列的mRNA。
图7:显示ppLuc(GC)-ag-A64(SEQ ID NO:44)的mRNA序列。
通过在紧接在A64聚腺苷酸-序列后的限制性位点使原始载体线性化,获得末端具有A64聚腺苷酸序列的mRNA。
图8:显示ppLuc(GC)-ag-组蛋白SL(SEQ ID NO:45)的mRNA序列。
A64聚腺苷酸序列被组蛋白SL替代。用于该实例的组蛋白茎环序列获自Cakmakci等人.(2008).Molecular and Cellular Biology(分子和细胞生物学),28(3),1182-1194。
图9:显示ppLuc(GC)-ag-A64-组蛋白SL(SEQ ID NO:46)的mRNA序列。
组蛋白SL附加在A64聚腺苷酸的3’。
图10:显示ppLuc(GC)-ag-A120(SEQ ID NO:47)的mRNA序列。
A64聚腺苷酸序列被A120聚腺苷酸序列替代。
图11:显示ppLuc(GC)-ag-A64-ag(SEQ ID NO:48)的mRNA序列。第二个α-珠蛋白3’-UTR附加在A64聚腺苷酸的3’。
图12:显示ppLuc(GC)-ag-A64-aCPSL(SEQ ID NO:49)的mRNA序列。
茎环附加在A64聚腺苷酸的3’。茎环已经针对其αCP-2KL蛋白特异性结合从文库中选择(Thisted等人.,(2001),The Journal of Biological Chemistry(生物化学杂志),276(20),17484-17496)。αCP-2KL是αCP-2的同种型,其是最强表达的αCP蛋白(α-珠蛋白mRNA聚(C)结合蛋白)(Makeyev等人.,(2000),Genomics(基因组),67(3),301-316),一组RNA结合蛋白,其结合α-珠蛋白3’-UTR(Chkheidze等人.,(1999),Molecular and CellularBiology(分子和细胞生物学),19(7),4572-4581)。
图13:显示ppLuc(GC)-ag-A64-PolioCL(SEQ ID NO:50)的mRNA序列。
来自脊髓灰质炎病毒基因组RNA的5’三叶草形附加在A64聚腺苷酸的3’。
图14:显示ppLuc(GC)-ag-A64-G30(SEQ ID NO:51)的mRNA序列
30个鸟苷酸的片段附加在A64聚腺苷酸的3’。
图15:显示ppLuc(GC)-ag-A64-U30(SEQ ID NO:52)的mRNA序列
30个尿苷酸的片段附加在A64聚腺苷酸的3’。
图16:显示ppLuc(GC)-ag-A64-SL(SEQ ID NO:53)的mRNA序列茎环附加在A64聚腺苷酸的3’。茎的上部和环取自(Babendure 等人.,(2006),RNA(纽约,N.Y.),12(5),851-861)。该茎环由长为17个碱基对的富含CG的茎和长为6个碱基的环组成。
图17:显示ppLuc(GC)-ag-A64-N32(SEQ ID NO:54)
通过在备选的限制性位点将原始载体线性化,获得在聚腺苷酸后有32个另外的核苷酸的mRNA。
图18:显示MmEPO(GC)-ag-A64-C30(SEQ ID NO:55)的mRNA序列
图19:显示MmEPO(GC)-ag-A64-C30-组蛋白SL(SEQ ID NO:56)的mRNA序列
图20:显示聚腺苷酸与组蛋白SL的组合以协同方式增加mRNA的蛋白表达。
检验聚腺苷酸序列、组蛋白SL以及聚腺苷酸与组蛋白SL的组合对mRNA的荧光素酶表达的作用。因此,将不同的mRNAs电穿孔至HeLa细胞中。在转染后6、24和48小时测量荧光素酶水平。不具有聚腺苷酸序列和组蛋白SL的mRNA有很少的荧光素酶表达。聚腺苷酸序列或组蛋白SL增加荧光素酶水平。然而,引人注意的是,聚腺苷酸和组蛋白SL的组合进一步强烈增加荧光素酶水平,高于用单独的每种元件所观察到的水平的数倍,因此它们是协同作用的。数据绘制为一式三份转染的平均值RLU±SD(相对光单位±标准偏差)。具体的RLU总结在实施例10.2中。
图21:显示聚腺苷酸与组蛋白SL的组合增加mRNA的蛋白表达与其顺序无关。
检验聚腺苷酸序列、组蛋白SL、聚腺苷酸与组蛋白SL的组合以及它们的顺序对mRNA的荧光素酶表达的作用。因此,将不同的mRNAs脂质转染至HeLa细胞中。在转染开始后6、24和48小时测量荧光素酶水平。A64聚腺苷酸序列或组蛋白SL都产生可比较的荧光素酶水平。将聚腺苷酸序列的长度由A64增加至A120或增加至A300适度地增加荧光素酶水平。相比之下,与延长聚腺苷酸序列相比,聚腺苷酸与组蛋白SL的组合增加荧光素酶水平要多得多。由于其增加荧光素酶水平高于用单独的每种元件所观察到的水平的数倍,因此,聚腺苷酸与组蛋白SL的组合协同作用。使用A64-组蛋白SL或组蛋白SL-A250 mRNA观察到聚腺苷酸与组蛋白SL的组合的协同作用,这与聚腺苷酸和组蛋白SL的顺序无关,并且与聚腺苷酸的长度无关。数据绘制为一式三份转染的平均值RLU±SD。具体的RLU总结在实施例10.3中。
图22:显示聚腺苷酸与组蛋白SL的组合对蛋白表达的增加是特异性的。
检验聚腺苷酸与组蛋白SL的组合或聚腺苷酸与备选序列的组合对mRNA的荧光素酶表达的作用。因此,将不同的mRNAs电穿孔至HeLa细胞中。在转染后6、24和48小时测量荧光素酶水平。聚腺苷酸序列或组蛋白SL都产生可比较的荧光素酶水平。聚腺苷酸与组蛋白SL的组合强烈增加荧光素酶水平,高于用单独的每种元件所观察到的水平的数倍,因此,组合是协同作用的。相比之下,与仅含有聚腺苷酸序列的mRNA相比,聚腺苷酸与其他序列中的任一种的组合对荧光素酶水平没有影响。因此,将聚腺苷酸与组蛋白SL组合特异性并且协同地起作用。数据绘制为一式三份转染的平均值RLU±SD。具体的RLU总结在实施例10.4中。
图23:显示聚腺苷酸与组蛋白SL的组合在体内以协同方式增加mRNA的蛋白表达。
检验聚腺苷酸序列、组蛋白SL和聚腺苷酸与组蛋白SL的组合在体内对mRNA的荧光素酶表达的作用。因此,将不同的mRNAs皮内注射到小鼠中。在注射后16小时将小鼠处死,并且测量注射部位的荧光素酶水平。荧光素酶由具有组蛋白SL或聚腺苷酸序列的mRNA表达。然而,令人注意的是,聚腺苷酸与组蛋白SL的组合强烈增加荧光素酶水平,高于用单独的每种元件所观察到的水平的数倍,因此,组合是协同作用的。数据绘制为平均值RLU±SEM(相对光单位±平均值的标准误差)。具体的RLU总结在实施例10.5中。
图24:显示曲妥珠单抗(GC)-ag-A64-C30(SEQ ID NO:57)的mRNA序列。该序列编码WO2008/083949中所述的包含轻链和重链的抗体曲妥珠单抗(赫赛汀(Herceptin))。
图25:显示曲妥珠单抗(GC)-ag-A64-C30-组蛋白SL(SEQ ID NO:58)的mRNA序列。该序列编码WO2008/083949中所述的包含轻链和重链的抗体曲妥珠单抗(赫赛汀(Herceptin))。
实施例:
下述实施例意欲进一步举例说明本发明,并且不应该解释为将本发明限制于此。
1.产生组蛋白-茎环共有序列
在实验之前,基于后生动物和原生动物组蛋白茎环序列确定组蛋白茎环共有序列。序列取自由Lopez等人.(Dávila López,M.,&Samuelsson,T.(2008),RNA(纽约,N.Y.),14(1),1-10.doi:10.1261/rna.782308)提供的附录,其通过检索基因组序列和表达的序列标签而鉴定了大量的天然组蛋白茎环序列。首先,将所有来自后生动物和原生动物的序列(4001条序列)、或所有来自原生动物(131条序列)或备选地来自后生动物(3870条序列)或来自脊椎动物(1333条序列)或来自人(84条序列)的序列分组并且比对。然后,为每个位置确定存在的核苷酸的量。基于这样得到的表,产生表示在所分析的序列中存在的所有核苷酸的5组不同的序列的共有序列。另外,也得到更加限制性的共有序列,其愈加强调保守的核苷酸。
2.制备DNA-模板
构建用于体外转录的载体,其包含T7启动子,之后接着富含GC的编码北美萤火虫荧光素酶的序列(ppLuc(GC)),α-珠蛋白的3’非翻译区(UTR)的中心部分(ag)和聚腺苷酸序列。聚腺苷酸序列紧接着限制性位点,该限制性位点用于在体外转录之前将载体线性化,从而获得末端为A64聚腺苷酸序列的mRNA。因此,通过体外转录由该载体获得的mRNA命名为“ppLuc(GC)-ag-A64”。
在体外转录之前在备选的限制性位点将该载体线性化允许获得延伸带有另外的3’A64核苷酸或缺少A64的mRNA。另外,原始载体被修饰以包含备用序列。总之,通过体外转录由这些载体获得下述mRNAs(图6-17中给出了mRNA序列):
ppLuc(GC)-ag (SEQ ID NO:43)
ppLuc(GC)-ag-A64 (SEQ ID NO:44)
ppLuc(GC)-ag-组蛋白SL (SEQ ID NO:45)
ppLuc(GC)-ag-A64-组蛋白SL (SEQ ID NO:46)
ppLuc(GC)-ag-A120 (SEQ ID NO:47)
ppLuc(GC)-ag-A64-ag (SEQ ID NO:48)
ppLuc(GC)-ag-A64-aCPSL (SEQ ID NO:49)
ppLuc(GC)-ag-A64-PolioCL (SEQ ID NO:50)
ppLuc(GC)-ag-A64-G30 (SEQ ID NO:51)
ppLuc(GC)-ag-A64-U30 (SEQ ID NO:52)
ppLuc(GC)-ag-A64-SL (SEQ ID NO:53)
ppLuc(GC)-ag-A64-N32 (SEQ ID NO:54)
此外,相应地按照上述制备编码治疗性蛋白EPO的DNA质粒序列。
总之,通过体外转录由这些载体获得下述mRNAs(图18-19中给出了mRNA序列):
MmEPO(GC)-ag-A64-C30(SEQ ID NO:55)
MmEPO(GC)-ag-A64-C30-组蛋白SL(SEQ ID NO:56)
此外,编码抗体曲妥珠单抗的DNA质粒序列可以相应地按照上述进行制备。
通过体外转录由这些载体获得下述mRNAs(图24和25中给出了mRNA序列):
曲妥珠单抗(GC)-ag-A64-C30(SEQ ID NO:57)
曲妥珠单抗(GC)-ag-A64-C30-组蛋白SL(SEQ ID NO:58)
3.体外转录
将实施例2所述的DNA模板线性化并且使用T7聚合酶在体外转录。然后,通过DNA酶处理消化该DNA模板。通过向转录反应中加入过量的N7-甲基-鸟苷-5′-三磷酸-5′-鸟苷,使得所有的mRNA-转录物包含5′-CAP结构。纯化这样得到的mRNA并且重悬在水中。
4.mRNA的酶促腺苷酸化
将两种mRNAs酶促腺苷酸化:
ppLuc(GC)-ag-A64和ppLuc(GC)-ag-组蛋白SL。
为了这一目的,按照供应商的使用说明,将RNA与大肠杆菌聚腺苷酸-聚合酶和ATP(聚腺苷酸聚合酶定制试剂盒(Poly(A)Polymerase Tailing Kit),Epicentre,Madison,USA)温育。纯化具有延伸的聚腺苷酸序列的mRNA并且重悬在水中。通过琼脂糖凝胶电泳确定聚腺苷酸序列的长度。起始mRNAs延伸大约250个腺苷酸,得到的mRNAs分别命名为:
ppLuc(GC)-ag-A300和ppLuc(GC)-ag-组蛋白SL-A250。
5.通过mRNA电穿孔进行荧光素酶表达
将HeLa细胞胰蛋白酶化处理并用opti-MEM洗涤。将每份200μlopti-MEM中的1x105个细胞用0.5μg ppLuc-编码mRNA电穿孔。单独电穿孔不编码ppLuc的mRNA作为对照。将电穿孔的细胞接种在24孔平板的1ml RPMI1640培养基中。在转染后6、24或48小时,吸出培养基,并将细胞在200μl裂解缓冲液(25mM Tris,pH7.5(HCl),2mM EDTA,10%甘油,1%Triton X-100,2mM DTT,1mM PMSF)中裂解。在测量ppLuc活性之前将裂解物保存在-20℃。
6.通过mRNA脂质转染进行荧光素酶表达
将HeLa细胞以每孔2x104个细胞的密度接种在96孔平板中。次日,将细胞在opti-MEM中洗涤,然后在150μl opti-MEM中用0.25μg Lipofectin-复合的ppLuc-编码mRNA转染。单独脂质转染不编码ppLuc的mRNA作为对照。在一些孔中,在转染开始后6小时,吸出opti-MEM,并且在200μl裂解缓冲液中裂解细胞。在其余的孔中,此时将opti-MEM更换为RPMI1640培养基。在这些孔中,在转染开始后24或48小时,吸出培养基,并且在200μl裂解缓冲液中裂解细胞。在测量ppLuc活性之前将裂解物保存在-20℃。
7.荧光素酶测量
使用50μl裂解物和200μl荧光素缓冲液(25mM甘氨酰甘氨酸,pH7.8(NaOH),15mMMgSO4,2mM ATP,75μM荧光素)在BioTek SynergyHT平板读数仪中在5秒测量时间内以相对光单位(RLU)测量ppLuc活性。通过从总RLU中减去对照RNA的RLU而计算具体的RLU。
8.通过皮内mRNA注射进行荧光素酶表达(体内荧光素酶表达)
小鼠用甲苯噻嗪(Rompun)和Ketavet的混合物麻醉。皮内注射每种ppLuc-编码mRNA(每次注射体积为50μl的0.5μg mRNA)。单独注射不编码ppLuc的mRNA作为对照。注射后16小时,将小鼠处死,并且收集组织。将组织样品在液氮中骤然冷冻,并且在800μl裂解缓冲液(25mM Tris,pH7.5(HCl),2mM EDTA,10%甘油,1%Triton X-100,2mM DTT,1mM PMSF)中在组织层(Qiagen)中裂解。随后,将样品在4℃以13500rpm离心10分钟。在测量ppLuc活性之前将裂解物保存在-80℃(参见7.荧光素酶测量)。
9.在HeLa细胞中的MmEPO表达
将HeLa细胞胰蛋白酶化处理并且用opti-MEM洗涤。将每份在200μlopti-MEM中的1x105个细胞用0.5μg MmEPO-编码mRNA电穿孔。单独电穿孔不相关的mRNA作为对照。将电穿孔的细胞接种在24-孔平板的1ml RPMI 1640培养基中。转染后6,24或48小时,从细胞采集并收集上清。用小鼠/大鼠促红细胞生成素Quantikine ELISA试剂盒(R&D系统(R&DSystems))按照供应商的使用说明测量上清中的EPO含量。
10.结果
10.1组蛋白茎环序列:
为了表征组蛋白茎环序列,将来自后生动物和原生动物(4001条序列)、或来自原生动物(131条序列)或备选地来自后生动物(3870条序列)或来自脊椎动物(1333条序列)或来自人(84条序列)的序列分组并且比对。然后,对于每个位置确定存在的核苷酸的量。基于这样得到的表,产生表示在所分析的序列中存在的所有核苷酸的5组不同的序列的共有序列。在组合的后生动物和原生动物的共有序列中,有3个核苷酸是保守的,即,环中的T/U和茎中的G和C(形成碱基对)。在结构上,典型地形成6个碱基对的茎和4个核苷酸的环。然而,背离的结构是常见的:在84条人组蛋白茎环中,有两条包含仅5个核苷酸的茎(包含4个碱基对和一个错配)。另一个人组蛋白茎环包含仅5个碱基对的茎。另外四条人组蛋白茎环包含6个核苷酸长的茎,但是分别在三个不同的位置包含一个错配。此外,四条人组蛋白茎环分别在两个不同位置包含一个摆动碱基对。由于已经在盘基网柄菌(D.discoideum)中鉴定了5个核苷酸的环,因此,关于所述环,不严格需要4个核苷酸的长度。
除了表示在所分析的序列中存在的所有核苷酸的共有序列之外,还获得了更加限制性的共有序列,其愈加强调保守核苷酸。总之,获得下述序列:
(Cons):表示所有存在的核苷酸
(99%):表示所有存在的核苷酸中的至少99%
(95%):表示所有存在的核苷酸中的至少95%
(90%):表示所有存在的核苷酸中的至少90%
组蛋白茎环序列分析的结果总结在下表1-5中(也参见图1-5):
表1:后生动物和原生动物组蛋白茎环共有序列:(基于4001条后生动物和原生动物组蛋白茎环序列的比对)(还参见图1)
表2:原生动物组蛋白茎环共有序列:(基于131条原生动物组蛋白茎环序列的比对)(还参见图2)
表3:后生动物组蛋白茎环共有序列:(基于3870条(包括1333条脊椎动物序列)后生动物组蛋白茎环序列的比对)(还参见图3)
表4:脊椎动物组蛋白茎环共有序列:(基于1333条脊椎动物组蛋白茎环序列的比对)(还参见图4)
表5:智人组蛋白茎环共有序列:(基于84条人组蛋白茎环序列的比对)(还参见图5)
其中所用的缩写定义如下:
10.2聚腺苷酸与组蛋白SL的组合以协同方式增加mRNA的蛋白表达。
为了研究聚腺苷酸与组蛋白SL的组合对mRNA的蛋白表达的作用,合成了在α-珠蛋白3’-UTR的3’具有不同的序列的mRNAs:仅以3’-UTR的3’结尾的mRNAs,由此缺少聚腺苷酸序列和组蛋白SL,或者包含A64聚腺苷酸序列或相反包含组蛋白SL,或者在3’-UTR的3’包含A64聚腺苷酸和组蛋白SL二者。将荧光素酶编码mRNAs或对照mRNA电穿孔至HeLa细胞中。在转染后6、24和48小时测量荧光素酶水平(见下表6和图20)。
表6:
由不具有聚腺苷酸序列和组蛋白SL的mRNA仅有少量荧光素酶表达。聚腺苷酸序列或组蛋白SL增加荧光素酶水平至相似的程度。每种mRNA产生比缺少聚腺苷酸和组蛋白SL二者的mRNA高得多的荧光素酶水平。然而,令人注意的是,聚腺苷酸与组蛋白SL的组合进一步强烈地增加荧光素酶水平,高于用每种单独的元件观察到的水平数倍。在相同的mRNA中由于组合聚腺苷酸与组蛋白SL引起的荧光素酶水平升高的幅度表明它们是协同作用的。
通过将来自聚腺苷酸-组蛋白SL mRNA(+/+)的信号除以来自组蛋白SL mRNA(-/+)加聚腺苷酸mRNA(+/-)的信号的和来量化聚腺苷酸与组蛋白SL之间的协同性(见下表7)。
表7:
这样计算的因子表明来自组合聚腺苷酸与组蛋白SL的mRNA的荧光素酶水平比如果单纯加合聚腺苷酸与组蛋白SL的作用将预测的荧光素酶水平高多少。来自组合聚腺苷酸与组蛋白SL的mRNA的荧光素酶水平是单纯加合它们的作用的水平的多至16.6倍高。该结果证实聚腺苷酸与组蛋白SL的组合在蛋白表达中实施了显著的协同性增加。
10.3聚腺苷酸与组蛋白SL的组合增加mRNA的蛋白表达与其顺序无关
聚腺苷酸与组蛋白SL的组合的作用可能取决于聚腺苷酸序列的长度以及聚腺苷酸与组蛋白SL的顺序。因此,合成具有增加的聚腺苷酸序列长度的mRNAs和具有相反顺序的聚腺苷酸与组蛋白SL的mRNA:两种mRNAs在3’-UTR的3’包含A120或A300聚腺苷酸序列。另一种mRNA在3’-UTR的3’首先包含组蛋白SL,其后接着A250聚腺苷酸序列。将荧光素酶编码mRNAs或对照mRNA脂质转染至HeLa细胞中。在转染开始后6、24和48小时测量荧光素酶水平(见下表8和图21)。
表8:
A64聚腺苷酸序列或组蛋白SL二者都产生可比较的荧光素酶水平。与之前的实验一致,A64与组蛋白SL的组合的确强烈增加荧光素酶水平,高于用单独的每种元件观察到的水平数倍。在相同的mRNA中由于组合聚腺苷酸与组蛋白SL导致的荧光素酶水平升高的幅度证明它们是协同作用的。如之前,基于A64-组蛋白SL、A64和组蛋白SL mRNA的荧光素酶水平定量A64与组蛋白SL之间的协同性(见下表9)。来自组合A64与组蛋白SL的mRNA的荧光素酶水平是单纯加合聚腺苷酸与组蛋白SL的作用的多至61.7倍高。
表9:
相比之下,聚腺苷酸序列的长度由A64增加至A120或增加至A300仅适度地增加荧光素酶水平(见表8和图19)。还将具有最长的聚腺苷酸序列(即A300)的mRNA与这样的mRNA进行比较,其中相似长度的聚腺苷酸序列与组蛋白SL组合,即,组蛋白SL-A250。除了具有长的聚腺苷酸序列之外,该mRNA中组蛋白SL与聚腺苷酸的顺序相对于A64-组蛋白SL mRNA是相反的。A250与组蛋白SL的组合强烈增加荧光素酶水平,高于用组蛋白SL或A300观察到的水平的数倍。同样地,如之前,比较来自组蛋白SL-A250mRNA的RLU与来自A300mRNA加组蛋白SL mRNA的RLU,来定量A250与组蛋白SL之间的协同性(见下表10)。来自组合A250与组蛋白SL的mRNA的荧光素酶水平是单纯加合聚腺苷酸与组蛋白SL的作用的多至17.0倍高。
表10:
总之,对于基本上不同长度的聚腺苷酸,已经证明组蛋白SL与聚腺苷酸的组合对由mRNA的蛋白表达的高度协同作用,并且同聚腺苷酸与组蛋白SL的顺序无关。
10.4通过聚腺苷酸与组蛋白SL的组合引起蛋白表达的增加是特异性的
为了研究聚腺苷酸与组蛋白SL的组合对由mRNA的蛋白表达是否是特异性的,合成具有与聚腺苷酸组合的备选序列的mRNAs:这些mRNAs在A64的3’分别包含七种不同序列中的一种。将荧光素酶编码mRNAs或对照mRNA电穿孔至HeLa细胞。在转染或6、24和48小时测量荧光素酶水平(见下表11和图22)。
表11:
聚腺苷酸序列或组蛋白SL二者都产生可比较的荧光素酶水平。同样地,聚腺苷酸与组蛋白SL的组合强烈增加荧光素酶水平,高于用单独的每种元件观察到的水平数倍,因此,二者是协同作用的。相比之下,与仅包含聚腺苷酸序列的mRNA相比,组合聚腺苷酸与任一种备选序列对荧光素酶水平没有作用。因此,聚腺苷酸与组蛋白SL的组合以协同方式增加由mRNA的蛋白表达,并且该作用是特异性的。
10.5聚腺苷酸与组蛋白SL的组合在体内以协同方式增加由mRNA的蛋白表达。
为了研究聚腺苷酸与组蛋白SL的组合在体内对由mRNA的蛋白表达的作用,将在α-珠蛋白3’-UTR的3’具有不同序列的荧光素酶编码mRNAs或对照mRNA皮内注射到小鼠中:在3’-UTR的3’包含A64聚腺苷酸序列或相反包含组蛋白SL、或包含A64聚腺苷酸与组蛋白SL二者的mRNAs。在注射后16小时测量荧光素酶水平(见下表12和图23)。
表12:
mRNA | 16小时的RLU |
ppLuc(GC)-ag-A64-组蛋白SL | 38081 |
ppLuc(GC)-ag-组蛋白SL | 137 |
ppLuc(GC)-ag-A64 | 4607 |
由具有组蛋白SL或聚腺苷酸序列的mRNA表达荧光素酶。然而,令人注意的是,聚腺苷酸与组蛋白SL的组合进一步强烈增加荧光素酶水平,高于用单独的每种元件观察到的水平数倍。在相同的mRNA中由于组合聚腺苷酸与组蛋白SL导致的荧光素酶水平增加的幅度表明它们是协同作用的。
通过将来自聚腺苷酸-组蛋白SL mRNA(+/+)的信号除以来自组蛋白SL mRNA(-/+)加聚腺苷酸mRNA(+/-)的信号的和而量化聚腺苷酸与组蛋白SL之间的协同性(见下表13)。
表13:
A64 | 组蛋白SL | 16小时的RLU | |
+ | + | 38081 | |
- | + | 137 | |
+ | - | 4607 | |
协同性 | 8.0 |
这样计算的因子表明来自组合聚腺苷酸与组蛋白SL的mRNA的荧光素酶水平比单纯加合聚腺苷酸与组蛋白SL的作用预测的水平高多少。来自组合聚腺苷酸与组蛋白SL的mRNA的荧光素酶水平是单纯加合其作用的水平的8倍高。这一结果证实聚腺苷酸与组蛋白SL的组合在体内蛋白表达中实施显著的协同增加。
11.抗体表达与表征
细胞系
人源化抗体的基于RNA的表达在CHO-K1或BHK-21(叙利亚仓鼠肾,HER2-阴性)细胞中进行。肿瘤细胞系BT-474强烈表达HER2,并且用于通过FACS分析记录抗体水平。依据供应商的信息,将除CHO之外的所有细胞系保持在补充有FCS和谷氨酰胺的RPMI培养基中。CHO细胞在补充有10%FCS的Ham’s F12中生长。所有细胞系均可以从德国细胞培养物保藏中心(German collection of cell cultures,DSMZ,Braunschweig,德国)获得。
抗体表达
将不同量的编码人源化抗体赫赛汀(Herceptin)(曲妥珠单抗)的mRNA(如图24和25定义的G/C富集的)通过电穿孔(对于CHO,300 V,450μF,对于BHK,300 V,150μF)转染到CHO或BHK细胞中。转染后,将细胞以200.000至400.000个细胞/孔的密度接种至24-孔细胞培养板中。为了收集分泌的蛋白,在细胞附着在塑料表面上后,用250ul新鲜的培养基更换培养基。收集分泌的蛋白24-96小时,并且保存在4℃。另外,将细胞收集在50ul含有0.5%BSA的磷酸盐缓冲的盐水中(1xPBS缓冲液),并且通过三个冷冻-解冻循环分解。通过离心澄清细胞裂解物并且保存在-80℃。
蛋白质印迹分析
为了检测转染的RNA的翻译,通过12%的SDS-PAGE分离来自细胞培养物上清或细胞裂解物的蛋白,并且印迹至硝基纤维素膜上。人源化抗体赫赛汀(Herceptin)(Roche)可以用作对照。印迹完成后,将膜用生物素酰化的山羊抗人IgG抗体(Dianova)、与辣根过氧化物酶缀合的链霉抗生物素(BD)和化学发光底物(SuperSignal West Pico,Pierce)连续地进行温育。用Fuji LAS-1000化学发光照相机检测染色。
FACS分析
功能性抗体的形成可以通过抗原表达靶细胞的FACS染色来证明。为了检验功能性抗体的产生,在48-96小时后收集RNA转染细胞的细胞培养物上清。将大约200.000个表达HER2的靶标BT-474细胞与对照抗体(赫赛汀,Roche)或细胞培养物上清一起温育。为了检测结合的抗体,将细胞用生物素酰化的山羊抗人IgG(Dianova)和PE-标记的链霉抗生物素(Invitrogen)染色。在FACSCanto II(BD)上分析细胞。
Claims (26)
1.mRNA在制备药物中的用途,所述mRNA包含或编码:
a)编码区,所述编码区编码至少一种肽或蛋白;
b)至少一种组蛋白茎环,其没有所述组蛋白茎环3’的组蛋白下游元件(HDE),和
c)聚腺苷酸序列或聚腺苷酸化信号;
其中所述肽或蛋白包含选自下述的治疗性蛋白:
(i)用于治疗代谢或内分泌紊乱的治疗性蛋白,
(ii)用于治疗循环系统疾病、呼吸系统疾病、肿瘤疾病、传染病或免疫缺陷的治疗性蛋白,
(iii)用于激素替代疗法的治疗性蛋白,
(iv)用于使体细胞重新编程成为多能或全能干细胞的治疗性蛋白,
(v)选自佐剂或免疫刺激性蛋白的治疗性蛋白;和
(vi)抗体,
其中所述mRNA是修饰的mRNA,
其中与野生型mRNA的编码区的G/C含量相比,增加编码至少一种肽或蛋白的编码区的G/C含量,
和/或
其中所述编码区被修饰,以使编码在细胞中相对稀少的tRNA的野生型序列的至少一个密码子交换为编码在细胞中相对常见且与所述相对稀少的tRNA携带相同的氨基酸的tRNA的密码子。
2.根据权利要求1的用途,其中与野生型mRNA编码的氨基酸序列相比,所述修饰的mRNA编码的氨基酸序列不被修饰。
3.根据权利要求1的用途,其中所述治疗性蛋白是用于治疗血液病症的治疗性蛋白。
4.根据权利要求1的用途,其中所述治疗性蛋白是用于治疗癌症的治疗性蛋白。
5.根据权利要求1的用途,其中所述至少一种组蛋白茎环与编码所述至少一种肽或蛋白的编码区是异源的。
6.根据权利要求1的用途,其中所述编码区不编码组蛋白。
7.根据权利要求1-6中任一项的用途,其中其编码区不编码报道蛋白或标记或选择蛋白。
8.根据权利要求1-6中任一项的用途,其中所述肽或蛋白包含选自下述的治疗性蛋白:
用于治疗代谢或内分泌紊乱的治疗性蛋白,其包括酸性鞘磷脂酶,Adipotide,Agalsidase-β,Alglucosidase,α-半乳糖苷酶A,α-葡糖苷酶,α-L-艾杜糖苷酸酶,α-N-乙酰葡糖苷酶,双调蛋白,血管生成素,β动物纤维素,β-葡糖醛酸糖苷酶,骨形态发生蛋白BMPs,CLN6蛋白,表皮生长因子(EGF),Epigen,表皮调节素,成纤维细胞生长因子,Galsulphase,葛瑞林,葡糖脑苷脂酶,GM-CSF,肝素-结合EGF-样生长因子(HB-EGF),肝细胞生长因子HGF,Hepcidin,人白蛋白,艾杜糖醛酸-2-硫酸酯酶,整联蛋白αVβ3,αVβ5和α5β1,拉罗尼酶,N-乙酰半乳糖胺-4-硫酸酯酶,N-乙酰葡糖胺-6-硫酸酯酶,神经生长因子NGF,神经调节蛋白,神经毡蛋白,肥胖抑制素,血小板衍生生长因子(PDGF),TGFβ受体,血小板生成素(THPO),转化生长因子TGF,VEGF,奈西立肽,胰蛋白酶,促肾上腺皮质激素(ACTH),心房钠尿肽(ANP),胆囊收缩素,胃泌素,瘦蛋白,催产素,生长抑素,加压素,降钙素,Exenatide,生长激素(GH),生长素,胰岛素,胰岛素样生长因子1IGF-1,Mecasermin rinfabate,IGF-1类似物,美卡舍明,培维索孟,普兰林肽,特立帕肽,贝卡普勒明,Dibotermin-α,醋酸组氨瑞林,奥曲肽,和帕利夫明;
用于治疗血液病症、循环系统疾病、呼吸系统疾病、肿瘤疾病、传染病或免疫缺陷的治疗性蛋白,其包括阿替普酶,阿尼普酶,抗凝血酶III(AT-III),比伐卢定,达贝泊汀α,屈曲克凝α,促红细胞生成素,依泊汀α,促血红细胞生长素,红细胞生成素,因子IX,因子VIIa,因子VIII,来匹卢定,蛋白质C浓缩剂,瑞替普酶,链激酶,替奈普酶,尿激酶,血管抑素,抗-CD22免疫毒素,地尼白介素-毒素连接物,Immunocyanin,MPS(Metallopanstimulin),Aflibercept,内皮抑素,胶原酶,人脱氧核糖核酸酶I,链道酶,透明质酸酶,木瓜蛋白酶,L-天冬酰胺酶,Peg-天冬酰胺酶,拉布立酶,人慢性促性腺素(HCG),人促卵泡激素(FSH),促黄体素-α,催乳素,α-1-蛋白酶抑制剂,乳糖酶,胰酶,腺苷脱氨酶,阿巴他塞,阿来法塞,阿那白滞素,依那西普,白细胞介素-1(IL-1)受体拮抗剂,阿那白滞素,胸腺素,TNF-α拮抗剂,恩夫韦肽,和胸腺素α1;
选自佐剂或免疫刺激性蛋白的治疗性蛋白,其包括模式识别受体TLR1,TLR2,TLR3,TLR4,TLR5,TLR6,TLR7,TLR8,TLR9,TLR10,TLR11;NOD1,NOD2,NOD3,NOD4,NOD5,NALP1,NALP2,NALP3,NALP4,NALP5,NALP6,NALP6,NALP7,NALP7,NALP8,NALP9,NALP10,NALP11,NALP12,NALP13,NALP14,l IPAF,NAIP,CIITA,RIG-I,MDA5和LGP2,TLR信号传导的信号转导剂,包括衔接子蛋白;小-GTP酶信号传导的组分,PIP信号传导的组分,MyD88-依赖性信号传导的组分,MyD88-非依赖性信号传导的组分;活化的激酶;活化的转录因子,热休克蛋白,gp96,纤维蛋白原,纤连蛋白的TypIII重复额外结构域A;或补体系统的成分,包括C1q,MBL,C1r,C1s,C2b,Bb,D,MASP-1,MASP-2,C4b,C3b,C5a,C3a,C4a,C5b,C6,C7,C8,C9,CR1,CR2,CR3,CR4,C1qR,C1INH,C4bp,MCP,DAF,H,I,P和CD59,或诱导的靶基因;或trif,flt-3配体,Gp96或纤连蛋白,诱导或增强先天性免疫应答的细胞因子,包括IL-1α,IL1β,IL-2,IL-6,IL-7,IL-8,IL-9,IL-12,IL-13,IL-15,IL-16,IL-17,IL-18,IL-21,IL-23,TNFα,IFNα,IFNβ,IFNγ,GM-CSF,G-CSF,M-CSF;趋化因子,包括IP-10,MCP-1,MIP-1α,RANTES,嗜酸性粒细胞趋化因子Eotaxin,CCL21;由巨噬细胞释放的细胞因子;以及IL-1R1;
细菌蛋白,原生动物蛋白,病毒蛋白,真菌蛋白;
以及钥孔血蓝蛋白(KLH),OspA;
雌激素,孕酮或黄体酮,和睾酮;
Oct-3/4,Sox基因家族,Klf家族,Myc家族,Nanog和LIN28;和
选自用于治疗肿瘤疾病的抗体的治疗性抗体,用于治疗免疫病症的抗体,用于治疗传染病的抗体,用于治疗血液病症的抗体,用于免疫调节的抗体,用于治疗糖尿病的抗体,用于治疗阿尔茨海默病的抗体,用于治疗哮喘的抗体,和用于治疗多种病症的抗体。
9.根据权利要求1-6中任一项的用途,其中所述肽或蛋白包含选自下述的治疗性蛋白:
Ang1,Ang2,Ang3,Ang4,ANGPTL2,ANGPTL3,ANGPTL4,ANGPTL5,ANGPTL6,ANGPTL7,BMP1,BMP2,BMP3,BMP4,BMP5,BMP6,BMP7,BMP8a,BMP8b,BMP10,BMP15,FGF,FGF-1,FGF-2,FGF-3,FGF-4,FGF-5,FGF-6,FGF-7,FGF-8,FGF-9,FGF-10,FGF-11,FGF-12,FGF-13,FGF-14,FGF-16,FGF-17,FGF-17,FGF-18,FGF-19,FGF-20,FGF-21,FGF-22,FGF-23,rhASB;galsulfase,芳基硫酸酯酶A(ARSA),芳基硫酸酯酶B(ARSB),脑源性神经营养因子(BDNF),神经营养因子-3(NT-3),神经营养因子4/5(NT-4/5),NRG1,NRG2,NRG3,NRG4,NRP-1,NRP-2,PDGF-A,PDGF-B,PDGF-C,PDGF-D,内皮因子,TGF-β1受体,TGF-β2受体,TGF-β3受体,巨核细胞生长和发育因子(MGDF),TGF-a,包括TGFβ1,TGFβ2和TGFβ3的TGF-β,VEGF-A,VEGF-B,VEGF-C,VEGF-D,VEGF-E,VEGF-F和PIGF,抗利尿激素,人甲状旁腺素残基1–34,骨形态发生蛋白2,促性腺素释放激素GnRH,角质形成细胞生长因子KGF;
组织型纤溶酶原激活物tPA,活化的蛋白C,脂肪酶,淀粉酶,蛋白酶,牛培加酶,PEG-ADA;
衔接子蛋白Trif和Cardif,RhoA,Ras,Rac1,Cdc42,Rab,PI3K,Src-激酶,MyD88,IRAK1,IRAK2,IRAK4,TIRAP,TICAM1,TICAM2,TRAF6,TBK1,IRF3,TAK1,Akt,MEKK1,MKK1,MKK3,MKK4,MKK6,MKK7,ERK1,ERK2,GSK3,PKC激酶,PKD激酶,GSK3激酶,JNK,p38MAPK,IKK,NF-κB,c-Fos,c-Jun,c-Myc,CREB,AP-1,Elk-1,ATF2,IRF-3,IRF-7,HSP10,HSP60,HSP65,HSP70,HSP75,HSP90,β-防卫素,细胞表面蛋白;
细菌热休克蛋白或伴侣蛋白,包括Hsp60,Hsp70,Hsp90,Hsp100;来自革兰氏阴性细菌的OmpA;细菌孔蛋白,包括OmpF;细菌毒素,包括来自百日咳博德特氏菌(Bordetellapertussis)的百日咳毒素(PT),来自百日咳博德特氏菌的百日咳腺苷酸环化酶毒素CyaA和CyaC,来自百日咳毒素的PT-9K/129G突变体,破伤风毒素,霍乱毒素(CT),霍乱毒素B-亚基,来自霍乱毒素的CTK63突变体,来自CT的CTE112K突变体,大肠杆菌(Escherichia coli)热不稳定性肠毒素(LT),来自热不稳定性肠毒素的B亚基(LTB),具有减少的毒性的大肠杆菌热不稳定性肠毒素突变体,包括LTK63,LTR72;苯酚可溶性调控蛋白;来自幽门螺杆菌(Helicobacter pylori)的嗜中性粒细胞活化蛋白(HP-NAP);表面活性蛋白D;来自布氏疏螺旋体(Borrelia burgdorferi)的外表面蛋白A脂蛋白,来自结核分枝杆菌(Mycobacterium tuberculosis)的Ag38(38kDa抗原);来自细菌菌毛的蛋白;霍乱弧菌(Vibrio cholerae)的肠毒素CT,来自革兰氏阴性细菌的菌毛的菌毛蛋白,和表面活性蛋白A和细菌鞭毛蛋白;
来自克鲁斯锥虫(Trypanosoma cruzi)的Tc52,来自Trypanosoma gondii的PFTG,原生动物热休克蛋白,来自利什曼原虫属物种(Leishmania spp.)的LeIF,来自刚地弓形虫(Toxoplasma gondii)的肌动蛋白抑制蛋白样蛋白;
呼吸道合胞病毒融合糖蛋白(F-蛋白),来自MMT病毒的包膜蛋白,小鼠白血病病毒蛋白,野生型麻疹病毒的血凝素蛋白;
真菌免疫调节性蛋白FIP;LZ-8;
Sox1,Sox2,Sox3,Sox15,Klf1,Klf2,Klf4,Klf5,c-myc,L-myc,N-myc;
131I-托西莫单抗,3F8,8H9,阿巴扶单抗,阿德木单抗,Afutuzumab,Alacizumabpegol,阿仑珠单抗,Amatuximab,AME-133v,AMG 102,麻安莫单抗,阿泊珠单抗,巴土昔单抗,贝妥莫单抗,贝利木单抗,贝伐珠单抗,比伐单抗-DM1,Blinatumomab,Brentuximabvedotin,Cantuzumab,美坎珠单抗,Cantuzumab ravtansine,卡罗单抗喷地肽,Carlumab,卡妥索单抗,西妥昔单抗,Citatuzumab bogatox,Cixutumumab,Clivatuzumabtetraxetan,CNTO 328,CNTO 95,Conatumumab,Dacetuzumab,Dalotuzumab,地舒单抗,地莫单抗,Drozitumab,Ecromeximab,依决洛单抗,Elotuzumab,Elsilimomab,Enavatuzumab,Ensituximab,依帕珠单抗,Ertumaxomab,Etaracizumab,Farletuzumab,FBTA05,Ficlatuzumab,Figitumumab,Flanvotumab,Galiximab,Ganitumab,GC1008,吉妥珠单抗,吉妥珠单抗奥佐米星,Girentuximab,Glembatumumab vedotin,GS6624,HuC242-DM4,HuHMFG1,HuN901-DM1,替伊莫单抗,Icrucumab,ID09C3,Indatuximab ravtansine,伊珠单抗奥佐米星,Intetumumab,Ipilimumab,Iratumumab,Labetuzumab,雷克萨单抗,林妥珠单抗,Lorvotuzumab mertansine,Lucatumumab,鲁昔单抗,Mapatumumab,Matuzumab,MDX-060,MEDI 522,米妥莫单抗,Mogamulizumab,MORab-003,MORab-009,Moxetumomabpasudotox,MT103,他那可单抗,Naptumomab estafenatox,Narnatumab,Necitumumab,尼妥珠单抗,Olaratumab,Onartuzumab,Oportuzumab monatox,Oregovomab,PAM4,帕尼单抗,Patritumab,Pemtumomab,帕妥珠单抗,普立昔单抗,Racotumomab,Radretumab,雷莫芦单抗,Rilotumumab,利妥昔单抗,Robatumumab,Samalizumab,SGN-30,SGN-40,西罗珠单抗,Siltuximab,Tabalumab,Tacatuzumab tetraxetan,帕他普莫单抗,Tenatumomab,Teprotumumab,TGN1412,Ticilimumab(=tremelimumab),Tigatuzumab,TNX-650,托西莫单抗,曲妥珠单抗,TRBS07,Tremelimumab,TRU-016,Tucotuzumab celmoleukin,Ublituximab,Urelumab,维妥珠单抗,Volociximab,伏妥莫单抗,WX-G250,Zalutumumab和他珠单抗;
依法利珠单抗,依帕珠单抗,Etrolizumab,Fontolizumab,Ixekizumab,美泊利单抗,Milatuzumab,汇集的免疫球蛋白,普立昔单抗,利妥昔单抗,Rontalizumab,卢利珠单抗,Sarilumab,维多珠单抗,Visilizumab,Reslizumab,阿达木单抗,Aselizumab,Atinumab,Atlizumab,贝利木单抗,Besilesomab,BMS-945429,Briakinumab,Brodalumab,卡那单抗,培舍珠单抗,厄利珠单抗,Fezakinumab,戈利木单抗,Gomiliximab,英夫利昔单抗,Mavrilimumab,那他珠单抗,Ocrelizumab,奥度莫单抗,奥法木单抗,Ozoralizumab,Pexelizumab,罗维珠单抗,SBI-087,Secukinumab,Sirukumab,他利珠单抗,托珠单抗,Toralizumab,TRU-015,优特克单抗,维帕莫单抗,阿佐莫单抗,Sifalimumab,鲁昔单抗,和Rho(D)免疫球蛋白;
阿非莫单抗,CR6261,埃巴单抗,Efungumab,艾韦单抗,非维珠单抗,Foravirumab,Ibalizumab,Libivirumab,Motavizumab,奈巴库单抗,Tuvirumab,乌珠单抗,巴土昔单抗,Pagibaximab,帕利珠单抗,Panobacumab,PRO 140,瑞非韦鲁,Raxibacumab,瑞加韦单抗,司韦单抗,Suvizumab,和替非珠单抗;
阿昔单抗,阿托木单抗,依库珠单抗,美泊利单抗和Milatuzumab;
抗胸腺细胞球蛋白,巴利昔单抗,西地珠单抗,达利珠单抗,Gavilimomab,伊诺莫单抗,莫罗莫那-CD3,奥度莫单抗和Siplizumab;
Gevokizumab,Otelixizumab和Teplizumab;
Bapineuzumab,Crenezumab,Gantenerumab,Ponezumab,R1450和Solanezumab;
Benralizumab,Enokizumab,Keliximab,Lebrikizumab,奥马珠单抗,Oxelumab,Pascolizumab和Tralokinumab;
Blosozumab,CaroRx,Fresolimumab,Fulranumab,Romosozumab,司他莫单抗,Tanezumab和雷珠单抗。
10.根据权利要求1-6中任一项的用途,其中所述至少一种组蛋白茎环选自下述式(I)或(II):
式(I),不具有茎边界元件的茎环序列:
式(II),具有茎边界元件的茎环序列:
其中:
茎1或茎2边界元件N1-6是1-6个N的连续序列,其中每个N彼此独立地选自下述核苷酸:所述核苷酸选自A,U,T,G和C;
茎1[N0-2GN3-5]与元件茎2反向互补或部分反向互补,并且是5-7个核苷酸的连续序列;
其中N0-2是0-2个N的连续序列,其中每个N彼此独立地选自下述核苷酸:所述核苷酸选自A,U,T,G和C;
其中N3-5是3-5个N的连续序列,其中每个N彼此独立地选自下述核苷酸:所述核苷酸选自A,U,T,G和C,并且
其中G是鸟苷,并且可以被胞苷替代,条件是其在茎2中的互补核苷酸胞苷被鸟苷替代;
环序列[N0-4(U/T)N0-4]位于元件茎1和茎2之间,并且是3-5个核苷酸的连续序列;
其中每个N0-4彼此独立地是0-4个N的连续序列,其中每个N彼此独立地选自下述核苷酸:所述核苷酸选自A,U,T,G和C;并且
其中U/T表示尿苷或胸苷;
茎2[N3-5CN0-2]与元件茎1反向互补或部分反向互补,并且是5-7个核苷酸的连续序列;
其中N3-5是3-5个N的连续序列,其中每个N彼此独立地选自下述核苷酸:所述核苷酸选自A,U,T,G和C;
其中N0-2是0-2个N的连续序列,其中每个N彼此独立地选自下述核苷酸:所述核苷酸选自A,U,T,G和C;并且
其中C是胞苷,并且可以被鸟苷替代,条件是其在茎1中的互补核苷酸鸟苷被胞苷替代;
其中
茎1和茎2能够彼此碱基配对
形成反向互补序列,其中碱基配对可以发生在茎1与茎2之间,或者
形成部分反向互补的序列,其中不完全的碱基配对可以发生在茎1和茎2之间。
11.根据权利要求10的用途,其中所述至少一种组蛋白茎环选自下式(Ia)或(IIa)中的至少一个:
式(Ia),不具有茎边界元件的茎环序列
式(IIa),具有茎边界元件的茎环序列。
12.根据权利要求1-6中任一项的用途,其中所述聚腺苷酸序列包含25至400个腺苷核苷酸的序列。
13.根据权利要求1-6中任一项的用途,其中所述聚腺苷酸序列包含50至400个腺苷核苷酸的序列。
14.根据权利要求1-6中任一项的用途,其中所述聚腺苷酸序列包含50至300个腺苷核苷酸的序列。
15.根据权利要求1-6中任一项的用途,其中所述聚腺苷酸序列包含50至250个腺苷核苷酸的序列。
16.根据权利要求1-6中任一项的用途,其中所述聚腺苷酸序列包含60至250个腺苷核苷酸的序列。
17.根据权利要求1-6中任一项的用途,其中所述聚腺苷酸化信号包含共有序列NN(U/T)ANA。
18.根据权利要求1-6中任一项的用途,其中所述聚腺苷酸化信号包含共有序列AA(U/T)AAA或A(U/T)(U/T)AAA。
19.根据权利要求8的用途,其中所述肿瘤疾病是癌症。
20.根据权利要求1-6中任一项的用途,其中所述肽或蛋白包含选自人佐剂蛋白的治疗性蛋白。
21.组合物或试剂盒在制备药物中的用途,所述组合物或试剂盒包含多种或多于一种权利要求1-20中任一项中定义的mRNA。
22.权利要求1-20中任一项定义的mRNA或权利要求21中定义的组合物或试剂盒在制备用于基因疗法的药物中的用途。
23.药物组合物在制备药物中的用途,所述药物组合物包含权利要求1-20中任一项定义的mRNA或权利要求21中定义的组合物。
24.药物组合物在制备药物中的用途,所述药物组合物包含权利要求1-20中任一项定义的mRNA和药用载体或权利要求21中定义的组合物和药用载体。
25.权利要求1-20中任一项定义的mRNA或权利要求21中定义的组合物或试剂盒在制备用于增加所述编码的肽或蛋白的表达的药物中的用途。
26.权利要求1-20中任一项定义的mRNA或权利要求21中定义的组合物或试剂盒在制备用于增加基因疗法中所述编码的肽或蛋白的表达的药物中的用途。
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Families Citing this family (183)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3578205A1 (en) | 2010-08-06 | 2019-12-11 | ModernaTX, Inc. | A pharmaceutical formulation comprising engineered nucleic acids and medical use thereof |
WO2012019630A1 (en) | 2010-08-13 | 2012-02-16 | Curevac Gmbh | Nucleic acid comprising or coding for a histone stem-loop and a poly(a) sequence or a polyadenylation signal for increasing the expression of an encoded protein |
JP6184945B2 (ja) | 2011-06-08 | 2017-08-23 | シャイアー ヒューマン ジェネティック セラピーズ インコーポレイテッド | mRNA送達のための脂質ナノ粒子組成物および方法 |
US9464124B2 (en) | 2011-09-12 | 2016-10-11 | Moderna Therapeutics, Inc. | Engineered nucleic acids and methods of use thereof |
WO2013120500A1 (en) | 2012-02-15 | 2013-08-22 | Curevac Gmbh | Nucleic acid comprising or coding for a histone stem-loop and a poly(a) sequence or a polyadenylation signal for increasing the expression of an encoded tumour antigen |
WO2013120499A1 (en) | 2012-02-15 | 2013-08-22 | Curevac Gmbh | Nucleic acid comprising or coding for a histone stem-loop and a poly (a) sequence or a polyadenylation signal for increasing the expression of an encoded pathogenic antigen |
WO2013120497A1 (en) | 2012-02-15 | 2013-08-22 | Curevac Gmbh | Nucleic acid comprising or coding for a histone stem-loop and a poly(a) sequence or a polyadenylation signal for increasing the expression of an encoded therapeutic protein |
WO2013120498A1 (en) | 2012-02-15 | 2013-08-22 | Curevac Gmbh | Nucleic acid comprising or coding for a histone stem-loop and a poly(a) sequence or a polyadenylation signal for increasing the expression of an encoded allergenic antigen or an autoimmune self-antigen |
KR102186497B1 (ko) | 2012-03-27 | 2020-12-04 | 큐어백 아게 | 인공 핵산 분자 |
RU2660565C2 (ru) | 2012-03-27 | 2018-07-06 | Кьюрвак Аг | Молекулы искусственной нуклеиновой кислоты, содержащие 5'utr гена top |
CA2859452C (en) | 2012-03-27 | 2021-12-21 | Curevac Gmbh | Artificial nucleic acid molecules for improved protein or peptide expression |
US9303079B2 (en) | 2012-04-02 | 2016-04-05 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of cytoplasmic and cytoskeletal proteins |
US9283287B2 (en) | 2012-04-02 | 2016-03-15 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of nuclear proteins |
US10501513B2 (en) | 2012-04-02 | 2019-12-10 | Modernatx, Inc. | Modified polynucleotides for the production of oncology-related proteins and peptides |
CA2868996A1 (en) | 2012-04-02 | 2013-10-10 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of proteins |
US10245229B2 (en) | 2012-06-08 | 2019-04-02 | Translate Bio, Inc. | Pulmonary delivery of mRNA to non-lung target cells |
US20150307542A1 (en) | 2012-10-03 | 2015-10-29 | Moderna Therapeutics, Inc. | Modified nucleic acid molecules and uses thereof |
PL2922554T3 (pl) | 2012-11-26 | 2022-06-20 | Modernatx, Inc. | Na zmodyfikowany na końcach |
AU2014220957A1 (en) | 2013-02-22 | 2015-07-30 | Curevac Ag | Combination of vaccination and inhibition of the PD-1 pathway |
CN105209490A (zh) | 2013-03-14 | 2015-12-30 | 夏尔人类遗传性治疗公司 | 用于递送mrna编码的抗体的方法和组合物 |
MX365409B (es) | 2013-03-14 | 2019-05-31 | Shire Human Genetic Therapies | Composiciones de ácido ribonucleico mensajero del regulador transmembrana de fibrosis quística y métodos y usos relacionados. |
SI2972360T1 (en) | 2013-03-15 | 2018-08-31 | Translate Bio, Inc. | Synergistic improvement in the delivery of nucleic acids via mixed formulations |
US8980864B2 (en) | 2013-03-15 | 2015-03-17 | Moderna Therapeutics, Inc. | Compositions and methods of altering cholesterol levels |
AR095196A1 (es) | 2013-03-15 | 2015-09-30 | Regeneron Pharma | Medio de cultivo celular libre de suero |
SG10201801428RA (en) | 2013-08-21 | 2018-03-28 | Curevac Ag | Method for increasing expression of rna-encoded proteins |
BR112016001192A2 (pt) | 2013-08-21 | 2017-08-29 | Curevac Ag | Vacina contra a raiva |
SG10201801431TA (en) | 2013-08-21 | 2018-04-27 | Curevac Ag | Respiratory syncytial virus (rsv) vaccine |
WO2015024669A1 (en) | 2013-08-21 | 2015-02-26 | Curevac Gmbh | Combination vaccine |
KR102571391B1 (ko) * | 2013-09-13 | 2023-08-29 | 제넨테크, 인크. | 정제된 재조합 폴리펩티드를 포함하는 방법 및 조성물 |
EP3052106A4 (en) | 2013-09-30 | 2017-07-19 | ModernaTX, Inc. | Polynucleotides encoding immune modulating polypeptides |
JP2016538829A (ja) | 2013-10-03 | 2016-12-15 | モデルナ セラピューティクス インコーポレイテッドModerna Therapeutics,Inc. | 低密度リポタンパク質受容体をコードするポリヌクレオチド |
WO2015062738A1 (en) | 2013-11-01 | 2015-05-07 | Curevac Gmbh | Modified rna with decreased immunostimulatory properties |
SG11201604198YA (en) | 2013-12-30 | 2016-07-28 | Curevac Ag | Methods for rna analysis |
EP3415629A1 (en) * | 2013-12-30 | 2018-12-19 | CureVac AG | Artificial nucleic acid molecules |
DK3090053T3 (en) | 2013-12-30 | 2019-02-25 | Curevac Ag | Artificial nucleic acid molecules |
WO2015101415A1 (en) * | 2013-12-30 | 2015-07-09 | Curevac Gmbh | Artificial nucleic acid molecules |
US11254951B2 (en) | 2014-12-30 | 2022-02-22 | Curevac Ag | Artificial nucleic acid molecules |
US10307472B2 (en) | 2014-03-12 | 2019-06-04 | Curevac Ag | Combination of vaccination and OX40 agonists |
EP3129050A2 (en) | 2014-04-01 | 2017-02-15 | CureVac AG | Polymeric carrier cargo complex for use as an immunostimulating agent or as an adjuvant |
US20170183389A1 (en) * | 2014-04-24 | 2017-06-29 | Accurna, Inc. | Method for improving protein expression, and composition for protein expression |
KR102459599B1 (ko) | 2014-06-10 | 2022-10-26 | 큐어백 리얼 이스테이트 게엠베하 | Rna생산을 증진하는 방법 및 수단 |
CA3179824A1 (en) | 2014-06-25 | 2015-12-30 | Acuitas Therapeutics Inc. | Lipids and lipid nanoparticle formulations for delivery of nucleic acids |
EP3461904A1 (en) | 2014-11-10 | 2019-04-03 | ModernaTX, Inc. | Alternative nucleic acid molecules containing reduced uracil content and uses thereof |
EP3227320B1 (en) * | 2014-12-03 | 2019-07-03 | Florida State University Research Foundation, Inc. | Modified fibroblast growth factor 1 (fgf-1) polypeptides with increased binding affinity for heparin and associated methods |
US11149278B2 (en) * | 2014-12-12 | 2021-10-19 | Curevac Ag | Artificial nucleic acid molecules for improved protein expression |
SG10201906673WA (en) * | 2014-12-30 | 2019-09-27 | Curevac Ag | Artificial nucleic acid molecules |
WO2016138340A1 (en) * | 2015-02-27 | 2016-09-01 | Saint Louis University | Tumor suppressor sall1 as a therapeutic agent for treating cancer |
EP3283059B1 (en) | 2015-04-13 | 2024-01-03 | CureVac Manufacturing GmbH | Method for producing rna compositions |
EP3283125B1 (en) | 2015-04-17 | 2021-12-29 | CureVac Real Estate GmbH | Lyophilization of rna |
BR112017018368B1 (pt) | 2015-04-22 | 2022-08-02 | Curevac Ag | Composição contendo rna para uso no tratamento ou profilaxia de doenças tumorais e/ou cancerosas, e uso de um rna para a preparação da composição |
US11384375B2 (en) | 2015-04-30 | 2022-07-12 | Curevac Ag | Immobilized poly(n)polymerase |
DK3294885T3 (da) | 2015-05-08 | 2020-08-10 | Curevac Real Estate Gmbh | Fremgangsmåde til at fremstille rna |
GB201508025D0 (en) | 2015-05-11 | 2015-06-24 | Ucl Business Plc | Fabry disease gene therapy |
US11559570B2 (en) | 2015-05-15 | 2023-01-24 | CureVac SE | Prime-boost regimens involving administration of at least one mRNA construct |
SG10201910431RA (en) | 2015-05-20 | 2020-01-30 | Curevac Ag | Dry powder composition comprising long-chain rna |
CN107530448A (zh) | 2015-05-20 | 2018-01-02 | 库瑞瓦格股份公司 | 包含长链rna的干粉组合物 |
US11608513B2 (en) | 2015-05-29 | 2023-03-21 | CureVac SE | Method for adding cap structures to RNA using immobilized enzymes |
US10760070B2 (en) | 2015-05-29 | 2020-09-01 | Curevac Real Estate Gmbh | Method for producing and purifying RNA, comprising at least one step of tangential flow filtration |
CA2990202A1 (en) | 2015-06-29 | 2017-01-05 | Acuitas Therapeutics Inc. | Lipids and lipid nanoparticle formulations for delivery of nucleic acids |
WO2017009376A1 (en) | 2015-07-13 | 2017-01-19 | Curevac Ag | Method of producing rna from circular dna and corresponding template dna |
US11364292B2 (en) | 2015-07-21 | 2022-06-21 | Modernatx, Inc. | CHIKV RNA vaccines |
EP3324979B1 (en) | 2015-07-21 | 2022-10-12 | ModernaTX, Inc. | Infectious disease vaccines |
TW202330904A (zh) | 2015-08-04 | 2023-08-01 | 美商再生元醫藥公司 | 補充牛磺酸之細胞培養基及用法 |
EP4101930A1 (en) | 2015-09-17 | 2022-12-14 | ModernaTX, Inc. | Polynucleotides containing a stabilizing tail region |
AU2016324310B2 (en) | 2015-09-17 | 2021-04-08 | Modernatx, Inc. | Compounds and compositions for intracellular delivery of therapeutic agents |
US10849920B2 (en) | 2015-10-05 | 2020-12-01 | Modernatx, Inc. | Methods for therapeutic administration of messenger ribonucleic acid drugs |
WO2017059902A1 (en) | 2015-10-07 | 2017-04-13 | Biontech Rna Pharmaceuticals Gmbh | 3' utr sequences for stabilization of rna |
EP3362576A1 (en) | 2015-10-12 | 2018-08-22 | CureVac AG | Automated method for isolation, selection and/or detection of microorganisms or cells comprised in a solution |
US20190218546A1 (en) | 2015-10-16 | 2019-07-18 | Modernatx, Inc. | Mrna cap analogs with modified phosphate linkage |
WO2017066791A1 (en) | 2015-10-16 | 2017-04-20 | Modernatx, Inc. | Sugar substituted mrna cap analogs |
WO2017066782A1 (en) | 2015-10-16 | 2017-04-20 | Modernatx, Inc. | Hydrophobic mrna cap analogs |
US20190225644A1 (en) | 2015-10-16 | 2019-07-25 | Modernatx, Inc. | Mrna cap analogs and methods of mrna capping |
WO2017066789A1 (en) | 2015-10-16 | 2017-04-20 | Modernatx, Inc. | Mrna cap analogs with modified sugar |
PL3718565T3 (pl) | 2015-10-22 | 2022-09-19 | Modernatx, Inc. | Szczepionki przeciwko wirusom układu oddechowego |
WO2017070624A1 (en) | 2015-10-22 | 2017-04-27 | Modernatx, Inc. | Tropical disease vaccines |
WO2017070613A1 (en) | 2015-10-22 | 2017-04-27 | Modernatx, Inc. | Human cytomegalovirus vaccine |
IL307179A (en) | 2015-10-28 | 2023-11-01 | Acuitas Therapeutics Inc | Novel lipids and lipid nanoparticle formulations for delivery of nucleic acids |
EP3373965A1 (en) | 2015-11-09 | 2018-09-19 | CureVac AG | Rotavirus vaccines |
DK3319622T3 (da) | 2015-12-22 | 2020-05-04 | Curevac Ag | Fremgangsmåde til fremstilling af rna-molekylesammensætninger |
DK3394030T3 (da) | 2015-12-22 | 2022-03-28 | Modernatx Inc | Forbindelser og sammensætninger til intracellulær afgivelse af midler |
US11248223B2 (en) | 2015-12-23 | 2022-02-15 | Curevac Ag | Method of RNA in vitro transcription using a buffer containing a dicarboxylic acid or tricarboxylic acid or a salt thereof |
US11723967B2 (en) | 2016-02-17 | 2023-08-15 | CureVac SE | Zika virus vaccine |
US11920174B2 (en) | 2016-03-03 | 2024-03-05 | CureVac SE | RNA analysis by total hydrolysis and quantification of released nucleosides |
WO2017177169A1 (en) | 2016-04-08 | 2017-10-12 | Rana Therapeutics, Inc. | Multimeric coding nucleic acid and uses thereof |
US11596699B2 (en) | 2016-04-29 | 2023-03-07 | CureVac SE | RNA encoding an antibody |
EP3452101A2 (en) | 2016-05-04 | 2019-03-13 | CureVac AG | Rna encoding a therapeutic protein |
EP3452493A1 (en) | 2016-05-04 | 2019-03-13 | CureVac AG | Nucleic acid molecules and uses thereof |
JP7114485B2 (ja) | 2016-05-18 | 2022-08-08 | モデルナティエックス インコーポレイテッド | ファブリー病の治療のためのα-ガラクトシダーゼAをコードするポリヌクレオチド |
US11478552B2 (en) | 2016-06-09 | 2022-10-25 | Curevac Ag | Hybrid carriers for nucleic acid cargo |
EP3842530A1 (en) | 2016-06-13 | 2021-06-30 | Translate Bio, Inc. | Messenger rna therapy for the treatment of ornithine transcarbamylase deficiency |
CN105920585B (zh) * | 2016-06-13 | 2019-07-09 | 浙江生创精准医疗科技有限公司 | Mcp-1单独或与其他细胞因子联合在治疗肝纤维化中的用途 |
EP3468537A1 (en) | 2016-06-14 | 2019-04-17 | Modernatx, Inc. | Stabilized formulations of lipid nanoparticles |
EP3474876A4 (en) * | 2016-06-22 | 2020-01-15 | City of Hope | TREATMENT OF MORBUS CANAVAN |
ES2964694T3 (es) * | 2016-09-15 | 2024-04-09 | Elicera Therapeutics Ab | Inmunoterapia de células T |
MA46584A (fr) | 2016-10-21 | 2019-08-28 | Modernatx Inc | Vaccin contre le cytomégalovirus humain |
WO2018089540A1 (en) | 2016-11-08 | 2018-05-17 | Modernatx, Inc. | Stabilized formulations of lipid nanoparticles |
EP3538550A1 (en) | 2016-11-10 | 2019-09-18 | Deutsches Krebsforschungszentrum Stiftung des Öffentlichen Rechts | Or10h1 modulators and uses thereof |
US11279923B2 (en) | 2016-11-28 | 2022-03-22 | Curevac Ag | Method for purifying RNA |
CN110177544A (zh) | 2016-11-29 | 2019-08-27 | 普尔泰克健康有限公司 | 用于递送治疗剂的外泌体 |
WO2018104540A1 (en) * | 2016-12-08 | 2018-06-14 | Curevac Ag | Rnas for wound healing |
WO2018107088A2 (en) | 2016-12-08 | 2018-06-14 | Modernatx, Inc. | Respiratory virus nucleic acid vaccines |
CN110582304A (zh) | 2016-12-08 | 2019-12-17 | 库尔维科公司 | 用于治疗或预防肝脏疾病的rna |
WO2018115525A1 (en) | 2016-12-23 | 2018-06-28 | Curevac Ag | Lassa virus vaccine |
WO2018115507A2 (en) | 2016-12-23 | 2018-06-28 | Curevac Ag | Henipavirus vaccine |
WO2018115527A2 (en) | 2016-12-23 | 2018-06-28 | Curevac Ag | Mers coronavirus vaccine |
EP3582790A4 (en) | 2017-02-16 | 2020-11-25 | ModernaTX, Inc. | VERY POWERFUL IMMUNOGENIC COMPOSITIONS |
CA3054062A1 (en) | 2017-02-27 | 2018-08-30 | Translate Bio, Inc. | Novel codon-optimized cftr mrna |
WO2018160540A1 (en) | 2017-02-28 | 2018-09-07 | Sanofi | Therapeutic rna |
CA3055653A1 (en) | 2017-03-15 | 2018-09-20 | Modernatx, Inc. | Lipid nanoparticle formulation |
HUE060693T2 (hu) | 2017-03-15 | 2023-04-28 | Modernatx Inc | Vegyület és készítmények terápiás szerek intracelluláris bejuttatására |
MA47790A (fr) | 2017-03-17 | 2021-05-05 | Modernatx Inc | Vaccins à base d'arn contre des maladies zoonotiques |
SG10202110491PA (en) | 2017-03-24 | 2021-11-29 | Curevac Ag | Nucleic acids encoding crispr-associated proteins and uses thereof |
WO2018191657A1 (en) | 2017-04-13 | 2018-10-18 | Acuitas Therapeutics, Inc. | Lipids for delivery of active agents |
AU2018256877B2 (en) | 2017-04-28 | 2022-06-02 | Acuitas Therapeutics, Inc. | Novel carbonyl lipids and lipid nanoparticle formulations for delivery of nucleic acids |
WO2018213476A1 (en) | 2017-05-16 | 2018-11-22 | Translate Bio, Inc. | Treatment of cystic fibrosis by delivery of codon-optimized mrna encoding cftr |
CN107245510B (zh) * | 2017-05-23 | 2020-10-30 | 中山大学附属第三医院 | 用于示踪免疫细胞的试剂盒及方法 |
WO2018232120A1 (en) | 2017-06-14 | 2018-12-20 | Modernatx, Inc. | Compounds and compositions for intracellular delivery of agents |
JP2020530980A (ja) | 2017-07-04 | 2020-11-05 | キュアバック アーゲー | 新規核酸分子 |
WO2019010191A1 (en) * | 2017-07-06 | 2019-01-10 | Regeneron Pharmaceuticals, Inc. | CELL CULTURE METHOD FOR PRODUCING GLYCOPROTEIN |
EP3437650A1 (en) * | 2017-07-31 | 2019-02-06 | Accanis Biotech F&E GmbH & Co KG | Treatment of local skin hypotrophy conditions |
JP7355731B2 (ja) | 2017-08-16 | 2023-10-03 | アクイタス セラピューティクス インコーポレイテッド | 脂質ナノ粒子製剤における使用のための脂質 |
US11542225B2 (en) | 2017-08-17 | 2023-01-03 | Acuitas Therapeutics, Inc. | Lipids for use in lipid nanoparticle formulations |
US11524932B2 (en) | 2017-08-17 | 2022-12-13 | Acuitas Therapeutics, Inc. | Lipids for use in lipid nanoparticle formulations |
WO2019036638A1 (en) | 2017-08-18 | 2019-02-21 | Modernatx, Inc. | METHODS FOR PREPARING MODIFIED RNA |
US11602557B2 (en) | 2017-08-22 | 2023-03-14 | Cure Vac SE | Bunyavirales vaccine |
CN107590533B (zh) * | 2017-08-29 | 2020-07-31 | 中国科学院计算技术研究所 | 一种用于深度神经网络的压缩装置 |
JP7275111B2 (ja) | 2017-08-31 | 2023-05-17 | モデルナティエックス インコーポレイテッド | 脂質ナノ粒子の生成方法 |
WO2019055807A1 (en) | 2017-09-14 | 2019-03-21 | Modernatx, Inc. | RNA VACCINES AGAINST ZIKA VIRUS |
EP3707271A1 (en) | 2017-11-08 | 2020-09-16 | CureVac AG | Rna sequence adaptation |
WO2019115635A1 (en) | 2017-12-13 | 2019-06-20 | Curevac Ag | Flavivirus vaccine |
AU2018392716A1 (en) | 2017-12-20 | 2020-06-18 | Translate Bio, Inc. | Improved composition and methods for treatment of ornithine transcarbamylase deficiency |
US11525158B2 (en) | 2017-12-21 | 2022-12-13 | CureVac SE | Linear double stranded DNA coupled to a single support or a tag and methods for producing said linear double stranded DNA |
EP3508499A1 (en) | 2018-01-08 | 2019-07-10 | iOmx Therapeutics AG | Antibodies targeting, and other modulators of, an immunoglobulin gene associated with resistance against anti-tumour immune responses, and uses thereof |
WO2020061367A1 (en) | 2018-09-19 | 2020-03-26 | Modernatx, Inc. | Compounds and compositions for intracellular delivery of therapeutic agents |
JP2022501367A (ja) | 2018-09-20 | 2022-01-06 | モデルナティエックス インコーポレイテッドModernaTX, Inc. | 脂質ナノ粒子の調製及びその投与方法 |
US11845989B2 (en) | 2019-01-23 | 2023-12-19 | Regeneron Pharmaceuticals, Inc. | Treatment of ophthalmic conditions with angiopoietin-like 7 (ANGPTL7) inhibitors |
KR20210132045A (ko) | 2019-01-23 | 2021-11-03 | 리제너론 파마슈티칼스 인코포레이티드 | 안지오포이에틴-유사 7(angtl7) 억제제를 사용하는 안구 질환의 트리트먼트 |
JP2022523117A (ja) | 2019-01-31 | 2022-04-21 | モデルナティエックス インコーポレイテッド | ボルテックスミキサならびにその関連する方法、システム、及び装置 |
KR20210135494A (ko) | 2019-01-31 | 2021-11-15 | 모더나티엑스, 인크. | 지질 나노입자의 제조 방법 |
US11351242B1 (en) | 2019-02-12 | 2022-06-07 | Modernatx, Inc. | HMPV/hPIV3 mRNA vaccine composition |
KR20230031981A (ko) | 2019-05-14 | 2023-03-07 | 프로벤션 바이오, 인코포레이티드 | 제1형 당뇨병을 예방하기 위한 방법 및 조성물 |
AU2020285639A1 (en) * | 2019-05-24 | 2021-12-23 | Empirico Inc. | Treatment of angiopoietin like 7 (ANGPTL7) related diseases |
EP3994171A1 (en) | 2019-07-05 | 2022-05-11 | iOmx Therapeutics AG | Antibodies binding igc2 of igsf11 (vsig3) and uses thereof |
CN112625097B (zh) * | 2019-08-27 | 2022-02-08 | 上海交通大学 | 灵芝免疫调节蛋白突变体及应用 |
CN110548132B (zh) * | 2019-10-24 | 2023-04-25 | 安徽医科大学附属巢湖医院 | TGF-β1蛋白在制备治疗抑郁症的药物中的应用 |
EP3822288A1 (en) | 2019-11-18 | 2021-05-19 | Deutsches Krebsforschungszentrum, Stiftung des öffentlichen Rechts | Antibodies targeting, and other modulators of, the cd276 antigen, and uses thereof |
US11241493B2 (en) | 2020-02-04 | 2022-02-08 | Curevac Ag | Coronavirus vaccine |
US11576966B2 (en) | 2020-02-04 | 2023-02-14 | CureVac SE | Coronavirus vaccine |
BR112022015843A2 (pt) * | 2020-02-10 | 2022-09-27 | Univ Utah Res Found | Composições e métodos de heparina de alto peso molecular para diagnóstico, tratamento e monitoramento de doenças inflamatórias mediadas por eosinófilos |
WO2021191865A1 (en) * | 2020-03-26 | 2021-09-30 | Dusa Pharmaceuticals, Inc. | Management of dermal neurofibromatosis lesions |
TW202204622A (zh) | 2020-04-09 | 2022-02-01 | 大陸商蘇州艾博生物科技有限公司 | 針對冠狀病毒之核酸疫苗 |
AU2021254312B2 (en) | 2020-04-09 | 2024-01-11 | Suzhou Abogen Biosciences Co., Ltd. | Lipid nanoparticle composition |
JP2023106635A (ja) | 2020-04-17 | 2023-08-02 | 中外製薬株式会社 | 二重特異性抗原結合分子ならびに、それに関連する組成物、組成物の製造のための使用、キット、および方法 |
KR20230030588A (ko) | 2020-06-30 | 2023-03-06 | 쑤저우 아보젠 바이오사이언시스 컴퍼니 리미티드 | 지질 화합물 및 지질 나노입자 조성물 |
EP4175668A1 (en) | 2020-07-06 | 2023-05-10 | iOmx Therapeutics AG | Antibodies binding igv of igsf11 (vsig3) and uses thereof |
TW202220677A (zh) | 2020-07-31 | 2022-06-01 | 日商中外製藥股份有限公司 | 含有表現嵌合受體之細胞的醫藥組成物 |
KR20230054672A (ko) | 2020-08-20 | 2023-04-25 | 쑤저우 아보젠 바이오사이언시스 컴퍼니 리미티드 | 지질 화합물 및 지질 나노입자 조성물 |
US11406703B2 (en) | 2020-08-25 | 2022-08-09 | Modernatx, Inc. | Human cytomegalovirus vaccine |
CN112175988B (zh) * | 2020-09-15 | 2021-06-15 | 广东省农业科学院蔬菜研究所 | 黄瓜韧皮部凝集素CsPL1在抗瓜类疫病中的应用 |
CA3173151A1 (en) | 2020-11-03 | 2022-05-12 | Deutsches Krebsforschungszentrum Stiftung Des Offentlichen Rechts | Target-cell restricted, costimulatory, bispecific and bivalent anti-cd28 antibodies |
EP4267178A1 (en) | 2020-12-22 | 2023-11-01 | CureVac SE | Rna vaccine against sars-cov-2 variants |
CN112516288B (zh) * | 2020-12-22 | 2023-04-18 | 西藏阿那达生物医药科技有限责任公司 | N-糖基化修饰之灵芝免疫调节蛋白的应用 |
WO2022152109A2 (en) | 2021-01-14 | 2022-07-21 | Suzhou Abogen Biosciences Co., Ltd. | Lipid compounds and lipid nanoparticle compositions |
WO2022152141A2 (en) | 2021-01-14 | 2022-07-21 | Suzhou Abogen Biosciences Co., Ltd. | Polymer conjugated lipid compounds and lipid nanoparticle compositions |
WO2022182768A1 (en) | 2021-02-26 | 2022-09-01 | Regeneron Pharmaceuticals, Inc. | Treatment of inflammation with glucocorticoids and angiopoietin-like 7 (angptl7) inhibitors |
CA3210650A1 (en) | 2021-03-03 | 2022-09-09 | Winfried Wels | Bispecific antibodies enhancing cell mediated immune responses |
BR112023022331A2 (pt) | 2021-05-12 | 2023-12-26 | Nexeos Diagnostics Inc | Métodos de fabricação de um composto de heparina de alto peso molecular |
AU2022281746A1 (en) | 2021-05-24 | 2023-09-14 | Suzhou Abogen Biosciences Co., Ltd. | Lipid compounds and lipid nanoparticle compositions |
AU2022297107A1 (en) | 2021-06-25 | 2024-01-18 | Chugai Seiyaku Kabushiki Kaisha | Use of anti-ctla-4 antibody |
TW202317627A (zh) | 2021-06-25 | 2023-05-01 | 日商中外製藥股份有限公司 | 抗ctla-4抗體 |
CN113425855B (zh) * | 2021-06-28 | 2023-11-07 | 深圳瑞吉生物科技有限公司 | 一种mRNA剂型的骨关节炎药物制剂及其制备方法和应用 |
WO2023044333A1 (en) | 2021-09-14 | 2023-03-23 | Renagade Therapeutics Management Inc. | Cyclic lipids and methods of use thereof |
WO2023044343A1 (en) | 2021-09-14 | 2023-03-23 | Renagade Therapeutics Management Inc. | Acyclic lipids and methods of use thereof |
CA3234127A1 (en) | 2021-10-08 | 2023-04-13 | Suzhou Abogen Biosciences Co., Ltd. | Lipid compounds and lipid nanoparticle compositions |
CN116064598B (zh) | 2021-10-08 | 2024-03-12 | 苏州艾博生物科技有限公司 | 冠状病毒的核酸疫苗 |
AR127312A1 (es) | 2021-10-08 | 2024-01-10 | Suzhou Abogen Biosciences Co Ltd | Compuestos lipídicos ycomposiciones de nanopartículas lipídicas |
CN113813369B (zh) * | 2021-11-09 | 2023-09-22 | 浙江省农业科学院 | 用于预防/治疗仔猪肠道损伤的egf/mmt复合物 |
CN113980987A (zh) * | 2021-12-06 | 2022-01-28 | 上海市农业科学院 | 一种提高植物抗镍性能的PgIREG1S和AlATP-PRTS双基因组及其应用 |
WO2023122752A1 (en) | 2021-12-23 | 2023-06-29 | Renagade Therapeutics Management Inc. | Constrained lipids and methods of use thereof |
WO2023196931A1 (en) | 2022-04-07 | 2023-10-12 | Renagade Therapeutics Management Inc. | Cyclic lipids and lipid nanoparticles (lnp) for the delivery of nucleic acids or peptides for use in vaccinating against infectious agents |
CN114711192B (zh) * | 2022-04-13 | 2022-11-29 | 中国科学院西北高原生物研究所 | 一种长效抑郁症动物模型的构建试剂盒及构建方法 |
WO2023215498A2 (en) | 2022-05-05 | 2023-11-09 | Modernatx, Inc. | Compositions and methods for cd28 antagonism |
WO2024037578A1 (en) | 2022-08-18 | 2024-02-22 | Suzhou Abogen Biosciences Co., Ltd. | Composition of lipid nanoparticles |
Family Cites Families (85)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5908779A (en) * | 1993-12-01 | 1999-06-01 | University Of Connecticut | Targeted RNA degradation using nuclear antisense RNA |
IL131979A0 (en) * | 1997-03-21 | 2001-03-19 | Enzo Therapeutics Inc | Vectors and viral vectors and packaging cell lines for propagating the same |
US6423885B1 (en) | 1999-08-13 | 2002-07-23 | Commonwealth Scientific And Industrial Research Organization (Csiro) | Methods for obtaining modified phenotypes in plant cells |
EP1800697B1 (de) | 2001-06-05 | 2010-04-14 | CureVac GmbH | Stabilisierte mRNA mit erhöhtem G/C-Gehalt für die Gentherapie |
US8021875B2 (en) | 2001-08-27 | 2011-09-20 | Roche Madison Inc. | Methods for expression of transgenes |
US7985553B2 (en) | 2001-10-29 | 2011-07-26 | Nathaniel Heintz | Method for isolating cell type-specific mRNAs |
DE10162480A1 (de) | 2001-12-19 | 2003-08-07 | Ingmar Hoerr | Die Applikation von mRNA für den Einsatz als Therapeutikum gegen Tumorerkrankungen |
DE10229872A1 (de) | 2002-07-03 | 2004-01-29 | Curevac Gmbh | Immunstimulation durch chemisch modifizierte RNA |
US9068234B2 (en) | 2003-01-21 | 2015-06-30 | Ptc Therapeutics, Inc. | Methods and agents for screening for compounds capable of modulating gene expression |
CA2514184C (en) | 2003-01-21 | 2016-04-12 | Ptc Therapeutics, Inc. | Methods for identifying compounds that modulate untranslated region-dependent gene expression and methods of using same |
DE10335833A1 (de) | 2003-08-05 | 2005-03-03 | Curevac Gmbh | Transfektion von Blutzellen mit mRNA zur Immunstimulation und Gentherapie |
BRPI0415204A (pt) | 2003-10-10 | 2006-12-05 | Powderject Vaccines Inc | construção de ácido nucleico, métodos de obtenção da expressão em células de mamìferos de um polipeptìdeo de interesse, e de imunização com ácido nucleico, partìculas revestidas, receptáculo de dosagem para um dispositivo de liberação mediada por partìculas, dispositivo de liberação mediada por partìculas, e, sequência de promotor quimérico isolada purificada |
SG147468A1 (en) * | 2003-10-24 | 2008-11-28 | Selexis Sa | High efficiency gene transfer and expression in mammalian cells by a multiple transfection procedure of matrix attachment region sequences |
DE102004035227A1 (de) | 2004-07-21 | 2006-02-16 | Curevac Gmbh | mRNA-Gemisch zur Vakzinierung gegen Tumorerkrankungen |
DE102004042546A1 (de) | 2004-09-02 | 2006-03-09 | Curevac Gmbh | Kombinationstherapie zur Immunstimulation |
DE102005023170A1 (de) | 2005-05-19 | 2006-11-23 | Curevac Gmbh | Optimierte Formulierung für mRNA |
LT2578685T (lt) | 2005-08-23 | 2019-06-10 | The Trustees Of The University Of Pennsylvania | Rnr, apimančios modifikuotus nukleozidus ir jų panaudojimo būdai |
DE102005046490A1 (de) | 2005-09-28 | 2007-03-29 | Johannes-Gutenberg-Universität Mainz | Modifikationen von RNA, die zu einer erhöhten Transkriptstabilität und Translationseffizienz führen |
DE102006035618A1 (de) | 2006-07-31 | 2008-02-07 | Curevac Gmbh | Nukleinsäure der Formel (I): GlXmGn, insbesondere als immunstimulierendes Adjuvanz |
EP2046954A2 (en) | 2006-07-31 | 2009-04-15 | Curevac GmbH | NUCLEIC ACID OF FORMULA (I): GIXmGn, OR (II): CIXmCn, IN PARTICULAR AS AN IMMUNE-STIMULATING AGENT/ADJUVANT |
DE102006061015A1 (de) | 2006-12-22 | 2008-06-26 | Curevac Gmbh | Verfahren zur Reinigung von RNA im präparativen Maßstab mittels HPLC |
DE102007001370A1 (de) | 2007-01-09 | 2008-07-10 | Curevac Gmbh | RNA-kodierte Antikörper |
WO2009030254A1 (en) | 2007-09-04 | 2009-03-12 | Curevac Gmbh | Complexes of rna and cationic peptides for transfection and for immunostimulation |
WO2009046739A1 (en) | 2007-10-09 | 2009-04-16 | Curevac Gmbh | Composition for treating prostate cancer (pca) |
WO2009046738A1 (en) | 2007-10-09 | 2009-04-16 | Curevac Gmbh | Composition for treating lung cancer, particularly of non-small lung cancers (nsclc) |
EP2548960B1 (en) | 2008-01-31 | 2018-01-31 | CureVac AG | Nucleic acids comprising formula (nugixmgnv)a and derivatives thereof as an immunostimulating agents/adjuvant |
GB0815872D0 (en) | 2008-09-01 | 2008-10-08 | Pasteur Institut | Novel method and compositions |
WO2010037408A1 (en) | 2008-09-30 | 2010-04-08 | Curevac Gmbh | Composition comprising a complexed (m)rna and a naked mrna for providing or enhancing an immunostimulatory response in a mammal and uses thereof |
US8343497B2 (en) | 2008-10-12 | 2013-01-01 | The Brigham And Women's Hospital, Inc. | Targeting of antigen presenting cells with immunonanotherapeutics |
CA3017298C (en) | 2009-05-15 | 2021-09-28 | Irx Therapeutics, Inc. | Compositions comprising primary cell-derived biologics for enhancing immune responses in patients |
US20110053829A1 (en) | 2009-09-03 | 2011-03-03 | Curevac Gmbh | Disulfide-linked polyethyleneglycol/peptide conjugates for the transfection of nucleic acids |
WO2011069529A1 (en) | 2009-12-09 | 2011-06-16 | Curevac Gmbh | Mannose-containing solution for lyophilization, transfection and/or injection of nucleic acids |
EP2955230A1 (en) | 2010-07-30 | 2015-12-16 | CureVac AG | Complexation of nucleic acids with disulfide-crosslinked cationic components for transfection and immunostimulation |
WO2012019630A1 (en) * | 2010-08-13 | 2012-02-16 | Curevac Gmbh | Nucleic acid comprising or coding for a histone stem-loop and a poly(a) sequence or a polyadenylation signal for increasing the expression of an encoded protein |
WO2012089225A1 (en) | 2010-12-29 | 2012-07-05 | Curevac Gmbh | Combination of vaccination and inhibition of mhc class i restricted antigen presentation |
WO2012116715A1 (en) | 2011-03-02 | 2012-09-07 | Curevac Gmbh | Vaccination in newborns and infants |
WO2012113413A1 (en) | 2011-02-21 | 2012-08-30 | Curevac Gmbh | Vaccine composition comprising complexed immunostimulatory nucleic acids and antigens packaged with disulfide-linked polyethyleneglycol/peptide conjugates |
WO2012116714A1 (en) | 2011-03-02 | 2012-09-07 | Curevac Gmbh | Vaccination in elderly patients |
EP2623121A1 (en) | 2012-01-31 | 2013-08-07 | Bayer Innovation GmbH | Pharmaceutical composition comprising a polymeric carrier cargo complex and an antigen |
WO2013113325A1 (en) | 2012-01-31 | 2013-08-08 | Curevac Gmbh | Negatively charged nucleic acid comprising complexes for immunostimulation |
WO2013113326A1 (en) | 2012-01-31 | 2013-08-08 | Curevac Gmbh | Pharmaceutical composition comprising a polymeric carrier cargo complex and at least one protein or peptide antigen |
WO2013120498A1 (en) | 2012-02-15 | 2013-08-22 | Curevac Gmbh | Nucleic acid comprising or coding for a histone stem-loop and a poly(a) sequence or a polyadenylation signal for increasing the expression of an encoded allergenic antigen or an autoimmune self-antigen |
WO2013120500A1 (en) | 2012-02-15 | 2013-08-22 | Curevac Gmbh | Nucleic acid comprising or coding for a histone stem-loop and a poly(a) sequence or a polyadenylation signal for increasing the expression of an encoded tumour antigen |
WO2013120497A1 (en) * | 2012-02-15 | 2013-08-22 | Curevac Gmbh | Nucleic acid comprising or coding for a histone stem-loop and a poly(a) sequence or a polyadenylation signal for increasing the expression of an encoded therapeutic protein |
WO2013120499A1 (en) * | 2012-02-15 | 2013-08-22 | Curevac Gmbh | Nucleic acid comprising or coding for a histone stem-loop and a poly (a) sequence or a polyadenylation signal for increasing the expression of an encoded pathogenic antigen |
KR102186497B1 (ko) | 2012-03-27 | 2020-12-04 | 큐어백 아게 | 인공 핵산 분자 |
RU2660565C2 (ru) | 2012-03-27 | 2018-07-06 | Кьюрвак Аг | Молекулы искусственной нуклеиновой кислоты, содержащие 5'utr гена top |
CA2859452C (en) | 2012-03-27 | 2021-12-21 | Curevac Gmbh | Artificial nucleic acid molecules for improved protein or peptide expression |
ES2719598T3 (es) | 2012-05-25 | 2019-07-11 | Curevac Ag | Inmovilización reversible y/o liberación controlada de ácidos nucleicos contenidos en nanopartículas mediante revestimientos poliméricos (biodegradables) |
PL2922554T3 (pl) | 2012-11-26 | 2022-06-20 | Modernatx, Inc. | Na zmodyfikowany na końcach |
AU2014220957A1 (en) | 2013-02-22 | 2015-07-30 | Curevac Ag | Combination of vaccination and inhibition of the PD-1 pathway |
WO2015024669A1 (en) | 2013-08-21 | 2015-02-26 | Curevac Gmbh | Combination vaccine |
WO2015024666A1 (en) | 2013-08-21 | 2015-02-26 | Curevac Gmbh | Composition and vaccine for treating lung cancer |
SG10201801428RA (en) | 2013-08-21 | 2018-03-28 | Curevac Ag | Method for increasing expression of rna-encoded proteins |
SG10201801431TA (en) | 2013-08-21 | 2018-04-27 | Curevac Ag | Respiratory syncytial virus (rsv) vaccine |
BR112016001192A2 (pt) | 2013-08-21 | 2017-08-29 | Curevac Ag | Vacina contra a raiva |
KR20160043103A (ko) | 2013-08-21 | 2016-04-20 | 큐어백 아게 | 전립선암 치료를 위한 조성물 및 백신 |
WO2015062738A1 (en) | 2013-11-01 | 2015-05-07 | Curevac Gmbh | Modified rna with decreased immunostimulatory properties |
DK3090053T3 (en) | 2013-12-30 | 2019-02-25 | Curevac Ag | Artificial nucleic acid molecules |
SG11201604198YA (en) | 2013-12-30 | 2016-07-28 | Curevac Ag | Methods for rna analysis |
WO2015101415A1 (en) | 2013-12-30 | 2015-07-09 | Curevac Gmbh | Artificial nucleic acid molecules |
US10307472B2 (en) | 2014-03-12 | 2019-06-04 | Curevac Ag | Combination of vaccination and OX40 agonists |
EP3129050A2 (en) | 2014-04-01 | 2017-02-15 | CureVac AG | Polymeric carrier cargo complex for use as an immunostimulating agent or as an adjuvant |
KR102459599B1 (ko) | 2014-06-10 | 2022-10-26 | 큐어백 리얼 이스테이트 게엠베하 | Rna생산을 증진하는 방법 및 수단 |
US11149278B2 (en) | 2014-12-12 | 2021-10-19 | Curevac Ag | Artificial nucleic acid molecules for improved protein expression |
WO2016097065A1 (en) | 2014-12-16 | 2016-06-23 | Curevac Ag | Ebolavirus and marburgvirus vaccines |
SG10201906673WA (en) | 2014-12-30 | 2019-09-27 | Curevac Ag | Artificial nucleic acid molecules |
EP3283059B1 (en) | 2015-04-13 | 2024-01-03 | CureVac Manufacturing GmbH | Method for producing rna compositions |
EP3283125B1 (en) | 2015-04-17 | 2021-12-29 | CureVac Real Estate GmbH | Lyophilization of rna |
BR112017018368B1 (pt) | 2015-04-22 | 2022-08-02 | Curevac Ag | Composição contendo rna para uso no tratamento ou profilaxia de doenças tumorais e/ou cancerosas, e uso de um rna para a preparação da composição |
US11384375B2 (en) | 2015-04-30 | 2022-07-12 | Curevac Ag | Immobilized poly(n)polymerase |
CN108064307A (zh) | 2015-04-30 | 2018-05-22 | 库瑞瓦格股份公司 | 使用固定化的限制酶进行体外转录的方法 |
DK3294885T3 (da) | 2015-05-08 | 2020-08-10 | Curevac Real Estate Gmbh | Fremgangsmåde til at fremstille rna |
US11559570B2 (en) | 2015-05-15 | 2023-01-24 | CureVac SE | Prime-boost regimens involving administration of at least one mRNA construct |
SG10201910431RA (en) | 2015-05-20 | 2020-01-30 | Curevac Ag | Dry powder composition comprising long-chain rna |
CN107530448A (zh) | 2015-05-20 | 2018-01-02 | 库瑞瓦格股份公司 | 包含长链rna的干粉组合物 |
US11608513B2 (en) | 2015-05-29 | 2023-03-21 | CureVac SE | Method for adding cap structures to RNA using immobilized enzymes |
US10760070B2 (en) | 2015-05-29 | 2020-09-01 | Curevac Real Estate Gmbh | Method for producing and purifying RNA, comprising at least one step of tangential flow filtration |
WO2016203025A1 (en) | 2015-06-17 | 2016-12-22 | Curevac Ag | Vaccine composition |
US20190017100A1 (en) | 2015-07-01 | 2019-01-17 | Curevac Ag | Method for analysis of an rna molecule |
WO2017009376A1 (en) | 2015-07-13 | 2017-01-19 | Curevac Ag | Method of producing rna from circular dna and corresponding template dna |
US20200085852A1 (en) | 2015-08-05 | 2020-03-19 | Curevac Ag | Epidermal mrna vaccine |
WO2017025120A1 (en) | 2015-08-07 | 2017-02-16 | Curevac Ag | Process for the in vivo production of rna in a host cell |
US20230167456A2 (en) | 2015-08-10 | 2023-06-01 | CureVac Manufacturing GmbH | Method of increasing the replication of a circular dna molecule |
MX2018001040A (es) | 2015-08-28 | 2018-06-15 | Curevac Ag | Moleculas de acido nucleico artificiales. |
-
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- 2012-02-15 WO PCT/EP2012/000671 patent/WO2013120497A1/en active Application Filing
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