Santaris Pharma A/s

Enzon Pharmaceuticals, Inc.

Roche Innovation Center Copenhagen A/s

Majken Westergaard

Charlotte Albaek Thrue

Henrik Frydenlund Hansen

Christoph Rosenbohm

Miriam Frieden

Troels Koch

Daniel Sejer Pedersen

Signe M Christensen

Nikolaj Dam Mikkelsen

Frank Winther Rasmussen

Margit Wissenbach

Kamille Dumong Petersen

Jens Bo Rode Hansen

Jens Bo Hansen

Henrik Orum

Charlotte Albæk Thrue

Marlene Asklund

Lene Sonderbye Kjaerulff

Bo Hansen

Henrik Ørum

Charlotte Thrue

Daniel Pedersen

Lene Sønderbye Kjærulff

Charlotte Albæck Thrue

A novel class of pharmaceuticals which comprises a Locked Nucleic Acid (LNA) which can be used in antisense therapy. These novel oligonucleotides have improved antisense properties. The novel oligonucleotides are composed of at least one LNA selected from beta-D-thio/amino-LNA or alpha-L-oxy/thio/amino-LNA. The oligonucleotides comprising LNA may also include DNA and/or RNA nucleotides.

Antisense design

The present disclosure relates to an LNA oligonucleotide consisting of a sequence selected from the group consisting of 5'-()GGcaagcatccTG-3&#x2032; and 5&#x2032;-()TTactgccttcTT-3&#x2032;, wherein capital letters designate a beta-D-oxy-LNA nucleotide analog, small letters designate a 2-deoxynucleotide, underline designates either a beta-D-oxy-LNA nucleotide analog or a 2-deoxynucleotide, subscript 's' designates a phosphorothioate link between neighboring nucleotides/LNA nucleotide analogs, and subscript 'x' designates either a phosphorothioate link or a phosphorodiester link between neighboring nucleotides/LNA nucleotide analogs, 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.

Potent LNA oligonucleotides for the inhibition of HIF-1A expression

The present disclosure relates to an LNA oligonucleotide consisting of a sequence selected from the group consisting of 5'-()GGcaagcatccTG-3&#x2032; and 5&#x2032;-()TTactgccttcTT-3&#x2032;, 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.

Potent LNA oligonucleotides for the inhibition of HIF-1a expression

Amino-LNA, thio-LNA and alpha-L-oxy-LN

The present disclosure relates to an LNA oligonucleotide consisting of a sequence selected from the group consisting of 5'-()GGcaagcatccTG-3&#x2032; and 5&#x2032;-()TTactgccttcTT-3&#x2032;, 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 neighboring nucleotides/LNA nucleotide analogues, and subscript 'x' designates either a phosphorothioate link or a phosphorodiester link between neighboring 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.

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

Oligonucleotides directed against the survivin gene are provided for modulating the expression of survivin. The compositions comprise oligonucleotides, particularly antisense oligonucleotides, targeted to nucleic acids encoding the survivin. Methods of using these compounds for modulation of survivin expression and for the treatment of diseases associated with either overexpression of survivin, expression of mutated survivin or both are provided. Examples of diseases are cancer such as lung, breast, colon, prostate, pancreas, lung, liver, thyroid, kidney, brain, testes, stomach, intestine, bowel, spinal cord, sinuses, bladder, urinary tract or ovaries cancers. The oligonucleotides may be composed of deoxyribonucleosides or a nucleic acid analogue such as for example locked nucleic acid or a combination thereof.

Oligomeric compounds for the modulation of survivin expression

The present invention is directed to novel oligonucleotides with improved antisense properties. The novel oligonucleotides comprise at least one Locked Nucleic Acid (LNA) selected from beta-D-thio/amino-LNA or alpha-L-oxy/thio/amino-LNA. The oligonucleotides comprising LNA may also include DNA and/or RNA nucleotides. The present invention also provides a new class of pharmaceuticals which comprise antisense oligonucleotides and are useful in antisense therapy.

Oligonucleotides with alternating segments of locked and non-locked nucleotides

Growing community of inventors

Birkerød, Denmark

Majken Westergaard