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    • 3. 发明申请
    • Potent LNA oligonucleotides for the inhibition of HIF-1a expression
    • 用于抑制HIF-1a表达的强大的LNA寡核苷酸
    • US20060252721A1
    • 2006-11-09
    • US11271686
    • 2005-11-09
    • Majken WestergaardCharlotte ThrueFrank RasmussenHenrik Hansen
    • Majken WestergaardCharlotte ThrueFrank RasmussenHenrik Hansen
    • A61K48/00C07H21/02
    • C12N15/113C12N2310/11C12N2310/315C12N2310/3231C12N2310/3341C12N2310/341C12N2310/345C12N2310/346
    • The present disclosure relates to an LNA oligonucleotide consisting of a sequence selected from the group consisting of 5′-(Tx)GxGxcsasasgscsastscscsTxGxT-3′ and 5′-(Gx)TxTxascstsgscscststscsTxTxA-3′, wherein capital letters designate a beta-D-oxy-LNA nucleotide analogue, small letters designate a 2-deoxynucleotide, underline designates either a beta-D-oxy-LNA nucleotide analogue or a 2-deoxynucleotide, subscript “s” designates a phosphorothioate link between neighbouring nucleotides/LNA nucleotide analogues, and subscript “x” designates either a phosphorothioate link or a phosphorodiester link between neighbouring nucleotides/LNA nucleotide analogues, and wherein the sequence is optionally extended by up to five 2-deoxynucleotide units. The LNA oligonucleotides are useful for modulating the expression of hypoxia-inducible factor-1a (HIF-1a), e.g. in the treatment of cancer diseases, inhibiting angiogenesis, inducing apoptosis, preventing cellular proliferation, or treating an angiogenic disease, e.g. diabetic retinopathy, macular degeneration (ARMD), psoriasis, rheumatoid arthritis and other inflammatory diseases.
    • 本公开内容涉及由选自下组的序列组成的LNA寡核苷酸:5' - (T x)X G x 例如,本发明的一个或多个实施方案,其中, x> T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T -3'和5' - (G x x)T x x T x 其中一个或多个第一个或更多个> 其中大写字母表示β-D-氧基,其中大写字母表示β-D-氧基, -LNA核苷酸类似物,小写字母表示2-脱氧核苷酸,下划线表示β-D-氧-LNA核苷酸类似物或2-脱氧核苷酸,下标“s”表示相邻核苷酸/ LNA核苷酸类似物之间的硫代磷酸酯连接,下标 “x”表示相邻核苷酸/ LNA核苷酸类似物之间的硫代磷酸酯连接或磷酸二酯连接,并且其中该序列是选择性的 最多延伸5个2-脱氧核苷酸单位。 LNA寡核苷酸可用于调节缺氧诱导因子-1a(HIF-1a)的表达,例如, 在治疗癌症疾病,抑制血管发生,诱导细胞凋亡,预防细胞增殖或治疗血管生成疾病,例如, 糖尿病性视网膜病变,黄斑变性(ARMD),牛皮癣,类风湿性关节炎等炎症性疾病。