公开(公告)号：US20120322848A1

公开(公告)日：2012-12-20

申请号：US13443557

申请日：2012-04-10

申请人： Christoph Rosenbohm ,  Lene S. Kjaerulff ,  Majken Westergaard ,  Margit Wissenbach ,  Jens B. Hansen ,  Marlene Asklund

发明人： Christoph Rosenbohm ,  Lene S. Kjaerulff ,  Majken Westergaard ,  Margit Wissenbach ,  Jens B. Hansen ,  Marlene Asklund

IPC分类号： A61K31/712 ,  A61P35/02 ,  A61P35/00

CPC分类号： C12N15/1135 ,  A61K38/00 ,  C12N2310/11 ,  C12N2310/315 ,  C12N2310/319 ,  C12N2310/3341

摘要： The present disclosure concerns LNA oligonucleotides having a (sub)sequence of the general formula 5′-(MeCx)(Tx)MeCxAsAstsCsCsastsgsgsMeCxAx(Gx)(c)-3′, and preferably of the general formula 5′-MeCxTxMeCxAsastscscsastsgsgsMeCxAxGxc-3′, wherein capital letters designate an LNA nucleotide analogue selected from β-D-oxy-LNA, β-D-thio-LNA, β-D-amino-LNA and α-L-oxy-LNA, small letters designate a deoxynucleotide, and underline designates either an LNA nucleotide analogue as defined above or a deoxynucleotide. Such LNA oligonucleotides exhibit surprisingly good properties with respect to inhibition of the expression of Survivin by means of an anti-sense mechanism, and thereby lead to reduction or inhibition of tumour development in vivo. The LNA oligonucleotides are superior to other LNA oligonucletides targeting Surviving mRNA measured by functional read outs such as apoptosis induction and proliferation inhibition, and is potent in down-regulating Survivin mRNA and protein in transfected cancer cell lines, and induce apoptosis in combination with Taxol superior compared to other LNA oligonucleotides.

摘要翻译： 本公开内容涉及具有通式5'（（MeCx）（Tx）MeCxAsAstsCsCsastsgsgsMeCxAx（Gx）（c）-3'，优选通式为5'-MeCxTxMeCxAsastscscsastsgsgsMeCxAxGxc-3'的（亚）序列的LNA寡核苷酸， 其中大写字母表示选自以下的LNA核苷酸类似物：-D-oxy-LNA，＆bgr; -D-thio-LNA，＆bgr; -D-氨基-LNA和α-L-氧-LNA，小字母表示脱氧核苷酸 ，下划线表示如上定义的LNA核苷酸类似物或脱氧核苷酸。 这样的LNA寡核苷酸在通过反义机制抑制存活蛋白的表现方面表现出惊人的良好性质，从而导致体内肿瘤发展的减少或抑制。 LNA寡核苷酸优于靶向通过功能读数（如凋亡诱导和增殖抑制）测量的存活mRNA的其他LNA寡核苷酸，并且在转染的癌细胞系中下调Survivin mRNA和蛋白质，并且与Taxol优异结合诱导凋亡有效 与其他LNA寡核苷酸相比。

公开(公告)号：US07622453B2

公开(公告)日：2009-11-24

申请号：US11021729

申请日：2004-12-23

申请人： Miriam Frieden ,  Jens B. Hansen ,  Henrik Orum ,  Majken Westergaard ,  Charlotte A. Thrue

发明人： Miriam Frieden ,  Jens B. Hansen ,  Henrik Orum ,  Majken Westergaard ,  Charlotte A. Thrue

IPC分类号： A01N61/00 ,  A01N43/04 ,  C12Q1/68 ,  C07H21/02 ,  C07H21/04

CPC分类号： C12N15/1135 ,  A61K48/00 ,  C07H21/00 ,  C12N2310/315 ,  C12N2310/3231

摘要： The present invention provides improved oligomeric compound, in particular oligonucleotide compounds, and methods for modulating the expression of the Bcl-2 gene in humans. In particular, this invention relates to oligomeric compounds of 10-30 nucleobases in length which comprise a target binding domain that is specifically hybridizable to a region ranging from base position No. 1459 (5′) to No. 1476 (3′) of the human Bcl-2 mRNA, said target binding domain having the formula: 5′-[(DNA/RNA)0-1-(LNA/LNA*)2-7-(DNA/RNA/LNA*)4-14-(LNA/LNA*)2-7-(DNA/RNA)0-1]-3′ and said target binding domain comprising at least two LNA nucleotides or LNA analogue nucleotides linked by a phosphorothioate group (—O—P(O,S)—O—). In particular the oligo is predominantly or fully thiolated. The invention also provides the use of such oligomers or conjugates or chimera for the treatment of various diseases associated with the expression of the Bcl-2 gene, such as cancer.

摘要翻译： 本发明提供了改进的低聚化合物，特别是寡核苷酸化合物，以及调节人类Bcl-2基因表达的方法。 特别地，本发明涉及长度为10-30个核碱基的寡聚化合物，其包含与从第1459（5'）至第1476（3'）的基础位置区别特异性杂交的靶结合结构域 所述靶结合结构域具有下式：5' - [（DNA / RNA）0-1-（LNA / LNA *）2-7-（DNA / RNA / LNA *）4-14-（ LNA / LNA *）2-7-（DNA / RNA）0-1] -3'，并且所述靶结合结构域包含由硫代磷酸酯基团连接的至少两个LNA核苷酸或LNA类似物核苷酸（-OP（O，S） - O-）。 特别地，寡核苷酸主要或完全硫醇化。 本发明还提供了这种寡聚物或缀合物或嵌合体用于治疗与Bcl-2基因（例如癌症）的表达相关的各种疾病的用途。