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    Modified INSM1-Promoter for Neuroendocrine Tumor Therapy and Diagnostics
    3.
    发明申请
    Modified INSM1-Promoter for Neuroendocrine Tumor Therapy and Diagnostics 有权
    改良的INSM1启动子用于神经内分泌肿瘤治疗和诊断

    公开(公告)号：US20120316225A1

    公开(公告)日：2012-12-13

    申请号：US13505823

    申请日：2010-11-08

    申请人： Mary B. Breslin ,  Michael S. Lan

    发明人： Mary B. Breslin ,  Michael S. Lan

    IPC分类号： A61K31/7088 ,  A61P35/00 ,  G01N21/76 ,  C12N15/85 ,  C12N15/861

    CPC分类号： C12N15/86 ,  C07K14/005 ,  C07K2319/55 ,  C07K2319/61 ,  C12N15/85 ,  C12N2710/10343 ,  C12N2710/16622 ,  C12N2710/16634 ,  C12N2830/008 ,  C12N2830/32 ,  C12N2830/40

    摘要： A modification of the existing INSM1 promoter region has been discovered that incorporated DNA elements that silence expression of neuronal genes in non-neuronal cells and that has increased the effectiveness and safety of using the INSM1 promoter for tumor treatment. One modification was addition of one or two tandem copies of neuronal restrictive silencer elements (NRSEs) derived either from the mouse nicotinic acetylcholine receptor (nAChR) or the rat superior cervical ganglion 10 (SCG10) promoters. These NRSEs were placed in the expression construct either directly upstream or downstream of the INSM1 promoter sequence. The most effective expression construct was the nAChR NRSE element positioned downstream of the INSM1 promoter. This expression construct increased the tissue specificity of the INSM1 promoter without a significant decrease in its activity. In addition, the modified INSM1 promoter was placed into a viral vector, adenovirus 5. Constructs with an insulator element, the chicken HS4 β-globin insulator element, with the INSM1 promoter was shown to decrease the interference of the viral genome on its expression. Constructs have been made that do not decrease the INSM1 promoter activity but significantly augment the tumor specificity of the promoter. Linking the construct to a reporter gene allowed for detection of the placement of the viral vector, and this detection can be used for diagnosing or locating neuroendocrine tumors.

    摘要翻译： 已经发现现有的INSM1启动子区域的修饰是掺入了在非神经元细胞中沉默神经元基因表达的DNA元件，并增加了使用INSM1启动子进行肿瘤治疗的有效性和安全性。 一个修改是从小鼠烟碱乙酰胆碱受体（nAChR）或大鼠上颈部神经节10（SCG10）启动子衍生的神经元限制性消音元件（NRSE）的一个或两个串联拷贝的添加。 将这些NRSEs直接置于INSM1启动子序列的上游或下游的表达构建体中。 最有效的表达构建体是位于INSM1启动子下游的nAChR NRSE元件。 该表达构建体增加了INSM1启动子的组织特异性，而其活性没有显着降低。 此外，将修饰的INSM1启动子置于病毒载体，腺病毒5中。具有绝缘体元件，具有INSM1启动子的鸡HS4和bgr - 球蛋白绝缘子元件的构建体显示可减少病毒基因组对其表达的干扰 。 已经建立了不降低INSM1启动子活性但显着增加启动子的肿瘤特异性的构建体。 将构建体连接到允许检测病毒载体的位置的报告基因，并且该检测可用于诊断或定位神经内分泌肿瘤。

    Vectors for tissue-specific replication
    4.
    发明申请
    Vectors for tissue-specific replication 审中-公开
    用于组织特异性复制的载体

    公开(公告)号：US20080076172A1

    公开(公告)日：2008-03-27

    申请号：US11977533

    申请日：2007-10-24

    申请人： Paul Hallenbeck ,  Yung-Nien Chang ,  Yawen Chiang

    发明人： Paul Hallenbeck ,  Yung-Nien Chang ,  Yawen Chiang

    IPC分类号： C12N15/00

    CPC分类号： C12N15/86 ,  A61K48/00 ,  A61K48/0058 ,  C12N2710/10343 ,  C12N2820/002 ,  C12N2830/002 ,  C12N2830/008 ,  C12N2830/32 ,  C12N2830/85 ,  C12N2840/20

    摘要： The invention generally relates to targeted gene therapy using recombinant vectors and particularly adenovirus vectors. The invention specifically relates to replication-conditional vectors and methods for using them. Such vectors are able to selectively replicate in a target tissue to provide a therapeutic benefit from the presence of the vector per se or from heterologous gene products expressed from the vector and distributed throughout the tissue. In such vectors, a gene essential for replication is placed under the control of a heterologous tissue-specific transcriptional regulatory sequence. Thus, replication is conditioned on the presence of a factor(s) that induces transcription or the absence of a factor(s) that inhibits trancription of the gene by means of the transcriptional regulatory sequence with this vector; therefore, a target tissue can be selectively treated.

    摘要翻译： 本发明一般涉及使用重组载体，特别是腺病毒载体的靶向基因治疗。 本发明具体涉及复制条件向量及其使用方法。 这样的载体能够在靶组织中选择性地复制以从载体本身的存在或从载体表达的分布在整个组织中的异源基因产物提供治疗益处。 在这样的载体中，将复制必需的基因置于异源组织特异性转录调控序列的控制之下。 因此，复制受到诱导转录或不存在通过用该载体通过转录调控序列抑制基因转录的因子的因子的影响; 因此，可以选择性地处理靶组织。

    ANIMALS TRANSGENIC FOR A TETRACYCLINE-REGULATED TRANSCRIPTIONAL INHIBITOR
    5.
    发明申请
    ANIMALS TRANSGENIC FOR A TETRACYCLINE-REGULATED TRANSCRIPTIONAL INHIBITOR 无效
    用于四环素调节的转录抑制剂的动物转基因

    公开(公告)号：US20040003417A1

    公开(公告)日：2004-01-01

    申请号：US09241347

    申请日：1999-02-02

    发明人： HERMANN BUJARD ,  MANFRED GOSSEN

    IPC分类号： A01K067/00 ,  A61K039/00 ,  C12N015/87 ,  C12N005/06

    CPC分类号： A01K67/0275 ,  A01K2217/05 ,  A01K2217/075 ,  A01K2217/20 ,  A01K2227/105 ,  A01K2267/0393 ,  A61K48/00 ,  C07K14/005 ,  C07K14/245 ,  C07K2319/00 ,  C07K2319/09 ,  C07K2319/61 ,  C07K2319/71 ,  C07K2319/80 ,  C12N15/62 ,  C12N15/63 ,  C12N15/635 ,  C12N15/67 ,  C12N15/85 ,  C12N15/8509 ,  C12N2710/16622 ,  C12N2830/003 ,  C12N2830/005 ,  C12N2830/006 ,  C12N2830/32

    摘要： Transgenic animals carrying a transgene comprising a nucleic acid molecule encoding protein useful for regulating the expression of genes in eukaryotic cells and organisms in a highly controlled manner are disclosed. In the regulatory system of the invention, transcription of a tet operator-linked nucleotide sequence is inhibited by a transcriptional inhibitor fuision protein composed of two polypeptides, a first polypeptide which binds to tet operator sequences and a second polypeptide which directly or indirectly inhibits transcription in eukaryotic cells. In various embodiment, the first polypeptide binds to tet operator sequences either: (i) in the absence but not the presence of tetracycline (or an analogue thereof) or (ii) in the presence but not the absence of tetracycline (or an analogue thereof). In a preferred embodiment, the transgene encoding the transcriptional inhibitor fusion protein is integrated at a predetermined location within the chromosome of the transgenic animal.

    摘要翻译： 公开了携带转基因的转基因，其包含编码可用于以高度受控的方式调控真核细胞和生物体中的基因表达的蛋白质的核酸分子。 在本发明的调节系统中，由tet操纵子连接的核苷酸序列的转录受到由两个多肽组成的转录抑制剂功能蛋白的抑制，所述两个多肽是结合tet操纵子序列的第一个多肽和直接或间接抑制转录的第二个多肽 真核细胞。 在各种实施方案中，第一多肽与tet操纵子序列结合：（i）在不存在但不存在四环素（或其类似物）的情况下，或（ii）在存在但不存在四环素（或其类似物）的情况下 ）。 在优选的实施方案中，编码转录抑制剂融合蛋白​​的转基因整合在转基因动物的染色体内的预定位置。

    Methods of expressing transgenes
    7.
    发明申请
    Methods of expressing transgenes 审中-公开
    表达转基因的方法

    公开(公告)号：US20030084468A1

    公开(公告)日：2003-05-01

    申请号：US10235400

    申请日：2002-09-05

    发明人： Aris N. Economides ,  Thomas M. DeChiara ,  Nicholas W. Gale ,  George D. Yancopoulos

    IPC分类号： A01K067/027 ,  C12Q001/68 ,  C12N005/06 ,  C12N015/85

    CPC分类号： A01K67/0275 ,  A01K2217/05 ,  C12N15/907 ,  C12N2800/30 ,  C12N2830/001 ,  C12N2830/008 ,  C12N2830/30 ,  C12N2830/32 ,  C12N2830/85 ,  C12N2840/20 ,  C12N2840/203 ,  C12N2840/44

    摘要： The present invention is a novel method of expressing transgenes in vivo by targeting protected transgene cassettes into predetermined loci, including ubiquitously expressed chromosomal loci, such that the activity of an exogenous promoter is maintained. The advantages of this method are that the expression pattern is determined primarily by the nature of the exogenous promoter and, therefore, is not subject to positional effects. The invention also encompasses the DNA targeting vectors, the targeted cells, as well as non-human organisms, especially mice, created from the targeted cells.

    摘要翻译： 本发明是通过将受保护的转基因盒定向到预定的位点（包括普遍表达的染色体基因座），从而维持外源启动子的活性而在体内表达转基因的新方法。 该方法的优点在于表达模式主要由外源启动子的性质决定，因此不受定位效应的影响。 本发明还包括从靶细胞产生的DNA靶向载体，靶细胞以及非人生物，特别是小鼠。

    Retroviral vector for the transfer and expression of genes for therapeutic purposes in eukaryotic cells
    8.
    发明授权
    Retroviral vector for the transfer and expression of genes for therapeutic purposes in eukaryotic cells 失效
    用于在真核细胞中用于治疗目的的基因的转移和表达的逆转录病毒载体

    公开(公告)号：US06312948B1

    公开(公告)日：2001-11-06

    申请号：US09433322

    申请日：1999-11-03

    申请人： Odile Cohen-Haguenauer

    发明人： Odile Cohen-Haguenauer

    IPC分类号： C12N1563

    CPC分类号： C12N15/86 ,  C12N2740/13043 ,  C12N2830/32 ,  C12N2830/85 ,  C12N2840/203 ,  C12N2840/206 ,  C12N2840/44

    摘要： The invention relates to a recombinantvector for the cloning and/or expression and/or transfer of an exogenous nucleotide sequence characterized in that it consists of any sequence contained in the ClaI—PvuII fragment comprising nucleotides 7702 to 1527 of the sequence given in FIG. 1 and comprising the LTR sequence included between nucleotides 7842 and 144, the PBS site starting at nucleotides 145, the packaging sequence included in the sequences of 250 nucleotides following the end of the LTR sequence, the said sequence being capable of controlling the cloning and/or expression and/or transfer of the exogenous sequence whatever its transcriptional orientation with respect to the transcriptional orientation of the virus. It relates to the use of this vector for the transfer and/or cloning and/or expression of genes, in particular in the contest of gene therapy.

    摘要翻译： 本发明涉及用于克隆和/或表达和/或转移外源核苷酸序列的重组载体，其特征在于其由包含在图1中给出的序列的核苷酸7702至1527的ClaI-PvuII片段中包含的任何序列组成。 1，并且包含核苷酸7842和144之间的LTR序列，从核苷酸145开始的PBS位点，包含在LTR序列结束后的250个核苷酸的序列中的包装序列，所述序列能够控制克隆和/ 或外源序列的表达和/或转移，无论其关于病毒的转录取向的转录方向如何。它涉及该载体用于转移和/或克隆和/或表达基因，特别是在 基因治疗比赛

    Tetracycline-inducible transcriptional inhibitor fusion proteins
    9.
    发明授权
    Tetracycline-inducible transcriptional inhibitor fusion proteins 有权
    四环素诱导型转录抑制剂融合蛋白

    公开(公告)号：US06271348B1

    公开(公告)日：2001-08-07

    申请号：US09489777

    申请日：2000-01-24

    申请人： Hermann Bujard ,  Manfred Gossen

    发明人： Hermann Bujard ,  Manfred Gossen

    IPC分类号： C07K1900

    CPC分类号： C07K14/005 ,  A01K67/0275 ,  A01K2217/05 ,  A01K2217/075 ,  A01K2217/20 ,  A01K2227/105 ,  A01K2267/0393 ,  A61K48/00 ,  C07K14/245 ,  C07K2319/00 ,  C07K2319/09 ,  C07K2319/61 ,  C07K2319/71 ,  C07K2319/80 ,  C12N15/62 ,  C12N15/63 ,  C12N15/635 ,  C12N15/67 ,  C12N15/85 ,  C12N15/8509 ,  C12N2710/16622 ,  C12N2830/003 ,  C12N2830/006 ,  C12N2830/32

    摘要： Methods of regulating gene expression in subjects using tetracycline-responsive fusion proteins are disclosed. In one embodiment, the method involves introducing into a cell the subject a nucleic acid molecule encoding a fusion protein which inhibits transcription, the fusion protein comprising a first polypeptide which binds to a tet operator sequence, operatively linked to a heterologous second polypeptide which inhibits transcription in eukaryotic cells; and modulating the concentration of a tetracycline, or analogue thereof, in the subject. The first polypeptide can binds to a tet operator sequence in the absence, but not the presence, of tetracycline. Alternatively, the first polypeptide can binds to a tet operator sequence in the presence, but not the absence, of tetracycline. In another embodiment, the method of the invention involves obtaining a cell from a subject, introducing into the cell a first nucleic acid molecule which operatively links a gene to at least one tet operator sequence, introducing into the cell a second nucleic acid molecule encoding an inhibitory fusion protein of the invention to form a modified cell, administering the modified cell to the subject and modulating the concentration of a tetracycline, or analogue thereof, in the subject. The first and second nucleic acid molecules can be linked or can be separate molecules.

    摘要翻译： 公开了使用四环素响应融合蛋白调节受试者基因表达的方法。 在一个实施方案中，该方法包括向受试者引入编码抑制转录的融合蛋白的核酸分子，该融合蛋白包含与tet操纵子序列结合的第一多肽，该第一多肽与抑制转录的异源第二多肽有效连接 在真核细胞中 并调节受试者中四环素或其类似物的浓度。 在不存在但不存在四环素的情况下，第一种多肽可以结合tet操纵子序列。 或者，第一多肽可以在四环素存在下但不存在时与tet操纵子序列结合。 在另一个实施方案中，本发明的方法涉及从受试者获得细胞，将在第一核酸分子中引入至少一个tet操纵子序列的第一核酸分子，将编码 本发明的抑制性融合蛋白以形成修饰的细胞，向受试者施用修饰的细胞并调节受试者中四环素或其类似物的浓度。 第一和第二核酸分子可以连接或可以是分开的分子。