Santaris Pharma A/s

Enzon Pharmaceuticals, Inc.

Jens Bo Hansen

Henrik Frydenlund Hansen

Majken Westergaard

Charlotte Albaek Thrue

Christoph Rosenbohm

Henrik Orum

Niels Fisker Nielsen

Miriam Frieden

Ellen Marie Straarup

Margit Wissenbach

Lene Sonderbye Kjaerulff

Marlene Asklund

Henrik Ørum

Maj HEDTJÄRN

Charlotte Albæck Thrue

The present disclosure concerns LNA oligonucleotides having a (sub)sequence of the general formula 5'-()(T)CAtccatggCA()(c)-3&#x2032;, and preferably of the general formula 5&#x2032;-TCAatccatggCAc-3&#x2032;, wherein capital letters designate an LNA nucleotide analogue selected from &#x3b2;-D-oxy-LNA, &#x3b2;-D-thio-LNA, &#x3b2;-D-amino-LNA and &#x3b1;-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 tumor development in vivo. The LNA oligonucleotides are superior to other LNA oligonucleotides 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.

LNA oligonucleotides and the treatment of cancer

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&#x2032;) of the human Bcl-2 mRNA, said target binding domain having the formula: 5&#x2032;-[(DNA/RNA)-(LNA/LNA*)-(DNA/RNA/LNA*)-(LNA/LNA*)-(DNA/RNA)]-3&#x2032; and said target binding domain comprising at least two LNA nucleotides or LNA analogue nucleotides linked by a phosphorothioate group (&#x2014;O&#x2014;P(O,S)&#x2014;O&#x2014;). 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.

Oligomeric compounds for the modulation of Bcl-2

Growing community of inventors

Vaerlose, Denmark

Jens Bo Hansen