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。