LNA oligonucleotides and the treatment of cancer
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United States of America Patent
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Issued Date -
Jul 13, 2006
app pub date -
Nov 9, 2005
filing date -
Nov 9, 2004
priority date (Note) -
Abandoned
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Abstract
The present disclosure concerns LNA oligonucleotides having a (sub)sequence of the general formula 5'-(.sup.MeC.sub.x)(T.sub.x).sup.MeC.sub.xA.sub.sA.sub.st.sub.sc.sub.sc.s-ub.sa.sub.st.sub.sg.sub.sg.sub.s.sup.MeC.sub.xA.sub.x(G.sub.x)(c)-3', and preferably of the general formula 5'-.sup.MeC.sub.xT.sub.x.sup.MeC.sub.xA.sub.sa.sub.st.sub.sc.sub.sc.sub.s-a.sub.st.sub.sg.sub.sg.sub.s.sup.MeC.sub.xA.sub.xG.sub.xc-3', wherein capital letters designate an LNA nucleotide analogue selected from .beta.-D-oxy-LNA, .beta.-D-thio-LNA, .beta.-D-amino-LNA and .alpha.-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.
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