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    Autologous upregulation mechanism allowing optimized cell type-specific and regulated gene expression cells
    11.
    发明申请
    Autologous upregulation mechanism allowing optimized cell type-specific and regulated gene expression cells 审中-公开
    自体上调机制允许优化的细胞类型特异性和调节基因表达细胞

    公开(公告)号：US20070166366A1

    公开(公告)日：2007-07-19

    申请号：US10555109

    申请日：2004-04-30

    申请人： Jian-Yun Dong ,  Semyon Rubinchik ,  Jan Woraratanadharm

    发明人： Jian-Yun Dong ,  Semyon Rubinchik ,  Jan Woraratanadharm

    IPC分类号： A61K48/00 ,  A61K9/127 ,  C12N15/88

    CPC分类号： A61K48/00 ,  A61K9/127 ,  A61K48/0058 ,  A61K48/0066 ,  C12N15/85 ,  C12N15/86 ,  C12N2710/10343 ,  C12N2800/107 ,  C12N2830/00 ,  C12N2830/003 ,  C12N2830/008 ,  C12N2830/32 ,  C12N2840/00

    摘要： The present invention provides methods for high level, regulated transgene transcription that is restricted to cell populations of specific types. The process is designed to work with any inducible expression regulation systems, adapting them to a tissue-specific expression pattern while simultaneously delivering maximal achievable expression levels. In particular, the invention utilizes hybrid promoters that contain the DNA elements for both cell type-specific and regulated transcription. By placing the gene of the transcriptional activation factor (TAF) under the control of this tissue-specific/drug-regulated (TSDR) promoter, this invention achieves high expression levels of TAF in specific target cells by first initiating TAF expression using cell-type specific transcription elements, and subsequently amplifying transcriptional activity by establishing an autoregulatory positive feedback loop. In non-target cells, cell type-specific elements of the TSDR promoter will be inactive, the TAF expression will not be initiated, and auto-upregulation will not occur. For cell type-specific promoters with leaky low-level activity in non-target cells, a variation of this system has been developed which combines autologous upregulation of TAF with the expression of cross-competing transcriptional silencers (TSi) to achieve a type of eukaryotic “genetic switch”—either shutting off transgene and TAF expression completely or promoting maximal expression levels, depending on the original activity level of the specific promoter in that particular cell.

    摘要翻译： 本发明提供限于特定类型的细胞群体的高水平，调节转基因转录的方法。 该过程被设计为与任何可诱导的表达调节系统一起工作，使其适应组织特异性表达模式，同时提供最大可实现的表达水平。 特别地，本发明利用含有细胞类型特异性和调节转录的DNA元件的杂合启动子。 通过将转录激活因子（TAF）的基因置于该组织特异性/药物调节（TSDR）启动子的控制下，本发明通过首先使用细胞型开始TAF表达来实现特异性靶细胞中TAF的高表达水平 特异性转录元件，随后通过建立自动调节阳性反馈环来扩增转录活性。 在非靶细胞中，TSDR启动子的细胞类型特异性元件将是无活性的，TAF表达将不会启动，并且不会发生自上调。 对于在非靶细胞中具有低水平低活性的细胞型特异性启动子，已经开发了该系统的变体，其将TAF的自体上调与交叉竞争的转录沉默子（TSi）的表达相结合以实现真核生物 “遗传开关” - 根据特定细胞中特异性启动子的原始活性水平，完全关闭转基因和TAF表达或促进最大表达水平。

    Vectors for tissue-specific replication
    12.
    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：US20070086985A1

    公开(公告)日：2007-04-19

    申请号：US11601071

    申请日：2006-11-17

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

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

    IPC分类号： A61K48/00 ,  C12N5/08 ,  C12N15/861

    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 transcription 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与该载体的转录调控序列抑制基因转录的因子的因素的制约; 因此，可以选择性地处理靶组织。

    REGULATABLE OR CONDITIONAL EXPRESSION SYSTEMS
    13.
    发明申请
    REGULATABLE OR CONDITIONAL EXPRESSION SYSTEMS 审中-公开
    可管理或条件表达系统

    公开(公告)号：US20070054872A1

    公开(公告)日：2007-03-08

    申请号：US11466797

    申请日：2006-08-24

    申请人： Thomas Reppen ,  David Lewis

    发明人： Thomas Reppen ,  David Lewis

    IPC分类号： A61K48/00 ,  C07H21/02

    CPC分类号： C12N15/85 ,  C12N2830/005 ,  C12N2830/008 ,  C12N2830/32 ,  C12N2840/102

    摘要： Endogenous gene regulation mechanisms together with microRNAs expressed in many organisms can be used to provide regulated or conditional expression of transgenes by placing an appropriate sequence, a microRNA binding site, within the transcribed gene. This microRNA-dependent transcription regulation can be further regulated using microRNA inhibitors.

    摘要翻译： 内源性基因调控机制与许多生物体中表达的微小RNA可以用于通过在转录的基因内放置适当的序列，即微小RNA结合位点来提供转基因的调节或条件表达。 这种microRNA依赖性转录调控可以使用微小RNA抑制剂进一步调控。

    Vectors for tissue-specific replication
    15.
    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：US20030129175A1

    公开(公告)日：2003-07-10

    申请号：US10323984

    申请日：2002-12-19

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

    IPC分类号： A61K048/00 ,  C12N015/86 ,  C12N005/08

    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 transcription 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与该载体的转录调控序列抑制基因转录的因子的因素的制约; 因此，可以选择性地处理靶组织。

    VECTORS FOR TISSUE-SPECIFIC REPLICATION
    17.
    发明申请
    VECTORS FOR TISSUE-SPECIFIC REPLICATION 失效
    用于组织特异性复制的载体

    公开(公告)号：US20030012767A1

    公开(公告)日：2003-01-16

    申请号：US09210936

    申请日：1998-12-15

    发明人： PAUL L. HALLENBECK ,  YUNG-NIEN CHANG ,  YAWEN L. CHIANG

    IPC分类号： A61K048/00 ,  C07H021/04 ,  C12N015/87

    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 ihibits transcription 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，复制是基于诱导转录的因子的存在或不存在通过使用该载体的转录调节序列抑制基因转录的因子的因子; 因此，可以选择性地处理靶组织。