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1. 发明申请

WO1998026046A2 A NOVEL TRANSCRIPTION FACTOR EXPRESSED IN CYCLING CELLS, NUCLEIC ACID MOLECULES ENCODING SAID TRANSCRIPTION FACTOR AND ITS PROMOTER REGION AND USES THEREOF 审中-公开
标题翻译：循环细胞中表达的新型转录因子，编码转录因子及其启动子区的核酸分子及其用途
公开(公告)号：WO1998026046A2
公开(公告)日：1998-06-18
申请号：PCT/NL1997000679
申请日：1997-12-09
申请人： INTROGENE B.V. , KORVER, Wouter , CLEVERS, Johannes, Carolus
发明人： INTROGENE B.V.
IPC分类号： C12N05/12
CPC分类号： C07K14/4738 , A61K38/00 , A61K48/00 , C07K16/18
摘要： A novel transcription factor and its encoding nucleic acid molecules, as well as its consensus DNA binding motif are disclosed. The invention also discloses the DNA promoter region of the novel transcription factor that drives ubiquitous expression of genes in cycling cells, but is silent in resting cells, and its use in gene therapeutic strategies for the treatment of, e.g., malignancies. Furthermore, monoclonal antibodies reacting with said transcription factor and their use for the detection of cycling cells are disclosed.
摘要翻译：公开了一种新的转录因子及其编码核酸分子，以及其共有DNA结合基序。本发明还公开了新型转录因子的DNA启动子区域，其驱动循环细胞中基因的普遍表达，但在静息细胞中沉默，以及其在用于治疗例如恶性肿瘤的基因治疗策略中的应用。此外，公开了与所述转录因子反应的单克隆抗体及其用于检测循环细胞的用途。

2. 发明申请

WO1997031111A2 A FAMILY OF ORGANIC ANION TRANSPORTERS, NUCLEIC ACIDS ENCODING THEM, CELLS COMPRISING THEM AND METHODS FOR USING THEM 审中-公开
标题翻译：有机阴离子运输系统的家族，编码它们的核酸，包含它们的细胞和使用它们的方法
公开(公告)号：WO1997031111A2
公开(公告)日：1997-08-28
申请号：PCT/NL1997000079
申请日：1997-02-21
申请人： INTROGENE B.V. , ACADEMISCH MEDISCH CENTRUM AMSTERDAM , HET NEDERLANDS KANKER INSTITUUT , OUDE ELFERINK, Ronald, Petrus, Johannes , PAULUSMA, Coenraad, Cornelis , BOSMA, Piter, Jabik , BORST, Piet , EVERS, Raymond , KOOL, Marcel
发明人： INTROGENE B.V. , ACADEMISCH MEDISCH CENTRUM AMSTERDAM , HET NEDERLANDS KANKER INSTITUUT
IPC分类号： C12N15/12
CPC分类号： C07K14/705 , A61K48/00
摘要： The present invention provides a novel family of organic anion transporters of which until now only one member was known. The family includes multispecific organic anion transporters related to the canalicular multispecific organic anion transporter. The cDNA encoding the latter is also provided. The rat and human cDNA are exemplified. Uses of nucleic acids based on this gene family and of cells comprising such nucleic acids as well as vectors comprising sequences thereof are also disclosed especially in the area of gene therapy.
摘要翻译：本发明提供了一种新型的有机阴离子转运体家族，迄今仅有一种成员是已知的。该家族包括与小管多特异性有机阴离子转运蛋白相关的多特异性有机阴离子转运蛋白。还提供了编码后者的cDNA。示例了大鼠和人cDNA。基于该基因家族的核酸和包含这些核酸的细胞的使用以及包含其序列的载体也特别在基因治疗领域中公开。

3. 发明申请

WO1997000326A1 PACKAGING SYSTEMS FOR HUMAN RECOMBINANT ADENOVIRUS TO BE USED IN GENE THERAPY 审中-公开
标题翻译：用于基因治疗的人类重组腺病毒的包装系统
公开(公告)号：WO1997000326A1
公开(公告)日：1997-01-03
申请号：PCT/NL1996000244
申请日：1996-06-14
申请人： INTROGENE B.V. , RIJKSUNIVERSITEIT LEIDEN , FALLAUX, Frits, Jacobus , HOEBEN, Robert, Cornelis , BOUT, Abraham , VALERIO, Domenico , VAN DER EB, Alex, Jan
发明人： INTROGENE B.V. , RIJKSUNIVERSITEIT LEIDEN
IPC分类号： C12N15/86
CPC分类号： C12N7/00 , A61K48/00 , C12N15/86 , C12N2710/10321 , C12N2710/10343 , C12N2710/10351 , C12N2710/10352 , C12N2830/00 , C12N2830/15 , C12N2830/42 , C12N2830/60
摘要： The invention provides improved methods and products based on adenoviral materials which can advantageously be used in for instance gene therapy. In one aspect an adenoviral vector is provided which has no overlap with a suitable packaging cell line which is another aspect of invention. This combination excludes the possibility of homologous recombination, thereby excluding the possibility of the formation of replication competent adenovirus. In another aspect an adenovirus based helper construct which by its size is incapable of being encapsidated. This helper virus can be transferred into any suitable host cell making it a packaging cell. Further a number of useful mutations to adenoviral based materials and combinations of such mutations are disclosed, which all have in common the safety of the methods and the products, in particular avoiding the production of replication competent adenovirus and/or interference with the immune system. Further a method of intracellular amplification is provided.
摘要翻译：本发明提供了可以有利地用于例如基因治疗的基于腺病毒材料的改进的方法和产品。在一个方面，提供了与适合的包装细胞系重叠的腺病毒载体，其是本发明的另一方面。该组合不包括同源重组的可能性，从而排除形成复制型腺病毒的可能性。在另一方面，基于腺病毒的辅助构建体，其大小不能被包被。这种辅助病毒可以转移到任何合适的宿主细胞中，使其成为包装细胞。此外，公开了一些对基于腺病毒的材料的有用的突变以及这些突变的组合，这些突变都具有方法和产物的安全性，特别是避免产生可复制的腺病毒和/或免疫系统的干扰。此外还提供了细胞内扩增的方法。

4. 发明申请

WO1998024924A1 GENETIC MODIFICATION OF PRIMATE HEMOPOIETIC REPOPULATING STEM CELLS 审中-公开
标题翻译： PRIMATE HEMOPOIETIC REPOPULATING STEM CELLS的遗传修饰
公开(公告)号：WO1998024924A1
公开(公告)日：1998-06-11
申请号：PCT/NL1997000631
申请日：1997-11-19
申请人： INTROGENE B.V. , EINERHAND, Markus, Peter, Wilhelmus , VALERIO, Domenico
发明人： INTROGENE B.V.
IPC分类号： C12N15/86
CPC分类号： C12N15/86 , A61K38/00 , A61K48/00 , C07K14/805 , C12N2750/14143
摘要： Genetic modification of pluripotent hemopoietic stem cells of primates (P-PHSC) by transduction of P-PHSC with a recombinant adeno-associated virus (AAV). The genome of the recombinant AAV comprises a DNA sequence flanked by the inverted terminal repeats (ITR) of AAV. The DNA sequence will normally comprise regulatory sequences which are functional in hemopoietic cells and, controlled by these regulatory sequences, a sequence coding for a protein or RNA with a therapeutic property when introduced into hemopoietic cells. Preferred examples of DNA sequences are the human lysosomal glococerebrosidase gene, a globin gene from the human beta -globin gene cluster, a DNA sequence encoding an RNA or protein with anti-viral activity, the alpha 1-antitrypsin gene and the human multidrug resistance gene I (MDRI). The invention provides for effective gene therapy with PHSC of primates, in particular humans.
摘要翻译：通过用重组腺相关病毒（AAV）转导P-PHSC对灵长类动物多能造血干细胞（P-PHSC）的遗传修饰。重组AAV的基因组包含侧翼为AAV的反向末端重复（ITR）的DNA序列。 DNA序列通常包含在造血细胞中功能的调控序列，并且由这些调控序列控制，当引入造血细胞时，编码具有治疗性质的蛋白质或RNA的序列。 DNA序列的优选实例是人溶酶体glococerebrosidase基因，来自人β-珠蛋白基因簇的珠蛋白基因，编码具有抗病毒活性的RNA或蛋白质的DNA序列，α1-抗胰蛋白酶基因和人多药耐药基因我（MDRI）。本发明提供用灵长类动物，特别是人的PHSC进行有效的基因治疗。

5. 发明申请

WO1998014217A1 METHODS AND MEANS FOR THE TREATMENT OF MALIGNANCIES 审中-公开
标题翻译：治疗恶性肿瘤的方法和手段
公开(公告)号：WO1998014217A1
公开(公告)日：1998-04-09
申请号：PCT/NL1997000542
申请日：1997-09-30
申请人： INTROGENE B.V. , BOUT, Abraham , VAN BEKKUM, Dirk, Willem
发明人： INTROGENE B.V.
IPC分类号： A61K48/00
CPC分类号： A61K39/0011 , A61K38/2006 , A61K38/202 , A61K48/00
摘要： The present invention provides novel means and methods for eliminating unwanted cells or organisms from a (mammalian) subject. In particular tumors can be combatted using the compositions according to the present invention. In a preferred embodiment solid tumors are injected with a burst of cytokine (in particular IL-1a or IL-3) together with a slow release source for a cytokine. To further boost the immune system an adjuvans is preferred. In a preferred embodiment the source for the slow release cytokine is a recombinant adenovirus. In an especially preferred embodiment the adjuvant comprises inactivated (cracked) adenovirus producing cells.
摘要翻译：本发明提供了从（哺乳动物）受试者中消除不需要的细胞或生物体的新颖手段和方法。特别是可以使用根据本发明的组合物来对抗肿瘤。在优选实施方案中，实体瘤与细胞因子的缓释源一起注射细胞因子（特别是IL-1a或IL-3）。为了进一步增强免疫系统，优选佐剂。在优选的实施方案中，缓释细胞因子的来源是重组腺病毒。在特别优选的实施方案中，佐剂包含失活（破裂的）腺病毒产生细胞。

6. 发明申请

WO1996035798A1 IMPROVED RETROVIRAL VECTORS, ESPECIALLY SUITABLE FOR GENE THERAPY 审中-公开
标题翻译：改进的退化载体，特别适用于基因治疗
公开(公告)号：WO1996035798A1
公开(公告)日：1996-11-14
申请号：PCT/NL1996000195
申请日：1996-05-07
申请人： INTROGENE B.V. , VOGELS, Ronald , BOESEN, Johannes, Jozephes, Bernardus , VAN ES, Helmuth, Hendrikus, Gerardus , VAN BEUSECHEM, Victor, Willem , VALERIO, Domenico
发明人： INTROGENE B.V.
IPC分类号： C12N15/86
CPC分类号： C12N15/86 , A61K48/00 , C12N7/00 , C12N2740/13023 , C12N2740/13043 , C12N2840/20 , C12N2840/203
摘要： The present invention relates to the field of molecular biology, especially recombinant DNA technology, especially concerning retroviral vectors. Retroviral vectors are very suitable vehicles for transferring genetic material of interest into certain cells in so-called gene therapy strategies. However, the retroviral vectors described so far are not ideal. They may give rise to recombination events resulting in helper (pathogenic) virus, they may express viral proteinaceous materials leading to immune responses, etc. These and other drawbacks are overcome by the vectors, cells, kits and methods of the present invention by providing a vector derived from a retrovirus, comprising a sequence responsible for transcriptional control, including an enhancer, which vector further comprises a site for insertion of at least one gene of interest, a packaging signal, said vector having no superfluous retroviral sequences and no open reading frame encoding at least parts of viral proteins, characterized in that the enhancer is an enhancer that is active in undifferentiated cells.
摘要翻译：本发明涉及分子生物学领域，特别是涉及逆转录病毒载体的重组DNA技术领域。逆转录病毒载体是用于将遗传物质转移到所谓基因治疗策略中的某些细胞的非常合适的载体。然而，迄今描述的逆转录病毒载体并不理想。它们可能引起导致辅助（致病性）病毒的重组事件，它们可以表达导致免疫应答的病毒蛋白质物质等。这些和其它缺点通过本发明的载体，细胞，试剂盒和方法来克服，衍生自逆转录病毒的载体，包含负责转录控制的序列，包括增强子，所述载体还包含用于插入至少一种目标基因的位点，包装信号，所述载体不具有多余的逆转录病毒序列，并且没有开放阅读框编码至少部分病毒蛋白质，其特征在于增强子是在未分化细胞中有活性的增强子。

7. 发明申请

WO1997020943A1 REGULATED PROTEIN EXPRESSION IN STABLY TRANSFECTED MAMMALIAN CELLS 审中-公开
标题翻译：稳定的蛋白质表达在稳定的转录的MAMMALIAN细胞
公开(公告)号：WO1997020943A1
公开(公告)日：1997-06-12
申请号：PCT/NL1996000472
申请日：1996-11-29
申请人： INTROGENE B.V. , EINERHAND, Markus, Peter, Wilhelmus , VALERIO, Domenico
发明人： INTROGENE B.V.
IPC分类号： C12N15/85
CPC分类号： C12N15/86 , C07K14/005 , C12N15/85 , C12N2750/14122 , C12N2750/14143 , C12N2830/003 , C12N2830/006
摘要： The invention is in the field of recombinant genetic materials, especially for use in gene therapy. Vectors used for transferring additional genetic information to cells in the field of gene therapy are often based on viruses. A group of viruses which has been proposed to use for transfection is the group of parvoviruses, in particular the use of adeno associated virus has been proposed. The invention provides improved methods and means for gene therapy and for preparing products to be used in gene therapy using parvovirus based materials. The invention particularly provides regulated expression of genes under control of the combination of a repressor moiety and an activator moiety, particularly for expression of products which are toxic to the host cell in which they are expressed. In this way it is possible to achieve stable transfection for expression of parvovirus toxic proteins so that amongst others a packaging cell line for producing recombinant parvovirus, in particular adeno associated virus is provided as well as virus produced therewith.
摘要翻译：本发明涉及重组遗传物质领域，尤其用于基因治疗。用于在基因治疗领域向细胞传递额外遗传信息的载体通常基于病毒。已经提出用于转染的一组病毒是一组细小病毒，特别是使用腺相关病毒。本发明提供用于基因治疗和用于使用基于细小病毒的材料的基因治疗中使用的产物的改进方法和手段。本发明特别提供了在抑制子部分和活化剂部分的组合的控制下的基因的调节表达，特别是对于其表达它们的宿主细胞具有毒性的产物的表达。以这种方式，可以实现细小病毒毒性蛋白质的表达的稳定转染，从而提供用于产生重组细小病毒，特别是腺相关病毒的包装细胞系以及由其产生的病毒。

8. 发明申请

WO1997007226A1 POLY(ORGANO)PHOSPHAZENES FOR USE IN SYNTHETIC TRANSFECTION SYSTEMS 审中-公开
标题翻译： POLY（ORGANO）PHOSPHAZENES用于合成转运系统
公开(公告)号：WO1997007226A1
公开(公告)日：1997-02-27
申请号：PCT/NL1996000324
申请日：1996-08-16
申请人： INTROGENE B.V. , OCTOPLUS B.V. , UNIVERSITEIT UTRECHT , HENNINK, Wilhelmus, Everhardus , BOUT, Abraham
发明人： INTROGENE B.V. , OCTOPLUS B.V. , UNIVERSITEIT UTRECHT
IPC分类号： C12N15/87
CPC分类号： C12N15/87 , A61K47/605 , A61K48/00
摘要： The present invention relates to a synthetic transfection system comprising as a carrier a cationic, water soluble or water dispersible polyphosphazene. In addition, it relates to a method for introducing DNA fragments in target cells, comprising contacting these DNA fragments with a polyphosphazene which is at least partially substituted with cationic substituents and subsequently contacting the obtained transfection system wits target cells. Finally, the invention involves the use of a polyphosphazene which is at least partially substituted with cationic substituents as transfection vehicle.
摘要翻译：本发明涉及一种合成转染系统，其包含阳离子，水溶性或水分散性聚磷腈作为载体。此外，本发明涉及在靶细胞中引入DNA片段的方法，包括使这些DNA片段与至少部分被阳离子取代基取代的聚磷腈接触，随后使得到的转染系统与靶细胞接触。最后，本发明涉及使用至少部分被阳离子取代基取代的聚磷腈作为转染载体。

9. 发明申请

WO1997005266A1 METHODS AND MEANS FOR TARGETED GENE DELIVERY 审中-公开
标题翻译：目的基因交付的方法和手段
公开(公告)号：WO1997005266A1
公开(公告)日：1997-02-13
申请号：PCT/NL1996000302
申请日：1996-07-25
申请人： INTROGENE B.V. , VALERIO, Domenico , VAN BEUSECHEM, Victor, Willem
发明人： INTROGENE B.V.
IPC分类号： C12N15/87
CPC分类号： C07K14/005 , A61K47/6898 , A61K47/6901 , A61K48/00 , B82Y5/00 , C07K14/70535 , C07K2319/32 , C12N7/00 , C12N15/86 , C12N15/87 , C12N2710/00088 , C12N2740/13043 , C12N2740/13045 , C12N2740/13052 , C12N2740/15022 , C12N2810/855 , C12N2810/859
摘要： The present invention provides a method of producing viral gene delivery vehicles which can be transferred to preselected cell types by using targeting conjugates. The gene delivery vehicules comprise: 1) the gene of interest (to be delivered); 2) a viral capsid or envelope carrying a member of a specific binding pair, the counterpart of which is not directly associated with the surface of the target cell. These vehicles can be made unable to bind to their natural receptor on the cell. The targeting conjugates are composed of the counterpart member of the specific binding pair linked to a targeting moiety which is a cell-type specific ligand (or fragments thereof). The number of the specific binding pair present on the viral vehicles can be for example an immunoglobulin binding moiety (e.g. capable of binding to a Fc fragment, protein A, protein G, FcR or an anti-Ig antibody), or biotin, avidin or streptavidin. The outer membrane or capsid of the virus may contain a substance which mediates entrance of the gene delivery vehicle into the target cell. Due to the specificity of the ligand, the high affinity of the binding pair and to the inability of the gene delivery vehicle to be targeted when used alone, the universality of the method for gene delivery, together with its high cell type selectively can easily be achievied by the use of various adequate targeting conjugates.
摘要翻译：本发明提供了可以通过使用靶向缀合物转移到预选细胞类型的病毒基因递送载体的生产方法。基因输送车辆包括：1）感兴趣的基因（待交付）; 2）携带特异性结合对的成员的病毒衣壳或信封，其对应物不与靶细胞的表面直接相关。这些载体可能不能与细胞上的天然受体结合。靶向缀合物由与作为细胞型特异性配体（或其片段）的靶向部分连接的特异性结合对的对应成员组成。存在于病毒载体上的特异性结合对的数目可以是例如免疫球蛋白结合部分（例如能够结合Fc片段，蛋白A，蛋白G，FcR或抗-Ig抗体）或生物素，抗生物素蛋白或链亲和素。病毒的外膜或衣壳可以含有介导基因递送载体进入靶细胞的入口的物质。由于配体的特异性，当单独使用时，结合对的高亲和力和基因递送载体的靶向性不足，基因递送方法的普及性及其高细胞型选择性可容易地通过使用各种适当的目标缀合物实现。

10. 发明申请

WO1996041875A1 p-53 BINDING PROTEIN CALLED Mdmx AND ENCODING SEQUENCES FOR SAID PROTEIN 审中-公开
标题翻译： p-53结合蛋白质被调用的Mdmx和编码序列的蛋白质
公开(公告)号：WO1996041875A1
公开(公告)日：1996-12-27
申请号：PCT/NL1996000239
申请日：1996-06-13
申请人： INTROGENE B.V. , RIJKSUNIVERSITEIT LEIDEN , VAN DER EB, Alex, Jan , JOCHEMSEN, Aart-Gerrit , SHVARTS, Avraam
发明人： INTROGENE B.V. , RIJKSUNIVERSITEIT LEIDEN
IPC分类号： C12N15/12
CPC分类号： C07K14/47
摘要： The present invention provides a method to identify new proteins associating to the p53 tumor suppressor protein as well as elucidating the genes encoding said proteins, with some examples of cDNAs isolated this way. It also relates to the results of said method, which are novel proteins having affinity for p53, as well as genes and other nucleic acid molecules encoding these novel proteins. In particular the invention also provides such a novel protein and its encoding sequences, which protein has homology with the Mdm2 protein and which therefore has been designated as Mdmx.
摘要翻译：本发明提供了鉴定与p53肿瘤抑制蛋白相关联的新蛋白质以及阐明编码所述蛋白质的基因的方法，以这种方式分离cDNA的一些实例。它还涉及所述方法的结果，其是对p53具有亲和性的新蛋白质，以及编码这些新蛋白质的基因和其他核酸分子。特别地，本发明还提供了这种新型蛋白质及其编码序列，该蛋白质与Mdm2蛋白质具有同源性，因此已被指定为Mdmx。

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