Abstract: The invention provides LNA therapeutics oligonucleotide carbohydrate conjugates with considerably enhanced potency, extended therapeutic index and reduced toxicity.

Abstract: The present invention relates to conjugates of LNA antisense oligonucleotides (oligomers) that target ApoB.

Abstract: The invention relates to the field of oligonucleotide therapeutics, and in particular to the use of a cleavable, e.g. a phosphodiester region covalently attached to a conjugate, a targeting group or blocking group to enhance the properties of the oligonucleotides, for example to improve the therapeutic index.

Abstract: Methods and compositions are disclosed for controlling expression of TNF receptors (TNFR1 and TNFR2) and of other receptors in the TNFR superfamily using compounds that modulate splicing of pre-mRNA encoding these receptors. More specifically these compounds cause the removal of the transmembrane domains of these receptors and produce soluble forms of the receptor which act as an antagonist to reduce TNF-? activity or activity of the relevant ligand. Reducing TNF-? activity provides a method of treating or ameliorating inflammatory diseases or conditions associated with TNF-? activity. Similarly, diseases associated with other ligands can be treated in like manner. In particular, the compounds of the invention are splice-splice switching oligomers (SSOs) which are small molecules that are stable in vivo, hybridize to the RNA in a sequence specific manner and, in conjunction with their target, are not degraded by RNAse H.

Abstract: The present invention relates to tumor necrosis factor (TNF) antagonists and corresponding nucleic acids derived from tumor necrosis factor receptors (TNFRs) and their use in the treatment of inflammatory diseases. These proteins are soluble secreted decoy receptors that bind to TNF and prevent TNF from signaling to cells. In particular, the proteins are mammalian TNFRs that lack exon 7 and which can bind TNF and can act as a TNF antagonist.

Abstract: The present invention relates to compositions and methods for preparing splice variants of TNFalpha receptor (TNFR) in vivo or in vitro, and the resulting TNFR protein variants. Such variants may be prepared by controlling the splicing of pre-mRNA molecules and regulating protein expression with splice switching oligonucleotides or splice switching oligomers (SSOs). The preferred SSOs according to the invention target exon 7 or 8 of TNFR1 (TNFRSF1A) or TNFR2 (TNFRSF1A) pre-mRNA, typically resulting in the production of TNFR variants which comprise a deletion in part or the entire exon 7 or 8 respectfully. SSOs targeting exon 7 are found to result in a soluble form of the TNFR, which has therapeutic benefit for treatment of inflammatory diseases. The SSO's are characterized in that they are substantially incapable or incapable of recruiting RNaseH.

Abstract: The present invention is directed to novel double-stranded short interfering (siRNA) analogues comprising locked nucleic acid (LNA) monomers. Such compounds induces sequence-specific post-transcriptional gene silencing in many organisms by a process known as RNA interference (RNAi). The compounds disclosed herein has improved properties compared to non-modified siRNAs and may, accordingly, be useful as therapeutic agents, e.g., in the treatment of various cancer forms. More particularly, the present invention is directed to siRNA analogues comprising a sense strand and an antisense strand, wherein each strand comprises 12-35 nucleotides and wherein the siRNA analogues comprise at least one locked nucleic acid (LNA) monomer.

Abstract: Methods and compositions are disclosed for controlling expression of TNF receptors (TNFR1 and TNFR2) and of other receptors in the TNFR superfamily using compounds that modulate splicing of pre-mRNA encoding these receptors. More specifically these compounds cause the removal of the transmembrane domains of these receptors and produce soluble forms of the receptor which act as an antagonist to reduce TNF-? activity or activity of the relevant ligand. Reducing TNF-? activity provides a method of treating or ameliorating inflammatory diseases or conditions associated with TNF-? activity. Similarly, diseases associated with other ligands can be treated in like manner. In particular, the compounds of the invention are splice-splice switching oligomers (SSOs) which are small molecules that are stable in vivo, hybridize to the RNA in a sequence specific manner and, in conjunction with their target, are not degraded by RNAse H.

Abstract: The present invention is directed to novel double-stranded short interfering (siRNA) analogues comprising locked nucleic acid (LNA) monomers. Such compounds induces sequence-specific post-transcriptional gene silencing in many organisms by a process known as RNA interference (RNAi). The compounds disclosed herein has improved properties compared to non-modified siRNAs and may, accordingly, be useful as therapeutic agents, e.g., in the treatment of various cancer forms. More particularly, the present invention is directed to siRNA analogues comprising a sense strand and an antisense strand, wherein each strand comprises 12-35 nucleotides and wherein the siRNA analogues comprise at least one locked nucleic acid (LNA) monomer.

Abstract: The invention provides LNA gapmer oligomers of between 10-20 nucleobases in length, which have a total of 1-3 phosphodiester internucleoside linkages. Such oligomers have been found to have superior bioavailability and have also been found to selectively accumulate in kidney cells.

Abstract: The present invention relates to tumor necrosis factor (TNF) antagonists and corresponding nucleic acids derived from tumor necrosis factor receptors (TNFRs) and their use in the treatment of inflammatory diseases. These proteins are soluble secreted decoy receptors that bind to TNF and prevent TNF from signaling to cells. In particular, the proteins are mammalian TNFRs that lack exon 7 and which can bind TNF and can act as a TNF antagonist.

Abstract: The invention provides for LNA oligomers, for the treatment of a metabolic or liver disorder, wherein the LNA oligomer is administered orally in a unit dose of less than 50 mgs/kg, wherein the LNA oligomer is administered in the presence of a penetration (permeation) enhancer.

Abstract: The present invention relates to compositions and methods for preparing splice variants of TNFalpha receptor (TNFR) in vivo or in vitro, and the resulting TNFR protein variants. Such variants may be prepared by controlling the splicing of pre-mRNA molecules and regulating protein expression with splice switching oligonucleotides or splice switching oligomers (SSOs). The preferred SSOs according to the invention target exon 7 or 8 of TNFR1 (TNFRSF1A) or TNFR2 (TNFRSF1A) pre-mRNA, typically resulting in the production of TNFR variants which comprise a deletion in part or the entire exon 7 or 8 respectfully. SSOs targeting exon 7 are found to result in a soluble form of the TNFR, which has therapeutic benefit for treatment of inflammatory diseases. The SSO's are characterized in that they are substantially incapable or incapable of recruiting RNaseH.

Abstract: Methods and compositions are disclosed for controlling expression of TNF receptors (TNFR1 and TNFR2) and of other receptors in the TNFR superfamily using compounds that modulate splicing of pre-mRNA encoding these receptors. More specifically these compounds cause the removal of the transmembrane domains of these receptors and produce soluble forms of the receptor which act as an antagonist to reduce TNF-? activity or activity of the relevant ligand. Reducing TNF-? activity provides a method of treating or ameliorating inflammatory diseases or conditions associated with TNF-? activity. Similarly, diseases associated with other ligands can be treated in like manner. In particular, the compounds of the invention are splice-splice switching oligomers (SSOs) which are small molecules that are stable in vivo, hybridize to the RNA in a sequence specific manner and, in conjunction with their target, are not degraded by RNAse H.

Abstract: The present invention relates to tumor necrosis factor (TNF) antagonists and corresponding nucleic acids derived from tumor necrosis factor receptors (TNFRs) and their use in the treatment of inflammatory diseases. These proteins are soluble secreted decoy receptors that bind to TNF and prevent TNF from signaling to cells. In particular, the proteins are mammalian TNFRs that lack exon 7 and which can bind TNF and can act as a TNF antagonist.

Abstract: A method for specifically determining the presence of a target by contacting said target in the presence of other targets with a probe capable of binding to said target to form a complex of said target with said probe, wherein the contacting is performed in the presence of a compound enhancing the specificity of said binding or the complex formed is contacted with a compound enhancing the specificity of said binding. This method opens the way to a better discrimination between related nucleic acid sequences in diagnostic assays.

Abstract: A method for specifically determining the presence of a target by contacting the target in the presence of other targets with a probe capable of binding to the target to form a complex of the target with the probe, where the contacting is performed in the presence of a compound enhancing the specificity of the binding or the complex formed is contacted with a compound enhancing the specificity of the binding. This method opens the way to a better discrimination between related nucleic acid sequences in diagnostic assays.

Abstract: 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?) of the human Bcl-2 mRNA, said target binding domain having the formula: 5?-[(DNA/RNA)0-1-(LNA/LNA*)2-7-(DNA/RNA/LNA*)4-14-(LNA/LNA*)2-7-(DNA/RNA)0-1]-3? and said target binding domain comprising at least two LNA nucleotides or LNA analogue nucleotides linked by a phosphorothioate group (—O—P(O,S)—O—). 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.

Abstract: The present invention relates to compositions and methods for preparing splice variants of TNFalpha receptor (TNFR) in vivo or in vitro, and the resulting TNFR protein variants. Such variants may be prepared by controlling the splicing of pre-mRNA molecules and regulating protein expression with splice switching oligonucleotides or splice switching oligomers (SSOs). The preferred SSOs according to the invention target exon 7 or 8 of TNFR1 (TNFRSF1A) or TNFR2 (TNFRSF1A) pre-mRNA, typically resulting in the production of TNFR variants which comprise a deletion in part or the entire exon 7 or 8 respectfully. SSOs targeting exon 7 are found to result in a soluble form of the TNFR, which has therapeutic benefit for treatment of inflammatory diseases. The SSO's are characterized in that they are substantially incapable or incapable of recruiting RNaseH.

Abstract: The current invention provides oligonucleotides which comprise a dinucleotide consisting of a 5? locked nucleic acid (LNA), a phosphorothioate internucleoside linkage bond to a 3? RNA or RNA analogue. The dinucleotide reduces the strength of hybridization of the oligonucleotide to a complementary nucleic acid target. The modification can be used to modulate hybridisation properties in both single stranded oligonucleotides and in double stranded siRNA complexes, particularly in oligonucleotides where the use of LNA results in excessively strong hybridisation properties.