Antisense oligonucleotides as inhibitors of TGF-R signaling

Abstract

The present invention relates to an antisense oligonucleotide having a length of at least 10 nucleotides, wherein at least two nucleotides are LNAs, their use as inhibitors of TGF-R signaling, a pharmaceutical composition containing the antisense oligonucleotide, and their use for the prevention and treatment of nervous system, neurodegenerative, fibrotic and hyperproliferative diseases.

Description

[0001] This application is a divisional application of the patent application with the application number 201580056200.1.

[0002] Specification

[0003] The present invention relates to antisense oligonucleotides, their use as inhibitors of TGF-R signaling, pharmaceutical compositions containing such antisense oligonucleotides, and their use for the prevention and treatment of diseases of the nervous system, neurodegeneration and hyperproliferative diseases including tumors.

[0004] TGF-β exists in humans in three known isoforms (TGF-β1, TGF-β2 and TGF-β3). These are upregulated in neurodegenerative diseases such as ALS and some human cancers, and increased expression of this growth factor has been demonstrated in the pathological conditions of neurodegenerative diseases, acute trauma and neuroinflammation and aging. The isoform of transforming growth factor-β (TGF-β1) is also thought to be involved in the pathogenesis of preeclampsia.

[0005] Activated TGF-β acts on target cells through three different receptor types: type I (TGFRI), also known as activin-like kinase (ALK; 53 kDa), type II (TGFRII; 70-100 kDa) and type III (TGFRIII; 200-400 kDa). TGF-β receptors are single-pass serine / threonine kinase receptors. While the type II receptor kinase is constitutively active, the type I receptor needs to be activated. This process is initiated by binding of the ligand to TGFRII; this triggers the transient formation of a complex containing the ligand and type I and type II receptors. Given the dimeric composition of the ligand, the receptor complex most likely consists of a tetrameric structure formed by two pairs of each receptor type.

[0006] TGF-β signaling occurs through its receptors and downstream via Smad proteins. Smad-dependent cell signaling, initiated by the binding of TGF-β isoforms to specific TGFRI / II receptor pairs, results in the phosphorylation of intracellular Smads, followed by the translocation of the activated Smad complex to the nucleus to affect specific target gene expression. Signaling divergence to other pathways and convergence from adjacent signaling pathways create a highly complex network. Depending on the context and cellular environment, TGF-β signaling leads to a variety of different cellular responses, such as cell proliferation, differentiation, motility, and apoptosis in tumor cells. In cancer, TGF-β can directly (termed the intrinsic effect of TGF-β signaling) or indirectly (termed the extrinsic effect) affect tumor growth by promoting tumor growth, inducing epithelial-mesenchymal transition (EMT), blocking anti-tumor immune responses, increasing tumor-associated fibrosis, regulating the extracellular matrix (ECN) and cell migration, and ultimately enhancing angiogenesis. Factors that determine whether TGF-β signaling has a tumor-initiating or tumor-suppressing function (e.g., concentration, time, local exposure) are a major area of research and discussion. Currently, it is hypothesized that the tumor-suppressing function of TGF-β signaling is lost in the early stages of cancer, similar to the loss-of-function mutations of other tumor suppressors. Thus, there are several pharmacological approaches for treating potential cancers by blocking the TGF-β signaling pathway, such as the studies of Galunisertib and TEW-7197, both of which are small molecule inhibitors of TGFRI and are in clinical trials, and LY3022859, an anti-TGFRII antibody.

[0007] Signals provided by proteins of the transforming growth factor (TGF-β) family represent a system that controls neural stem cells under physiological conditions, but similar to other cell types, neural stem cells are released from this control upon transformation to cancer stem cells. TGF-β is a multifunctional cytokine involved in various physiological and pathophysiological processes of the brain. It is induced in the adult brain after injury or hypoxia and during neurodegenerative processes when it regulates and inhibits the inflammatory response. After injury, although TGF-β is generally neuroprotective, it limits the self-repair of the brain by inhibiting neural stem cell proliferation and inducing fibrotic / glial scar formation. Similar to its effects on neural stem cells, TGF-β exhibits anti-proliferative control over most cell types; however, paradoxically, many tumors evade TGF-β control. In addition, these tumors develop mechanisms to convert the anti-proliferative effects of TGF-β into oncogenic signals, mainly by orchestrating a large number of TGF-β-mediated effects on the stroma, migration and invasion, angiogenesis, and most importantly, immune escape mechanisms. Thus, TGF-β is involved in tumor progression (see Figure 3 ).

[0008] Thus, TGF receptor II (transforming growth factor, β receptor II; symbols used interchangeably: TGF-β type II receptor, TGFBR2; AAT3; FAA3; LDS1B; LDS2; LDS2B; MFS2; RIIC; TAAD2; TGFR-2; TGFβ-RII, TGF-RII, TGF-R II ) (in particular its inhibition) has been validated as a target for treating neurodegenerative diseases such as ALS and hyperproliferative diseases such as cancer and fibrotic diseases.

[0009] Thus, an object of the present application is to provide a pharmaceutically active compound capable of inhibiting the expression of TGF receptor II (TGF-R II ) and thus reducing the amount of TGF receptor II (TGF-R II ) and reducing the activity of TGF-β downstream signal transduction.

[0010] The object of the present invention is solved by the teaching of the independent claims. Further advantageous features, aspects and details of the present invention are apparent from the dependent claims, the description, the drawings and the examples of the present application.

[0011] Surprisingly, among thousands of candidate substances, such as protein-nucleotide complexes, siRNAs, microRNAs (miRNAs), ribozymes, aptamers, CpG oligomers, DNA-zymes, riboswitches, lipids, peptides, small molecules, modifiers of rafts or caveolae, modifiers of the Golgi apparatus, antibodies and their derivatives, in particular chimeras, Fab fragments and Fc fragments, antisense oligonucleotides containing LNA( Locked Nucleic Acids) are the most promising candidates for the uses disclosed herein.

[0012] Thus, the present invention relates to antisense oligonucleotides consisting of 10 to 28 nucleotides and salts and optical isomers of said antisense oligonucleotides, and at least two of the 10 to 28 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing with a region of the gene encoding TGF-R II or with a region of the mRNA encoding TGF-R II , wherein the region of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R IIThe region of the mRNA contains the sequence TGGTCCATTC (Seq. ID No. 4) or the sequence CCCTAAACAC (Seq. ID No. 5) or the sequence ACTACCAAAT (Seq. ID No. 6) or the sequence GGACGCGTAT (Seq. ID No. 7) or the sequence GTCTATGACG (Seq. ID No. 8) or the sequence TTATTAATGC (Seq. ID No. 9), and the antisense oligonucleotides respectively contain sequences capable of hybridizing with the sequence TGGTCCATTC (Seq. ID No. 4) or the sequence CCCTAAACAC (Seq. ID No. 5) or the sequence ACTACCAAAT (Seq. ID No. 6) or the sequence GGACGCGTAT (Seq. ID No. 7) or the sequence GTCTATGACG (Seq. ID No. 8) or the sequence TTATTAATGC (Seq. ID No. 9).

[0013] Putting it slightly differently, the present invention relates to antisense oligonucleotides consisting of 10 to 28 nucleotides, and salts and optical isomers of said antisense oligonucleotides, and at least two nucleotides out of the 10 to 28 nucleotides are LNA, and the antisense oligonucleotides are capable of hybridizing with the open reading frame region of the gene encoding TGF-R II or with the region of the mRNA encoding TGF-R II wherein the open reading frame region of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II contains the sequence TGGTCCATTC (Seq. ID No. 4) or the sequence CCCTAAACAC (Seq. ID No. 5) or the sequence ACTACCAAAT (Seq. ID No. 6) or the sequence GGACGCGTAT (Seq. ID No. 7) or the sequence GTCTATGACG (Seq. ID No. 8) or the sequence TTATTAATGC (Seq. ID No. 9), and the antisense oligonucleotides respectively contain sequences capable of hybridizing with the sequence TGGTCCATTC (Seq. ID No. 4) or the sequence CCCTAAACAC (Seq. ID No. 5) or the sequence ACTACCAAAT (Seq. ID No. 6) or the sequence GGACGCGTAT (Seq. ID No. 7) or the sequence GTCTATGACG (Seq. ID No. 8) or the sequence TTATTAATGC (Seq. ID No. 9).

[0014] Alternatively, the present invention relates to an antisense oligonucleotide consisting of 10 to 28 nucleotides, and salts and optical isomers of said antisense oligonucleotide, and at least two of the 10 to 28 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing with a region of a gene encoding TGF-R II or a region of an mRNA encoding TGF-R II wherein the region of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II comprises the sequence TGGTCCATTC (Seq.ID No.4) or the sequence CCCTAAACAC (Seq.ID No.5) or the sequence ACTACCAAAT (Seq.ID No.6) or the sequence GGACGCGTAT (Seq.ID No.7) or the sequence GTCTATGACG (Seq.ID No.8) or the sequence TTATTAATGC (Seq.ID No.9), and the antisense oligonucleotide comprises a sequence complementary to said sequence TGGTCCATTC (Seq.ID No.4) or the sequence CCCTAAACAC (Seq.ID No.5) or the sequence ACTACCAAAT (Seq.ID No.6) or the sequence GGACGCGTAT (Seq.ID No.7) or the sequence GTCTATGACG (Seq.IDNo.8) or the sequence TTATTAATGC (Seq.ID No.9).

[0015] Put slightly differently, the present invention relates to an antisense oligonucleotide consisting of 10 to 28 nucleotides, and salts and optical isomers of said antisense oligonucleotide, and at least two of the 10 to 28 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing with a region of the open reading frame of a gene encoding TGF-R II or with a region of an mRNA encoding TGF-R II wherein the region of the open reading frame of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R IIThe region of the mRNA contains the sequence TGGTCCATTC (Seq.ID No.4), or the sequence CCCTAAACAC (Seq.ID No.5), or the sequence ACTACCAAAT (Seq.ID No.6), or the sequence GGACGCGTAT (Seq.ID No.7), or the sequence GTCTATGACG (Seq.ID No.8), or the sequence TTATTAATGC (Seq.ID No.9), and the antisense oligonucleotides respectively contain sequences complementary to the sequence TGGTCCATTC (Seq.ID No.4), or the sequence CCCTAAACAC (Seq.ID No.5), or the sequence ACTACCAAAT (Seq.ID No.6), or the sequence GGACGCGTAT (Seq.ID No.7), or the sequence GTCTATGACG (Seq.ID No.8), or the sequence TTATTAATGC (Seq.ID No.9).

[0016] Preferably, the present invention relates to antisense oligonucleotides consisting of 10 to 28 nucleotides, and salts and optical isomers of said antisense oligonucleotides, and at least two of the 10 to 28 nucleotides are LNA, and the antisense oligonucleotides are capable of hybridizing with a region of the gene encoding TGF-R II or a region of the mRNA encoding TGF-R II wherein the region of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II contains the sequence TGGTCCATTC (Seq.ID No.4), and the antisense oligonucleotide contains a sequence capable of hybridizing with said sequence TGGTCCATTC (Seq.ID No.4).

[0017] Put slightly differently, the present invention relates to antisense oligonucleotides consisting of 10 to 28 nucleotides, and salts and optical isomers of said antisense oligonucleotides, and at least two of the 10 to 28 nucleotides are LNA, and the antisense oligonucleotides are capable of hybridizing with a region of the open reading frame of the gene encoding TGF-R II or a region of the mRNA encoding TGF-R II wherein the region of the open reading frame of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II contains the sequence TGGTCCATTC (Seq.ID No.4), and the antisense oligonucleotide contains a sequence capable of hybridizing with said sequence TGGTCCATTC (Seq.ID No.4).

[0018] Alternatively, the present invention relates to an antisense oligonucleotide consisting of 10 to 28 nucleotides, and salts and optical isomers of said antisense oligonucleotide, and at least two of the 10 to 28 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing to a region of the gene encoding TGF-R II or to a region of the mRNA encoding TGF-R II wherein the region of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II contains the sequence TGGTCCATTC (Seq.ID No.4), and the antisense oligonucleotide contains a sequence capable of hybridizing to said sequence TGGTCCATTC (Seq.ID No.4).

[0019] Put slightly differently, the present invention relates to an antisense oligonucleotide consisting of 10 to 28 nucleotides, and salts and optical isomers of said antisense oligonucleotide, and at least two of the 10 to 28 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing to a region of the open reading frame of the gene encoding TGF-R II or to a region of the mRNA encoding TGF-R II wherein the region of the open reading frame of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II contains the sequence TGGTCCATTC (Seq.ID No.4), and the antisense oligonucleotide contains a sequence capable of hybridizing to said sequence TGGTCCATTC (Seq.ID No.4).

[0020] Preferably, the present invention relates to an antisense oligonucleotide consisting of 10 to 28 nucleotides, and salts and optical isomers of said antisense oligonucleotide, and at least two of the 10 to 28 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing to a region of the gene encoding TGF-R II or to a region of the mRNA encoding TGF-R II wherein the region of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II contains the sequence CCCTAAACAC (Seq.ID No.5), and the antisense oligonucleotide contains a sequence capable of hybridizing to said sequence CCCTAAACAC (Seq.ID No.5).

[0021] Putting it slightly differently, the present invention relates to antisense oligonucleotides consisting of 10 to 28 nucleotides, as well as salts and optical isomers of said antisense oligonucleotides, and at least two of the 10 to 28 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing with a region of the open reading frame of the gene encoding TGF-R II or a region of the mRNA encoding TGF-R II wherein the region of the open reading frame of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II contains the sequence CCCTAAACAC (Seq.ID No.5), and the antisense oligonucleotide contains a sequence capable of hybridizing with said sequence CCCTAAACAC (Seq.ID No.5).

[0022] Alternatively, the present invention relates to antisense oligonucleotides consisting of 10 to 28 nucleotides, as well as salts and optical isomers of said antisense oligonucleotides, and at least two of the 10 to 28 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing with a region of the gene encoding TGF-R II or a region of the mRNA encoding TGF-R II wherein the region of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II contains the sequence CCCTAAACAC (Seq.ID No.5), and the antisense oligonucleotide contains a sequence complementary to said sequence CCCTAAACAC (Seq.ID No.5).

[0023] Putting it slightly differently, the present invention relates to antisense oligonucleotides consisting of 10 to 28 nucleotides, as well as salts and optical isomers of said antisense oligonucleotides, and at least two of the 10 to 28 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing with a region of the open reading frame of the gene encoding TGF-R II or a region of the mRNA encoding TGF-R II wherein the region of the open reading frame of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II contains the sequence CCCTAAACAC (Seq.ID No.5), and the antisense oligonucleotide contains a sequence complementary to said sequence CCCTAAACAC (Seq.ID No.5).

[0024] Preferably, the present invention relates to an antisense oligonucleotide composed of 10 to 28 nucleotides, as well as salts and optical isomers of the antisense oligonucleotide, and at least two of the 10 to 28 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing with a region of a gene encoding TGF-R II or a region of an mRNA encoding TGF-R II , wherein the region of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II contains the sequence ACTACCAAAT (Seq. ID No.6), and the antisense oligonucleotide contains a sequence capable of hybridizing with the sequence ACTACCAAAT (Seq.ID No.6).

[0025] Put slightly differently, the present invention relates to an antisense oligonucleotide composed of 10 to 28 nucleotides, as well as salts and optical isomers of the antisense oligonucleotide, and at least two of the 10 to 28 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing with a region of the open reading frame of a gene encoding TGF-R II or a region of an mRNA encoding TGF-R II , wherein the region of the open reading frame of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II contains the sequence ACTACCAAAT (Seq.ID No.6), and the antisense oligonucleotide contains a sequence capable of hybridizing with the sequence ACTACCAAAT (Seq.IDNo.6).

[0026] Alternatively, the present invention relates to an antisense oligonucleotide composed of 10 to 28 nucleotides, as well as salts and optical isomers of the antisense oligonucleotide, and at least two of the 10 to 28 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing with a region of a gene encoding TGF-R II or a region of an mRNA encoding TGF-R II , wherein the region of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II contains the sequence ACTACCAAAT (Seq.ID No.6), and the antisense oligonucleotide contains a sequence capable of being complementary to the sequence ACTACCAAAT (Seq. ID No.6).

[0027] Putting it slightly differently, the present invention relates to antisense oligonucleotides consisting of 10 to 28 nucleotides, as well as salts and optical isomers of said antisense oligonucleotides, and at least two of the 10 to 28 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing with a region of the open reading frame of the gene encoding TGF-R II or a region of the mRNA encoding TGF-R II wherein the region of the open reading frame of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II contains the sequence ACTACCAAAT (Seq.ID No.6), and the antisense oligonucleotide contains a sequence capable of hybridizing with said sequence ACTACCAAAT (Seq.ID No.6).

[0028] Preferably, the present invention relates to antisense oligonucleotides consisting of 10 to 28 nucleotides, as well as salts and optical isomers of said antisense oligonucleotides, and at least two of the 10 to 28 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing with a region of the gene encoding TGF-R II or a region of the mRNA encoding TGF-R II wherein the region of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II contains the sequence GGACGCGTAT (Seq.ID No.7), and the antisense oligonucleotide contains a sequence capable of hybridizing with said sequence GGACGCGTAT (Seq.ID No.7).

[0029] Putting it slightly differently, the present invention relates to antisense oligonucleotides consisting of 10 to 28 nucleotides, as well as salts and optical isomers of said antisense oligonucleotides, and at least two of the 10 to 28 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing with a region of the open reading frame of the gene encoding TGF-R II or a region of the mRNA encoding TGF-R II wherein the region of the open reading frame of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II contains the sequence GGACGCGTAT (Seq.ID No.7), and the antisense oligonucleotide contains a sequence capable of hybridizing with said sequence GGACGCGTAT (Seq.ID No.7).

[0030] Alternatively, the present invention relates to an antisense oligonucleotide composed of 10 to 28 nucleotides, and salts and optical isomers of the antisense oligonucleotide, and at least two of the 10 to 28 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing with a region of a gene encoding TGF-R II or a region of an mRNA encoding TGF-R II wherein the region of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II contains the sequence GGACGCGTAT (Seq.ID No.7), and the antisense oligonucleotide contains a sequence capable of complementary to the sequence GGACGCGTAT (Seq.ID No.7).

[0031] Put slightly differently, the present invention relates to an antisense oligonucleotide composed of 10 to 28 nucleotides, and salts and optical isomers of the antisense oligonucleotide, and at least two of the 10 to 28 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing with a region of the open reading frame of a gene encoding TGF-R II or a region of an mRNA encoding TGF-R II wherein the region of the open reading frame of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II contains the sequence GGACGCGTAT (Seq.ID No.7), and the antisense oligonucleotide contains a sequence capable of complementary to the sequence GGACGCGTAT (Seq.ID No.7).

[0032] Preferably, the present invention relates to an antisense oligonucleotide composed of 10 to 28 nucleotides, and salts and optical isomers of the antisense oligonucleotide, and at least two of the 10 to 28 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing with a region of a gene encoding TGF-R II or a region of an mRNA encoding TGF-R II wherein the region of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II contains the sequence GTCTATGACG (Seq.ID No.8), and the antisense oligonucleotide contains a sequence capable of hybridizing with the sequence GTCTATGACG (Seq.ID No.8).

[0033] Putting it slightly differently, the present invention relates to antisense oligonucleotides consisting of 10 to 28 nucleotides, as well as salts and optical isomers of said antisense oligonucleotides, and at least two of the 10 to 28 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing with a region of the open reading frame of the gene encoding TGF-R II or a region of the mRNA encoding TGF-R II wherein the region of the open reading frame of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II contains the sequence GTCTATGACG (Seq.ID No.8), and the antisense oligonucleotide contains a sequence capable of hybridizing with said sequence GTCTATGACG (Seq.ID No.8).

[0034] Alternatively, the present invention relates to antisense oligonucleotides consisting of 10 to 28 nucleotides, as well as salts and optical isomers of said antisense oligonucleotides, and at least two of the 10 to 28 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing with a region of the gene encoding TGF-R II or a region of the mRNA encoding TGF-R II wherein the region of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II contains the sequence GTCTATGACG (Seq.ID No.8), and the antisense oligonucleotide contains a sequence complementary to said sequence GTCTATGACG (Seq.ID No.8).

[0035] Putting it slightly differently, the present invention relates to antisense oligonucleotides consisting of 10 to 28 nucleotides, as well as salts and optical isomers of said antisense oligonucleotides, and at least two of the 10 to 28 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing with a region of the open reading frame of the gene encoding TGF-R II or a region of the mRNA encoding TGF-R II wherein the region of the open reading frame of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II contains the sequence GTCTATGACG (Seq.ID No.8), and the antisense oligonucleotide contains a sequence complementary to said sequence GTCTATGACG (Seq.ID No.8).

[0036] Preferably, the present invention relates to an antisense oligonucleotide composed of 10 to 28 nucleotides, as well as salts and optical isomers of the antisense oligonucleotide, and at least two of the 10 to 28 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing with a region of the gene encoding TGF-R II or a region of the mRNA encoding TGF-R II , wherein the region of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II contains the sequence TTATTAATGC (Seq. ID No.9), and the antisense oligonucleotide contains a sequence capable of hybridizing with the sequence TTATTAATGC (Seq.ID No.9).

[0037] Put slightly differently, the present invention relates to an antisense oligonucleotide composed of 10 to 28 nucleotides, as well as salts and optical isomers of the antisense oligonucleotide, and at least two of the 10 to 28 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing with a region of the open reading frame of the gene encoding TGF-R II or a region of the mRNA encoding TGF-R II , wherein the region of the open reading frame of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II contains the sequence TTATTAATGC (Seq.ID No.9), and the antisense oligonucleotide contains a sequence capable of hybridizing with the sequence TTATTAATGC (Seq.IDNo.9).

[0038] Alternatively, the present invention relates to an antisense oligonucleotide composed of 10 to 28 nucleotides, as well as salts and optical isomers of the antisense oligonucleotide, and at least two of the 10 to 28 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing with a region of the gene encoding TGF-R II or a region of the mRNA encoding TGF-R II , wherein the region of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II contains the sequence TTATTAATGC (Seq.ID No.9), and the antisense oligonucleotide contains a sequence complementary to the sequence TTATTAATGC (Seq. ID No.9).

[0039] Stated slightly differently, the present invention relates to antisense oligonucleotides consisting of 10 to 28 nucleotides, as well as salts and optical isomers of said antisense oligonucleotides, and at least two of the 10 to 28 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing with a region of the open reading frame of the gene encoding TGF-R II or a region of the mRNA encoding TGF-R II wherein a region of the open reading frame of the gene encoding TGF-R II or a region of the mRNA encoding TGF-R II contains the sequence TTATTAATGC (Seq.ID No.9), and the antisense oligonucleotide contains a sequence capable of complementing said sequence TTATTAATGC (Seq.ID No.9).

[0040] The antisense oligonucleotides of the present invention preferably contain 2 to 10 LNA units, more preferably 3 to 9 LNA units, still more preferably contain 4 to 8 LNA units, and also preferably contain at least 6 non-LNA units, more preferably at least 7 non-LNA units, and most preferably at least 8 non-LNA units. The non-LNA units are preferably DNA units. The LNA units are preferably located at the 3'-end (also referred to as the 3’-end) and the 5'-end (also referred to as the 5’-end). Preferably, there is at least one, more preferably at least two LNA units at the 3'-end and / or the 5'-end.

[0041] Therefore, it is preferred that the antisense oligonucleotides of the present invention contain 3 to 10 LNA units, and in particular contain 1 to 5 LNA units at the 5'-end of the antisense oligonucleotide, and 1 to 5 LNA units at the 3'-end of the antisense oligonucleotide, and contain at least 7, more preferably at least 8 DNA units between the LNA units.

[0042] In addition, the antisense oligonucleotide may contain common nucleobases such as adenine, guanine, cytosine, thymine and uracil, as well as common derivatives thereof. The antisense oligonucleotides of the present invention may also contain modified internucleotide bridges such as phosphorothioates or dithiophosphates in place of the phosphate ester bridge. Such modifications may be present only in the LNA segment of the antisense oligonucleotide, or only in the non-LNA segment of the antisense oligonucleotide.

[0043] Therefore, the present invention also relates to antisense oligonucleotides consisting of 12 to 24 nucleotides, as well as salts and optical isomers of said antisense oligonucleotides, and at least 3 of the 12 to 24 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing with a region of the gene encoding TGF-R II or a region of the mRNA encoding TGF-R II wherein the region of the gene encoding TGF-RII region of the gene or encoding TGF-R IIThe region of the mRNA contains the sequences CTGGTCCATTC (Seq. ID No. 296), TGGTCCATTCA (Seq. ID No. 297), CTGGTCCATTCA (Seq. ID No. 298), TCCCTAAACAC (Seq. ID No. 299), CCCTAAACACT (Seq. ID No. 300), TCCCTAAACACT (Seq. ID No. 301), CACTACCAAAT (Seq. ID No. 302), ACTACCAAATA (Seq. ID No. 303), CACTACCAAATA (Seq. ID No. 304), TGGACGCGTAT (Seq. ID No. 305), GGACGCGTATC (Seq. ID No. 306), TGGACGCGTATC (Seq. ID No. 307), GGTCTATGACG (Seq. ID No. 308), GTCTATGACGA (Seq. ID No. 309), GGTCTATGACGA (Seq. ID No. 310), TTTATTAATGC (Seq. ID No. 311), TTATTAATGCC (Seq. ID No. 312), or TTTATTAATGCC (Seq. ID No. 313), and the antisense oligonucleotides respectively contain sequences capable of hybridizing with the sequences CTGGTCCATTC (Seq. ID No. 296), TGGTCCATTCA (Seq. ID No. 297), CTGGTCCATTCA (Seq. ID No. 298), TCCCTAAACAC (Seq. ID No. 299), CCCTAAACACT (Seq. ID No. 300), TCCCTAAACACT (Seq. ID No. 301), CACTACCAAAT (Seq. ID No. 302), ACTACCAAATA (Seq. ID No. 303), CACTACCAAATA (Seq. ID No. 304), TGGACGCGTAT (Seq. ID No. 305), GGACGCGTATC (Seq. ID No. 306), TGGACGCGTATC (Seq. ID No. 307), GGTCTATGACG (Seq. ID No. 308), GTCTATGACGA (Seq. ID No. 309), GGTCTATGACGA (Seq. ID No. 310), TTTATTAATGC (Seq. ID No. 311), TTATTAATGCC (Seq. ID No.Sequences hybridizing with or TTTATTAATGCC (Seq.ID No. 313).

[0044] Alternatively, the present invention relates to antisense oligonucleotides composed of 12 to 24 nucleotides, and salts and optical isomers of said antisense oligonucleotides, and at least 3 of the 12 to 24 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing with the region of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II wherein the region of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R IIThe regions of the mRNA contain the sequences CTGGTCCATTC (Seq. ID No. 296), TGGTCCATTCA (Seq. ID No. 297), CTGGTCCATTCA (Seq. ID No. 298), TCCCTAAACAC (Seq. ID No. 299), CCCTAAACACT (Seq. ID No. 300), TCCCTAAACACT (Seq. ID No. 301), CACTACCAAAT (Seq. ID No. 302), ACTACCAAATA (Seq. ID No. 303), CACTACCAAATA (Seq. ID No. 304), TGGACGCGTAT (Seq. ID No. 305), GGACGCGTATC (Seq. ID No. 306), TGGACGCGTATC (Seq. ID No. 307), GGTCTATGACG (Seq. ID No. 308), GTCTATGACGA (Seq. ID No. 309), GGTCTATGACGA (Seq. ID No. 310), TTTATTAATGC (Seq. ID No. 311), TTATTAATGCC (Seq. ID No. 312), or TTTATTAATGCC (Seq. ID No. 313), and the antisense oligonucleotides respectively contain sequences capable of hybridizing with the sequences CTGGTCCATTC (Seq. ID No. 296), TGGTCCATTCA (Seq. ID No. 297), CTGGTCCATTCA (Seq. ID No. 298), TCCCTAAACAC (Seq. ID No. 299), CCCTAAACACT (Seq. ID No. 300), TCCCTAAACACT (Seq. ID No. 301), CACTACCAAAT (Seq. ID No. 302), ACTACCAAATA (Seq. ID No. 303), CACTACCAAATA (Seq. ID No. 304), TGGACGCGTAT (Seq. ID No. 305), GGACGCGTATC (Seq. ID No. 306), TGGACGCGTATC (Seq. ID No. 307), GGTCTATGACG (Seq. ID No. 308), GTCTATGACGA (Seq. ID No. 309), GGTCTATGACGA (Seq. ID No. 310), TTTATTAATGC (Seq. ID No. 311), TTATTAATGCC (Seq. ID No.a sequence complementary to TTTATTAATGCC (Seq.ID No.312) or TTTATTAATGCC (Seq.ID No.313).

[0045] Preferably, the present invention also relates to antisense oligonucleotides composed of 12 to 24 nucleotides, as well as salts and optical isomers of said antisense oligonucleotides, and at least three of the 2 to 24 nucleotides are LNA, and the antisense oligonucleotides are capable of hybridizing with a region of the gene encoding TGF-R II or a region of the mRNA encoding TGF-R II wherein the region of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II contains the sequence CTGGTCCATTC (Seq.ID No.296), TGGTCCATTCA (Seq.ID No.297), or CTGGTCCATTCA (Seq.ID No.298), and the antisense oligonucleotide contains a sequence capable of hybridizing with the sequence CTGGTCCATTC (Seq.ID No.296), TGGTCCATTCA (Seq.ID No.297), or CTGGTCCATTCA (Seq.ID No.298).

[0046] Put slightly differently, the present invention also relates to antisense oligonucleotides composed of 12 to 24 nucleotides, as well as salts and optical isomers of said antisense oligonucleotides, and at least three of the 10 to 24 nucleotides are LNA, and the antisense oligonucleotides are capable of hybridizing with a region of the gene encoding TGF-R II or a region of the mRNA encoding TGF-R II wherein the region of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II contains the sequence CTGGTCCATTC (Seq.IDNo.296), TGGTCCATTCA (Seq.ID No. 297), or CTGGTCCATTCA (Seq.ID No.298), and the antisense oligonucleotide contains a sequence complementary to the sequence CTGGTCCATTC (Seq.ID No.296), TGGTCCATTCA (Seq.IDNo.297), or CTGGTCCATTCA (Seq.ID No.298).

[0047] Preferably, the present invention also relates to antisense oligonucleotides composed of 12 to 24 nucleotides, as well as salts and optical isomers of said antisense oligonucleotides, and at least three of the 2 to 24 nucleotides are LNA, and the antisense oligonucleotides are capable of hybridizing with a region of the gene encoding TGF-RII region of the gene or encoding TGF-R II hybridizes to the region of the mRNA encoding TGF-R II region of the gene or encoding TGF-R II region of the mRNA encoding TGF-R contains the sequence TCCCTAAACAC (Seq. ID No. 299), CCCTAAACACT (Seq. ID No. 300), or TCCCTAAACACT (Seq. ID No. 301), and the antisense oligonucleotide contains a sequence capable of hybridizing to the sequence TCCCTAAACAC (Seq. ID No. 299), CCCTAAACACT (Seq. ID No. 300), or TCCCTAAACACT (Seq. ID No. 301).

[0048] Putting it slightly differently, the present invention also relates to antisense oligonucleotides consisting of 12 to 24 nucleotides and salts and optical isomers of said antisense oligonucleotides, and at least three of the 2 to 24 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing to the region of the gene encoding TGF-R II region of the gene or encoding TGF-R II hybridizes to the region of the mRNA encoding TGF-R II region of the gene or encoding TGF-R II region of the mRNA encoding TGF-R contains the sequence TCCCTAAACAC (Seq. ID No. 299), CCCTAAACACT (Seq. ID No. 300), or TCCCTAAACACT (Seq. ID No. 301), and the antisense oligonucleotide contains a sequence complementary to the sequence TCCCTAAACAC (Seq. ID No. 299), CCCTAAACACT (Seq. ID No. 300), or TCCCTAAACACT (Seq. ID No. 301).

[0049] Preferably, the present invention also relates to antisense oligonucleotides consisting of 12 to 24 nucleotides and salts and optical isomers of said antisense oligonucleotides, and at least three of the 2 to 24 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing to the region of the gene encoding TGF-R II region of the gene or encoding TGF-R II hybridizes to the region of the mRNA encoding TGF-R II region of the gene or encoding TGF-R IIThe region of the mRNA contains the sequence CACTACCAAAT (Seq. ID No. 302), ACTACCAAATA (Seq. ID No. 303), or CACTACCAAATA (Seq. ID No. 304), and the antisense oligonucleotide contains a sequence capable of hybridizing with the sequence CACTACCAAAT (Seq. ID No. 302), ACTACCAAATA (Seq. ID No. 303), or CACTACCAAATA (Seq. ID No. 304).

[0050] Putting it slightly differently, the present invention also relates to antisense oligonucleotides consisting of 12 to 24 nucleotides and salts and optical isomers of said antisense oligonucleotides, and at least three of the 2 to 24 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing with a region of the gene encoding TGF-R II or a region of the mRNA encoding TGF-R II wherein the region of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II contains the sequence CACTACCAAAT (Seq. ID No. 302), ACTACCAAATA (Seq. ID No. 303), or CACTACCAAATA (Seq. ID No. 304), and the antisense oligonucleotide contains a sequence complementary to the sequence CACTACCAAAT (Seq. ID No. 302), ACTACCAAATA (Seq. ID No. 303), or CACTACCAAATA (Seq. ID No. 304).

[0051] Preferably, the present invention also relates to antisense oligonucleotides consisting of 12 to 24 nucleotides and salts and optical isomers of said antisense oligonucleotides, and at least three of the 2 to 24 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing with a region of the gene encoding TGF-R II or a region of the mRNA encoding TGF-R II wherein the region of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R IIThe region of the mRNA contains the sequence TGGACGCGTAT (Seq.ID No.305), GGACGCGTATC (Seq.ID No.306), or TGGACGCGTATC (Seq.ID No.307), and the antisense oligonucleotide contains a sequence capable of hybridizing with the sequence TGGACGCGTAT (Seq.ID No.305), GGACGCGTATC (Seq.ID No.306), or TGGACGCGTATC (Seq.ID No.307).

[0052] Putting it slightly differently, the present invention also relates to antisense oligonucleotides consisting of 12 to 24 nucleotides, and salts and optical isomers of said antisense oligonucleotides, and at least three of the 2 to 24 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing with the region of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II where the region of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II contains the sequence TGGACGCGTAT (Seq.ID No.305), GGACGCGTATC (Seq.ID No.306), or TGGACGCGTATC (Seq.ID No.307), and the antisense oligonucleotide contains a sequence complementary to the sequence TGGACGCGTAT (Seq.ID No.305), GGACGCGTATC (Seq.ID No.306), or TGGACGCGTATC (Seq.ID No.307).

[0053] Preferably, the present invention also relates to antisense oligonucleotides consisting of 12 to 24 nucleotides, and salts and optical isomers of said antisense oligonucleotides, and at least three of the 2 to 24 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing with the region of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II where the region of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R IIThe region of the mRNA contains the sequence GGTCTATGACG (Seq.ID No.308), GTCTATGACGA (Seq.ID No.309), or GGTCTATGACGA (Seq.ID No.310), and the antisense oligonucleotide contains a sequence capable of hybridizing with the sequence GGTCTATGACG (Seq.ID No.308), GTCTATGACGA (Seq.ID No.309), or GGTCTATGACGA (Seq.ID No.310).

[0054] Putting it slightly differently, the present invention also relates to antisense oligonucleotides consisting of 12 to 24 nucleotides and salts and optical isomers of said antisense oligonucleotides, and at least three of the 2 to 24 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing with the region of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II wherein the region of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II contains the sequence GGTCTATGACG (Seq.ID No.308), GTCTATGACGA (Seq.ID No.309), or GGTCTATGACGA (Seq.ID No.310), and the antisense oligonucleotide contains a sequence complementary to the sequence GGTCTATGACG (Seq.ID No.308), GTCTATGACGA (Seq.ID No.309), or GGTCTATGACGA (Seq.ID No.310).

[0055] Preferably, the present invention also relates to antisense oligonucleotides consisting of 12 to 24 nucleotides and salts and optical isomers of said antisense oligonucleotides, and at least three of the 2 to 24 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing with the region of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II wherein the region of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R IIThe region of the mRNA contains the sequence TTTATTAATGC (Seq. ID No. 311), TTATTAATGCC (Seq. ID No. 312), or TTTATTAATGCC (Seq. ID No. 313), and the antisense oligonucleotide contains a sequence capable of hybridizing with the sequence TTTATTAATGC (Seq. ID No. 311), TTATTAATGCC (Seq. ID No. 312), or TTTATTAATGCC (Seq. ID No. 313).

[0056] Stated slightly differently, the present invention also relates to antisense oligonucleotides composed of 12 to 24 nucleotides, as well as salts and optical isomers of said antisense oligonucleotides, and at least three of the 2 to 24 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing with the region of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II wherein the region of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II contains the sequence TTTATTAATGC (Seq. ID No. 311), TTATTAATGCC (Seq. ID No. 312), or TTTATTAATGCC (Seq. ID No. 313), and the antisense oligonucleotide contains a sequence complementary to the sequence TTTATTAATGC (Seq. ID No. 311), TTATTAATGCC (Seq. ID No. 312), or TTTATTAATGCC (Seq. ID No. 313).

[0057] The antisense oligonucleotides of the present invention preferably contain 3 to 10 LNA units, more preferably 3 to 9 LNA units, even more preferably contain 4 to 8 LNA units, and also preferably contain at least 6 non-LNA units, more preferably at least 7 non-LNA units, and most preferably at least 8 non-LNA units. The non-LNA units are preferably DNA units. The LNA units are preferably located at the 3'-end (also referred to as the 3’-end) and the 5'-end (also referred to as the 5’-end). Preferably, there is at least one or more, more preferably at least two LNA units at the 3'-end and / or 5'-end.

[0058] Therefore, it is preferred that the antisense oligonucleotides of the present invention contain 3 to 10 LNA units, and in particular contain 1 to 5 LNA units at the 5'-end of the antisense oligonucleotide, and 1 to 5 LNA units at the 3'-end of the antisense oligonucleotide, and contain at least 7, more preferably at least 8 DNA units between the LNA units.

[0059] In addition, the antisense oligonucleotides can contain common nucleobases such as adenine, guanine, cytosine, thymine, and uracil and their common derivatives. The antisense oligonucleotides of the present invention can also contain modified internucleotide bridges such as phosphorothioates or dithiophosphates to replace the phosphate ester bridge. Such modifications can be present only in the LNA segment of the antisense oligonucleotide or only in the non-LNA segment of the antisense oligonucleotide.

[0060] Accordingly, the present invention also relates to antisense oligonucleotides consisting of 14 to 20, more preferably 14 to 18 nucleotides, and salts and optical isomers of said antisense oligonucleotides, and at least 4 of the 14 to 20, more preferably 14 to 18 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing with a region of the gene encoding TGF-R II or a region of the mRNA encoding TGF-R II wherein the region of the gene encoding TGF-R II or a region of the mRNA encoding TGF-R IIThe regions of the mRNA contain the sequences ACTGGTCCATTC (Seq.ID No.314), TGGTCCATTCAT (Seq.ID No.315), CTGGTCCATTCAT (Seq.ID No.316), ACTGGTCCATTCA (Seq.ID No.317), ACTGGTCCATTCAT (Seq.ID No.318), CTCCCTAAACAC (Seq.ID No.319), CCCTAAACACTA (Seq.ID No.320), TCCCTAAACACTA (Seq.ID No.321), CTCCCTAAACACT (Seq.ID No.322), CTCCCTAAACACTA (Seq.ID No.323), ACACTACCAAAT (Seq.ID No.324), ACTACCAAATAG (Seq.ID No.325), CACTACCAAATAG (Seq.ID No.326), ACACTACCAAATA (Seq.ID No.327), ACACTACCAAATAG (Seq.ID No.328), GTGGACGCGTAT (Seq.ID No.329), GGACGCGTATCG (Seq.ID No.330), TGGACGCGTATCG (Seq.ID No.331), GTGGACGCGTATC (Seq.ID No.332), GTGGACGCGTATCG (Seq.ID No.333), CGGTCTATGACG (Seq.ID No.334), GTCTATGACGAG (Seq.ID No.335), GGTCTATGACGAG (Seq.ID No.336), CGGTCTATGACGA (Seq.ID No.337), CGGTCTATGACGAG (Seq.ID No.338), CTTTATTAATGC (Seq.ID No.339), TTATTAATGCCT (Seq.ID No.340), TTTATTAATGCCT (Seq.ID No.341), CTTTATTAATGCC (Seq.ID No.342), or CTTTATTAATGCCT (Seq.ID No.343), and the antisense oligonucleotides respectively contain sequences capable of hybridizing with the sequences ACTGGTCCATTC (Seq.ID No.314), TGGTCCATTCAT (Seq.ID No.315), CTGGTCCATTCAT (Seq.ID No.Sequences hybridizing with ACTGGTCCATTCA (Seq.ID No.316), ACTGGTCCATTCA (Seq.ID No.317), ACTGGTCCATTCAT (Seq. ID No.318), CTCCCTAAACAC (Seq.ID No.319), CCCTAAACACTA (Seq.ID No.320), TCCCTAAACACTA (Seq.ID No.321), CTCCCTAAACACT (Seq.ID No.322), CTCCCTAAACACTA (Seq.ID No.323), ACACTACCAAAT (Seq.ID No.324), ACTACCAAATAG (Seq.IDNo.325), CACTACCAAATAG (Seq.ID No.326), ACACTACCAAATA (Seq.ID No.327), ACACTACCAAATAG (Seq.ID No.328), GTGGACGCGTAT (Seq. ID No.329), GGACGCGTATCG (Seq.ID No.330), TGGACGCGTATCG (Seq.ID No.331), GTGGACGCGTATC (Seq. ID No.332), GTGGACGCGTATCG (Seq.ID No.333), CGGTCTATGACG (Seq.ID No.334), GTCTATGACGAG (Seq.IDNo.335), GGTCTATGACGAG (Seq.ID No.336), CGGTCTATGACGA (Seq.ID No.337), CGGTCTATGACGAG (Seq.ID No.338), CTTTATTAATGC (Seq.ID No.339), TTATTAATGCCT (Seq.ID No.340), TTTATTAATGCCT (Seq.ID No.341), CTTTATTAATGCC (Seq.ID No.342), or CTTTATTAATGCCT (Seq. ID No.343).

[0061] Alternatively, the present invention also relates to antisense oligonucleotides composed of 14 to 20, more preferably 14 to 18 nucleotides, and salts and optical isomers of said antisense oligonucleotides, and at least 4 of the 14 to 20, more preferably 14 to 18 nucleotides are LNA, and the antisense oligonucleotides are capable of hybridizing with the region of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II wherein the encoding TGF-R IIregion of the gene or encoding TGF-R IIThe regions of the mRNA contain the sequences ACTGGTCCATTC (Seq.ID No.314), TGGTCCATTCAT (Seq.ID No.315), CTGGTCCATTCAT (Seq.ID No.316), ACTGGTCCATTCA (Seq.ID No.317), ACTGGTCCATTCAT (Seq.ID No.318), CTCCCTAAACAC (Seq.ID No.319), CCCTAAACACTA (Seq.ID No.320), TCCCTAAACACTA (Seq.ID No.321), CTCCCTAAACACT (Seq.ID No.322), CTCCCTAAACACTA (Seq.ID No.323), ACACTACCAAAT (Seq.ID No.324), ACTACCAAATAG (Seq.ID No.325), CACTACCAAATAG (Seq.ID No.326), ACACTACCAAATA (Seq.ID No.327), ACACTACCAAATAG (Seq.ID No.328), GTGGACGCGTAT (Seq.ID No.329), GGACGCGTATCG (Seq.ID No.330), TGGACGCGTATCG (Seq.ID No.331), GTGGACGCGTATC (Seq.ID No.332), GTGGACGCGTATCG (Seq.ID No.333), CGGTCTATGACG (Seq.ID No.334), GTCTATGACGAG (Seq.ID No.335), GGTCTATGACGAG (Seq.ID No.336), CGGTCTATGACGA (Seq.ID No.337), CGGTCTATGACGAG (Seq.ID No.338), CTTTATTAATGC (Seq.ID No.339), TTATTAATGCCT (Seq.ID No.340), TTTATTAATGCCT (Seq.ID No.341), CTTTATTAATGCC (Seq.ID No.342), or CTTTATTAATGCCT (Seq.ID No.343), and the antisense oligonucleotides respectively contain sequences capable of hybridizing to the sequences ACTGGTCCATTC (Seq.ID No.314), TGGTCCATTCAT (Seq.ID No.315), CTGGTCCATTCAT (Seq.ID No.Sequences complementary to ACTGGTCCATTCA (Seq.ID No.316), ACTGGTCCATTCA (Seq.ID No.317), ACTGGTCCATTCAT (Seq.ID No.318), CTCCCTAAACAC (Seq.ID No.319), CCCTAAACACTA (Seq.ID No.320), TCCCTAAACACTA (Seq.ID No.321), CTCCCTAAACACT (Seq.ID No.322), CTCCCTAAACACTA (Seq.ID No.323), ACACTACCAAAT (Seq.ID No.324), ACTACCAAATAG (Seq.ID No.325), CACTACCAAATAG (Seq.ID No.326), ACACTACCAAATA (Seq.ID No.327), ACACTACCAAATAG (Seq.ID No.328), GTGGACGCGTAT (Seq.ID No.329), GGACGCGTATCG (Seq.ID No.330), TGGACGCGTATCG (Seq.ID No.331), GTGGACGCGTATC (Seq.ID No.332), GTGGACGCGTATCG (Seq.ID No.333), CGGTCTATGACG (Seq.ID No.334), GTCTATGACGAG (Seq.ID No.335), GGTCTATGACGAG (Seq.ID No.336), CGGTCTATGACGA (Seq.ID No.337), CGGTCTATGACGAG (Seq.ID No.338), CTTTATTAATGC (Seq.ID No.339), TTATTAATGCCT (Seq.ID No.340), TTTATTAATGCCT (Seq.ID No.341), CTTTATTAATGCC (Seq.ID No.342), or CTTTATTAATGCCT (Seq.ID No.343).

[0062] Preferably, the present invention also relates to antisense oligonucleotides composed of 14 to 20, more preferably 14 to 18 nucleotides, and salts and optical isomers of the antisense oligonucleotides, and at least 4 of the 14 to 20, more preferably 14 to 18 nucleotides are LNA, and the antisense oligonucleotides are capable of hybridizing with the region of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II wherein the encoding TGF-RII region of the gene or encoding TGF-R II region of the mRNA encoding TGF-R contains the sequences ACTGGTCCATTC (Seq.ID No.314), TGGTCCATTCAT (Seq.ID No.315), CTGGTCCATTCAT (Seq.ID No.316), ACTGGTCCATTCA (Seq.ID No.317), ACTGGTCCATTCAT (Seq.ID No.318), and the antisense oligonucleotide contains a sequence capable of hybridizing with the sequences ACTGGTCCATTC (Seq.ID No.314), TGGTCCATTCAT (Seq.ID No.315), CTGGTCCATTCAT (Seq.ID No.316), ACTGGTCCATTCA (Seq.ID No.317), ACTGGTCCATTCAT (Seq.ID No.318).

[0063] Putting it slightly differently, the present invention also relates to antisense oligonucleotides consisting of 14 to 20, more preferably 14 to 18 nucleotides, and salts and optical isomers of said antisense oligonucleotides, and at least 4 of the 14 to 20, more preferably 14 to 18 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing with the region of the gene encoding TGF-R II region of the gene or encoding TGF-R II region of the mRNA encoding TGF-R, wherein the region of the gene encoding TGF-R II region of the gene or encoding TGF-R II region of the mRNA encoding TGF-R contains the sequences ACTGGTCCATTC (Seq.ID No. 314), TGGTCCATTCAT (Seq.ID No.315), CTGGTCCATTCAT (Seq.ID No.316), ACTGGTCCATTCA (Seq.ID No.317), ACTGGTCCATTCAT (Seq.ID No.318), and the antisense oligonucleotide contains a sequence complementary to the sequences ACTGGTCCATTC (Seq.ID No.314), TGGTCCATTCAT (Seq.ID No.315), CTGGTCCATTCAT (Seq.ID No.316), ACTGGTCCATTCA (Seq.ID No.317), ACTGGTCCATTCAT (Seq.ID No.318).

[0064] Preferably, the present invention also relates to antisense oligonucleotides composed of 14 to 20, more preferably 14 to 18 nucleotides, and salts and optical isomers of the antisense oligonucleotides, and at least 4 of the 14 to 20, more preferably 14 to 18 nucleotides are LNA, and the antisense oligonucleotides are capable of hybridizing with a region of the gene encoding TGF-R II or a region of the mRNA encoding TGF-R II , wherein the region of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II contains the sequences CTCCCTAAACAC (Seq.ID No.319), CCCTAAACACTA (Seq.ID No.320), TCCCTAAACACTA (Seq.ID No.321), CTCCCTAAACACT (Seq.ID No.322), or CTCCCTAAACACTA (Seq.ID No.323), and the antisense oligonucleotides contain sequences capable of hybridizing with the sequences CTCCCTAAACAC (Seq.ID No.319), CCCTAAACACTA (Seq.ID No.320), TCCCTAAACACTA (Seq.ID No.321), CTCCCTAAACACT (Seq.ID No.322), or CTCCCTAAACACTA (Seq.ID No.323).

[0065] Put slightly differently, the present invention also relates to antisense oligonucleotides composed of 14 to 20, more preferably 14 to 18 nucleotides, and salts and optical isomers of the antisense oligonucleotides, and at least 4 of the 14 to 20, more preferably 14 to 18 nucleotides are LNA, and the antisense oligonucleotides are capable of hybridizing with a region of the gene encoding TGF-R II or a region of the mRNA encoding TGF-R II , wherein the region of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R IIThe region of the mRNA contains the sequence CTCCCTAAACAC (Seq.ID No. 319), CCCTAAACACTA (Seq.ID No.320), TCCCTAAACACTA (Seq.ID No.321), CTCCCTAAACACT (Seq.ID No.322), or CTCCCTAAACACTA (Seq.ID No.323), and the antisense oligonucleotide contains a sequence capable of complementing the sequence CTCCCTAAACAC (Seq.ID No.319), CCCTAAACACTA (Seq.ID No.320), TCCCTAAACACTA (Seq.ID No.321), CTCCCTAAACACT (Seq.ID No.322), or CTCCCTAAACACTA (Seq.ID No.323).

[0066] Preferably, the present invention also relates to antisense oligonucleotides composed of 14 to 20, more preferably 14 to 18 nucleotides, and salts and optical isomers of the antisense oligonucleotides, and at least 4 of the 14 to 20, more preferably 14 to 18 nucleotides are LNA, and the antisense oligonucleotide is capable of binding to the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II hybridizes, wherein the region of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II contains the sequence ACACTACCAAAT (Seq.ID No.324), ACTACCAAATAG (Seq.ID No.325), CACTACCAAATAG (Seq.ID No.326), ACACTACCAAATA (Seq.ID No.327), or ACACTACCAAATAG (Seq.ID No.328), and the antisense oligonucleotide contains a sequence capable of hybridizing with the sequence ACACTACCAAAT (Seq.ID No.324), ACTACCAAATAG (Seq.ID No.325), CACTACCAAATAG (Seq.ID No.326), ACACTACCAAATA (Seq.ID No.327), or ACACTACCAAATAG (Seq.ID No.328).

[0067] Stated slightly differently, the present invention also relates to antisense oligonucleotides consisting of 14 to 20, more preferably 14 to 18 nucleotides, and salts and optical isomers of said antisense oligonucleotides, and at least 4 of the 14 to 20, more preferably 14 to 18 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing to a region of the gene encoding TGF-R II or to a region of the mRNA encoding TGF-R II wherein the region of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II contains the sequence ACACTACCAAAT (Seq.ID No. 324), ACTACCAAATAG (Seq.ID No.325), CACTACCAAATAG (Seq.ID No.326), ACACTACCAAATA (Seq.ID No.327), or ACACTACCAAATAG (Seq.ID No.328), and the antisense oligonucleotide contains a sequence capable of complementing the sequence ACACTACCAAAT (Seq.ID No.324), ACTACCAAATAG (Seq.ID No.325), CACTACCAAATAG (Seq.ID No.326), ACACTACCAAATA (Seq.ID No.327), or ACACTACCAAATAG (Seq.ID No.328).

[0068] Preferably, the present invention also relates to antisense oligonucleotides consisting of 14 to 20, more preferably 14 to 18 nucleotides, and salts and optical isomers of said antisense oligonucleotides, and at least 4 of the 14 to 20, more preferably 14 to 18 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing to a region of the gene encoding TGF-R II or to a region of the mRNA encoding TGF-R II wherein the region of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R IIThe region of the mRNA contains the sequence GTGGACGCGTAT (Seq.ID No.329), GGACGCGTATCG (Seq.ID No.330), TGGACGCGTATCG (Seq.ID No.331), GTGGACGCGTATC (Seq.ID No.332), or GTGGACGCGTATCG (Seq.ID No.333), and the antisense oligonucleotide contains a sequence capable of hybridizing with the sequence GTGGACGCGTAT (Seq.ID No.329), GGACGCGTATCG (Seq.ID No.330), TGGACGCGTATCG (Seq.ID No.331), GTGGACGCGTATC (Seq.ID No.332), or GTGGACGCGTATCG (Seq.ID No.333).

[0069] Putting it slightly differently, the present invention also relates to antisense oligonucleotides composed of 14 to 20, more preferably 14 to 18 nucleotides, and salts and optical isomers of the antisense oligonucleotides, and at least 4 of the 14 to 20, more preferably 14 to 18 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing with a region of the gene encoding TGF-R II or a region of the mRNA encoding TGF-R II wherein the region of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II contains the sequence GTGGACGCGTAT (Seq.ID No. 329), GGACGCGTATCG (Seq.ID No.330), TGGACGCGTATCG (Seq.ID No.331), GTGGACGCGTATC (Seq.ID No.332), or GTGGACGCGTATCG (Seq.ID No.333), and the antisense oligonucleotide contains a sequence complementary to the sequence GTGGACGCGTAT (Seq.ID No.329), GGACGCGTATCG (Seq.ID No.330), TGGACGCGTATCG (Seq.ID No.331), GTGGACGCGTATC (Seq.ID No.332), or GTGGACGCGTATCG (Seq.ID No.333).

[0070] Preferably, the present invention also relates to antisense oligonucleotides consisting of 14 to 20, more preferably 14 to 18 nucleotides, and salts and optical isomers of said antisense oligonucleotides, and at least 4 of the 14 to 20, more preferably 14 to 18 nucleotides are LNA, and the antisense oligonucleotides are capable of hybridizing with a region of the gene encoding TGF-R II or a region of the mRNA encoding TGF-R II , wherein the region of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II contains the sequences CGGTCTATGACG (Seq.ID No.334), GTCTATGACGAG (Seq.ID No.335), GGTCTATGACGAG (Seq.ID No.336), CGGTCTATGACGA (Seq.ID No.337), or CGGTCTATGACGAG (Seq.ID No.338), and the antisense oligonucleotides contain sequences capable of hybridizing with said sequences CGGTCTATGACG (Seq.ID No.334), GTCTATGACGAG (Seq.ID No.335), GGTCTATGACGAG (Seq.ID No.336), CGGTCTATGACGA (Seq.ID No.337), or CGGTCTATGACGAG (Seq.ID No.338).

[0071] Putting it slightly differently, the present invention also relates to antisense oligonucleotides consisting of 14 to 20, more preferably 14 to 18 nucleotides, and salts and optical isomers of said antisense oligonucleotides, and at least 4 of the 14 to 20, more preferably 14 to 18 nucleotides are LNA, and the antisense oligonucleotides are capable of hybridizing with a region of the gene encoding TGF-R II or a region of the mRNA encoding TGF-R II , wherein the region of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R IIThe region of the mRNA contains the sequences CGGTCTATGACG (Seq.ID No. 334), GTCTATGACGAG (Seq.ID No. 335), GGTCTATGACGAG (Seq.ID No. 336), CGGTCTATGACGA (Seq.ID No. 337), or CGGTCTATGACGAG (Seq.ID No. 338), and the antisense oligonucleotide contains a sequence capable of complementary to the sequences CGGTCTATGACG (Seq.ID No. 334), GTCTATGACGAG (Seq.ID No. 335), GGTCTATGACGAG (Seq.ID No. 336), CGGTCTATGACGA (Seq.ID No. 337), or CGGTCTATGACGAG (Seq.ID No. 338).

[0072] Preferably, the present invention also relates to antisense oligonucleotides composed of 14 to 20, more preferably 14 to 18 nucleotides, and salts and optical isomers of the antisense oligonucleotides, and at least 4 of the 14 to 20, more preferably 14 to 18 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing with a region of the gene encoding TGF-R II or a region of the mRNA encoding TGF-R II wherein the region of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II contains the sequences CTTTATTAATGC (Seq.ID No. 339), TTATTAATGCCT (Seq.ID No. 340), TTTATTAATGCCT (Seq.ID No. 341), CTTTATTAATGCC (Seq.ID No. 342), or CTTTATTAATGCCT (Seq.ID No. 343), and the antisense oligonucleotide contains a sequence capable of hybridizing with the sequences CTTTATTAATGC (Seq.ID No. 339), TTATTAATGCCT (Seq.ID No. 340), TTTATTAATGCCT (Seq.ID No. 341), CTTTATTAATGCC (Seq.ID No. 342), or CTTTATTAATGCCT (Seq.ID No. 343).

[0073] Stated slightly differently, the present invention also relates to antisense oligonucleotides consisting of 14 to 20, more preferably 14 to 18 nucleotides, and salts and optical isomers of said antisense oligonucleotides, and at least 4 of the 14 to 20, more preferably 14 to 18 nucleotides are LNA, and the antisense oligonucleotide is capable of binding to the region of the gene encoding TGF-R II or to the region of the mRNA encoding TGF-R II wherein the region of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II contains the sequence CTTTATTAATGC (Seq.ID No. 339), TTATTAATGCCT (Seq.ID No. 340), TTTATTAATGCCT (Seq.ID No. 341), CTTTATTAATGCC (Seq.ID No. 342), or CTTTATTAATGCCT (Seq.ID No. 343), and the antisense oligonucleotide contains a sequence capable of binding to said sequence CTTTATTAATGC (Seq.ID No. 339), TTATTAATGCCT (Seq.ID No. 340), TTTATTAATGCCT (Seq.ID No. 341), CTTTATTAATGCC (Seq.ID No. 342), or CTTTATTAATGCCT (Seq.ID No. 343).

[0074] The antisense oligonucleotides of the present invention preferably contain 4 to 11 LNA units, more preferably 4 to 10 LNA units, more preferably 4 to 8 LNA units, and also preferably contain at least 6 non-LNA units, more preferably at least 7 non-LNA units, most preferably at least 8 non-LNA units. The non-LNA units are preferably DNA units. The LNA units are preferably located at the 3'-end (also referred to as the 3' terminus) and the 5'-end (also referred to as the 5' terminus). Preferably, there is at least one, more preferably at least two LNA units at the 3'-end and / or 5'-end.

[0075] Thus, preferably the antisense oligonucleotides of the present invention contain 3 to 10 LNA units, and in particular 1 to 5 LNA units at the 5'-end of the antisense oligonucleotide and 1 to 5 LNA units at the 3'-end of the antisense oligonucleotide, and contain at least 7, more preferably at least 8 DNA units between the LNA units.

[0076] In addition, the antisense oligonucleotides can contain common nucleobases such as adenine, guanine, cytosine, thymine, and uracil and their common derivatives. The antisense oligonucleotides of the present invention can also contain modified internucleotide bridges such as phosphorothioates or dithiophosphates to replace the phosphate bridges. Such modifications can be present only in the LNA segment of the antisense oligonucleotide or only in the non-LNA segment of the antisense oligonucleotide.

[0077] Accordingly, the present invention relates to antisense oligonucleotides consisting of 10 to 28 nucleotides, and salts and optical isomers of said antisense oligonucleotides, and at least two of the 10 to 28 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing with a region of a gene encoding TGF-R II or a region of an mRNA encoding TGF-R II wherein said antisense oligonucleotide is represented by the following sequence: 5'-N 1 -GTCATAGA-N 2 -3' (Seq.ID No.12) or 5'-N 3 -ACGCGTCC-N 4 -3' (Seq.IDNo.98) or 5'-N 11 -TGTTTAGG-N 12 -3' (Seq.ID No.10) or 5'-N 5 -TTTGGTAG-N 6 -3' (Seq.IDNo.11) or 5'-N 7 -AATGGACC-N 8 -3' (Seq.ID No.100) or 5'-N 9 -ATTAATAA-N 10 -3' (Seq.IDNo.101), wherein

[0078] N 1 represents: CATGGCAGACCCCGCTGCTC-, ATGGCAGACCCCGCTGCTC-,TGGCAGACCCCGCTGCTC-, GGCAGACCCCGCTGCTC-,GCAGACCCCGCTGCTC-, CAGACCCCGCTGCTC-,AGACCCCGCTGCTC-,GACCCCGCTGCTC-,ACCCCGCTGCTC-,CCCCGCTGCTC-, CCCGCTGCTC-,CCGCTGCTC-,CGCTGCTC-,GCTGCTC-, CTGCTC-,TGCTC-,GCTC-,CTC-,TC-, or C-;

[0079] N 2 represents: -C, -CC, -CCG, -CCGA, -CCGAG, -CCGAGC, -CCGAGCC, -CCGAGCCC, -CCGAGCCCC, -CCGAGCCCCC, -CCGAGCCCCCA, -CCGAGCCCCCAG, -CCGAGCCCCCAGC, -CCGAGCCCCCAGCG, -CCGAGCCCCCAGCGC, -CCGAGCCCCCAGCGCA, -CCGAGCCCCCAGCGCAG, -CCGAGCCCCCAGCGCAGC, -CCGAGCCCCCAGCGCAGCG, or –CCGAGCCCCCAGCGCAGCGG;

[0080] N 3 represents: GGTGGGATCGTGCTGGCGAT-, GTGGGATCGTGCTGGCGAT-, TGGGATCGTGCTGGCGAT-, GGGATCGTGCTGGCGAT-, GGATCGTGCTGGCGAT-, GATCGTGCTGGCGAT-, ATCGTGCTGGCGAT-, TCGTGCTGGCGAT-, CGTGCTGGCGAT-, GTGCTGGCGAT-, TGCTGGCGAT-, GCTGGCGAT-, CTGGCGAT-, TGGCGAT-, GGCGAT-, GCGAT-, CGAT-, GAT-, AT-, or T-;

[0081] N 4 represents: -ACAGGACGATGTGCAGCGGC, -ACAGGACGATGTGCAGCGG, -ACAGGACGATGTGCAGCG, -ACAGGACGATGTGCAGC, -ACAGGACGATGTGCAG, -ACAGGACGATGTGCA, -ACAGGACGATGTGC, -ACAGGACGATGTG, -ACAGGACGATGT, -ACAGGACGATG, -ACAGGACGAT, -ACAGGACGA, -ACAGGACG, -ACAGGAC, -ACAGGA, -ACAGG, -ACAG, -ACA, -AC, or -A;

[0082] N 5Represent: GCCCAGCCTGCCCCAGAAGAGCTA-, CCCAGCCTGCCCCAGAAGAGCTA-, CCAGCCTGCCCCAGAAGAGCTA-, CAGCCTGCCCCAGAAGAGCTA-, AGCCTGCCCCAGAAGAGCTA-, GCCTGCCCCAGAAGAGCTA-, CCTGCCCCAGAAGAGCTA-, CTGCCCCAGAAGAGCTA-, TGCCCCAGAAGAGCTA-, GCCCCAGAAGAGCTA-, CCCCAGAAGAGCTA-, CCCAGAAGAGCTA-, CCAGAAGAGCTA-, CAGAAGAGCTA-, AGAAGAGCTA-, GAAGAGCTA-, AAGAGCTA-, AGAGCTA-, GAGCTA-, AGCTA-, GCTA-, CTA-, TA-, or A-;

[0083] N 6 Represent: -TGTTTAGGGAGCCGTCTTCAGGAA, -TGTTTAGGGAGCCGTCTTCAGGA, -TGTTTAGGGAGCCGTCTTCAGG, -TGTTTAGGGAGCCGTCTTCAG, -TGTTTAGGGAGCCGTCTTCA, -TGTTTAGGGAGCCGTCTTC, -TGTTTAGGGAGCCGTCTT, -TGTTTAGGGAGCCGTCT, -TGTTTAGGGAGCCGTC, -TGTTTAGGGAGCCGT, -TGTTTAGGGAGCCG, -TGTTTAGGGAGCC, -TGTTTAGGGAGC, -TGTTTAGGGAG, -TGTTTAGGGA, -TGTTTAGGG, -TGTTTAGG, -TGTTTAG, -TGTTTA, -TGTTT, -TGTT, -TGT, -TG, or –T;

[0084] N 7Represent: TGAATCTTGAATATCTCATG-, GAATCTTGAATATCTCATG-, AATCTTGAATATCTCATG-, ATCTTGAATATCTCATG-, TCTTGAATATCTCATG-, CTTGAATATCTCATG-, TTGAATATCTCATG-, TGAATATCTCATG-, GAATATCTCATG-, AATATCTCATG-, ATATCTCATG-, TATCTCATG-, ATCTCATG-, TCTCATG-, CTCATG-, TCATG-, CATG-, ATG-, TG-, or G-;

[0085] N 8 Represent: -AGTATTCTAGAAACTCACCA, -AGTATTCTAGAAACTCAC C, -AGTATTCTAGAAACTCAC, -AGTATTCTAGAAACTCA, -AGTATTCTAGAAACTC, -AGTATTCTAGAAACT, -AGTATTCTAGAA AC, -AGTATTCTAGAAA, -AGTATTCTAGAA, -AGTATTCTAGA, -AGTATTCTAG, -AGTATTCTA, -AGTATTCT, -AGTATTC, -AGT ATT, -AGTAT, -AGTA, -AGT, -AG, or -A;

[0086] N 9 Represent: ATTCATATTTATATACAGGC-,

[0087] TTCATATTTATATACAGGC-, TCATATTTATATACAGGC-, CATATTTATATACAGGC-, ATATTTATATACAGGC-, TATTTATATACAGGC-, ATTTATATACAGGC-, TTTATATACAGGC-, TTATATACAGGC-, TATATACAGGC-, ATATACAGGC-, TATACAGGC-, ATACAGGC-, TACAGGC-, ACAGGC-, CAGGC-, AGGC-, GGC-, GC-, or C-;

[0088] N 10Represent: -AGTGCAAATGTTATTGGCTA, -AGTGCAAATGTTATTGGCT, -AGTGCAAATGTTATTGGC, -AGTGCAAATGTTATTGG, -AGTGCAAATGTTATTG, -AGTGCAAATGTTATT, -AGTGCAAATGTTAT, -AGTGCAAATGTTA, -AGTGCAAATGTT, -AGTGCAAATGT, -AGTGCAAATG, -AGTGCAAAT, -AGTGCAAA, -AGTGCAA, -AGTGCA, -AGTGC, -AGTG, -AGT, -AG, or -A;

[0089] N 11 Represent: TGCCCCAGAAGAGCTATTTGGTAG-, GCCCCAGAAGAGCTATTTGGTAG-, CCCCAGAAGAGCTATTTGGTAG-, CCCAGAAGAGCTATTTGGTAG-, CCAGAAGAGCTATTTGGTAG-, CAGAAGAGCTATTTGGTAG-, AGAAGAGCTATTTGGTAG-, GAAGAGCTATTTGGTAG-, AAGAGCTATTTGGTAG-, AGAGCTATTTGGTAG-, GAGCTATTTGGTAG-, AGCTATTTGGTAG-, GCTATTTGGTAG-, CTATTTGGTAG-, TATTTGGTAG-, ATTTGGTAG-, TTTGGTAG-, TTGGTAG-, TGGTAG-, GGTAG-, GTAG-, TAG-, AG- or G-

[0090] N 12Represented by: -GAGCCGTCTTCAGGAATCTTCTCC, -GAGCCGTCTTCAGGAATCTTCTC, -GAGCCGTCTTCAGGAATCTTCT, -GAGCCGTCTTCAGGAATCTTC, -GAGCCGTCTTCAGGAATCTT, -GAGCCGTCTTCAGGAATCT, -GAGCCGTCTTCAGGAATC, -GAGCCGTCTTCAGGAAT, -GAGCCGTCTTCAGGAA, -GAGCCGTCTTCAGGA, -GAGCCGTCTTCAGG, -GAGCCGTCTTCAG, -GAGCCGTCTTCA, -GAGCCGTCTTC, -GAGCCGTCTT, -GAGCCGTCT, -GAGCCGTC, -GAGCCGT, -GAGCCG, -GAGCC, -GAGC, -GAG, -GA, or –G.

[0091] Accordingly, the present invention relates to an antisense oligonucleotide consisting of 10 to 28 nucleotides, and salts and optical isomers of said antisense oligonucleotide, and at least two of the 10 to 28 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing with a region of a gene encoding TGF-R II or a region of an mRNA encoding TGF-R II wherein said antisense oligonucleotide is represented by the following sequence 5'-N 1 -GTCATAGA-N 2 -3' (Seq.ID No.12) or 5'-N 3 -ACGCGTCC-N 4 -3' (Seq.IDNo.98) or 5'-N 11 -TGTTTAGG-N 12 -3' (Seq.ID No.10) or 5'-N 5 -TTTGGTAG-N 6 -3' (Seq.IDNo.11) or 5'-N 7 -AATGGACC-N 8 -3' (Seq.ID No.100) or 5'-N 9 -ATTAATAA-N 10 -3' (Seq.IDNo.101), wherein the residues N 1 to N 12 have the specifically defined meanings as disclosed herein.

[0092] Furthermore, the present invention relates to an antisense oligonucleotide consisting of 10 to 28 nucleotides, and salts and optical isomers of the antisense oligonucleotide, and at least two of the 10 to 28 nucleotides are LNAs, and the antisense oligonucleotide is capable of hybridizing with a region of a gene encoding TGF-R II or a region of an mRNA encoding TGF-R II wherein the antisense oligonucleotide is represented by the following sequence 5'-N 1 -GTCATAGA-N 2 -3'(Seq.ID No.12), wherein

[0093] N 1 represents: CATGGCAGACCCCGCTGCTC-, ATGGCAGACCCCGCTGCTC-,TGGCAGACCCCGCTGCTC-, GGCAGACCCCGCTGCTC-,GCAGACCCCGCTGCTC-, CAGACCCCGCTGCTC-,AGACCCCGCTGCTC-,GACCCCGCTGCTC-,ACCCCGCTGCTC-,CCCCGCTGCTC-, CCCGCTGCTC-,CCGCTGCTC-,CGCTGCTC-,GCTGCTC-, CTGCTC-,TGCTC-,GCTC-,CTC-,TC-, or C-;

[0094] N 2 represents: -C,-CC,-CCG,-CCGA,-CCGAG,-CCGAGC,-CCGAGCC,-CC GAGCCC,-CCGAGCCCC,-CCGAGCCCCC,-CCGAGCCCCCA,- CCGAGCCCCCAG,-CCGAGCCCCCAGC,-CCGAGCCCCCAGCG,-CCGAGCCCCCAGCGC,-CCGAGCCCCCAGCGCA,-CCGAGC CCCCAGCGCAG,-CCGAGCCCCCAGCGCAGC,-CCGAGCCCCC AGCGCAGCG, or –CCGAGCCCCCAGCGCAGCGG.

[0095] The antisense oligonucleotides of formula S1 (Seq.ID No.12) preferably contain 2 to 10 LNA units, more preferably 3 to 9 LNA units, still more preferably 4 to 8 LNA units, and also preferably contain at least 6 non-LNA units, more preferably at least 7 non-LNA units, and most preferably at least 8 non-LNA units. The non-LNA units are preferably DNA units. The LNA units are preferably located at the 3'-end (also referred to as the 3’-end) and the 5'-end (also referred to as the 5’-end). Preferably, there are at least one or more, more preferably at least two LNA units at the 3'-end and / or 5'-end.

[0096] Therefore, it is preferred that the antisense oligonucleotides of the present invention are designed as GAPmers containing 2 to 10 LNA units, and in particular contain 1 to 5 LNA units at the 5'-end of the antisense oligonucleotide, and 1 to 5 LNA units at the 3'-end of the antisense oligonucleotide, and contain at least 7, more preferably at least 8 DNA units between the LNA units. More preferably, the antisense oligonucleotide contains 2 to 4 LNA units at the 5'-end, 2 to 4 LNA units at the 3'-end, still more preferably contains 3 to 4 LNA units at the 5'-end and 3 to 4 LNA units at the 3'-end, and preferably contains at least 7 non-LNA units, most preferably at least 8 non-LNA units, such as DNA units between two LNA segments.

[0097] In addition, the antisense oligonucleotides may contain common nucleobases, such as adenine, guanine, cytosine, thymine and uracil, and their common derivatives, such as 5-methylcytosine or 2-aminoadenine. The antisense oligonucleotides of the present invention may also contain modified internucleotide bridges, such as phosphorothioate or dithiophosphonate instead of the phosphate ester bridge. Such modifications may exist only in the LNA segment of the antisense oligonucleotide, or only in the non-LNA segment of the antisense oligonucleotide. The LNA units are in particular residues b 1 to b 9 are preferred.

[0098] Therefore, preferred are the antisense oligonucleotides of formula (S1):

[0099] 5’-N 1 -GTCATAGA-N 2 -3’(Seq.ID No.12)

[0100] wherein

[0101] N 1Represented by: CATGGCAGACCCCGCTGCTC-, ATGGCAGACCCCGCTGCTC-, TGGCAGACCCCGCTGCTC-, GGCAGACCCCGCTGCTC-, GCAGACCCCGCTGCTC-, CAGACCCCGCTGCTC-, AGACCCCGCTGCTC-, GACCCCGCTGCTC-, ACCCCGCTGCTC-, CCCCGCTGCTC-, CCCGCTGCTC-, CCGCTGCTC-, CGCTGCTC-, GCTGCTC-, CTGCTC-, TGCTC-, GCTC-, CTC-, TC-, or C-;

[0102] and

[0103] N 2 Selected from: -C, -CC, -CCG, -CCGA, -CCGAG, -CCGAGC, -CCGAGCC, -CCGAGCCC, -CCGAGCCCC, -CCGAGCCCCC, -CCGAGCCCCCA, -CCGAGCCCCCAG, -CCGAGCCCCCAGC, -CCGAGCCCCCAGCG, -CCGAGCCCCCAGCGC, -CCGAGCCCCCAGCGCA, -CCGAGCCCCCAGCGCAG, -CCGAGCCCCCAGCGCAGC, -CCGAGCCCCCAGCGCAGCG, or -CCGAGCCCCCAGCGCAGCGG.

[0104] Preferably, the antisense oligonucleotide of general formula (S1) has 10 to 28 nucleotides and has at least 1 LNA nucleotide at the 3'-end and at least 1 LNA nucleotide at the 5'-end. The LNA nucleotides (LNA units), in particular those disclosed in the "Locked Nucleic Acids" " and "Preferred LNA" sections are suitable, and the nucleotide bridges, in particular those disclosed in the "Inter-Nucleotide Linkages (IL)" section are suitable.

[0105] More preferably, the antisense oligonucleotide of general formula (S1) has 11 - 24 nucleotides and has at least two LNA nucleotides at the 3'-end and at least two LNA nucleotides at the 5'-end.

[0106] Still more preferably, the antisense oligonucleotide of formula (S1) has 12 to 20, more preferably 13 to 19, even more preferably 14 to 18 nucleotides, and has 2 to 5, preferably 3 to 5, more preferably 3 to 4 LNA units at the 3'-end and 2 to 5, preferably 3 and 5, more preferably 3 to 4 LNA units at the 5'-end. Preferably, the antisense oligonucleotide is a GAPmer in the form of LNA segment - DNA segment - LNA segment B. Preferably, the antisense oligonucleotide contains at least 6, more preferably at least 7, most preferably at least 8 non-LNA units, such as DNA units between two LNA segments. The nucleobases applicable to non-LNA units and LNA units are disclosed in the "Nucleobases" section.

[0107] Also preferred is the antisense oligonucleotide of formula (S1):

[0108] 5’-N 1 -GTCATAGA-N 2 -3’

[0109] wherein

[0110] N 1 represents: TGGCAGACCCCGCTGCTC-, GGCAGACCCCGCTGCTC-, GCAGACCCCGCTGCTC-, CAGACCCCGCTGCTC-, AGACCCCGCTGCTC-, GACCCCGCTGCTC-, ACCCCGCTGCTC-, CCCCGCTGCTC-, CCCGCTGCTC-, CCGCTGCTC-, CGCTGCTC-, GCTGCTC-, CTGCTC-, TGCTC-, GCTC-, CTC-, TC-, or C-;

[0111] and

[0112] N 2 is selected from: -C, -CC, -CCG, -CCGA, -CCGAG, -CCGAGC, -CCGAGCC, -CCGAGCCC, -CCGAGCCCC, -CCGAGCCCCC, -CCGAGCCCCCA, -CCGAGCCCCCAG, -CCGAGCCCCCAGC, -CCGAGCCCCCAGCG, -CCGAGCCCCCAGCGC, -CCGAGCCCCCAGCGCA, -CCGAGCCCCAGCGCAG, or -CCGAGCCCCCAGCGCAGC.

[0113] Also preferred is the antisense oligonucleotide of formula (S1):

[0114] 5’-N 1 -GTCATAGA-N 2 -3’

[0115] wherein

[0116] N 1 represents: GACCCCGCTGCTC-, ACCCCCGCTGCTC-, CCCCGCTGCTC-, CCCGCTGCTC-, CCGCTGCTC-, CGCTGCTC-, GCTGCTC-, CTGCTC-, TGCTC-, GCTC-, CTC-, TC-, or C-;

[0117] and

[0118] N 2 is selected from: -C, -CC, -CCG, -CCGA, -CCGAG, -CCGAGC, -CCGAGCC, -CCGAGCCC, -CCGAGCCCC, -CCGAGCCCCC, -CCGAGCCCCCA, -CCGAGCCCCCAG, or -CCGAGCCCCCAGC.

[0119] Also preferred is an antisense oligonucleotide of formula (S1):

[0120] 5’-N 1 -GTCATAGA-N 2 -3’

[0121] wherein

[0122] N 1 represents: CGCTGCTC-, GCTGCTC-, CTGCTC-, TGCTC-, GCTC-, CTC-, TC-, or C-;

[0123] and

[0124] N 2 is selected from: -C, -CC, -CCG, -CCGA, -CCGAG, -CCGAGC, -CCGAGCC, or -CCGAGCCC.

[0125] Preferably, the present invention relates to antisense oligonucleotides composed of 12 to 24 nucleotides, and salts and optical isomers of said antisense oligonucleotides, and at least 3 of the 12 to 24 nucleotides are LNA, and the antisense oligonucleotides are capable of hybridizing to a region of a gene encoding TGF-R II or to a region of an mRNA encoding TGF-R II wherein said antisense oligonucleotides have the following sequence 5’-N 1A-CGTCATAGAC-N 2A -3’ (Seq.ID No.69) indicates that, where

[0126] N 1A indicates: CATGGCAGACCCCGCTGCT-, ATGGCAGACCCCGCTGCT-, TGGCAGACCCCGCTGCT-, GGCAGACCCCGCTGCT-, GCAGACCCCGCTGCT-, CAGACCCCGCTGCT-, AGACCCCGCTGCT-, GACCCCGCTGCT-, ACCCCGCTGCT-, CCCGCTGCT-, CCGCTGCT-, CGCTGCT-, GCTGCT-, CTGCT-, TGCT-, GCT-, CT-, or T-;

[0127] N 2A indicates: -C, -CG, -CGA, -CGAG, -CGAGC, -CGAGCC, -CGAGCCC, -CGAGCCCC, -CGAGCCCCC, -CGAGCCCCCAG, -CGAGCCCCCAGC, -CGAGCCCCCAGCG, -CGAGCCCCCAGCGC, -CGAGCCCCCAGCGCA, -CGAGCCCCCAGCGCAG, -CGAGCCCCCAGCGCAGC, -CGAGCCCCCAGCGCAGCG, or –CGAGCCCCCAGCGCAGCGG.

[0128] Preferably N 1A indicates: TGGCAGACCCCGCTGCT-, GGCAGACCCCGCTGCT-, GCAGACCCCGCTGCT-, CAGACCCCGCTGCT-, AGACCCCGCTGCT-, GACCCCGCTGCT-, ACCCCGCTGCT-, CCCGCTGCT-, CCGCTGCT-, CGCTGCT-, GCTGCT-, CTGCT-, TGCT-, GCT-, CT-, or T-;

[0129] and

[0130] N 2ARepresent: -C, -CG, -CGA, -CGAG, -CGAGC, -CGAGCC, -CGAGCCC, -CGAGCCCC, -CGAGCCCCC, -CGAGCCCCCA, -CGAGCCCCCAG, -CGAGCCCCCAGC, -CGAGCCCCCAGCG, -CGAGCCCCCAGCGC, -CGAGCCCCCAGCGCA, -CGAGCCCCCAGCGCAG, or -CGAGCCCCCAGCGCAGC.

[0131] More preferably N 1A Represent: GACCCCGCTGCT-, ACCCCGCTGCT-, CCCCGCTGCT-, CCCGCTGCT-, CCGCTGCT-, CGCTGCT-, GCTGCT-, CTGCT-, TGCT-, GCT-, CT-, or T-; and

[0132] N 2A Represent: -C, -CG, -CGA, -CGAG, -CGAGC, -CGAGCC, -CGAGCCC, -CGAGCCCC, -CGAGCCCCC, -CGAGCCCCCA, -CGAGCCCCCAG, or -CGAGCCCCCAGC.

[0133] More preferably N 1A Represent: CGCTGCT-, GCTGCT-, CTGCT-, TGCT-, GCT-, CT-, or T-; and

[0134] N 2A Represent: -C, -CG, -CGA, -CGAG, -CGAGC, -CGAGCC, or -CGAGCCC.

[0135] Preferably, the antisense oligonucleotide of the general formula (S1A / Seq.ID No.69) has 12 to 24 nucleotides and has at least 1 LNA nucleotide at the 3'-end and at least 1 LNA nucleotide at the 5'-end. The LNA nucleotides (LNA units), in particular the LNA nucleotides (LNA units) disclosed in the "Locked Nucleic Acid" and "Preferred LNA" sections, are suitable, and the nucleotide bridges, in particular those disclosed in the "Inter-Nucleotide Linkage (IL)" section, are suitable. " and the LNA nucleotides (LNA units) disclosed in the "Preferred LNA" section are suitable, and the nucleotide bridges, in particular those disclosed in the "Inter-Nucleotide Linkage (IL)" section, are suitable.

[0136] More preferably, the antisense oligonucleotide of the general formula (S1A) has 12 to 22 nucleotides and has at least 2 LNA nucleotides at the 3'-end and at least two LNA nucleotides at the 5'-end.

[0137] Still more preferably, the antisense oligonucleotide of formula (S1A) has 12 to 20, more preferably 13 to 19, still more preferably 14 to 18 nucleotides, and has 2 to 5, preferably 3 to 5, still more preferably 3 to 4 LNA units at the 3'-end and 2 to 5, preferably 3 and 5, still more preferably 3 to 4 LNA units at the 5'-end. Preferably, the antisense oligonucleotide is a GAPmer in the form of an LNA segment - A-DNA segment - LNA segment B. Preferably, the antisense oligonucleotide contains at least 6, more preferably at least 7, most preferably at least 8 non-LNA units, such as DNA units between two LNA segments. The nucleobases applicable to non-LNA units and LNA units are disclosed in the "Nucleobases" section.

[0138] In addition, the present invention relates to an antisense oligonucleotide composed of 10 to 28 nucleotides, and salts and optical isomers of the antisense oligonucleotide, and at least two of the 10 to 28 nucleotides are LNA, and the antisense oligonucleotide can hybridize with a region of the gene encoding TGF-R II or a region of the mRNA encoding TGF-R II and is represented by the following sequence 5'-N 3 -ACGCGTCC-N 4 -3' (SEQ ID NO:98), where

[0139] N 3 represents: GGTGGGATCGTGCTGGCGAT-, GTGGGATCGTGCTGGCGAT-, TGGGATCGTGCTGGCGAT-, GGGATCGTGCTGGCGAT-, GGATCGTGCTGGCGAT-, GATCGTGCTGGCGAT-, ATCGTGCTGGCGAT-, TCGTGCTGGCGAT-, CGTGCTGGCGAT-, GTGCTGGCGAT-, TGCTGGCGAT-, GCTGGCGAT-, CTGGCGAT-, TGGCGAT-, GGCGAT-, GCGAT-, CGAT-, GAT-, AT-, or T-;

[0140] N 4Represent: -ACAGGACGATGTGCAGCGGC, -ACAGGACGATGTGCAGCGG, -ACAGGACGATGTGCAGCG, -ACAGGACGATGTGCAGC, -ACAGGACGATGTGCAG, -ACAGGACGATGTGCA, -ACAGGACGATGTGC, -ACAGGACGATGTG, -ACAGGACGATGT, -ACAGGACGATG, -ACAGGACGAT, -ACAGGACGA, -ACAGGACG, -ACAGGAC, -ACAGGA, -ACAGG, -ACAG, -ACA, -AC, or -A.

[0141] The antisense oligonucleotides of formula S2 (Seq.ID No.98) preferably contain 2 to 10 LNA units, more preferably 3 to 9 LNA units, even more preferably 4 to 8 LNA units, and also preferably contain at least 6 non-LNA units, more preferably at least 7 non-LNA units, and most preferably at least 8 non-LNA units. The non-LNA units are preferably DNA units. The LNA units are preferably located at the 3'-end (also referred to as the 3’-end) and the 5'-end (also referred to as the 5’-end). Preferably, there is at least one, more preferably at least two LNA units at the 3'-end and / or 5'-end.

[0142] Thus, the antisense oligonucleotides of the present invention are preferably designed as GAPmers containing 2 to 10 LNA units, and in particular contain 1 to 5 LNA units at the 5'-end of the antisense oligonucleotide, and 1 to 5 LNA units at the 3'-end of the antisense oligonucleotide, and contain at least 7, more preferably at least 8 DNA units between the LNA units. More preferably, the antisense oligonucleotide contains 2 to 4 LNA units at the 5'-end, 2 to 4 LNA units at the 3'-end, even more preferably contains 3 to 4 LNA units at the 5'-end and 3 to 4 LNA units at the 3'-end, and preferably contains at least 7 non-LNA units, most preferably at least 8 non-LNA units, such as DNA units between two LNA segments.

[0143] In addition, the antisense oligonucleotides can contain common nucleobases, such as adenine, guanine, cytosine, thymine and uracil, and their common derivatives, such as 5-methylcytosine or 2-aminoadenine. The antisense oligonucleotides of the present invention can also contain modified internucleotide bridges, such as phosphorothioates or dithiophosphates to replace the phosphate ester bridge. Such modifications can exist only in the LNA segments of the antisense oligonucleotide, or only in the non-LNA segments of the antisense oligonucleotide. The LNA units are in particular the residues b 1 to b9 is preferred.

[0144] Therefore, preferred is the antisense oligonucleotide of formula (S2):

[0145] 5'-N 3 -ACGCGTCC-N 4 -3’ (Seq.ID No.98)

[0146] wherein

[0147] N 3 represents: GGTGGGATCGTGCTGGCGAT-, GTGGGATCGTGCTGGCGAT-, TGGGATCGTGCTGGCGAT-, GGGATCGTGCTGGCGAT-, GGATCGTGCTGGCGAT-, GATCGTGCTGGCGAT-, ATCGTGCTGGCGAT-, TCGTGCTGGCGAT-, CGTGCTGGCGAT-, GTGCTGGCGAT-, TGCTGGCGAT-, GCTGGCGAT-, CTGGCGAT-, TGGCGAT-, GGCGAT-, GCGAT-, CGAT-, GAT-, AT-, or T-;

[0148] and

[0149] N 4 represents: -ACAGGACGATGTGCAGCGGC, -ACAGGACGATGTGCAGCGG, -ACAGGACGATGTGCAGCG, -ACAGGACGATGTGCAGC, -ACAGGACGATGTGCAG, -ACAGGACGATGTGCA, -ACAGGACGATGTGC, -ACAGGACGATGTG, -ACAGGACGATGT, -ACAGGACGATG, -ACAGGACGAT, -ACAGGACGA, -ACAGGACG, -ACAGGAC, -ACAGGA, -ACAGG, -ACAG, -ACA, -AC, or –A.

[0150] Preferably, the antisense oligonucleotide of general formula (S2) has 10 to 28 nucleotides and has at least 1 LNA nucleotide at the 3'-end and at least 1 LNA nucleotide at the 5'-end. LNA nucleotides (LNA units), in particular those disclosed in the "Locked nucleic acid" " and "Preferred LNA" sections are suitable, and nucleotide bridges, in particular those disclosed in the "Inter-nucleotide linkage (IL)" section are suitable.

[0151] More preferably, the antisense oligonucleotide of formula (S2) has 11-24 nucleotides and has at least two LNA nucleotides at the 3'-end and at least two LNA nucleotides at the 5'-end.

[0152] Even more preferably, the antisense oligonucleotide of formula (S2) has 12 to 20, more preferably 13 to 19, even more preferably 14 to 18 nucleotides, and has 2 to 5, preferably 3 to 5, more preferably 3 to 4 LNA units at the 3'-end and 2 to 5, preferably 3 to 5, more preferably 3 to 4 LNA units at the 5'-end. Preferably, the antisense oligonucleotide is a GAPmer in the form of an LNA segment - DNA segment - LNA segment B. Preferably, the antisense oligonucleotide contains at least 6, more preferably at least 7, most preferably at least 8 non-LNA units, such as DNA units between two LNA segments. The nucleobases applicable to non-LNA units and LNA units are disclosed in the "Nucleobases" section.

[0153] Also preferred is the antisense oligonucleotide of formula (S2):

[0154] 5’-N 3 -ACGCGTCC-N 4 -3’

[0155] where

[0156] N 3 represents: TGGGATCGTGCTGGCGAT-, GGGATCGTGCTGGCGAT-, GGATCGTGCTGGCGAT-, GATCGTGCTGGCGAT-, ATCGTGCTGGCGAT-, TCGTGCTGGCGAT-, CGTGCTGGCGAT-, GTGCTGGCGAT-, TGCTGGCGAT-, GCTGGCGAT-, CTGGCGAT-, TGGCGAT-, GGCGAT-, GCGAT-, CGAT-, GAT-, AT-, or T-;

[0157] and

[0158] N 4Represent: -ACAGGACGATGTGCAGCG, -ACAGGACGATGTGCAGC, -A CAGGACGATGTGCAG, -ACAGGACGATGTGCA, -ACAGGACGATGTGC, -ACAGGACGATGTG, -ACAGGACGATGT, -ACAGGACG ATG, -ACAGGACGAT, -ACAGGACGA, -ACAGGACG, -ACAGGA C, -ACAGGA, -ACAGG, -ACAG, -ACA, -AC, or –A.

[0159] Also preferred are antisense oligonucleotides of formula (S2):

[0160] 5’-N 3 -ACGCGTCC-N 4 -3’

[0161] wherein

[0162] N 3 represents: TCGTGCTGGCGAT-, CGTGCTGGCGAT-, GTGCTGGCGAT-, TGCTGGCGAT-, GCTGGCGAT-, CTGGCGAT-, TGGCGAT-, GGCGAT-, GCGAT-, CGAT-, GAT-, AT-, or T-;

[0163] and

[0164] N 4 represents: -ACAGGACGATGTG, -ACAGGACGATGT, -ACAGGACGATG, -ACAGGACGAT, -ACAGGACGA, -ACAGGACG, -ACAGGAC, -ACAGGA, -ACAGG, -ACAG, -ACA, -AC, or –A.

[0165] Also preferred are antisense oligonucleotides of formula (S2):

[0166] 5’-N 3 -ACGCGTCC-N 4 -3’

[0167] wherein

[0168] N 3 represents: CTGGCGAT-, TGGCGAT-, GGCGAT-, GCGAT-, CGAT-, GAT-, AT-, or T-;

[0169] and

[0170] N 4 represents: -ACAGGACG, -ACAGGAC, -ACAGGA, -ACAGG, -ACAG, -ACA, -AC, or –A.

[0171] Preferably, the present invention relates to antisense oligonucleotides consisting of 12 to 24 nucleotides, as well as salts and optical isomers of said antisense oligonucleotides, and at least 3 of the 12 to 24 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing with a region of the gene encoding TGF-R II or a region of the mRNA encoding TGF-R II and is represented by the following sequence 5'-N 3A -TACGCGTCCA-N 4A -3' (Seq.ID No.70), where

[0172] N 3A represents: GGTGGGATCGTGCTGGCGA-, GTGGGATCGTGCTGGCGA-, TGGGATCGTGCTGGCGA-, GGGATCGTGCTGGCGA-, GGATCGTGCTGGCGA-, GATCGTGCTGGCGA-, ATCGTGCTGGCGA-, TCGTGCTGGCGA-, CGTGCTGGCGA-, GTGCTGGCGA-, TGCTGGCGA-, GCTGGCGA-, CTGGCGA-, TGGCGA-, GGCGA-, GCGA-, CGA-, GA-, or A-;

[0173] N 4A represents: -CAGGACGATGTGCAGCGGC, -CAGGACGATGTGCAGCGG, -CAGGACGATGTGCAGCG, -CAGGACGATGTGCAGC, -CAGGACGATGTGCAG, -CAGGACGATGTGCA, -CAGGACGATGTGC, -CAGGACGATGTG, -CAGGACGATGT, -CAGGACGATG, -CAGGACGAT, -CAGGACGA, -CAGGACG, -CAGGAC, -CAGGA, -CAGG, -CAG, -CA, or -C.

[0174] Preferably N 3ARepresent: TGGGATCGTGCTGGCGA-, GGGATCGTGCTGGCGA-, GGATCGTGCTGGCGA-, GATCGTGCTGGCGA-, ATCGTGCTGGCGA-, TCGTGCTGGCGA-, CGTGCTGGCGA-, GTGCTGGCGA-, TGCTGGCGA-, GCTGGCGA-, CTGGCGA-, TGGCGA-, GGCGA-, GCGA-, CGA-, GA-, or A-;

[0175] and

[0176] N 4A Represent: -CAGGACGATGTGCAGCG, -CAGGACGATGTGCAGC, -CAGGACGATGTGCAG, -CAGGACGATGTGCA, -CAGGACGATGTGC, -CAGGACGATGTG, -CAGGACGATGT, -CAGGACGATG, -CAGGACGAT, -CAGGACGA, -CAGGACG, -CAGGAC, -CAGGA, -CAGG, -CAG, -CA, or -C.

[0177] More preferably N 3A Represent: TCGTGCTGGCGA-, CGTGCTGGCGA-, GTGCTGGCGA-, TGCTGGCGA-, GCTGGCGA-, CTGGCGA-, TGGCGA-, GGCGA-, GCGA-, CGA-, GA-, or A-; and

[0178] N 4A Represent: -CAGGACGATGTG, -CAGGACGATGT, -CAGGACGATG, -CAGGACGAT, -CAGGACGA, -CAGGACG, -CAGGAC, -CAGGA, -CAGG, -CAG, -CA, or -C.

[0179] More preferably N 3A Represent: CTGGCGA-, TGGCGA-, GGCGA-, GCGA-, CGA-, GA-, or A-; and

[0180] N 4A Represent: -CAGGACG, -CAGGAC, -CAGGA, -CAGG, -CAG, -CA, or -C.

[0181] Preferably, the antisense oligonucleotide of general formula (S2A / Seq.ID No.70) has 2 to 4 nucleotides and has at least 1 LNA nucleotide at the 3'-end and at least 1 LNA nucleotide at the 5'-end. LNA nucleotides (LNA units), in particular those disclosed in the “Locked nucleic acid” ” and “Preferred LNA” sections are suitable, and nucleotide bridges, in particular those disclosed in the “Inter-nucleotide linkage (IL)” section are suitable.

[0182] More preferably, the antisense oligonucleotide of general formula (S2A) has 12 to 22 nucleotides and has at least two LNA nucleotides at the 3'-end and at least two LNA nucleotides at the 5'-end.

[0183] Even more preferably, the antisense oligonucleotide of general formula (S2A) has 12 to 20, more preferably 13 to 19, more preferably 14 to 18 nucleotides, and has 2 to 5, preferably 3 to 5, more preferably 3 to 4 LNA units at the 3'-end and 2 to 5, preferably 3 to 5, more preferably 3 to 4 LNA units at the 5'-end. Preferably, the antisense oligonucleotide is a GAPmer in the form of an LNA segment - DNA segment - LNA segment B. Preferably, the antisense oligonucleotide contains at least 6, more preferably at least 7, most preferably at least 8 non-LNA units, such as DNA units between two LNA segments. The nucleobases applicable to non-LNA units and LNA units are disclosed in the “Nucleobase” section.

[0184] Furthermore, the present invention relates to antisense oligonucleotides composed of 10 to 28 nucleotides, and salts and optical isomers of said antisense oligonucleotides, and at least two of the 10 to 28 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing with a region of the gene encoding TGF-R II or a region of the mRNA encoding TGF-R II wherein the antisense oligonucleotide is represented by the following sequence 5'-N 11 -TGTTTAGG-N 12 -3’ (Seq.ID No.10), wherein:

[0185] N 11Represented by: TGCCCCAGAAGAGCTATTTGGTAG-, GCCCCAGAAGAGCTATTTGGTAG-,CCCCAGAAGAGCTATTTGGTAG-, CCCAGAAGAGCTATTTGGTAG-,CCAGAAGAGCTATTTGGTAG-,CAGAAGAGCTATTTGGTAG-, AGAAGAGCTATTTGGTAG-,GAAGAGCTATTTGGTAG-,AAGAGCTATTTGGTAG-,AGAGCTATTTGGTAG-,GAGCTATTTGGTAG-,AGCTATTTGGTAG-,GCTATTTGGTAG-, CTATTTGGTAG-,TATTTGGTAG-,ATTTGGTAG-,TTTGGTAG-,TTGGTAG-,TGGTAG-,GGTAG-,GTAG-,TAG-,AG- or G-

[0186] N 12 Represented by: -GAGCCGTCTTCAGGAATCTTCTCC,

[0187] -GAGCCGTCTTCAGGAATCTTCTC, -GAGCCGTCTTCAGGAATCTTCT, -GAGCCGTCTTCAGGAATCTTC,-GAGCCGTCTTCAGGAATCTT,-GAGCCGTCTTCAGGAATCT, -GAGCCGTCTTCAGGAATC,-GAGCCGTCTTCAGGAAT, -GAGCCGTCTTCAGGAA,-GAGCCGTCTTCAGGA,-GAGCCGTCTTCAGG,-GAGCCGTCTTCAG,-GAGCCGTCTTCA, -GAGCCGTCTTC,-GAGCCGTCTT,-GAGCCGTCT, -GAGCCGTC,-GAGCCGT,-GAGCCG,-GAGCC,-GAGC,-GAG,-GA, or –G.

[0188] The antisense oligonucleotides of formula S3 (Seq.ID No.10) preferably comprise 2 to 10 LNA units, more preferably 3 to 9 LNA units, still more preferably 4 to 8 LNA units, and also preferably comprise at least 6 non-LNA units, more preferably at least 7 non-LNA units, and most preferably at least 8 non-LNA units. The non-LNA units are preferably DNA units. The LNA units are preferably located at the 3'-end (also referred to as the 3’-end) and the 5'-end (also referred to as the 5’-end). Preferably, there is at least one, more preferably at least two LNA units at the 3'-end and / or 5'-end.

[0189] Therefore, it is preferred that the antisense oligonucleotides of the present invention are designed as GAPmers containing 2 to 10 LNA units, and particularly contain 1 to 5 LNA units at the 5'-end of the antisense oligonucleotide, and 1 to 5 LNA units at the 3'-end of the antisense oligonucleotide, and contain at least 7, more preferably at least 8 DNA units between the LNA units. More preferably, the antisense oligonucleotide contains 2 to 4 LNA units at the 5'-end, 2 to 4 LNA units at the 3'-end, still more preferably contains 3 to 4 LNA units at the 5'-end and 3 to 4 LNA units at the 3'-end, and preferably contains at least 7 non-LNA units, most preferably at least 8 non-LNA units, such as DNA units between two LNA segments.

[0190] In addition, the antisense oligonucleotides may contain common nucleobases, such as adenine, guanine, cytosine, thymine and uracil, and their common derivatives, such as 5-methylcytosine or 2-aminoadenine. The antisense oligonucleotides of the present invention may also contain modified internucleotide bridges, such as phosphorothioates or dithiophosphates instead of phosphate bridges. Such modifications may be present only in the LNA segments of the antisense oligonucleotide, or only in the non-LNA segments of the antisense oligonucleotide. The LNA units are particularly residues b 1 to b 9 are preferred.

[0191] Therefore, preferred are the antisense oligonucleotides of formula (S3):

[0192] 5’-N 11 -TGTTTAGG-N 12 -3’(Seq.ID No.10)

[0193] wherein

[0194] N 11Represent: TGCCCCAGAAGAGCTATTTGGTAG-, GCCCCAGAAGAGCTATTTGGTAG-,CCCCAGAAGAGCTATTTGGTAG-, CCCAGAAGAGCTATTTGGTAG-,CCAGAAGAGCTATTTGGTAG-,CAGAAGAGCTATTTGGTAG-, AGAAGAGCTATTTGGTAG-,GAAGAGCTATTTGGTAG-,AAGAGCTATTTGGTAG-,AGAGCTATTTGGTAG-,GAGCTATTTGGTAG-,AGCTATTTGGTAG-,GCTATTTGGTAG-, CTATTTGGTAG-,TATTTGGTAG-,ATTTGGTAG-,TTTGGTAG-,TTGGTAG-,TGGTAG-,GGTAG-,GTAG-,TAG-,AG- or G-, and

[0195] N 12 Represent: -GAGCCGTCTTCAGGAATCTTCTCC,

[0196] -GAGCCGTCTTCAGGAATCTTCTC, -GAGCCGTCTTCAGGAATCTTCT, -GAGCCGTCTTCAGGAATCTTC,-GAGCCGTCTTCAGGAATCTT,-GAGCCGTCTTCAGGAATCT, -GAGCCGTCTTCAGGAATC,-GAGCCGTCTTCAGGAAT, -GAGCCGTCTTCAGGAA,-GAGCCGTCTTCAGGA,-GAGCCGTCTTCAGG,-GAGCCGTCTTCAG,-GAGCCGTCTTCA, -GAGCCGTCTTC,-GAGCCGTCTT,-GAGCCGTCT, -GAGCCGTC,-GAGCCGT,-GAGCCG,-GAGCC,-GAGC,-GAG,-GA, or –G。

[0197] Preferably, the antisense oligonucleotide of general formula (S3) has 10 to 28 nucleotides and has at least 1 LNA nucleotide at the 3'-end and at least 1 LNA nucleotide at the 5'-end. LNA nucleotides (LNA units), in particular those disclosed in the "Locked Nucleic Acid" " and "Preferred LNA" sections are suitable, and nucleotide bridges, in particular those disclosed in the "Inter-Nucleotide Linkage (IL)" section are suitable.

[0198] More preferably, the antisense oligonucleotides of formula (S3) have 11 - 24 nucleotides and have at least two LNA nucleotides at the 3'-end and at least two LNA nucleotides at the 5'-end.

[0199] Even more preferably, the antisense oligonucleotides of formula (S3) have 12 to 20, more preferably 13 to 19, more preferably 14 to 18 nucleotides, and have 2 to 5, preferably 3 to 5, more preferably 3 to 4 LNA units at the 3'-end and 2 to 5, preferably 3 to 5, more preferably 3 to 4 LNA units at the 5'-end. Preferably, the antisense oligonucleotide is a GAPmer in the form of LNA segment - DNA segment - LNA segment B. Preferably, the antisense oligonucleotide contains at least 6, more preferably at least 7, most preferably at least 8 non-LNA units, such as DNA units between two LNA segments. The nucleobases applicable to non-LNA units and LNA units are disclosed in the "Nucleobases" section.

[0200] Also preferred are the antisense oligonucleotides of formula (S3):

[0201] 5’-N 11 -TGTTTAGG-N 12 -3’

[0202] wherein

[0203] N 11 represents: AGAAGAGCTATTTGGTAG-, GAAGAGCTATTTGGTAG-, AAGAGCTATTTGGTAG-, AGAGCTATTTGGTAG-, GAGCTATTTGGTAG-, AGCTATTTGGTAG-, GCTATTTGGTAG-, CTATTTGGTAG-, TATTTGGTAG-, ATTTGGTAG-, TTTGGTAG-, TTGGTAG-, TGGTAG-, GGTAG-, GTAG-, TAG-, AG- or G-;

[0204] and

[0205] N 12Represented by: -GAGCCGTCTTCAGGAATC, -GAGCCGTCTTCAGGAAT, -GAGCCGTCTTCAGGAA, -GAGCCGTCTTCAGGA, -GAGCCGTCTTCAGG, -GAGCCGTCTTCAG, -GAGCCGTCTTCA, -GAGCCGTCTTC, -GAGCCGTCTT, -GAGCCGTCT, -GAGCCGTC, -GAGCCGT, -GAGCCG, -GAGCC, -GAGC, -GAG, -GA, or –G.

[0206] Also preferred are the antisense oligonucleotides of formula (S3):

[0207] 5’-N 11 -TGTTTAGG-N 12 -3’

[0208] wherein

[0209] N 11 represents: AGCTATTTGGTAG-, GCTATTTGGTAG-, CTATTTGGTAG-, TATTTGGTAG-, ATTTGGTAG-, TTTGGTAG-, TTGGTAG-, TGGTAG-, GGTAG-, GTAG-, TAG-, AG- or G-;

[0210] and

[0211] N 12 represents: -GAGCCGTCTTCAG, -GAGCCGTCTTCA, -GAGCCGTCTTC, -GAGCCGTCTT, -GAGCCGTCT, -GAGCCGTC, -GAGCCGT, -GAGCCG, -GAGCC, -GAGC, -GAG, -GA, or –G.

[0212] Also preferred are the antisense oligonucleotides of formula (S3):

[0213] 5’-N 11 -TGTTTAGG-N 12 -3’

[0214] wherein

[0215] N 11 represents: TTTGGTAG-, TTGGTAG-, TGGTAG-, GGTAG-, GTAG-, TAG-, AG- or G-; and

[0216] N 12Represented by: -GAGCCGTC, -GAGCCGT, -GAGCCG, -GAGCC, -GAGC, -GAG, -GA, or –G.

[0217] Preferably, the present invention relates to antisense oligonucleotides composed of 12 to 24 nucleotides, as well as salts and optical isomers of the antisense oligonucleotides, and at least 3 of the 12 to 24 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing with a region of the gene encoding TGF-R II or a region of the mRNA encoding TGF-R II and is represented by the following sequence 5'-N 11A -GTGTTTAGGG-N 12A -3' (Seq.ID No.71), where:

[0218] N 11A Represented by: TGCCCCAGAAGAGCTATTTGGTA-, GCCCCAGAAGAGCTATTTGGTA-, CCCCAGAAGAGCTATTTGGTA-, CCCAGAAGAGCTATTTGGTA-, CCAGAAGAGCTATTTGGTA-, CAGAAGAGCTATTTGGTA-, AGAAGAGCTATTTGGTA-, GAAGAGCTATTTGGTA-, AAGAGCTATTTGGTA-, AGAGCTATTTGGTA-, GAGCTATTTGGTA-, AGCTATTTGGTA-, GCTATTTGGTA-, CTATTTGGTA-, TATTTGGTA-, ATTTGGTA-, TTTGGTA-, TTGGTA-, TGGTA-, GGTA-, GTA-, TA-, or A-,

[0219] N 12A ​Represented by: -AGCCGTCTTCAGGAATCTTCTCC, -AGCCGTCTTCAGGAATCTTCTC, -AGCCGTCTTCAGGAATCTTCT, -AGCCGTCTTCAGGAATCTTC, -AGCCGTCTTCAGGAATCTT, -AGCCGTCTTCAGGAATCT, -AGCCGTCTTCAGGAATC, -AGCCGTCTTCAGGAAT, -AGCCGTCTTCAGGAA, -AGCCGTCTTCAGGA, -AGCCGTCTTCAGG, -AGCCGTCTTCAG, -AGCCGTCTTCA, -AGCCGTCTTC, -AGCCGTCTT, -AGCCGTCT, -AGCCGTC, -AGCCGT, -AGCCG, -AGCC, -AGC, -AG, or -A.

[0220] Preferably N 11A Represented by: AGAAGAGCTATTTGGTA-, GAAGAGCTATTTGGTA-, AAGAGCTATTTGGTA-, AGAGCTATTTGGTA-, GAGCTATTTGGTA-, AGCTATTTGGTA-, GCTATTTGGTA-, CTATTTGGTA-, TATTTGGTA-, ATTTGGTA-, TTTGGTA-, TTGGTA-, TGGTA-, GGTA-, GTA-, TA-, or A-; and

[0221] N 12A Represented by: -AGCCGTCTTCAGGAATC, -AGCCGTCTTCAGGAAT, -AGCCGTCTTCAGGAA, -AGCCGTCTTCAGGA, -AGCCGTCTTCAGG, -AGCCGTCTTCAG, -AGCCGTCTTCA, -AGCCGTCTTC, -AGCCGTCTT, -AGCCGTCT, -AGCCGTC, -AGCCGT, -AGCCG, -AGCC, -AGC, -AG, or -A.

[0222] More preferably N 11A Represented by: AGCTATTTGGTA-, GCTATTTGGTA-, CTATTTGGTA-, TATTTGGTA-, ATTTGGTA-, TTTGGTA-, TTGGTA-, TGGTA-, GGTA-, GTA-, TA-, or A-; and

[0223] N 12ARepresent: -AGCCGTCTTCAG, -AGCCGTCTTCA, -AGCCGTCTTC, -AGCCGTCTT, -AGCCGTCT, -AGCCGTC, -AGCCGT, -AGCCG, -AGCC, -AGC, -AG, or -A.

[0224] More preferably N 11A Represent: TTTGGTA-, TTGGTA-, TGGTA-, GGTA-, GTA-, TA-, or A-; and

[0225] N 12A Represent: -AGCCGTC, -AGCCGT, -AGCCG, -AGCC, -AGC, -AG, or -A.

[0226] Preferably, the antisense oligonucleotide of general formula (S3A / Seq.ID No.71) has 12 to 24 nucleotides and has at least 1 LNA nucleotide at the 3'-end and at least 1 LNA nucleotide at the 5'-end. The LNA nucleotides (LNA units), in particular the LNA nucleotides (LNA units) disclosed in the "Locked Nucleic Acid" and "Preferred LNA" sections, are suitable, and the nucleotide bridges, in particular those disclosed in the "Inter-Nucleotide Linkage (IL)" section, are suitable. The LNA nucleotides (LNA units) disclosed in the "Locked Nucleic Acid" and "Preferred LNA" sections are suitable, and the nucleotide bridges, in particular those disclosed in the "Inter-Nucleotide Linkage (IL)" section, are suitable.

[0227] More preferably, the antisense oligonucleotide of general formula (S3A) has 12 to 22 nucleotides and has at least 2 LNA nucleotides at the 3'-end and at least two LNA nucleotides at the 5'-end.

[0228] Even more preferably, the antisense oligonucleotide of general formula (S3A) has 12 to 20, more preferably 13 to 19, more preferably 14 to 18 nucleotides, and has 2 to 5, preferably 3 to 5, more preferably 3 to 4 LNA units at the 3'-end and 2 to 5, preferably 3 and 5, more preferably 3 to 4 LNA units at the 5'-end. Preferably, the antisense oligonucleotide is a GAPmer in the form of LNA segment - DNA segment - LNA segment B. Preferably, the antisense oligonucleotide contains at least 6, more preferably at least 7, most preferably at least 8 non-LNA units, such as DNA units between two LNA segments. The nucleobases applicable to non-LNA units and LNA units are disclosed in the "Nucleobases" section.

[0229] Furthermore, the present invention relates to antisense oligonucleotides composed of 10 to 28 nucleotides, and salts and optical isomers of said antisense oligonucleotides, and at least two of the 10 to 28 nucleotides are LNA, and the antisense oligonucleotide is capable of binding to the coding sequence of TGF-R IIregion of the gene or encoding TGF-R II hybridizes to a region of the mRNA, wherein the antisense oligonucleotide consists of the following sequence 5'-N 5 -TTTGGTAG-N 6 -3’ (Seq.ID No.11), wherein:

[0230] N 5 represents: GCCCAGCCTGCCCCAGAAGAGCTA-, CCCAGCCTGCCCCAGAAGAGCTA-, CCAGCCTGCCCCAGAAGAGCTA-, CAGCCTGCCCCAGAAGAGCTA-, AGCCTGCCCCAGAAGAGCTA-, GCCTGCCCCAGAAGAGCTA-, CCTGCCCCAGAAGAGCTA-, CTGCCCCAGAAGAGCTA-, TGCCCCAGAAGAGCTA-, GCCCCAGAAGAGCTA-, CCCCAGAAGAGCTA-, CCCAGAAGAGCTA-, CCAGAAGAGCTA-, CAGAAGAGCTA-, AGAAGAGCTA-, GAAGAGCTA-, AAGAGCTA-, AGAGCTA-, GAGCTA-, AGCTA-, GCTA-, CTA-, TA-, or A-;

[0231] N 6 represents: -TGTTTAGGGAGCCGTCTTCAGGAA, -TGTTTAGGGAGCCGTCTTCAGGA, -TGTTTAGGGAGCCGTCTTCAGG, -TGTTTAGGGAGCCGTCTTCAG, -TGTTTAGGGAGCCGTCTTCA, -TGTTTAGGGAGCCGTCTTC, -TGTTTAGGGAGCCGTCTT, -TGTTTAGGGAGCCGTCT, -TGTTTAGGGAGCCGTC, -TGTTTAGGGAGCCGT, -TGTTTAGGGAGCCG, -TGTTTAGGGAGCC, -TGTTTAGGGAGC, -TGTTTAGGGAG, -TGTTTAGGGA, -TGTTTAGGG, -TGTTTAGG, -TGTTTAG, -TGTTTA, -TGTTT, -TGTT, -TGT, -TG, or –T.

[0232] The antisense oligonucleotides of formula S4 (Seq.ID No.11) preferably contain 2 to 10 LNA units, more preferably 3 to 9 LNA units, still more preferably 4 to 8 LNA units, and also preferably contain at least 6 non-LNA units, more preferably at least 7 non-LNA units, and most preferably at least 8 non-LNA units. The non-LNA units are preferably DNA units. The LNA units are preferably located at the 3'-end (also referred to as the 3’-end) and the 5'-end (also referred to as the 5’-end). Preferably, there is at least one, more preferably at least two LNA units at the 3'-end and / or 5'-end.

[0233] Therefore, it is preferred that the antisense oligonucleotides of the present invention are designed as GAPmers containing 2 to 10 LNA units, and in particular contain 1 to 5 LNA units at the 5'-end of the antisense oligonucleotide, and 1 to 5 LNA units at the 3'-end of the antisense oligonucleotide, and contain at least 7, more preferably at least 8 DNA units between the LNA units. More preferably, the antisense oligonucleotide contains 2 to 4 LNA units at the 5'-end, 2 to 4 LNA units at the 3'-end, still more preferably contains 3 to 4 LNA units at the 5'-end and 3 to 4 LNA units at the 3'-end, and preferably contains at least 7 non-LNA units, most preferably at least 8 non-LNA units, such as DNA units between two LNA segments.

[0234] In addition, the antisense oligonucleotides may contain common nucleobases, such as adenine, guanine, cytosine, thymine and uracil, and their common derivatives, such as 5-methylcytosine or 2-aminoadenine. The antisense oligonucleotides of the present invention may also contain modified internucleotide bridges, such as phosphorothioates or dithiophosphates to replace the phosphate ester bridge. Such modifications may be present only in the LNA segments of the antisense oligonucleotide, or only in the non-LNA segments of the antisense oligonucleotide. The LNA units are in particular residues b 1 to b 9 are preferred.

[0235] Therefore, preferred are the antisense oligonucleotides of formula (S4):

[0236] 5’-N 5 -TTTGGTAG-N 6 -3’(Seq.ID No.11)

[0237] wherein

[0238] N 5Represented by: GCCCAGCCTGCCCCAGAAGAGCTA-, CCCAGCCTGCCCCAGAAGAGCTA-, CCAGCCTGCCCCAGAAGAGCTA-, CAGCCTGCCCCAGAAGAGCTA-, AGCCTGCCCCAGAAGAGCTA-, GCCTGCCCCAGAAGAGCTA-, CCTGCCCCAGAAGAGCTA-, CTGCCCCAGAAGAGCTA-, TGCCCCAGAAGAGCTA-, GCCCCAGAAGAGCTA-, CCCCAGAAGAGCTA-, CCCAGAAGAGCTA-, CCAGAAGAGCTA-, CAGAAGAGCTA-, AGAAGAGCTA-, GAAGAGCTA-, AAGAGCTA-, AGAGCTA-, GAGCTA-, AGCTA-, GCTA-, CTA-, TA-, or A-;

[0239] and

[0240] N 6 Selected from: -TGTTTAGGGAGCCGTCTTCAGGAA,

[0241] -TGTTTAGGGAGCCGTCTTCAGGA, -TGTTTAGGGAGCCGTCTTCAGG, -TGTTTAGGGAGCCGTCTTCAG, -TGTTTAGGGAGCCGTCTTCA, -TGTTTAGGGAGCCGTCTTC, -TGTTTAGGGAGCCGTCTT, -TGTTTAGGGAGCCGTCT, -TGTTTAGGGAGCCGTC, -TGTTTAGGGAGCCGT, -TGTTTAGGGAGCCG, -TGTTTAGGGAGCC, -TGTTTAGGGAGC, -TGTTTAGGGAG, -TGTTTAGGGA, -TGTTTAGGG, -TGTTTAGG, -TGTTTAG, -TGTTTA, -TGTTT, -TGTT, -TGT, -TG, or -T.

[0242] Preferably, the antisense oligonucleotide of general formula (S4) has 10 to 28 nucleotides and has at least 1 LNA nucleotide at the 3'-end and at least 1 LNA nucleotide at the 5'-end. The LNA nucleotides (LNA units), in particular those disclosed in the "Locked Nucleic Acid " and "Preferred LNA" sections are suitable, and the nucleotide bridges, in particular those disclosed in the "Inter-Nucleotide Linkage (IL)" section are suitable.

[0243] More preferably, the antisense oligonucleotides of formula (S4) have 11-24 nucleotides and have at least two LNA nucleotides at the 3'-end and at least two LNA nucleotides at the 5'-end.

[0244] Even more preferably, the antisense oligonucleotides of formula (S4) have 12 to 20, more preferably 13 to 19, more preferably 14 to 18 nucleotides and have 2 to 5, preferably 3 to 5, more preferably 3 to 4 LNA units at the 3'-end and 2 to 5, preferably 3 to 5, more preferably 3 to 4 LNA units at the 5'-end. Preferably, the antisense oligonucleotides are GAPmers in the form of LNA-segment - A-DNA-segment - LNA-segment B. Preferably, the antisense oligonucleotides contain at least 6, more preferably at least 7, most preferably at least 8 non-LNA units, such as DNA units between two LNA segments. The nucleobases applicable to non-LNA units and LNA units are disclosed in the "Nucleobases" section.

[0245] Also preferred are the antisense oligonucleotides of formula (S4):

[0246] 5’-N 5 -TTTGGTAG-N 6 -3’

[0247] wherein

[0248] N 5 represents: CCTGCCCCAGAAGAGCTA-, CTGCCCCAGAAGAGCTA-, TGCCCCAGAAGAGCTA-, GCCCCAGAAGAGCTA-, CCCCAGAAGAGCTA-, CCCAGAAGAGCTA-, CCAGAAGAGCTA-, CAGAAGAGCTA-, AGAAGAGCTA-, GAAGAGCTA-, AAGAGCTA-, AGAGCTA-, GAGCTA-, AGCTA-, GCTA-, CTA-, TA-, or A-; and

[0249] N 6Selected from: -TGTTTAGGGAGCCGTCTT, -TGTTTAGGGAGCCGTCT, -TGTTTAGGGAGCCGTC, -TGTTTAGGGAGCCGT, -TGTTTAGGGAGCCG, -TGTTTAGGGAGCC, -TGTTTAGGGAGC, -TGTTTAGGGAG, -TGTTTAGGGA, -TGTTTAGGG, -TGTTTAGG, -TGTTTAG, -TGTTTA, -TGTTT, -TGTT, -TGT, -TG, or -T.

[0250] Also preferred are the antisense oligonucleotides of formula (S4):

[0251] 5’-N 5 -TTTGGTAG-N 6 -3’

[0252] wherein

[0253] N 5 represents: CCCAGAAGAGCTA-, CCAGAAGAGCTA-, CAGAAGAGCTA-, AGAAGAGCTA-, GAAGAGCTA-, AAGAGCTA-, AGAGCTA-, GAGCTA-, AGCTA-, GCTA-, CTA-, TA-, or A-; and

[0254] N 6 is selected from: -TGTTTAGGGAGCC, -TGTTTAGGGAGC, -TGTTTAGGGAG, -TGTTTAGGGA, -TGTTTAGGG, -TGTTTAGG, -TGTTTAG, -TGTTTA, -TGTTT, -TGTT, -TGT, -TG, or -T.

[0255] Also preferred are the antisense oligonucleotides of formula (S4):

[0256] 5’-N 5 -TTTGGTAG-N 6 -3’

[0257] wherein

[0258] N 5 represents: AAGAGCTA-, AGAGCTA-, GAGCTA-, AGCTA-, GCTA-, CTA-, TA-, or A-; and

[0259] N 6Selected from: -TGTTTAGG, -TGTTTAG, -TGTTTA, -TGTTT, -TGTT, -TGT, -TG, or -T.

[0260] Preferably, the present invention relates to antisense oligonucleotides consisting of 12 to 24 nucleotides, as well as salts and optical isomers of said antisense oligonucleotides, and at least 3 of the 12 to 24 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing with a region of the gene encoding TGF-R II or a region of the mRNA encoding TGF-R II and is represented by the following sequence 5'-N 5A -ATTTGGTAGT-N 6A -3' (Seq.ID No.72), wherein

[0261] N 5A represents: GCCCAGCCTGCCCCAGAAGAGCT-, CCCAGCCTGCCCCAGAAGAGCT-, CCAGCCTGCCCCAGAAGAGCT-, CAGCCTGCCCCAGAAGAGCT-, AGCCTGCCCCAGAAGAGCT-, GCCTGCCCCAGAAGAGCT-, CCTGCCCCAGAAGAGCT-, CTGCCCCAGAAGAGCT-, TGCCCCAGAAGAGCT-, GCCCCAGAAGAGCT-, CCCCAGAAGAGCT-, CCCAGAAGAGCT-, CCAGAAGAGCT-, CAGAAGAGCT-, AGAAGAGCT-, GAAGAGCT-, AAGAGCT-, AGAGCT-, GAGCT-, AGCT-, GCT-, CT-, or T-; and

[0262] N 6A ​Represented by: -GTTTAGGGAGCCGTCTTCAGGAA, -GTTTAGGGAGCCGTCTTCAGGA, -GTTTAGGGAGCCGTCTTCAGG, -GTTTAGGGAGCCGTCTTCAG, -GTTTAGGGAGCCGTCTTCA, -GTTTAGGGAGCCGTCTTC, -GTTTAGGGAGCCGTCTT, -GTTTAGGGAGCCGTCT, -GTTTAGGGAGCCGTC, -GTTTAGGGAGCCGT, -GTTTAGGGAGCCG, -GTTTAGGGAGCC, -GTTTAGGGAGC, -GTTTAGGGAG, -GTTTAGGGA, -GTTTAGGG, -GTTTAGG, -GTTTAG, -GTTTA, -GTTT, -GTT, -GT, or -G.

[0263] Preferably N 5A Represented by: CCTGCCCCAGAAGAGCT-, CTGCCCCAGAAGAGCT-, TGCCCCAGAAGAGCT-, GCCCCAGAAGAGCT-, CCCAGAAGAGCT-, CCCAGAAGAGCT-, CCAGAAGAGCT-, CAGAAGAGCT-, AGAAGAGCT-, GAAGAGCT-, AAGAGCT-, AGAGCT-, GAGCT-, AGCT-, GCT-, CT-, or T-; and

[0264] N 6A Represented by: -GTTTAGGGAGCCGTCTT, -GTTTAGGGAGCCGTCT, -GTTTAGGGAGCCGTC, -GTTTAGGGAGCCGT, -GTTTAGGGAGCCG, -GTTTAGGGAGCC, -GTTTAGGGAGC, -GTTTAGGGAG, -GTTTAGGGA, -GTTTAGGG, -GTTTAGG, -GTTTAG, -GTTTA, -GTTT, -GTT, -GT, or -G.

[0265] More preferably N 5A Represented by: CCCAGAAGAGCT-, CCAGAAGAGCT-, CAGAAGAGCT-, AGAAGAGCT-, GAAGAGCT-, AAGAGCT-, AGAGCT-, GAGCT-, AGCT-, GCT-, CT-, or T-; and

[0266] N 6ARepresent: -GTTTAGGGAGCC, -GTTTAGGGAGC, -GTTTAGGGAG, -GTTTAGGGA, -GTTTAGGG, -GTTTAGG, -GTTTAG, -GTTTA, -GTTT, -GTT, -GT, or -G.

[0267] More preferably N 5A Represent: AAGAGCT-, AGAGCT-, GAGCT-, AGCT-, GCT-, CT-, or T-; and

[0268] N 6A Represent: -GTTTAGG, -GTTTAG, -GTTTA, -GTTT, -GTT, -GT, or -G.

[0269] Preferably, the antisense oligonucleotide of the general formula (S4A / Seq.ID No.72) has 2 to 4 nucleotides and has at least 1 LNA nucleotide at the 3'-end and at least 1 LNA nucleotide at the 5'-end. LNA nucleotides (LNA units), in particular those disclosed in the "Locked Nucleic Acid" " and "Preferred LNA" sections are suitable, and nucleotide bridges, in particular those disclosed in the "Inter-Nucleotide Linkage (IL)" section are suitable.

[0270] More preferably, the antisense oligonucleotide of the general formula (S4A) has 12 to 22 nucleotides and has at least two LNA nucleotides at the 3'-end and at least two LNA nucleotides at the 5'-end.

[0271] Even more preferably, the antisense oligonucleotide of the general formula (S4A) has 12 to 20, more preferably 13 to 19, more preferably 14 to 18 nucleotides, and has 2 to 5, preferably 3 to 5, more preferably 3 to 4 LNA units at the 3'-end and 2 to 5, preferably 3 and 5, more preferably 3 to 4 LNA units at the 5'-end. Preferably, the antisense oligonucleotide is a GAPmer in the form of an LNA segment - A-DNA segment - LNA segment B. Preferably, the antisense oligonucleotide contains at least 6, more preferably at least 7, most preferably at least 8 non-LNA units, such as DNA units between two LNA segments. The nucleobases applicable to non-LNA units and LNA units are disclosed in the "Nucleobases" section.

[0272] Furthermore, the present invention relates to antisense oligonucleotides composed of 10 to 28 nucleotides and salts and optical isomers of said antisense oligonucleotides, at least two of the 10 to 28 nucleotides being LNA, and the antisense oligonucleotide being capable of binding to the coding sequence of TGF-R IIregion of the gene or encoding TGF-R II hybridizes to the region of the mRNA encoding TGF-R, wherein the antisense oligonucleotide is represented by the following sequence 5'-N 7 -AATGGACC-N 8 -3' (Seq.ID No.100), wherein

[0273] N 7 represents: TGAATCTTGAATATCTCATG-, GAATCTTGAATATCTCATG-, AATCTTGAATATCTCATG-, ATCTTGAATATCTCATG-, TCTTGAATATCTCATG-, CTTGAATATCTCATG-, TTGAATATCTCATG-, TGAATATCTCATG-, GAATATCTCATG-, AATATCTCATG-, ATATCTCATG-, TATCTCATG-, ATCTCATG-, TCTCATG-, CTCATG-, TCATG-, CATG-, ATG-, TG-, or G-;

[0274] N 8 represents: -AGTATTCTAGAAACTCACCA, -AGTATTCTAGAAACTCACC, -AGTATTCTAGAAACTCAC, -AGTATTCTAGAAACTCA, -AGTATTCTAGAAACTC, -AGTATTCTAGAAACT, -AGTATTCTAGAAAC, -AGTATTCTAGAAA, -AGTATTCTAGAA, -AGTATTCTAGA, -AGTATTCTAG, -AGTATTCTA, -AGTATTCT, -AGTATTC, -AGTATT, -AGTAT, -AGTA, -AGT, -AG, or -A.

[0275] The antisense oligonucleotide of formula S6 (Seq.ID No.100) preferably comprises 2 to 10 LNA units, more preferably 3 to 9 LNA units, still more preferably 4 to 8 LNA units, and also preferably comprises at least 6 non-LNA units, more preferably at least 7 non-LNA units, most preferably at least 8 non-LNA units. The non-LNA units are preferably DNA units. The LNA units are preferably located at the 3'-end (also referred to as the 3' terminus) and the 5'-end (also referred to as the 5' terminus). Preferably, there is at least one, more preferably at least two LNA units at the 3'-end and / or the 5'-end.

[0276] Thus, preferably, the antisense oligonucleotides of the present invention are designed as GAPmers containing 2 to 10 LNA units, and in particular contain 1 to 5 LNA units at the 5'-end of the antisense oligonucleotide, and 1 to 5 LNA units at the 3'-end of the antisense oligonucleotide, and contain at least 7, more preferably at least 8 DNA units between the LNA units. More preferably, the antisense oligonucleotide contains 2 to 4 LNA units at the 5'-end, 2 to 4 LNA units at the 3'-end, even more preferably contains 3 to 4 LNA units at the 5'-end and 3 to 4 LNA units at the 3'-end, and preferably contains at least 7 non-LNA units, most preferably at least 8 non-LNA units, such as DNA units between two LNA segments.

[0277] In addition, the antisense oligonucleotide may contain common nucleobases such as adenine, guanine, cytosine, thymine and uracil, as well as their common derivatives such as 5-methylcytosine or 2-aminoadenine. The antisense oligonucleotides of the present invention may also contain modified internucleotide bridges such as phosphorothioates or dithiophosphates instead of phosphate bridges. Such modifications may be present only in the LNA segments of the antisense oligonucleotide, or only in the non-LNA segments of the antisense oligonucleotide. The LNA units are in particular residues b 1 to b 9 as are preferred.

[0278] Therefore, preferred are the antisense oligonucleotides of formula (S6):

[0279] 5’-N 7 -AATGGACC-N 8 -3’ (Seq.ID No.100)

[0280] wherein

[0281] N 7 represents: TGAATCTTGAATATCTCATG-, GAATCTTGAATATCTCATG-, AATCTTGAATATCTCATG-, ATCTTGAATATCTCATG-, TCTTGAATATCTCATG-, CTTGAATATCTCATG-, TTGAATATCTCATG-, TGAATATCTCATG-, GAATATCTCATG-, AATATCTCATG-, ATATCTCATG-, TATCTCATG-, ATCTCATG-, TCTCATG-, CTCATG-, TCATG-, CATG-, ATG-, TG-, or G-;

[0282] and

[0283] N 8 Selected from: -AGTATTCTAGAAACTCACCA, -AGTATTCTAGAAACTCAC C, -AGTATTCTAGAAACTCAC, -AGTATTCTAGAAACTCA, -AGTATTCTAGAAACTC, -AGTATTCTAGAAACT, -AGTATTCTAGAA AC, -AGTATTCTAGAAA, -AGTATTCTAGAA, -AGTATTCTAGA, -AGTATTCTAG, -AGTATTCTA, -AGTATTCT, -AGTATTC, -AGT ATT, -AGTAT, -AGTA, -AGT, -AG, or -A.

[0284] Preferably, the antisense oligonucleotide of general formula (S6) has 10 to 28 nucleotides and has at least 1 LNA nucleotide at the 3'-end and at least 1 LNA nucleotide at the 5'-end. The LNA nucleotides (LNA units), in particular those disclosed in the "Locked nucleic acid" " and "Preferred LNA" sections are suitable, and the nucleotide bridges, in particular those disclosed in the "Inter-nucleotide linkage (IL)" section are suitable.

[0285] More preferably, the antisense oligonucleotide of general formula (S6) has 11 - 24 nucleotides, and has at least two LNA nucleotides at the 3'-end and at least two LNA nucleotides at the 5'-end.

[0286] Even more preferably, the antisense oligonucleotide of general formula (S6) has 12 to 20, more preferably 13 to 19, more preferably 14 to 18 nucleotides, and has 2 to 5, preferably 3 to 5, more preferably 3 to 4 LNA units at the 3'-end and 2 to 5, preferably 3 and 5, more preferably 3 to 4 LNA units at the 5'-end. Preferably, the antisense oligonucleotide is a GAPmer in the form of an LNA segment - A - DNA segment - LNA segment B. Preferably, the antisense oligonucleotide contains at least 6, more preferably at least 7, most preferably at least 8 non - LNA units, such as DNA units between two LNA segments. The nucleobases applicable to non - LNA units and LNA units are disclosed in the "Nucleobases" section.

[0287] Also preferred is the antisense oligonucleotide of formula (S6):

[0288] 5’-N 7 -AATGGACC-N 8 -3’

[0289] wherein

[0290] N 7 represents: AATCTTGAATATCTCATG-, ATCTTGAATATCTCATG-, TCTTGAATATCTCATG-, CTTGAATATCTCATG-, TTGAATATCTCATG-, TGAATATCTCATG-, GAATATCTCATG-, AATATCTCATG-, ATATCTCATG-, TATCTCATG-, ATCTCATG-, TCTCATG-, CTCATG-, TCATG-, CATG-, ATG-, TG-, or G-; and

[0291] N 8 is selected from: -AGTATTCTAGAAACTCAC, -AGTATTCTAGAAACTCA, -AGTATTCTAGAAACTC, -AGTATTCTAGAAACT, -AGTATTCTAGAAAC, -AGTATTCTAGAAA, -AGTATTCTAGAA, -AGTATTCTAGA, -AGTATTCTAG, -AGTATTCTA, -AGTATTCT, -AGTATTC, -AGTATT, -AGTAT, -AGTA, -AGT, -AG, or -A.

[0292] Also preferred are the antisense oligonucleotides of formula (S6):

[0293] 5'-N 7 -AATGGACC-N 8 -3'

[0294] wherein

[0295] N 7 represents: TGAATATCTCATG-, GAATATCTCATG-, AATATCTCATG-, ATATCTCATG-, TATCTCATG-, ATCTCATG-, TCTCATG-, CTCATG-, TCATG-, CATG-, ATG-, TG-, or G-; and

[0296] N 8 is selected from: -AGTATTCTAGAAA, -AGTATTCTAGAA, -AGTATTCTAGA, -AGTATTCTAG, -AGTATTCTA, -AGTATTCT, -AGTATTC, -AGTATT, -AGTAT, -AGTA, -AGT, -AG, or -A.

[0297] Also preferred are antisense oligonucleotides of formula (S6):

[0298] 5’-N 7 -AATGGACC-N 8 -3’

[0299] wherein

[0300] N 7 represents: ATCTCATG-, TCTCATG-, CTCATG-, TCATG-, CATG-, ATG-, TG-, or G-; and

[0301] N 8 is selected from: -AGTATTCT, -AGTATTC, -AGTATT, -AGTAT, -AGTA, -AGT, -AG, or -A.

[0302] Preferably, the present invention relates to antisense oligonucleotides consisting of 12 to 24 nucleotides, as well as salts and optical isomers of said antisense oligonucleotides, and at least 3 of the 12 to 24 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing to a region of the gene encoding TGF-R II or to a region of the mRNA encoding TGF-R II and is represented by the following sequence 5’-N 7A -GAATGGACCA-N 8A -3’ (Seq.ID No.73), wherein

[0303] N 7A represents: TGAATCTTGAATATCTCAT-, GAATCTTGAATATCTCAT-, AATCTTGAATATCTCAT-, ATCTTGAATATCTCAT-, TCTTGAATATCTCAT-, CTTGAATATCTCAT-, TTGAATATCTCAT-, TGAATATCTCAT-, GAATATCTCAT-, AATATCTCAT-, ATATCTCAT-, TATCTCAT-, ATCTCAT-, TCTCAT-, CTCAT-, TCAT-, CAT-, AT-, or T-;

[0304] N 8ARepresent: -GTATTCTAGAAACTCACCA, -GTATTCTAGAAACTCACC, -GTATTCTAGAAACTCAC, -GTATTCTAGAAACTCA, -GTATTCTAGAAACTC, -GTATTCTAGAAACT, -GTATTCTAGAAAC, -GTATTCTAGAAA, -GTATTCTAGAA, -GTATTCTAGA, -GTATTCTAG, -GTATTCTA, -GTATTCT, -GTATTC, -GTATT, -GTAT, -GTA, -GT, or -G.

[0305] Preferably N 7A Represent: AATCTTGAATATCTCAT-, ATCTTGAATATCTCAT-, TCTTGAATATCTCAT-, CTTGAATATCTCAT-, TTGAATATCTCAT-, TGAATATCTCAT-, GAATATCTCAT-, AATATCTCAT-, ATATCTCAT-, TATCTCAT-, ATCTCAT-, TCTCAT-, CTCAT-, TCAT-, CAT-, AT-, or T-;

[0306] and

[0307] N 8A Represent: -GTATTCTAGAAACTCAC, -GTATTCTAGAAACTCA, -GTATTCTAGAAACTC, -GTATTCTAGAAACT, -GTATTCTAGAAAC, -GTATTCTAGAAA, -GTATTCTAGAA, -GTATTCTAGA, -GTATTCTAG, -GTATTCTA, -GTATTCT, -GTATTC, -GTATT, -GTAT, -GTA, -GT, or -G.

[0308] More preferably N 7A Represent: TGAATATCTCAT-, GAATATCTCAT-, AATATCTCAT-, ATATCTCAT-, TATCTCAT-, ATCTCAT-, TCTCAT-, CTCAT-, TCAT-, CAT-, AT-, or T-; and

[0309] N 8ARepresent: -GTATTCTAGAAA, -GTATTCTAGAA, -GTATTCTAGA, -GTATTCTAG, -GTATTCTA, -GTATTCT, -GTATTC, -GTATT, -GTAT, -GTA, -GT, or -G.

[0310] More preferably N 7A Represent: ATCTCAT-, TCTCAT-, CTCAT-, TCAT-, CAT-, AT-, or T-; and

[0311] N 8A Represent: -GTATTCT, -GTATTC, -GTATT, -GTAT, -GTA, -GT, or -G.

[0312] Preferably, the antisense oligonucleotide of general formula (S6A / Seq.ID No.73) has 12 to 24 nucleotides and has at least 1 LNA nucleotide at the 3'-end and at least 1 LNA nucleotide at the 5'-end. The LNA nucleotides (LNA units), in particular the LNA nucleotides (LNA units) disclosed in the "Locked Nucleic Acid" and "Preferred LNA" sections, are suitable, and the nucleotide bridges, in particular those disclosed in the "Inter-Nucleotide Linkages (IL)" section, are suitable. The LNA nucleotides (LNA units) disclosed in the "Locked Nucleic Acid" and "Preferred LNA" sections are suitable, and the nucleotide bridges, in particular those disclosed in the "Inter-Nucleotide Linkages (IL)" section, are suitable.

[0313] More preferably, the antisense oligonucleotide of general formula (S6A) has 12 to 22 nucleotides and has at least 2 LNA nucleotides at the 3'-end and at least two LNA nucleotides at the 5'-end.

[0314] Even more preferably, the antisense oligonucleotide of general formula (S6A) has 12 to 20, more preferably 13 to 19, more preferably 14 to 18 nucleotides, and has 2 to 5, preferably 3 to 5, more preferably 3 to 4 LNA units at the 3'-end and 2 to 5, preferably 3 and 5, more preferably 3 to 4 LNA units at the 5'-end. Preferably, the antisense oligonucleotide is a GAPmer in the form of LNA segment - DNA segment - LNA segment B. Preferably, the antisense oligonucleotide contains at least 6, more preferably at least 7, most preferably at least 8 non-LNA units, such as DNA units between two LNA segments. The nucleobases applicable to non-LNA units and LNA units are disclosed in the "Nucleobases" section.

[0315] Furthermore, the present invention relates to antisense oligonucleotides composed of 10 to 28 nucleotides, as well as salts and optical isomers of said antisense oligonucleotides, and at least two of the 10 to 28 nucleotides are LNA, and the antisense oligonucleotide is capable of binding to the coding sequence of TGF-R IIregion of the gene or encoding TGF-R II hybridizes to the region of the mRNA, wherein the antisense oligonucleotide is represented by the following sequence 5'-N 9 -ATTAATAA-N 10 -3’ (Seq.ID No.101), wherein

[0316] N 9 represents: ATTCATATTTATATACAGGC-, TTCATATTTATATACAGGC-, TCATATTTATATACAGGC-, CATATTTATATACAGGC-, ATATTTATATACAGGC-, TATTTATATACAGGC-, ATTTATATACAGGC-, TTTATATACAGGC-, TTATATACAGGC-, TATATACAGGC-, ATATACAGGC-, TATACAGGC-, ATACAGGC-, TACAGGC-, ACAGGC-, CAGGC-, AGGC-, GGC-, GC-, or C-;

[0317] N 10 represents: -AGTGCAAATGTTATTGGCTA, -AGTGCAAATGTTATTGGCT, -AGTGCAAATGTTATTGGC, -AGTGCAAATGTTATTGG, -AGTGCAAATGTTATTG, -AGTGCAAATGTTATT, -AGTGCAAATGTTAT, -AGTGCAAATGTTA, -AGTGCAAATGTT, -AGTGCAAATGT, -AGTGCAAATG, -AGTGCAAAT, -AGTGCAAA, -AGTGCAA, -AGTGCA, -AGTGC, -AGTG, -AGT, -AG, or -A.

[0318] The antisense oligonucleotide of formula S7 (Seq.ID No.101) preferably comprises 2 to 10 LNA units, more preferably 3 to 9 LNA units, even more preferably 4 to 8 LNA units, and also preferably comprises at least 6 non-LNA units, more preferably at least 7 non-LNA units, most preferably at least 8 non-LNA units. The non-LNA units are preferably DNA units. The LNA units are preferably located at the 3' end (also referred to as the 3’ terminus) and the 5' end (also referred to as the 5’ terminus). Preferably, there is at least one, more preferably at least two LNA units at the 3' end and / or the 5' end.

[0319] Thus, preferably, the antisense oligonucleotides of the present invention are designed as GAPmers containing 2 to 10 LNA units, and particularly contain 1 to 5 LNA units at the 5'-end of the antisense oligonucleotide, and 1 to 5 LNA units at the 3'-end of the antisense oligonucleotide, and contain at least 7, more preferably at least 8 DNA units between the LNA units. More preferably, the antisense oligonucleotide contains 2 to 4 LNA units at the 5'-end, 2 to 4 LNA units at the 3'-end, even more preferably contains 3 to 4 LNA units at the 5'-end and 3 to 4 LNA units at the 3'-end, and preferably contains at least 7 non-LNA units, most preferably at least 8 non-LNA units, such as DNA units between two LNA segments.

[0320] In addition, the antisense oligonucleotides may contain common nucleobases such as adenine, guanine, cytosine, thymine and uracil, as well as their common derivatives such as 5-methylcytosine or 2-aminoadenine. The antisense oligonucleotides of the present invention may also contain modified internucleotide bridges such as phosphorothioates or dithiophosphates instead of phosphate bridges. Such modifications may be present only in the LNA segments of the antisense oligonucleotide, or only in the non-LNA segments of the antisense oligonucleotide. The LNA units are particularly residues b 1 to b 9 as described herein are preferred.

[0321] Therefore, preferred are the antisense oligonucleotides of formula (S7):

[0322] 5’-N 9 -ATTAATAA-N 10 -3’ (Seq.ID No.101)

[0323] wherein

[0324] N 9 represents: ATTCATATTTATATACAGGC-,

[0325] TTCATATTTATATACAGGC-, TCATATTTATATACAGGC-, CATATTTATATACAGGC-, ATATTTATATACAGGC-, TATTTATATACAGGC-, ATTTATATACAGGC-, TTTATATACAGGC-, TTATATACAGGC-, TATATACAGGC-, ATATACAGGC-, TATACAGGC-, ATACAGGC-, TACAGGC-, ACAGGC-, CAGGC-, AGGC-, GGC-, GC-, or C-;

[0326] and

[0327] N 10 is selected from: -AGTGCAAATGTTATTGGCTA, -AGTGCAAATGTTATTGGCT, -AGTGCAAATGTTATTGGC, -AGTGCAAATGTTATTGG, -AGTGCAAATGTTATTG, -AGTGCAAATGTTATT, -AGTGCAAATGTTAT, -AGTGCAAATGTTA, -AGTGCAAATGTT, -AGTGCAAATGT, -AGTGCAAATG, -AGTGCAAAT, -AGTGCAAA, -AGTGCAA, -AGTGCA, -AGTGC, -AGTG, -AGT, -AG, or -A.

[0328] Preferably, the antisense oligonucleotide of general formula (S7) has 10 to 28 nucleotides and has at least 1 LNA nucleotide at the 3'-end and at least 1 LNA nucleotide at the 5'-end. The LNA nucleotides (LNA units), in particular those disclosed in the "Locked nucleic acid" " and "Preferred LNA" sections are suitable, and the nucleotide bridges, in particular those disclosed in the "Inter-nucleotide linkage (IL)" section are suitable.

[0329] More preferably, the antisense oligonucleotide of general formula (S7) has 11 - 24 nucleotides, and has at least two LNA nucleotides at the 3'-end and at least two LNA nucleotides at the 5'-end.

[0330] Even more preferably, the antisense oligonucleotide of general formula (S7) has 12 to 20, more preferably 13 to 19, more preferably 14 to 18 nucleotides, and has 2 to 5, preferably 3 to 5, more preferably 3 to 4 LNA units at the 3'-end and 2 to 5, preferably 3 and 5, more preferably 3 to 4 LNA units at the 5'-end. Preferably, the antisense oligonucleotide is a GAPmer in the form of an LNA segment - DNA segment - LNA segment B. Preferably, the antisense oligonucleotide contains at least 6, more preferably at least 7, most preferably at least 8 non-LNA units, such as DNA units between two LNA segments. The nucleobases applicable to non-LNA units and LNA units are disclosed in the "Nucleobases" section.

[0331] Also preferred is the antisense oligonucleotide of formula (S7):

[0332] 5’-N 9 -ATTAATAA-N 10 -3’

[0333] wherein

[0334] N 9 represents: TCATATTTATATACAGGC-, CATATTTATATACAGGC-, ATATTTATATACAGGC-, TATTTATATACAGGC-, ATTTATATACAGGC-, TTTATATACAGGC-, TTATATACAGGC-, TATATACAGGC-, ATATACAGGC-, TATACAGGC-, ATACAGGC-, TACAGGC-, ACAGGC-, CAGGC-, AGGC-, GGC-, GC-, or C-; and

[0335] N 10 is selected from: -AGTGCAAATGTTATTGGC, -AGTGCAAATGTTATTGG, -AGTGCAAATGTTATTG, -AGTGCAAATGTTATT, -AGTGCAAATGTTAT, -AGTGCAAATGTTA, -AGTGCAAATGTT, -AGTGCAAATGT, -AGTGCAAATG, -AGTGCAAAT, -AGTGCAAA, -AGTGCAA, -AGTGCA, -AGTGC, -AGTG, -AGT, -AG, or -A.

[0336] Also preferred is an antisense oligonucleotide of formula (S7):

[0337] 5'-N 9 -ATTAATAA-N 10 -3'

[0338] wherein

[0339] N 9 represents: TTTATATACAGGC-, TTATATACAGGC-, TATATACAGGC-, ATATACAGGC-, TATACAGGC-, ATACAGGC-, TACAGGC-, ACAGGC-, CAGGC-, AGGC-, GGC-, GC-, or C-; and

[0340] N 10 is selected from: -AGTGCAAATGTTA, -AGTGCAAATGTT, -AGTGCAAATGT, -AGTGCAAATG, -AGTGCAAAT, -AGTGCAAA, -AGTGCAA, -AGTGCA, -AGTGC, -AGTG, -AGT, -AG, or -A.

[0341] Also preferred are antisense oligonucleotides of formula (S7):

[0342] 5’-N 9 -ATTAATAA-N 10 -3’

[0343] wherein

[0344] N 9 represents: ATACAGGC-, TACAGGC-, ACAGGC-, CAGGC-, AGGC-, GGC-, GC-, or C-; and

[0345] N 10 is selected from: -AGTGCAAA, -AGTGCAA, -AGTGCA, -AGTGC, -AGTG, -AGT, -AG, or -A.

[0346] Preferably, the present invention relates to antisense oligonucleotides consisting of 12 to 24 nucleotides, as well as salts and optical isomers of said antisense oligonucleotides, and at least 3 of the 12 to 24 nucleotides are LNA, and the antisense oligonucleotide is capable of hybridizing to a region of the gene encoding TGF-R II or to a region of the mRNA encoding TGF-R II wherein the antisense oligonucleotide is represented by the following sequence 5’-N 9A -CATTAATAAA-N 10A -3’ (Seq.ID No.74), wherein

[0347] N 9A represents: ATTCATATTTATATACAGG-, TTCATATTTATATACAGG-, TCATATTTATATACAGG-, CATATTTATATACAGG-, ATATTTATATACAGG-, TATTTATATACAGG-, ATTTATATACAGG-, TTTATATACAGG-, TTATATACAGG-, TATATACAGG-, ATATACAGG-, TATACAGG-, ATACAGG-, TACAGG-, ACAGG-, CAGG-, AGG-, GG-, or G-;

[0348] N 10ARepresent: -GTGCAAATGTTATTGGCTA, -GTGCAAATGTTATTGGCT, -GTGCAAATGTTATTGGC, -GTGCAAATGTTATTGG, -GTGCAAATGTTATTG, -GTGCAAATGTTATT, -GTGCAAATGTTAT, -GTGCAAATGTTA, -GTGCAAATGTT, -GTGCAAATGT, -GTGCAAATG, -GTGCAAAT, -GTGCAAA, -GTGCAA, -GTGCA, -GTGC, -GTG, -GT, or -G.

[0349] Preferably N 9A Represent: TCATATTTATATACAGG-, CATATTTATATACAGG-, ATATTTATATACAGG-, TATTTATATACAGG-, ATTTATATACAGG-, TTTATATACAGG-, TTATATACAGG-, TATATACAGG-, ATATACAGG-, TATACAGG-, ATACAGG-, TACAGG-, ACAGG-, CAGG-, AGG-, GG-, or G-;

[0350] and

[0351] N 10A Represent: -GTGCAAATGTTATTGGC, -GTGCAAATGTTATTGG, -GTGCAAATGTTATTG, -GTGCAAATGTTATT, -GTGCAAATGTTAT, -GTGCAAATGTTA, -GTGCAAATGTT, -GTGCAAATGT, -GTGCAAATG, -GTGCAAAT, -GTGCAAA, -GTGCAA, -GTGCA, -GTGC, -GTG, -GT, or -G.

[0352] More preferably N 9A Represent: TTTATATACAGG-, TTATATACAGG-, TATATACAGG-, ATATACAGG-, TATACAGG-, ATACAGG-, TACAGG-, ACAGG-, CAGG-, AGG-, GG-, or G-; and

[0353] N 10ARepresent: -GTGCAAATGTTA, -GTGCAAATGTT, -GTGCAAATGT, -GTGCAAATG, -GTGCAAAT, -GTGCAAA, -GTGCAA, -GTGCA, -GTGC, -GTG, -GT, or -G.

[0354] More preferably N 9A Represent: ATACAGG-, TACAGG-, ACAGG-, CAGG-, AGG-, GG-, or G-; and

[0355] N 10A Represent: -GTGCAAA, -GTGCAA, -GTGCA, -GTGC, -GTG, -GT, or -G.

[0356] Preferably, the antisense oligonucleotide of the general formula (S7A / Seq.ID No.74) has 2 to 4 nucleotides and has at least 1 LNA nucleotide at the 3'-end and at least 1 LNA nucleotide at the 5'-end. LNA nucleotides (LNA units), in particular those disclosed in the "Locked nucleic acid" and "Preferred LNA" sections, are suitable, and nucleotide bridges, in particular those disclosed in the "Inter-nucleotide linkage (IL)" section, are suitable. ” and those disclosed in the “Preferred LNA” section are suitable, and nucleotide bridges, in particular those disclosed in the “Inter-nucleotide linkage (IL)” section, are suitable.

[0357] More preferably, the antisense oligonucleotide of the general formula (S7A) has 12 to 22 nucleotides and has at least two LNA nucleotides at the 3'-end and at least two LNA nucleotides at the 5'-end.

[0358] Even more preferably, the antisense oligonucleotide of the general formula (S7A) has 12 to 20, more preferably 13 to 19, more preferably 14 to 18 nucleotides, and has 2 to 5, preferably 3 to 5, more preferably 3 to 4 LNA units at the 3'-end and 2 to 5, preferably 3 to 5, more preferably 3 to 4 LNA units at the 5'-end. Preferably, the antisense oligonucleotide is a GAPmer in the form of an LNA segment - A-DNA segment - LNA segment B. Preferably, the antisense oligonucleotide contains at least 6, more preferably at least 7, most preferably at least 8 non-LNA units, such as DNA units between two LNA segments. The nucleobases applicable to non-LNA units and LNA units are disclosed in the "Nucleobases" section.

[0359] Furthermore, the present invention relates to antisense oligonucleotides composed of 8 to 18, preferably 10 to 28 nucleotides, and salts and optical isomers of said antisense oligonucleotides, and at least two of the 8 to 28, preferably 10 to 28 nucleotides are LNA, and the antisense oligonucleotide is capable of binding to the coding sequence of TGF-RII region of the gene or encoding TGF-R II hybridizes to the region of the mRNA, wherein the antisense oligonucleotide consists of the following sequence 5'-(N 13 ) m -GTAGTGTT-(N 14 ) n -3' (Seq.ID No.99), wherein

[0360] N 13 represents: CCCAGCCTGCCCCAGAAGAGCTATTTG-, CCAGCCTGCCCCAGAAGAGCTATTTG-, CAGCCTGCCCCAGAAGAGCTATTTG-, AGCCTGCCCCAGAAGAGCTATTTG-, GCCTGCCCCAGAAGAGCTATTTG-, CCTGCCCCAGAAGAGCTATTTG-, CTGCCCCAGAAGAGCTATTTG-, TGCCCCAGAAGAGCTATTTG-, GCCCCAGAAGAGCTATTTG-, CCCCAGAAGAGCTATTTG-, CCCAGAAGAGCTATTTG-, CCAGAAGAGCTATTTG-, CAGAAGAGCTATTTG-, AGAAGAGCTATTTG-, GAAGAGCTATTTG-, AAGAGCTATTTG-, AGAGCTATTTG-, GAGCTATTTG-, AGCTATTTG-, GCTATTTG-, CTATTTG-, TATTTG-, ATTTG-, TTTG-, TTG-, TG-, or G-;

[0361] and

[0362] N 14 is selected from: -TAGGGAGCCGTCTTCAGGAATCTTCTC,

[0363] -TAGGGAGCCGTCTTCAGGAATCTTCT, -TAGGGAGCCGT CTTCAGGAATCTTC, -TAGGGAGCCGTCTTCAGGAATCTT, -TAGGGAGCCGTCTTCAGGAATCT, -TAGGGAGCCGTCTTCAGGA ATC, -TAGGGAGCCGTCTTCAGGAAT, -TAGGGAGCCGTCTTCAGGAA, -TAGGGAGCCGTCTTCAGGA, -TAGGGAGCCGTCTTC AGG, -TAGGGAGCCGTCTTCAG, -TAGGGAGCCGTCTTCA, -TAGGGAGCCGTCTTC, -TAGGGAGCCGTCTT, -TAGGGAGCCGTC T, -TAGGGAGCCGTC, -TAGGGAGCCGT, -TAGGGAGCCG, -TAGGGAGCC, -TAGGGAGC, -TAGGGAG, -TAGGGA, -TAGGG, -TA GG, -TAG, -TA, or -T;

[0364] m represents 0 or 1;

[0365] n represents 0 or 1;

[0366] and n + m = 1 or 2.

[0367] The antisense oligonucleotide of formula S5 (Seq.ID No 99) preferably contains 2 to 10 LNA units, more preferably 3 to 9 LNA units, still more preferably 4 to 8 LNA units, and also preferably contains at least 6 non-LNA units, more preferably at least 7 non-LNA units, and most preferably at least 8 non-LNA units. The non-LNA units are preferably DNA units. The LNA units are preferably located at the 3'-end (also referred to as the 3’-end) and the 5'-end (also referred to as the 5’-end). Preferably, there is at least one, more preferably at least two LNA units at the 3'-end and / or the 5'-end.

[0368] Accordingly, it is preferred that the antisense oligonucleotides of the present invention are designed as GAPmers containing 2 to 10 LNA units, and in particular contain 1 to 5 LNA units at the 5'-end of the antisense oligonucleotide, and 1 to 5 LNA units at the 3'-end of the antisense oligonucleotide, and contain at least 7, more preferably at least 8 DNA units between the LNA units. More preferably, the antisense oligonucleotide contains 2 to 4 LNA units at the 5'-end, 2 to 4 LNA units at the 3'-end, even more preferably contains 3 to 4 LNA units at the 5'-end and 3 to 4 LNA units at the 3'-end, and preferably contains at least 7 non-LNA units, most preferably at least 8 non-LNA units, such as DNA units between two LNA segments.

[0369] In addition, the antisense oligonucleotide may contain common nucleobases, such as adenine, guanine, cytosine, thymine and uracil, and their common derivatives, such as 5-methylcytosine or 2-aminoadenine. The antisense oligonucleotides of the present invention may also contain modified internucleotide bridges, such as phosphorothioates or dithiophosphates instead of phosphate bridges. Such modifications may be present only in the LNA segments of the antisense oligonucleotide, or only in the non-LNA segments of the antisense oligonucleotide. The LNA units are in particular residues b 1 to b 9 as described herein are preferred.

[0370] Accordingly, preferred are the antisense oligonucleotides of formula (S5):

[0371] 5’-(N 13 ) m -GTAGTGTT-(N 14 ) n -3’

[0372] wherein

[0373] N 13Represented by: GCCTGCCCCAGAAGAGCTATTTG-, CCTGCCCCAGAAGAGCTATTTG-, CTGCCCCAGAAGAGCTATTTG-, TGCCCCAGAAGAGCTATTTG-, GCCCCAGAAGAGCTATTTG-, CCCCAGAAGAGCTATTTG-, CCCAGAAGAGCTATTTG-, CCAGAAGAGCTATTTG-, CAGAAGAGCTATTTG-, AGAAGAGCTATTTG-, GAAGAGCTATTTG-, AAGAGCTATTTG-, AGAGCTATTTG-, GAGCTATTTG-, AGCTATTTG-, GCTATTTG-, CTATTTG-, TATTTG-, ATTTG-, TTTG-, TTG-, TG-, or G-; and

[0374] N 14 Selected from: -TAGGGAGCCGTCTTC, -TAGGGAGCCGTCTT, -TAGGGAGCCGTCT, -TAGGGAGCCGTC, -TAGGGAGCCGT, -TAGGGAGCCG, -TAGGGAGCC, -TAGGGAGC, -TAGGGAG, -TAGGGA, -TAGGG, -TAGG, -TAG, -TA, or -T; and

[0375] m represents 0 or 1; n represents 0 or 1; and n + m = 1 or 2.

[0376] Preferably, the antisense oligonucleotide of general formula (S5) has 10 to 28 nucleotides and has at least 1 LNA nucleotide at the 3'-end and at least 1 LNA nucleotide at the 5'-end. LNA nucleotides (LNA units), in particular those disclosed in the "Locked Nucleic Acid" " and "Preferred LNA" sections are suitable, and nucleotide bridges, in particular those disclosed in the "Inter-Nucleotide Linkage (IL)" section are suitable.

[0377] More preferably, the antisense oligonucleotide of general formula (S5) has 11 - 24 nucleotides, and has at least two LNA nucleotides at the 3'-end and at least two LNA nucleotides at the 5'-end.

[0378] Even more preferably, the antisense oligonucleotide of formula (S5) has 12 to 20, more preferably 13 to 19, even more preferably 14 to 18 nucleotides, and has 2 to 5, preferably 3 to 5, even more preferably 3 to 4 LNA units at the 3'-end and 2 to 5, preferably 3 and 5, even more preferably 3 to 4 LNA units at the 5'-end. Preferably, the antisense oligonucleotide is a GAPmer in the form of LNA segment - DNA segment - LNA segment B. Preferably, the antisense oligonucleotide contains at least 6, more preferably at least 7, most preferably at least 8 non-LNA units, such as DNA units between two LNA segments. The nucleobases applicable to non-LNA units and LNA units are disclosed in the "Nucleobases" section.

[0379] Also preferred is the antisense oligonucleotide of formula (S5):

[0380] 5’-(N 13 ) m -GTAGTGTT-(N 14 ) n -3’

[0381] wherein

[0382] N 13 represents: CCCCAGAAGAGCTATTTG-, CCCAGAAGAGCTATTTG-, CCAGAAGAGCTATTTG-, CAGAAGAGCTATTTG-, AGAAGAGCTATTTG-, GAAGAGCTATTTG-, AAGAGCTATTTG-, AGAGCTATTTG-, GAGCTATTTG-, AGCTATTTG-, GCTATTTG-, CTATTTG-, TATTTG-, ATTTG-, TTTG-, TTG-, TG-, or G-; and

[0383] N 14 is selected from: -TAGGGAGCCG, -TAGGGAGCC, -TAGGGAGC, -TAGGGAG, -TAGGGA, -TAGGG, -TAGG, -TAG, -TA, or -T; and

[0384] m represents 0 or 1; n represents 0 or 1; and n + m = 1 or 2.

[0385] Also preferred is the antisense oligonucleotide of formula (S5):

[0386] 5’-(N 13 ) m -GTAGTGTT-(N 14 ) n -3’

[0387] wherein

[0388] N 13 represents: GAAGAGCTATTTG-, AAGAGCTATTTG-, AGAGCTATTTG-, GAGCTATTTG-, AGCTATTTG-, GCTATTTG-, CTATTTG-, TATTTG-, ATTTG-, TTTG-, TTG-, TG-, or G-; and

[0389] N 14 is selected from: -TAGGG, -TAGG, -TAG, -TA, or -T; and

[0390] m represents 0 or 1; n represents 0 or 1; and n + m = 1 or 2.

[0391] Also preferred is the antisense oligonucleotide of formula (S5):

[0392] 5’-(N 13 ) m -GTAGTGTT-(N 14 ) n -3’

[0393] wherein

[0394] N 13 represents: CAGAAGAGCTATTTG-, AGAAGAGCTATTTG-, GAAGAGCTATTTG-, AAGAGCTATTTG-, AGAGCTATTTG-, GAGCTATTTG-, AGCTATTTG-, GCTATTTG-, CTATTTG-, TATTTG-, ATTTG-, TTTG-, TTG-, TG-, or G-; and

[0395] N 14Selected from: -TAGGGAGCCGTCTTCAGGAATCT, -TAGGGAGCCGTCTTCAGGAATC, -TAGGGAGCCGTCTTCAGGAAT, -TAGGGAGCCGTCTTCAGGAA, -TAGGGAGCCGTCTTCAGGA, -TAGGGAGCCGTCTTCAGG, -TAGGGAGCCGTCTTCAG, -TAGGGAGCCGTCTTCA, -TAGGGAGCCGTCTTC, -TAGGGAGCCGTCTT, -TAGGGAGCCGTCT, -TAGGGAGCCGTC, -TAGGGAGCCGT, -TAGGGAGCCG, -TAGGGAGCC, -TAGGGAGC, -TAGGGAG, -TAGGGA, -TAGGG, -TAGG, -TAG, -TA, or -T; and

[0396] m represents 0 or 1; n represents 0 or 1; and n + m = 1 or 2.

[0397] Also preferred are the antisense oligonucleotides of formula (S5):

[0398] 5'-(N 13 ) m -GTAGTGTT-(N 14 ) n -3'

[0399] wherein

[0400] N 13 represents: GAGCTATTTG-, AGCTATTTG-, GCTATTTG-, CTATTTG-, TATTTG-, ATTTG-, TTTG-, TTG-, TG-, or G-; and

[0401] N 14 is selected from: -TAGGGAGCCGTCTTCAGG, -TAGGGAGCCGTCTTCAG, -TAGGGAGCCGTCTTCA, -TAGGGAGCCGTCTTC, -TAGGGAGCCGTCTT, -TAGGGAGCCGTCT, -TAGGGAGCCGTC, -TAGGGAGCCGT, -TAGGGAGCCG, -TAGGGAGCC, -TAGGGAGC, -TAGGGAG, -TAGGGA, -TAGGG, -TAGG, -TAG, -TA, or -T; and

[0402] m represents 0 or 1; n represents 0 or 1; and n + m = 1 or 2.

[0403] Also preferred are the antisense oligonucleotides of formula (S5):

[0404] 5'-(N 13 ) m -GTAGTGTT-(N 14 ) n -3'

[0405] wherein

[0406] N 13 represents: ATTTG-, TTTG-, TTG-, TG-, or G-; and

[0407] N 14 is selected from: -TAGGGAGCCGTCT, -TAGGGAGCCGTC, -TAGGGAGCCGT, -TAGGGAGCCG, -TAGGGAGCC, -TAGGGAGC, -TAGGGAG, -TAGGGA, -TAGGG, -TAGG, -TAG, -TA, or -T; and

[0408] m represents 0 or 1; n represents 0 or 1; and n + m = 1 or 2.

[0409] Preferably, the antisense oligonucleotides of general formula (S5 / Seq.ID No.99) have 12 to 24 nucleotides and have at least 1 LNA nucleotide at the 3'-end and at least 1 LNA nucleotide at the 5'-end. LNA nucleotides (LNA units), in particular the LNA nucleotides (LNA units) disclosed in the "Locked nucleic acids" " and "Preferred LNA" sections are suitable, and nucleotide bridges, in particular those disclosed in the "Inter-nucleotide linkages (IL)" section) are suitable.

[0410] More preferably, the antisense oligonucleotides of general formula (S5) have 12 to 22 nucleotides and have at least 2 LNA nucleotides at the 3'-end and at least two LNA nucleotides at the 5'-end.

[0411] Even more preferably, the antisense oligonucleotides of general formula (S5) have 12 to 20, more preferably 13 to 19, even more preferably 14 to 18 nucleotides, and have 2 to 5, preferably 3 to 5, even more preferably 3 to 4 LNA units at the 3'-end and 2 to 5, preferably 3 to 5, even more preferably 3 to 4 LNA units at the 5'-end. Preferably, the antisense oligonucleotide is a GAPmer in the form of an LNA segment - DNA segment - LNA segment B. Preferably, the antisense oligonucleotide contains at least 6, more preferably at least 7, most preferably at least 8 non-LNA units, such as DNA units between two LNA segments. The nucleobases applicable to non-LNA units and LNA units are disclosed in the "Nucleobases" section.

[0412] Another aspect of the invention relates to antisense oligonucleotides having a length of 10 to 28 nucleotides, preferably 10 to 24 nucleotides, more preferably 11 to 22 nucleotides or 12 to 20 nucleotides, even more preferably 13 to 19 nucleotides and most preferably 14 to 18 nucleotides, and salts and optical isomers of said antisense oligonucleotides, wherein at least two nucleotides, preferably at least three nucleotides, more preferably at least four nucleotides are LNA, and the antisense oligonucleotide sequences of 10 to 28 nucleotides, preferably 10 to 24 nucleotides, more preferably 11 to 22 nucleotides or 12 to 20 nucleotides, even more preferably 13 to 19 nucleotides and most preferably 14 to 18 nucleotides are selected from the group of sequences of 10 to 28 nucleotides, preferably 10 to 24 nucleotides, more preferably 11 to 22 nucleotides or 12 to 20 nucleotides, even more preferably 13 to 19 nucleotides and most preferably 14 to 18 nucleotides contained in the sequences selected from the following:

[0413] GAATCTTGAATATCTCATGAATGGACCAGTATTCTAGAA AC (Seq.ID No.75: 383 - 423 of Seq.ID No.1),

[0414] TTCATATTTATATACAGGCATTAATAAAGTGCAAATGTTA T (Seq.ID No.77: 2245 - 2285 of Seq.ID No.1),

[0415] TGAGGAAGTGCTAACACAGCTTATCCTATGACAATGTCA AAG (Seq.ID No.78: 2315 - 2356 of Seq.ID No.1),

[0416] GCCTGCCCCAGAAGAGCTATTTGGTAGTGTTTAGGGAGC CGTCTTCAGG(Seq.ID No.79:2528-2576 of Seq.ID No.1),

[0417] CGCAGGTCCTCCCAGCTGATGACATGCCGCGTCAGGTAC TCCTGTAGGT(Seq.ID No.81:3205-3253 of Seq.ID No.1),

[0418] ATGTCGTTATTAACCGACTTCTGAACGTGCGGTGGGATC GTGCTGGCGATACGCGTCCACAGGACGATGTGCAGCGGC(Seq.ID No.83:4141-4218 of Seq.ID No.1),

[0419] GGCCACAGGCCCCTGAGCAGCCCCCGACCCATGGCAGA CCCCGCTGCTCGTCATAGACCGAGCCCCCAGCGCAG(Seq.IDNo.84:4216-4289 of Seq.ID No.1),

[0420] ATGTCGTTATTAACCGACTTCTGAACGTGCGGTGGGATC GTGCTGGCGATACGCGTCCACAGGACGATGTGCAGCGGCCACAGGCCCCTGAGCAGCCCCCGACCCATGGCAGACCCCGCTGCTCGTCATAGACCGAGCCCCCAGCGCAG(Seq.ID No.86: 4141-4289 of Seq.ID No.1),

[0421] TTGAATATCTCATGAATGGACCAGTATTCTA(Seq.ID No. 87:388-418 of Seq.IDNo.1),

[0422] CAAGTGGAATTTCTAGGCGCCTCTATGCTACTG(Seq.ID No.88:483-515 of Seq.IDNo.1),

[0423] ATTTATATACAGGCATTAATAAAGTGCAAAT(Seq.ID No. 89:2250-2280 of Seq.IDNo.1),

[0424] AAGTGCTAACACAGCTTATCCTATGACAATGT (Seq.ID No. 90: 2320 - 2351 of Seq.IDNo.1),

[0425] CCCCAGAAGAGCTATTTGGTAGTGTTTAGGGAGCCGTCT (Seq.ID No.91: 2533 - 2571 ofSeq.ID No.1),

[0426] CTGGTCGCCCTCGATCTCTCAACACGTTGTCCTTCATGC TTTCGACACAGGGGTGCTCCCGCACCTTGGAACCAAATG(Seq.ID No.92: 2753 - 2830of Seq.ID No.1),

[0427] GTCCTCCCAGCTGATGACATGCCGCGTCAGGTACTCCTG

[0428] (Seq.ID No.93: 3210 - 3248of Seq.ID No.1),

[0429] CTCAGCTTCTGCTGCCGGTTAACGCGGTAGCAGTAGAAG A(Seq.ID No.94: 3655 - 3694ofSeq.ID No.1),

[0430] GTTATTAACCGACTTCTGAACGTGCGGTGGGATCGTGCT GGCGATACGCGTCCACAGGACGATGTGCA(Seq.ID No.95: 4146 - 4213of Seq.ID No.1),

[0431] CAGGCCCCTGAGCAGCCCCCGACCCATGGCAGACCCCG CTGCTCGTCATAGACCGAGCCCCCAG(Seq.ID No.96: 4221 - 4284of Seq.ID No.1),

[0432] CACGCGCGGGGGTGTCGTCGCTCCGTGCGCGCGAGTGA CTCACTCAACTTCA(Seq.ID No.97: 4495 - 4546of Seq.ID No.1),

[0433] wherein the antisense oligonucleotide is capable of selectively hybridizing to only the gene encoding TGF-R II or the mRNA encoding TGF-R II across the entire human transcriptome.

[0434] The antisense oligonucleotides having the sequences contained in SEQ ID NOs: 75, 77, 78, 79, 81, 83, 84, 86 - 97 have 2 to 5, preferably 3 to 5, more preferably 3 to 4 LNA units at the 3'-end, and 2 to 5, preferably 3 to 5, more preferably 3 to 4 LNA units at the 5'-end, and preferably have a structure of a GAPmer in the form of LNA segment - DNA segment - LNA segment B. LNA nucleotides (LNA units), in particular those disclosed in the "Locked Nucleic Acid (LNA)" section, are suitable, and internucleotide bridges, in particular those disclosed in the "Internucleotide Linkage (IL)" section, are suitable. Preferably, the antisense oligonucleotide contains at least 6, more preferably at least 7, most preferably at least 8 non-LNA units, such as DNA units, between the two LNA fragments. The nucleobases suitable for non-LNA units and LNA units are disclosed in the "Nucleobases" section. Suitable examples of the antisense oligonucleotides are represented by formulas (S1) to (S7), (S1A) to (S4A), (S6A), and (S7A).

[0435] Seq.ID No.1 represents the antisense strand (cDNA) (5'-3' antisense sequence) of the cDNA of Homo sapiens transforming growth factor beta receptor II (TGF-R II ) transcript variant 2.

[0436] Seq.ID No.2 represents the sense strand (5'-3' sense sequence) of the cDNA of Homo sapiens transforming growth factor beta receptor II (70 / 80 kDa) (TGF-R II ) transcript variant 2. Alternatively, the sequence of Seq.ID No.2 can also be considered to represent the sequence of the mRNA of Homo sapiens transforming growth factor beta receptor II (TGF-R II ) transcript variant 2 (Seq.ID No.3), but written in DNA code, i.e., in G, C, A, T code instead of RNA code.

[0437] Seq.ID No.3 represents the mRNA (5'-3' sense sequence) of Homo sapiens transforming growth factor beta receptor II (TGF-R II ) transcript variant 2. Obviously, the mRNA shown in Seq.ID No.3 is written in RNA code, i.e., in G, C, A, U code.

[0438] It should be understood that the "coding DNA strand" as used herein refers to the DNA strand that is identical to the mRNA (except written in DNA code) and contains codons for protein translation. It is not used as a template for transcription into mRNA. Thus, the terms "coding DNA strand", "sense DNA strand", and "non-template DNA strand" can be used interchangeably. In addition, the "non-coding DNA strand" as used herein refers to the DNA strand that is complementary to the "coding DNA strand" and serves as a template for mRNA transcription. Thus, the terms "non-coding DNA strand", "antisense DNA strand", and "template DNA strand" can be used interchangeably

[0439] The term "antisense oligonucleotide" refers to an oligomer or polymer of ribonucleic acid (RNA) or deoxyribonucleic acid (DNA) or mimetics or variants thereof, such as having modified internucleotide linkages such as phosphorothioate linkages and / or one or more modified nucleobases such as 5-methylcytosine and / or one or more modified nucleotide units such as LNA, such as β-D-oxy-LNA antisense oligonucleotides. The term "antisense oligonucleotide" includes oligonucleotides composed of naturally occurring nucleobases, sugars, and covalent nucleotide (backbone) linkages, as well as oligonucleotides with non-naturally occurring moieties having similar functions. Such modified or substituted oligonucleotides are generally superior to the native form due to desired properties such as enhanced cellular uptake, enhanced affinity for nucleic acid targets, and increased stability in the presence of nucleases. Antisense oligonucleotides are short catalytic RNAs or catalytic oligonucleotides that hybridize to a target nucleic acid and inhibit its expression

[0440] The term "nucleoside" is well known to those skilled in the art and refers to a pentose moiety such as ribose, deoxyribose, or modified or locked ribose, or modified or locked deoxyribose such as LNA as disclosed in detail below. The nucleobase is attached to the glycosidic carbon atom (the 1'-position of the pentose), and an internucleotide linkage is formed between the 3'-oxygen or sulfur atom, preferably the 3'-oxygen atom, of the nucleoside and the 5'-oxygen or sulfur atom, preferably the 5'-oxygen atom, of an adjacent nucleoside, and the internucleotide linkage does not belong to the nucleoside (see Figure 2 )

[0441] The term "nucleotide" is well known to those skilled in the art and refers to a pentose moiety such as ribose, deoxyribose, or modified or locked ribose or modified or locked deoxyribose, such as LNA as disclosed in detail below. The nucleobase is attached to the glycosidic carbon atom (the 1'-position of the pentose), and an internucleotide linkage is formed between the 3'-oxygen or sulfur atom, preferably the 3'-oxygen atom, of the nucleotide and the 5'-oxygen or sulfur atom, preferably the 5'-oxygen atom, of an adjacent nucleotide, and the internucleotide linkage is part of the nucleotide (see Figure 2 )

[0442] Nucleobase

[0443] The term "nucleobase" is abbreviated as "B" herein and refers to the five standard nucleotide bases adenine (A), thymine (T), guanine (G), cytosine (C) and uracil (U) and their modifications or analogs or analogs having the ability to form Watson-Crick base pairs with bases in a complementary strand. Modified nucleobases include other synthetic and natural nucleobases such as 5-methylcytosine (C*), 5-hydroxymethylcytosine, N 4 -methylcytosine, xanthine, hypoxanthine, 7-deazaxanthine, 2-aminoadenine, 6-methyladenine, 6-methylguanine, 6-ethyladenine, 6-ethylguanine, 2-propyladenine, 2-propylguanine, 6-carboxyuracil, 5-halouracil, 5,6-dihydrouracil, 5-cytosine, 5-propynyluracil, 5-propynylcytosine, 6-azauracil, 6-azacytosine, 6-azathymine, 5-uracil (pseudouracil), 4-thiouracil, 8-fluoroadenine, 8-chloroadenine, 8-bromoadenine, 8-iodoadenine, 8-aminoadenine, 8-thioadenine, 8-thioalkyladenine, 8-hydroxyadenine, 8-fluoroguanine, 8-chloroguanine, 8-bromoguanine, 8-iodoguanine, 8-amino guanine, 8-thioguanine, 8-thioalkylguanine, 8-hydroxyguanine, 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, 5-trifluoromethyluracil, 5-fluorocytosine, 5-bromocytosine, 5-chlorocytosine, 5-iodocytosine, 5-trifluoromethylcytosine, 7-methylguanine, 7-methyladenine, 8-azaguanine, 8-azaadenine, 7-deazaguanine, 7-deazaadenine, 7-deaza-8-azaaadenine, 3-deazaguanine, 3-deazaadenine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, etc., and 5-methylcytosine and / or 2-aminoadenine substitution is preferred because these modifications have been shown to increase nucleic acid duplex stability.

[0444] Preferred antisense oligonucleotides of the present invention may contain analogs of nucleobases. The nucleobase of only one nucleotide unit of the antisense oligonucleotide may be replaced by an analog of a nucleobase, or two, three, four, five or even all of the nucleobases in the antisense oligonucleotide may be replaced by analogs of nucleobases (such as 5-methylcytosine, or N 6 -methyladenine or 2-aminoadenine). Preferably, an LNA unit may be linked to an analog of a nucleobase such as 5-methylcytosine.

[0445] It should be recognized that when referring to the sequence of nucleotides or monomers, what is meant is the sequence of bases (e.g., A, T, G, C or U). However, except for the specific examples disclosed in Tables 3 to 8, the representation of antisense oligonucleotides by the letter codes A, T, G, C and U is to be understood such that the antisense oligonucleotides can contain any nucleobase disclosed herein, any 3'-terminal group disclosed herein, any 5'-terminal group disclosed herein, and any internucleotide linkage (also referred to as an internucleotide bridge) disclosed herein. The nucleotides A, T, G, C and U should also be understood to be LNA nucleotides or non-LNA nucleotides, such as preferably DNA nucleotides.

[0446] Only in the specific examples disclosed in Tables 4 to 9, the nucleobases, LNA units, non-LNA units, internucleotide linkages and terminal groups are further specified as described in the "Text Description" section before Table 2.

[0447] The antisense oligonucleotides disclosed herein and salts of the antisense oligonucleotides have been shown to be complementary to a target (gene encoding TGF-R II or mRNA encoding TGF-R II ), i.e., hybridize well enough and have sufficient specificity and especially selectivity to produce the desired inhibitory effect.

[0448] The term "salt" refers to a physiologically and / or pharmaceutically acceptable salt of the antisense oligonucleotides of the present invention. The antisense oligonucleotides contain nucleobases such as adenine, guanine, thymine, cytosine or derivatives thereof, which are basic and form salts such as chlorides or mesylates. The internucleotide linkages preferably contain negatively charged oxygen or sulfur atoms that form salts such as sodium, lithium or potassium salts. Thus, pharmaceutically acceptable base addition salts are formed with inorganic or organic bases. Examples of suitable organic and inorganic bases are bases derived from metal ions, such as aluminum, alkali metal ions such as sodium or potassium, alkaline earth metal ions such as calcium or magnesium, or amine salt ions or alkali metal or alkaline earth metal hydroxides, -carbonates or -bicarbonates. Examples include aqueous LiOH, NaOH, KOH, NH4OH, potassium carbonate, ammonia and sodium bicarbonate, ammonium salts, primary, secondary and tertiary amines, such as tetraalkylammonium hydroxides, lower alkylamines such as methylamine, tert-butylamine, procaine, ethanolamine, arylalkylamines such as dibenzylamine and N,N-dibenzylethylenediamine, lower alkylpiperidines such as N-ethylpiperidine, cycloalkylamines such as cyclohexylamine or dicyclohexylamine, morpholine, glucosamine, N-methyl- and N,N-dimethylglucosamine, 1-adamantanamine, benzathine penicillin or salts derived from amino acids such as arginine, lysine, ornithine or amides of the original neutral or acidic amino acids, chloroprocaine, choline, procaine, etc.

[0449] Because antisense oligonucleotides are basic, they form pharmaceutically acceptable salts with organic and inorganic acids. Examples of suitable acids for such acid addition salt formation are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, para-aminosalicylic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, sulfonic acid, phosphonic acid, perchloric acid, nitric acid, formic acid, propionic acid, gluconic acid, lactic acid, tartaric acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid, para-aminobenzoic acid, para-hydroxybenzoic acid, methanesulfonic acid, ethanesulfonic acid, nitrous acid, hydroxyethanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, sulfanilic acid, camphorsulfonic acid, boric acid, mandelic acid, o-methylmandelic acid, hydrogen-benzenesulfonic acid, picric acid, adipic acid, D-o-tolyltartaric acid, malic acid, toluic acid, (o, m, p)-xylene carboxylic acid, naphthylamine sulfonic acid and other mineral or carboxylic acids known to those skilled in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in a conventional manner.

[0450] In the context of the present invention, "hybridization" refers to nucleic acid hybridization, in which single-stranded nucleic acids (DNA or RNA) interact with another single-stranded nucleic acid having a very similar or even complementary sequence. Thus, the interaction occurs through hydrogen bonds (base pairing) between specific nucleobases.

[0451] As used herein, the term "complementarity" (DNA and RNA base pair complementarity) refers to the ability of two nucleic acids to pair precisely. The nucleotides in a base pair are complementary when their shapes allow them to bond together through hydrogen bonds. Thus, a pair of adenine and thymidine (or uracil) forms two hydrogen bonds and a cytosine-guanine pair forms three hydrogen bonds. The "complementary sequence" as used herein refers to a DNA or RNA sequence such that when they are aligned antiparallel to each other, the nucleobases at each position in the sequence will be complementary, much like looking in a mirror and seeing the opposite.

[0452] The term "specifically hybridizable" as used herein denotes a sufficient degree of complementarity or exact base pairing between an antisense oligonucleotide and a target sequence such that stable and specific binding occurs between the antisense oligonucleotide and the DNA or RNA target. Although 100% complementarity is preferred, the sequence of the oligonucleotides according to the present invention need not have 100% complementarity with the sequence of the target nucleic acid to which it is specifically hybridizable. Thus, "100% complementarity" means that the antisense oligonucleotide hybridizes to the target over its entire or whole length without mismatches. In other words, in the present invention, an antisense compound is defined as specifically hybridizable when the compound binds to the target DNA or RNA molecule under physiological or pathological conditions but nonspecific binding of the antisense oligonucleotide to non-target sequences is highly unlikely or even impossible.

[0453] Accordingly, the present invention preferably relates to an antisense oligonucleotide, wherein the antisense oligonucleotide binds to the mRNA encoding TGF RII with 100% complementarity and does not bind to any other region in the complete human transcriptome. Further preferably, the present invention relates to an antisense oligonucleotide, wherein the antisense oligonucleotide has 100% complementarity with the mRNA encoding TGF RII over its entire length and does not have off-target effects. Alternatively, the present invention preferably relates to an antisense oligonucleotide having 100% complementarity with the mRNA encoding TGF RII but no complementarity with another mRNA of the human transcriptome. Thus, the term "human transcriptome" refers to the total collection of transcripts in the human organism, which means transcripts of all cell types and environmental conditions (at any given time).

[0454] Specificity

[0455] Common to the antisense oligonucleotides of the present invention is that they are specific for the region of the gene or mRNA encoding TGF-R II According to the present invention, preferably, in the human transcriptome, the antisense oligonucleotide has 100% complementarity with the mRNA encoding TGF-R II over its entire length. In addition, an object of the present invention is to find antisense oligonucleotides without cross-reactivity within the transcriptome of mammals other than monkeys; in particular, the antisense oligonucleotide has cross-reactivity only with the transcriptome of great apes. This should avoid failure. Thus, the antisense oligonucleotides of the present invention have a high degree of specificity in hybridization with the gene or mRNA encoding TGF-R II The antisense oligonucleotides of the present invention preferably specifically bind with 100% complementarity over their entire length to the gene encoding TGF-R II or the mRNA encoding TGF-R II and do not bind to any other region in the complete human transcriptome. This means that the antisense oligonucleotides of the present invention hybridize to the target (TGF-R II mRNA) without mismatches.

[0456] As used herein, the term "mRNA" can include mRNA containing introns (also known as precursor mRNA) as well as mRNA without any introns.

[0457] The antisense oligonucleotides of the present invention are capable of binding or hybridizing to pre-mRNA and / or mRNA. This means that the antisense oligonucleotides can bind or hybridize at or within the intron regions of pre-mRNA, or can bind or hybridize at the overlapping intron-exon regions of pre-mRNA, or can bind or hybridize at or within the exon regions of pre-mRNA and at or within the exon regions of mRNA (see Figure 1 ). Preferred are antisense oligonucleotides capable of binding or hybridizing to pre-mRNA and mRNA. Binding or hybridization of the antisense oligonucleotide (ASO) to pre-mRNA inhibits 5'-cap formation, inhibits splicing of pre-mRNA to obtain mRNA and activates ribonuclease H that cleaves pre-mRNA. Binding or hybridization of the antisense oligonucleotide (ASO) to mRNA activates ribonuclease H, which cleaves mRNA and inhibits the binding of ribosomal subunits.

[0458] The antisense oligonucleotides of the present invention consist of at least 10 and no more than 28, preferably no more than 24, more preferably no more than 20 nucleotides, and thus consist of 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 nucleotides, preferably consisting of 11 to 20, or 11 to 19, or 12 to 19, or 13 to 19, or 13 to 18 nucleotides, and more preferably consisting of 14 to 18 nucleotides, wherein at least two, preferably three of these nucleotides are locked nucleic acids (LNA). Shorter antisense oligonucleotides, i.e., antisense oligonucleotides having fewer than 10 nucleotides are also possible, but the shorter the antisense oligonucleotide, the higher the risk that hybridization will no longer be strong enough and selectivity will be reduced or lost. Non-selective antisense oligonucleotides have the risk of binding to undesired regions in the human transcriptome and to undesired mRNAs encoding other proteins that are not TGF-R II , thus causing undesired side effects. Longer antisense oligonucleotides having more than 20 nucleotides are also possible, but further increasing the length makes the synthesis of such antisense oligonucleotides more complex and expensive without any further benefit of increasing the selectivity or strength of hybridization or better stability with respect to degradation.

[0459] Accordingly, the present invention relates to antisense oligonucleotides consisting of 10 to 20 nucleotides, wherein at least two nucleotides and preferably the 3' and 5' terminal nucleotides are LNA. Thus, preferably at least the terminal 3' nucleotide is LNA and at least the 5' terminal nucleotide is LNA. In the case where there are more than 2 LNAs, preferably the additional LNAs are linked to the 3' or 5' terminal LNA, just like the gapmers disclosed herein.

[0460] One nucleotide structural unit present in the antisense oligonucleotides of the present invention can be represented by the following general formulas (B1) and (B2):

[0461]

[0462] wherein

[0463] B represents a nucleobase;

[0464] IL’ represents -X”-P(=X’)(X - )-;

[0465] R represents -H, -F, -OH, -NH2, -OCH3, -OCH2CH2OCH3 and R # represents -H:

[0466] or R and R # together form a bridge -R # -R-, which is selected from -CH2-O-, -CH2-S-, -CH2-NH-, -CH2-N(CH3)-, -CH2-N(C2H5)-, -CH2-CH2-O-, -CH2-CH2-S-, -CH2-CH2-NH-, -CH2-CH2-N(CH3)-, or -CH2-CH2-N(C2H5)-;

[0467] X’ represents =O or =S;

[0468] X - represents -O - , -OH, -OR H , -NHR H , -N(R H )2, -OCH2CH2OR H , -OCH2CH2SR H , -BH3 - , -R H , -SH, -SR H , or -S - ;

[0469] X” represents -O-, -NH-, -NR H -, -CH2-, or -S-;

[0470] Y is -O-, -NH-, -NR H -, -CH2- or -S-;

[0471] R H is selected from hydrogen and C 1-4 -alkyl and preferably -CH3 or -C2H5 and most preferably -CH3.

[0472] Preferably X - represents -O - , -OH, -OCH3, -NH(CH3), -N(CH3)2, -OCH2CH2OCH3, -OCH2CH2SCH3, -BH3 - , -CH3, -SH, -SCH3, or -S - ; and more preferably -O - , -OH, -OCH3, -N(CH3)2, -OCH2CH2OCH3, -BH3 - , -SH, -SCH3, or -S - .

[0473] IL’ preferably represents -O-P(O)(O - ), -O-P(O)(S - ), -O-P(S)(S - ), -S-P(O)(O - ), -S-P(O)(S - ), -S-P(S)(S - ), -O-P(O)(O - ), -O-P(O)(S - ), -S-P(O)(O - ), -O-P(O)(R H ), -O-P(O)(OR H ), -O-P(O)(NHR H ), -O-P(O)[N(R H )2]-, -O-P(O)(BH3 - ), -O-P(O)(OCH2CH2OR H ), -O-P(O)(OCH2CH2SR H ), -O-P(O)(O - ), -NR H -P(O)(O - ), where R H is selected from hydrogen and C 1-4 -alkyl.

[0474] The group -P-P(O)(R H )-O- is preferably -O-P(O)(CH3)-O- or -O-P(O)(C2H5)-O- and most preferably -O-P(O)(CH3)-O-.

[0475] The group -O-P(O)(OR H)-O- is preferably -P-P(O)(OCH3)-O- or -O-P(O)(OC2H5)-O-, and most preferably -O-P(O)(OCH3)-O-.

[0476] The group -O-P(O)(NHR H )-O- is preferably -O-P(O)(NHCH3)-O- or -O-P(O)(NHC2H5)-O-, and most preferably -O-P(O)(NHCH3)-O-.

[0477] The group -O-P(O)[N(R H )2]-O- is preferably -O-P(O)[N(CH3)2]-O- or -O-P(O)[N(C2H5)2]-O-, and most preferably -O-P(O)[N(CH3)2]-O-.

[0478] The group -O-P(O)(OCH2CH2OR H )-O- is preferably -O-P(O)(OCH2CH2OCH3)-O- or -O-P(O)(OCH2CH2OC2H5)-O-, and most preferably -O-P(O)(OCH2CH2OCH3)-O-.

[0479] The group -O-P(O)(OCH2CH2SR H )-O- is preferably -O-P(O)(OCH2CH2SCH3)-O- or -O-P(O)(OCH2CH2SC2H5)-O-, and most preferably -O-P(O)(OCH2CH2SCH3)-O-.

[0480] The group -O-P(O)(O - )-NR H - is preferably -O-P(O)(O - )-NH- or -O-P(O)(O - )-N(CH3)- and most preferably -O-P(O)(O - )-NH-.

[0481] The group -NR H -P(O)(O - )-O- is preferably -NH-P(O)(O - )-O- or -N(CH3)-P(O)(O - )-O- and most preferably -NH-P(O)(O - )-O-.

[0482] More preferably, IL’ represents -O-P(O)(O - )-, -O-P(O)(S -)-, -O-P(S)(S - )-, -O-P(O)(NHR H )-, or -O-P(O)[N(R H )2]-, and more preferably IL’ represents -O-P(O)(O - )-, -O-P(O)(S - )-, or -O-P(S)(S - )-, and most preferably IL’ represents -O-P(O)(S - )-, or -O-P(S)(S - )-.

[0483] Preferably, Y represents -O-.

[0484] Preferably, B represents a nucleobase selected from A, T, G, C, U.

[0485] Preferably, IL represents -O-P(=O)(S - )- or -O-P(=S)(S - )-.

[0486] The above definitions of B, Y and IL′ also apply to formula b 1 to b 9 .

[0487] Therefore, the following general formulas (B3) to (B6) are preferred:

[0488]

[0489] wherein

[0490] B represents a nucleobase and preferably A, T, G, C, U;

[0491] R represents -H, -F, -OH, -NH2, -N(CH3)2, -OCH3, -OCH2CH2OCH3, -OCH2CH2CH2OH, -OCH2CH2CH2NH2 and preferably -H;

[0492] R ＊ represents the moiety -R as defined below # -R- and is preferably selected from, for example, -C(R a R b )-O-, -C(R a R b )-NR c -, -C(R a R b )-S-, and -C(R a R b )-C(R a R b)-O-, wherein the substituent R a 、R b and R c have the meanings as defined herein. More preferably, R ＊ is selected from -CH2-O-, -CH2-S-, -CH2-NH-, -CH2-N(CH3)-, -CH2-CH2-O-, or -CH2-CH2-S-, and more preferably -CH2-O-, -CH2-S-, -CH2-CH2-O-, or -CH2-CH2-S-, and more preferably -CH2-O-, -CH2-S-, or -CH2-CH2-O-, and more preferably -CH2-O- or -CH2-S-, and most preferably -CH2-O-.

[0493] Examples of preferred nucleotides of non-LNA units are as follows:

[0494]

[0495]

[0496] Internucleotide linkage (IL)

[0497] The monomers of the antisense oligonucleotides described herein are coupled together by internucleotide linkages. Suitably, each monomer is linked to the adjacent 3'-monomer by an internucleotide linkage. Those of ordinary skill in the art will understand that in the context of the present invention, the 5'-monomer at the oligomer terminus does not contain a 5'-internucleotide linkage, although it may or may not contain a 5'-terminal group. The term "internucleotide linkage" is intended to denote a group capable of covalently coupling two nucleotides, two nucleotide analogues such as two LNAs, and a nucleotide and a nucleotide analogue such as LNA. Specific and preferred examples include phosphate groups and phosphorothioate groups.

[0498] The nucleotides or their consecutive nucleotide sequences of the antisense oligonucleotides of the present invention are coupled together by internucleotide linkages. Each nucleotide is suitably linked to the adjacent 3'-nucleotide through the 5'-position by an internucleotide linkage.

[0499] Antisense oligonucleotides can be modified in several different ways. Modifications within the backbone are possible and refer to antisense oligonucleotides in which the phosphate groups (also called phosphodiester groups) in their internucleotide backbones are partially or completely replaced by other groups. Preferred modified antisense oligonucleotide backbones include, for example, phosphorothioates, chiral phosphorothioates, dithiophosphates, phosphotriesters, aminoalkylphosphates, methyl, ethyl, and C3-C 10Alkyl phosphonates, including 3′-alkylene phosphonates and chiral phosphonates, phosphinates, amino phosphates, including 3′-aminoamino phosphates and aminoalkyl phosphoramidates, phosphorothioamidates, thioalkyl phosphates, thioalkyl phosphotriesters and borane phosphates, 2′-5′ linked analogs thereof, and those of opposite polarity, wherein adjacent nucleotide units are linked 3′-5′ to 5′-3′ or 2′-5′ to 5′-2′. Also further included and disclosed herein in detail are their various salt, mixed salt and free acid forms.

[0500] Suitable internucleotide linkage connections include those listed in WO2007 / 031091, such as the internucleotide linkages listed in the first paragraph on page 34 of WO2007 / 031091 (incorporated herein by reference). In some embodiments, it is preferred to modify the internucleotide linkage from its normal phosphodiester to an internucleotide linkage more resistant to nuclease attack, such as modification to a phosphorothioate or boranophosphate, both of which are resistant to RNase H-mediated cleavage and also allow the antisense inhibition pathway in reducing the expression of the target gene.

[0501] The internucleotide linkage consists of a group IL′ bonded to the 3′ carbon atom of the ribose moiety and a group Y bonded to the 5′ carbon atom of the contiguous ribose moiety, as shown by the following formula (IL’Y).

[0502]

[0503] The internucleotide linkage IL is represented by -IL′-Y-. 1L′ represents -X”-P(=X’)(X - )-, such that IL is represented by -X”-P(=X’)(X - )-Y-, wherein the substituents X - , X’, X” and Y have the meanings disclosed herein.

[0504] The internucleotide linkage IL = -X”-P(=X’)(X - )-Y- is preferably selected from:

[0505] -O-P(O)(O - )-O-, -O-P(O)(S - )-O-, -O-P(S)(S - )-O-, -S-P(O)(O - )-O-, -S-P(O)(S - )-O-, -S-P(S)(S - )-O-, -O-P(O)(O - )-S-, -O-P(O)(S -)-S-,-SP(O)(O - )-S-,-OP(O)(R H )-O-, -OP(O)(OR H )-O-,-OP(O)(NHR H )-O-,-OP(O)[N(R H )2]-O-, -OP(O)(BH3 - )-O-,-OP(O)(OCH2CH2OR H )-O-,-OP(O)(OCH2CH2SR H )-P-,-OP(O)(O - )-NR H -, -NR H -P(O)(O - )-O-, where R H Selected from hydrogen and C 1-4 -alkyl.

[0506] Group-PP(O)(R H )-P- is preferably -OP(O)(CH3)-O- or -OP(O)(C2H5)-O- and most preferably -OP(O)(CH3)-O-.

[0507] Group -OP(O)(OR H )-O- is preferably -PP(O)(OCH3)-P- or -OP(O)(OC2H5)-P- and most preferably -PP(O)(OCH3)-P-.

[0508] Group-PP(O)(NHR H )-O- is preferably -OP(O)(NHCH3)-O- or -OP(O)(NHC2H5)-O- and most preferably -OP(O)(NHCH3)-O-.

[0509] Group -PP(O)[N(R H )2]-P- is preferably -PP(O)[N(CH3)2]-P- or -OP(O)[N(C2H5)2]-O- and most preferably -OP(O)[N(CH3)2]-O-.

[0510] Group -OP(O)(OCH2CH2OR H )-O- is preferably -OP(O)(OCH2CH2OCH3)-O- or -PP(O)(OCH2CH2OC2H5)-O- and most preferably -OP(O)(OCH2CH2OCH3)-O-.

[0511] The group -O-P(O)(OCH2CH2SR H )-O- is preferably -O-P(O)(OCH2CH2SCH3)-O- or -O-P(O)(OCH2CH2SC2H5)-P-, and most preferably -P-P(O)(OCH2CH2SCH3)-O-.

[0512] The group -O-P(O)(O - )-NR H - is preferably -O-P(O)(O-)-NH- or -O-P(O)(O - )-N(CH3)-, and most preferably -P-P(O)(O - )-NH-.

[0513] The group -NR H -P(O)(O - )-O- is preferably -NH-P(O)(O - )-O- or -N(CH3)-P(O)(O - )-O-, and most preferably -NH-P(O)(O - )-O-.

[0514] More preferably, IL represents -O-P(O)(O - )-O-, -O-P(O)(S - )-O-, -O-P(S)(S - )-O-, -O-P(O)(NHR H )-O-, or -O-P(O)[N(R H )2]-O-, and even more preferably IL represents -O-P(O)(O - )-O-, -O-P(O)(S - )-O-, or -O-P(S)(S - )-O-, and most preferably IL represents -O-P(O)(S - )-O-, or -O-P(O)(O - )-O-.

[0515] Therefore, IL is preferably a phosphate group (-O-P(O)(O - )-O-), a thiophosphate group (-O-P(O)(S - )-O-), or a dithiophosphate group (-O-P(S)(S - )-O-).

[0516] The nucleotide units or nucleosides of the antisense oligonucleotides are linked to each other by internucleotide linkages such that different internucleotide linkages can be present within one antisense oligonucleotide. The LNA units are preferably linked by internucleotide linkages other than phosphate groups. The LNA units are linked to each other by IL groups preferably selected from -O-P(O)(S - )-O-, -O-P(S)(S - )-O-, -O-P(O)(NHR H )-O-, and -O-P(O)[N(R H )2]-O- and more preferably selected from -O-P(O)(S - )-O- and -O-P(S)(S - )-O-.

[0517] The non-LNA units are linked to each other by IL groups preferably selected from -O-P(O)(O - )-O-, -O-P(O)(S - )-O-, -O-P(S)(S - )-O-, -O-P(O)(NHR H )-O-, and -O-P(O)[N(R H )2]-O- and more preferably selected from -O-P(O)(O - )-O-, -O-P(O)(S - )-O- and -O-P(S)(S - )-O-.

[0518] The non-LNA units are linked to the LNA units by IL groups preferably selected from -O-P(O)(S - )-O-, -O-P(S)(S - )-O-, -O-P(O)(NHR H )-O-, and -O-P(O)[N(R H )2]-O- and more preferably selected from -O-P(O)(S - )-O- and -O-P(S)(S - )-O-.

[0519] As used herein, the term "LNA unit" refers to a locked nucleotide, i.e., a nucleotide having a bicyclic structure, particularly a bicyclic ribose structure, more particularly a bicyclic ribose structure represented by the general formula (II). The bridge "locks" the ribose in the 3'-endo (north) conformation. The ribose moiety of the LNA nucleotide is modified with an additional bridge connecting the 2'-oxygen and the 4'-carbon. Optionally, the term used for LNA is bicyclic nucleotide or bridged nucleotide, and thus, an alternative term for the LNA unit is bicyclic nucleotide unit or bridged nucleotide unit.

[0520] As used herein, the term "non-LNA unit" refers to a nucleotide that is not locked, i.e., a nucleotide that does not have a bicyclic sugar moiety, particularly no bicyclic ribose structure, and more particularly no bicyclic ribose structure as shown in general formula (II). The non-LNA unit is most preferably a DNA unit.

[0521] As used herein, the term "DNA unit" refers to a nucleotide containing 2-deoxyribose as the sugar. Thus, the nucleotide is made up of a nucleobase and 2-deoxyribose.

[0522] As used herein, the term "unit" refers to a segment or fragment or part of an antisense oligonucleotide of the present invention. Thus, a "unit" is not a complete molecule; it is a segment or fragment or part of an antisense oligonucleotide that has at least one position for covalent linkage to another segment or fragment or part of the antisense oligonucleotide. For example, the general structures (B1) to (B6) are units because they can be covalently linked through group Y and IL' or -O- and -O-P(O)(S - )- respectively. Preferably, a unit is a moiety consisting of a pentose structure, a nucleobase linked to the pentose structure, a 5'-group, and an IL' group.

[0523] As used herein, the term "structural unit" or "monomer" refers to a molecule, particularly a nucleoside for synthesizing the antisense oligonucleotides of the present invention. An example is an LNA molecule of general formula (I), where Y represents a 5'-terminal group and IL' represents a 3'-terminal group.

[0524]

[0525] Sulfur (S) containing the internucleotide linkages provided herein is preferred.

[0526] In the backbone, a phosphorothioate moiety is preferred, where at least 50% of the internucleotide linkages are phosphorothioate groups. It is also preferred that LNA units (if present) are linked through phosphorothioate as the internucleotide linkage. Most preferably, it is a complete phosphorothioate backbone, i.e., most preferably when all nucleotide units and LNA units (if present) are linked to each other through a phosphorothioate group as defined below: -O-P(O)(S - )-O-, which is synonymous with -O-P(O,S)-O- or -O-P(O - )(S)-O-.

[0527] In the case where the antisense oligonucleotide is a gapmer, it is preferred that the LNA region has a group selected from -O-P(O)(S - )-O- and -O-P(S)(S -)-O- internucleotide linkages, and the non-LNA region (middle part) has internucleotide linkages selected from -O-P(O)(O - )-O-, -O-P(O)(S - )-O- and -O-P(S)(S - )-O- internucleotide linkages, and the LNA region is linked to the non-LNA region through internucleotide linkages selected from -O-P(O)(O - )-O-, -O-P(O)(S - )-O- and -O-P(S)(S - )-O-.

[0528] Even more preferably, all internucleotide linkages are 9 in a decamer and 19 in a 20-mer and are selected from -O-P(O)(S - )-O- and -O-P(S)(S - )-O-. More preferably, all internucleotide linkages are phosphorothioate groups (-O-P(O)(S - )-O-) or phosphorodithioate groups (-O-P(S)(S - )-O-).

[0529] Locked nucleic acid

[0530] Particularly preferably, some nucleotides of the general formula (B1) or (B2) in the antisense oligonucleotide are replaced by so-called LNA (locked nucleic acid). The abbreviation LNA is a registered trademark, but in this text, the term "LNA" is used only in a descriptive manner.

[0531] Preferably, the terminal nucleotides are replaced by LNA, more preferably the last 1 to 4 nucleotides at the 3'-end and / or the last 1 to 4 nucleotides at the 5'-end are replaced by LNA. It is also preferred that at least the terminal nucleotides at the 3'-end and 5'-end are each replaced by LNA.

[0532] As used herein, the term "LNA" refers to a bicyclic nucleotide analogue known as "locked nucleic acid". It can refer to an LNA monomer, or when used in the context of an "LNA antisense oligonucleotide" or an "antisense oligonucleotide containing LNA", LNA refers to an oligonucleotide containing one or more such bicyclic nucleotide analogues. LNA nucleotides are characterized by the presence of a linking group (such as a bridge) between C2' and C4' of the ribose sugar ring, such as the bivalent group R # -R shown. The LNA used in the antisense oligonucleotides of the present invention preferably has the structure of the general formula (I),

[0533]

[0534] For all chiral centers, the asymmetric groups can be found in the R or S orientation;

[0535] wherein X is selected from -O-, -S-, -N(R N )-, -C(R 6 R 7 )-, preferably X is -O-;

[0536] B is selected from hydrogen, optionally substituted C 1-4 -alkoxy, optionally substituted C 1-4 -alkyl, optionally substituted C 1-4 -acyloxy, nucleobases and nucleobase analogs, preferably B is a nucleobase or a nucleobase analog, most preferably a standard nucleobase.

[0537] When the moiety of formula (I) is an LNA unit of the antisense oligonucleotide of the present invention, Y represents a part of the internucleotide linkage with an adjacent nucleotide, or when the moiety of formula (I) is a monomer or structural unit for synthesizing the antisense oligonucleotide of the present invention, Y represents a 5'-terminal group. The 5'-carbon atom optionally includes substituents R 4 and R 5 ;

[0538] When the moiety of formula (I) is an LNA unit of the antisense oligonucleotide of the present invention, IL' represents a part of the internucleotide linkage with an adjacent nucleotide, or when the moiety of formula (I) is a monomer or structural unit for synthesizing the antisense oligonucleotide of the present invention, IL' represents a 3'-terminal group.

[0539] R # and R together represent a divalent linking group composed of 1-4 groups or atoms selected from -C(R a R b )-, -C(R a )=C(R b )-, -C(R a )=N-, -O-, -Si(R a )2-, -S-, -SO2-, -N(R c )-, and >C=Z, wherein Z is selected from -O-, -S-, and -N(R a )-, R a , R b and R c are independently selected from hydrogen, optionally substituted C 1-12 -alkyl, optionally substituted C 2-6 -alkenyl, optionally substituted C 2-6 -alkynyl, hydroxy, optionally substituted C 1-12 -alkoxy, C1-6 -alkoxy-C 1-6 -alkyl, C 2-6 -alkenyloxy, carboxyl, C 1-12 -alkoxycarbonyl, C 1-12 -alkylcarbonyl, formyl, aryl, aryloxy-carbonyl, aryloxy, arylcarbonyl, heteroaryl, heteroaryloxy-carbonyl, heteroaryloxy, heteroarylcarbonyl, amino, mono- and di(C 1-6 -alkyl)amino, carbamoyl, mono- and di(C 1-6 -alkyl)-amino-carbonyl, amino-C 1-6 -alkylene-amino-carbonyl, mono- and di(C 1-6 -alkyl)amino-C 1-6 -alkylene-amino-carbonyl, C 1-6 -alkyl-carbonylamino, carbamoyl, C 1-6 -alkanoyloxy, sulfonyl, C 1-6 -alkyl sulfonyloxy, nitro, azido, thioalkyl, C 1-6 -alkylthio, halogen, wherein the aryl and heteroaryl may be optionally substituted, wherein two vicinal substituents R a and R b may together represent optionally substituted methylene(=CH2), wherein for all chiral centers, the asymmetric groups may be found in the R or S orientation;

[0540] The substituents R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 each independently selected from hydrogen, optionally substituted C 1-12 -alkyl, optionally substituted C 2-6 -alkenyl, optionally substituted C 2-6 -alkynyl, hydroxy, C 1-12 -alkoxy, C 1-6 -alkoxy-C 1-6 -alkyl, C 2-6 -alkenyloxy, carboxyl, C 1-12 -alkoxycarbonyl, C 1-12 -alkylcarbonyl, formyl, aryl, aryloxy-carbonyl, aryloxy, arylcarbonyl, heteroaryl, heteroaryloxycarbonyl, heteroaryloxy, heteroarylcarbonyl, amino, mono- and di(C 1-6 -alkyl)amino, carbamoyl, mono- and di(C 1-6 -alkyl)-amino-carbonyl, amino-C 1-6 -alkyl-amino-carbonyl, mono- and di(C 1-6-alkyl)amino-C 1-6 -alkyl -aminocarbonyl, C 1-6 -alkyl-carbamoylamino, carbamoyl, C 1-6 -alkanoyloxy, sulfonyl, C 1-6 -alkylsulfonyloxy, nitro, azido, thioalkyl, C 1-6 -alkylthio, halogen, wherein aryl and heteroaryl may be optionally substituted, and wherein two geminal substituents together may represent oxo, thioxo, imino or optionally substituted methylene;

[0541] wherein R N is selected from hydrogen and C 1-4 -alkyl, and wherein two adjacent (non-geminal) substituents may represent an additional bond that results in a double bond; and when present and not participating in a double bond, R N is selected from hydrogen and C 1-4 -alkyl; and its base salts and its acid addition salts. For all chiral centers, the asymmetric groups may be found in the R or S orientation.

[0542] In a preferred embodiment, R # and R together represent a double group composed of groups selected from -C(R a R b )-C(R a R b )-, -C(R a R b )-O-, -C(R a R b )-NR c -, -C(R a R b )-S-, and -C(R a R b )-C(R a R b )-O-, wherein each R a , R b and R c may be optionally independently selected.

[0543] In some embodiments, R a and R b may be optionally independently selected from hydrogen and C 1-6 -alkyl, such as methyl, and preferably hydrogen.

[0544] In a preferred embodiment, R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from hydrogen, halogen, C1-6 -alkyl, substituted C 1-6 -alkyl, C 2-6 -alkenyl, substituted C 2-6 -alkenyl, C 2-6 -alkynyl or substituted C 2-6 -alkynyl, C 1-6 alkoxy, substituted C 1-6 alkoxy, acyl, substituted acyl, C 1-6 -aminoalkyl or substituted C 1-6 -aminoalkyl. For all chiral centers, the asymmetric groups can be found in the R or S orientation.

[0545] In a preferred embodiment, R 1 , R 2 , R 3 , R 4 and R 5 are hydrogen.

[0546] In some embodiments, R 1 , R 2 and R 3 are independently selected from hydrogen, halogen, C 1-6 -alkyl, substituted C 1-6 -alkyl, C 2-6 -alkenyl, substituted C 2-6 -alkenyl, C 2-6 -alkynyl, or substituted C 2-6 -alkenyl, C 1-6 -alkoxy, substituted C 1-6 -alkoxy, acyl, substituted acyl, C 1-6 -aminoalkyl or substituted C 1-6 -aminoalkyl. For all chiral centers, the asymmetric groups can be found in the R or S orientation. In a preferred embodiment, R 1 , R 2 and R 3 are hydrogen.

[0547] In a preferred embodiment, R 4 and R 5 are each independently selected from -H, -CH3, -CH2-CH3, -CH2-O-CH3 and -CH=CH2. Suitably, in some embodiments, R 4 or R 5 is hydrogen, while the other group (R 4 or R 5 respectively) is selected from C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, substituted C 2-6-alkynyl, substituted C 2-6 -alkynyl or substituted acyl (-C(=O)-). Each of the substituent groups is monosubstituted or polysubstituted, and the substituents are independently selected from halogen, C 1-6 -alkyl, substituted C 1-6 -alkyl, C 2-6 -alkenyl, substituted C 2-6 -alkenyl, C 2-6 -alkynyl, substituted C 2-6 -alkynyl, -OJ1, -SJ1, -NJ1J2, -N3, -COOJ1, -CN, -O-C(=O)NJ1J2, -N(H)C(=NH)NJ1J2 or -N(H)C(=X)N(H)J2, where X is O or S; and each J1 and J2 is independently -H, C 1-6 -alkyl, substituted C 1-6 -alkyl, C 2-6 -alkenyl, substituted C 2-6 -alkenyl, C 2-6 -alkynyl, substituted C 2-6 -alkynyl, C 1-6 -aminoalkyl, substituted C 1-6 -aminoalkyl or a protecting group. In some embodiments, R 4 or R 5 is substituted C 1-6 -alkyl. In some embodiments, R 4 or R 5 is substituted methylene, and the preferred substituents include one or more groups independently selected from -F, -NJ1J2, -N3, -CN, -OJ1, -SJ1, -O-C(=O)NJ1J2, -N(H)C(=NH)NJ1J2 or -N(H)C(=O)N(H)J2. In some embodiments, each J1 and J2 is independently -H or C 1-6 -alkyl. In some embodiments, R 4 or R 5 is methyl, ethyl or methoxymethyl. In some embodiments, R 4 or R 5 is methyl. In another embodiment, R 4 or R 5 is ethylene. In some embodiments, R 4 or R 5 is substituted acyl. In some embodiments, R 4 or R 5is -O-C(=O)NJ1J2. For all chiral centers, the asymmetric groups can be found in the R or S orientation. Such 5′-modified bicyclic nucleotides are disclosed in WO 2007 / 134181A, the entire content of which is incorporated herein by reference.

[0548] In some embodiments, B is a nucleobase, including nucleobase analogs and naturally occurring nucleobases, such as purines or pyrimidines, or substituted purines or substituted pyrimidines, such as the nucleobases described herein, such as nucleobases selected from adenine, cytosine, thymine, adenine, uracil and / or modified or substituted nucleobases, such as 5-thiazolidinyl-uracil, 2-thio-uracil, 5-propynyl-uracil, 2′-thio-thymine, 5-methylcytosine, 5-thiazolo-cytosine, 5-propynyl-cytosine and 2,6-diaminopurine.

[0549] In a preferred embodiment, R # and R together represent a group selected from -C(R a R b )-O-, -C(R a R b )-C(R c R d )-O-, -C(R a R b )-C(R c R d )-C(R e R f )-O-, -C(R a R b )-O-C(R d R e )-, -C(R a R b )-O-C(R d R e )-O-, -C(R a R b )-C(R d R e )-, -C(R a R b )-C(R c R d )-C(R e R f )-, -C(R a )=C(R b )-C(R d R e )-, -C(R a R b )-N(R c )-, -C(Ra R b )-C(R d R e )-N(R c )-,-C(R a R b )-N(R c )-O-,-C(R a R b )-S-,-and-C(R a R b )-C(R d R e )-S- of the bivalent group,R a ,R b ,R c ,R d ,R e ,and R f each independently selected from hydrogen,optionally substituted C 1-12 -alkyl,optionally substituted C 2-6 -alkenyl,optionally substituted C 2-6 -alkynyl,hydroxy,C 1-12 -alkoxy,C 1-6 -alkoxy-C 1-6 -alkyl,C 2-6 -alkenyloxy,carboxy,C 1-12 -alkoxycarbonyl,C 1-12 -alkylcarbonyl,formyl,aryl,aryloxy-carbonyl,aryloxy,arylcarbonyl,heteroaryl,heteroaryloxycarbonyl,heteroaryloxy,heteroarylcarbonyl,amino,mono-and di(C 1-6 -alkyl)amino,carbamoyl,mono-and di(C 1-6 -alkyl)-amino-carbonyl,amino-C 1-6 -alkyl-aminocarbonyl,mono-and di(C 1-6 -alkyl)amino-C 1-6 -alkyl-aminocarbonyl,C 1-6 -alkyl-carbonylamino,carbamoyl,C 1-6 -alkanoyloxy,sulfonyl,C 1-6 -alkylsulfonyloxy,nitro,azido,thioalkyl,C 1-6 -alkylthio,halogen,wherein aryl and heteroaryl may be optionally substituted,wherein two geminal substituents R a and R b together may represent optionally substituted methylene(=CH2).For all chiral centers,the asymmetric groups may be found in the R or S orientation.

[0550] In another embodiment,R #Together with R, represents a bivalent group selected from -CH2-O-, -CH2-S-, -CH2-NH-, -CH2-N(CH3)-, -CH2-CH2-O-, -CH2-CH(CH3)-, -CH2-CH2-S-, -CH2-CH2-NH-, -CH2-CH2-CH2-, -CH2-CH2-CH2-O-, -CH2-CH2-CH(CH3)-, -CH=CH-CH2-, -CH2-O-CH2-O-, -CH2-NH-O-, -CH2-N(CH3)-O-, -CH2-O-CH2-, -CH(CH3)-O-, -CH(CH2-O-CH3)-O-, -CH2-CH2-, and -CH=CH-. For all chiral centers, the asymmetric groups can be found in the R or S orientation.

[0551] In some embodiments, R # and R together represent the bivalent group -C(R a R b )-N(R c )-O-, where R a and R b are independently selected from hydrogen, halogen, C 1-6 -alkyl, substituted C 1-6 -alkyl, C 2-6 -alkenyl, substituted C 2-6 -alkenyl, C 2-6 -alkynyl or substituted C 2-6 -alkynyl, C 1-6 -alkoxy, substituted C 1-6 -alkoxy, acyl, substituted acyl, C 1-6 -aminoalkyl or substituted C 1-6 -aminoalkyl, such as hydrogen, and where R c is selected from hydrogen, halogen, C 1-6 -alkyl, substituted C 1-6 -alkyl, C 2-6 -alkenyl, substituted C 2-6 -alkenyl, C 2-6 -alkynyl or substituted C 2-6 -alkynyl, C 1-6 -alkoxy, substituted C 1-6 -alkoxy, acyl, substituted acyl, C 1-6 -aminoalkyl or substituted C 1-6 -aminoalkyl, preferably hydrogen.

[0552] In a preferred embodiment, R # and R together represent the bivalent group -C(R a R b)-O-C(R d R e )-P-, wherein R a , R b , R d , and R e are independently selected from hydrogen, halogen, C 1-6 -alkyl, substituted C 1-6 -alkyl, C 2-6 -alkenyl, substituted C 2-6 -alkenyl, C 2-6 -alkynyl or substituted C 2-6 -alkynyl, C 1-6 -alkoxy, substituted C 1-6 -alkoxy, acyl, substituted acyl, C 1-6 -aminoalkyl or substituted C 1-6 -aminoalkyl, and preferably hydrogen.

[0553] In a preferred embodiment, R # and R form a bivalent -CH(Z)-P-, wherein Z is selected from C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, substituted C 1-6 -alkyl, substituted C 2-6 -alkenyl, substituted C 2-6 -alkynyl, acyl, substituted acyl, substituted amide, thiol or substituted thiol; and wherein each substituent is independently mono- or polysubstituted by an optionally protected substituent, where the substituents are independently selected from halogen, oxo, hydroxy, -OJ1, -NJ1J2, -SJ1, -N3, -OC(=X)J1, -OC(=X)NJ1J2, -NJ 3 C(=X)NJ1J2 and -CN, wherein each J1, J2 and J3 is independently -H or C 1-6 -alkyl, X is O, S or NJ1. In a preferred embodiment, Z is C 1-6 -alkyl or substituted C 1-6 -alkyl. In a further preferred embodiment, Z is methyl. In a preferred embodiment, Z is substituted C 1-6 -alkyl. In a preferred embodiment, the substituent is C 1-6 -alkoxy. In some embodiments, Z is CH3OCH2-. For all chiral centers, the asymmetric groups can be found in the R or S orientation. This bicyclic nucleotide is disclosed in US 7,399,845, the entire content of which is incorporated herein by reference. In a preferred embodiment, R 1 , R 2 , R 3 , R4 and R 5 is hydrogen. In a preferred embodiment, R 1 , R 2 and R 3 are hydrogen, and one or both of R 4 , R 5 may not be hydrogen as described above and as described in WO 2007 / 134181.

[0554] In a preferred embodiment, R # and R together represent a bivalent group containing a substituted amino group in the bridge, such as the bivalent group -CH2-N(R c ), where R c is C 1-12 -alkoxy. In a preferred embodiment, R # and R together represent the bivalent group -Cq3q4-NOR-, where q3 and q4 are independently selected from hydrogen, halogen, C 1-6 -alkyl, substituted C 1-6 -alkyl, C 2-6 -alkenyl, substituted C 2-6 -alkenyl, C 2-6 -alkynyl or substituted C 2-6 -alkynyl, C 1-6 -alkoxy, substituted C 1-6 -alkoxy, acyl, substituted acyl, C 1-6 -aminoalkyl or substituted C 1-6 -aminoalkyl; where each substituent is independently mono- or polysubstituted by a substituent independently selected from the following: halogen, -OJ1, -SJ1, -NJ1J2, -COOJ1, -CN, -OC(=O)NJ1J2, -NH-C(=NH)NJ1J2 or -NH-C(=X)NHJ2, where X is O or S; J1 and J2 are each independently -H, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 1-6 -aminoalkyl or a protecting group. For all chiral centers, the asymmetric groups can be found in the R or S orientation. Such bicyclic nucleotides are disclosed in WO2008 / 150729, the entire content of which is incorporated herein by reference. In a preferred embodiment, R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from hydrogen, halogen, C 1-6 -alkyl, substituted C 1-6 -alkyl, C 2-6 -alkenyl, substituted C2-6 -enyl, C 2-6 - alkynyl or substituted C 2-6 - alkynyl, C 1-6 - alkoxy, substituted C 1-6 - alkoxy, acyl, substituted acyl, C 1-6 - aminoalkyl or substituted C 1-6 - aminoalkyl. In a preferred embodiment, R 1 , R 2 , R 3 , R 4 and R 5 are hydrogen. In a preferred embodiment, R 1 , R 2 and R 3 are hydrogen, one or both of R 4 , R 5 may not be hydrogen as described above and in WO 2007 / 134181.

[0555] In a preferred embodiment, R # and R together represent a bivalent group -C(R a R b )-O-, where R a and R b are each independently halogen, C 1-12 - alkyl, substituted C 1-12 - alkyl, C 2-6 - alkenyl, substituted C 2-6 - alkenyl, C 2-6 - alkynyl, substituted C 2-6 - alkynyl, C 1-12 - alkoxy, substituted C 1-12 - alkoxy, -OJ1, -SJ1, -S(O)J1, -SO2-J1, -NJ1J2, -N3, -CN, -C(=O)OJ1, -C(=O)NJ1J2, -C(=O)J1, -OC(=O)NJ1J2, -NH-C(=NH)NJ1J2, -NH-C(=O)NJ1J2, or -NH-C(=S)NJ1J2; or R a and R b together are =C(q3)(q4); q3 and q4 are each independently -H, halogen, C 1-12 - alkyl or substituted C 1-12 - alkyl; each substituent is independently selected from halogen, C 1-6 - alkyl, substituted C 1-6 - alkyl, C 2-6 - alkenyl, substituted 2-6 - alkenyl, C2-6 -alkynyl, substituted C 2-6 -alkynyl, -OJ1, -SJ1, -NJ1J2, -N3, -CN, -C(=O)OJ1, -C(=O)NJ1J2, -C(=O)J1, -OC(=O)NJ1J2, -NH-C(=O)NJ1J2, or -NH-C(=S)NJ1J2; each J1 and J2 is independently -H, C 1-6 -alkyl, substituted C 1-6 -alkyl, C 2-6 -alkenyl, substituted C 2-6 -alkenyl, C 2-6 -alkynyl, substituted C 2-6 -alkynyl, C 1-6 -aminoalkyl, substituted C 1-6 -aminoalkyl or a protecting group. Such compounds are disclosed in WO2009006478A, the entire content of which is incorporated herein by reference.

[0556] In a preferred embodiment, R # and R form a bivalent -Q-, where Q is -C(q1)(q2)C(q3)(q4)-, -C(q1)=C(q3)-, -C[=C(q1)(q2 ) -C(q3)(q4)- or -C(q1)(q2)-C[=C(q3)(q4)]-;

[0557] q1, q2, q3, q4 are each independently -H, halogen, C 1-12 -alkyl, substituted C 1-12 -alkyl, C 2-6 -alkenyl, substituted C 1-12 -alkoxy, -OJ1, -SJ1, -S(O)J1, -SO2-J1, -NJ1J2, -N3, -CN, -C(=O)OJ1, -C(=O)NJ1J2, -C(=O)J1, -OC(=O)NJ1J2, -NH-C(=NH)NJ1J2, -NH-C(=O)NJ1J2, or -NH-C(=S)NJ1J2; each J1 and J2 is independently of each other -H, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 1-6 -aminoalkyl or a protecting group; and optionally when Q is -C(q1)(q2)C(q3)(q4)- and one of q3 or q4 is -CH3, then at least one of q3 or q4 or one of q1 and q2 is not -H. In a preferred embodiment, R 1 , R 2 , R3 and R 4 and R 5 is hydrogen. For all chiral centers, the asymmetric groups can be found in the R or S orientation. Such bicyclic nucleotides are disclosed in WO2008 / 154401, the entire content of which is incorporated herein by reference. In a preferred embodiment, R 1 and R 2 and R 3 and R 4 and R 5 are each independently selected from hydrogen, halogen, C 1-6 -alkyl, substituted C 1-6 -alkyl, C 2-6 -alkenyl, substituted C 2-6 -alkenyl, C 2-6 -alkynyl or substituted C 2-6 -alkynyl, C 1-6 -alkoxy, substituted C 1-6 -alkoxy, acyl, substituted acyl, C 1-6 -aminoalkyl or substituted C 1-6 -aminoalkyl. In a preferred embodiment, R 1 and R 2 and R 3 and R 4 and R 5 are hydrogen. In a preferred embodiment, R 1 and R 2 and R 3 are hydrogen, and one or both of R 4 and R 5 may not be hydrogen as described above and in WO 2007 / 134181 or WO2009 / 067647 (αL bicyclic nucleic acid analogs).

[0558] As used herein, the term "C1-C6-alkyl" refers to -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -C5H 11 , -CH(CH3)-C3H7, -CH2-CH(CH3)-C2H5, -CH(CH3)-CH(CH3)2, -C(CH3)2-C2H5, -CH2-C(CH3)3, -CH(C2H5)2, -C2H4-CH(CH3)2, -C6H 13, -C3H6-CH(CH3)2, -C2H4-CH(CH3)-C2H5, -CH(CH3)-C4H9, -CH2-CH(CH3)-C3H7, -CH(CH3)-CH2-CH(CH3)2, -CH(CH3)-CH(CH3)-C2H5, -CH2-CH(CH3)-CH(CH3)2, -CH2-C(CH3)2-C2H5, -C(CH3)2-C3H7, -C(CH3)2-CH(CH3)2, -C2H4-C(CH3)3, -CH2-CH(C2H5)2, and -CH(CH3)-C(CH3)3. The term "C1-C6-alkyl" shall also include "C1-C6-cycloalkyl", such as cyclo-C3H5, cyclo-C4H7, cyclo-C5H9, and cyclo-C6H 11 .

[0559] Preferably -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, and -C5H 11 . Particularly preferred are -CH3, -C2H5, -C3H7, and -CH(CH3)2.

[0560] The term "C1-C6-alkyl" shall also include "C1-C6-cycloalkyl", such as cyclo-C3H5, cyclo-C4H7, cyclo-C5H9, and cyclo-C6H 11 .

[0561] As used herein, the term "C 1-12 -alkyl" refers to C1-C6-alkyl, -C7H 15 , -C8H 17 , -C9H 19 , -C 10 H 21 , -C 11 H 23 , -C 12 H 25 .

[0562] As used herein, the term "C1-C6-alkylene" refers to -CH2-, -C2H4-, -CH(CH3)-, -C3H6-, -CH2-CH(CH3)-, -CH(CH3)-CH2-, -C(CH3)2-, -C4H8-, -CH2-C(CH3)2-, -C(CH3)2-CH2-, -C2H4-CH(CH3)-, -CH(CH3)-C2H4-, -CH2-CH(CH3)-CH2-, -CH(CH3)-CH(CH3)-, -C5H 10-, -CH(CH3)-C3H6-, -CH2-CH(CH3)-C2H4-, -C2H4-CH(CH3)-CH2-, -C3H6-CH(CH3)-, -C2H4-C(CH3)2-, -C(CH3)2-C2H4-, -CH2-C(CH3)2-CH2-, -CH2-CH(CH3)-CH(CH3)-, -CH(CH3)-CH2-CH(CH3)-, -CH(CH3)-CH(CH3)-CH2-, -CH(CH3)-CH(CH3)-CH(CH3)-, -C(CH3)2-C3H6-, -CH2-C(CH3)2-C2H4-, -C2H4-C(CH3)2-CH2-, -C3H6-C(CH3)2-, -CH(CH3)-C4H8-, -C6H 12 -, -CH2-CH(CH3)-C3H6-, -C2H4-CH(CH3)-C2H4-, -C3H6-CH(CH3)-CH2-, -C4H8-CH(CH3)-, -C2H4-CH(CH3)-CH(CH3)-, -CH2-CH(CH3)-CH(CH3)-CH2-, -CH2-CH(CH3)-CH2-CH(CH3)-, -CH(CH3)-C2H4-CH(CH3)-, -CH(CH3)-CH2-CH(CH3)-CH2-, and -CH(CH3)-CH(CH3)-C2H4-.

[0563] As used herein, the term "C2-C6-alkenyl" means -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -C2H4-CH=CH2, -CH2-CH=CH-CH3, -CH=CH-C2H5, -CH2-C(CH3)=CH2, -CH(CH3)-CH=CH, -CH=C(CH3)2, -C(CH3)=CH-CH3, -CH=CH-CH=CH2, -C3H6-CH=CH2, -C2H4-CH=CH-CH3, -CH2-CH=CH-C2H5, -CH=CH-C3H7, -CH2-CH=CH-CH=CH2, -CH=CH-CH=CH-CH3, -CH=CH-CH2-CH=CH2, -C(CH3)=CH-CH=CH2, -CH=C(CH3)-CH=CH2, -CH=CH-C(CH3)=CH2, -C2H4-C(CH3)=CH2, -CH2-CH(CH3)-CH=CH2, -CH(CH3)-CH2-CH=CH2, -CH2-CH=C(CH3)2, -CH2-C(CH3)=CH-CH3, -CH(CH3)-CH=CH-CH3, -CH=CH-CH(CH3)2, -CH=C(CH3)-C2H5, -C(CH3)=CH-C2H5, -C(CH3)=C(CH3)2, -C(CH3)2-CH=CH2, -CH(CH3)-C(CH3)=CH2, -C(CH3)=CH-CH=CH2, -CH=C(CH3)-CH=CH2, -CH=CH-C(CH3)=CH2, -C4H8-CH=CH2, -C3H6-CH=CH-CH3, -C2H4-CH=CH-C2H5, -CH2-CH=CH-C3H7, -CH=CH-C4H9, -C3H6-C(CH3)=CH2, -C2H4-CH(CH3)-CH=CH2, -CH2-CH(CH3)-CH2-CH=CH2, -CH(CH3)-C2H4-CH=CH2, -C2H4-CH=C(CH3)2, -C2H4-C(CH3)=CH-CH3, -CH2-CH(CH3)-CH=CH-CH3, -CH(CH3)-CH2-CH=CH-CH3, -CH2-CH=CH-CH(CH3)2, -CH2-CH=C(CH3)-C2H5, -CH2-C(CH3)=CH-C2H5, -CH(CH3)-CH=CH-C2H5, -CH=CH-CH2-CH(CH3)2, -CH=CH-CH(CH3)-C2H5,-CH=C(CH3)-C3H7, -C(CH3)=CH-C3H7, -CH2-CH(CH3)-C(CH3)=CH2, -CH(CH3)-CH2-C(CH3)=CH2, -CH(CH3)-CH(CH3)-CH=CH2, -CH2-C(CH3)2-CH=CH2, -C(CH3)2-CH2-CH=CH2, -CH2-C(CH3)=C(CH3)2, -CH(CH3)-CH=C(CH3)2, -C(CH3)2-CH=CH-CH3, -CH(CH3)-C(CH3)=CH-CH3, -CH=C(CH3)-CH(CH3)2, -C(CH3)=CH-CH(CH3)2, -C(CH3)=C(CH3)-C2H5, -CH=CH-C(CH3)3, -C(CH3)2-C(CH3)=CH2, -CH(C2H5)-C(CH3)=CH2, -C(CH3)(C2H5)-CH=CH2, -CH(CH3)-C(C2H5)=CH2, -CH2-C(C3H7)=CH2, -CH2-C(C2H5)=CH-CH3, -CH(C2H5)-CH=CH-CH3, -C(C4H9)=CH2, -C(C3H7)=CH-CH3, -C(C2H5)=CH-C2H5, -C(C2H5)=C(CH3)2, -C[C(CH3)3]=CH2, -C[CH(CH3)(C2H5)]=CH2, -C[CH2-CH(CH3)2]=CH2, -C2H4-CH=CH-CH=CH2, -CH2-CH=CH-CH2-CH=CH2, -CH=CH-C2H4-CH=CH2, -CH2-CH=CH-CH=CH-CH3, -CH=CH-CH2-CH=CH-CH3, -CH=CH-CH=CH-C2H5, -CH2-CH=CH-C(CH3)=CH2, -CH2-CH=C(CH3)-CH=CH2, -CH2-C(CH3)=CH-CH=CH2, -CH(CH3)-CH=CH-CH=CH2, -CH=CH-CH2-C(CH3)=CH2, -CH=CH-CH(CH3)-CH=CH2, -CH=C(CH3)-CH2-CH=CH2, -C(CH3)=CH-CH2-CH=CH2, -CH=CH-CH=C(CH3)2, -CH=CH-C(CH3)=CH-CH3, -CH=C(CH3)-CH=CH-CH3, -C(CH3)=CH-CH=CH-CH3, -CH=C(CH3)-C(CH3)=CH2-C(CH3)=CH-C(CH3)=CH2, -C(CH3)=C(CH3)-CH=CH2, and -CH=CH-CH=CH-CH=CH2.,

[0564] Preferably -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -C2H4-CH=CH2, -CH2-CH=CH-CH3. Particularly preferred are -CH=CH2, -CH2-CH=CH2, and -CH=CH-CH3.

[0565] As used herein, the term "C2-C6-alkynyl" refers to -C≡CH, -C≡C-CH3, -CH2-C≡CH, -C2H4-C≡CH, -CH2-C≡C-CH3, -C≡C-C2H5, -C3H6-C≡CH, -C2H4-C≡C-CH3, -CH2-C≡C-C2H5, -C≡C-C3H7, -CH(CH3)-C≡CH, -CH2-CH(CH3)-C≡CH, -CH(CH3)-CH2-C≡CH, -CH(CH3)-C≡C-CH3, -C4H8-C≡CH, -C3H6-C≡C-CH3, -C2H4-C≡C-C2H5, -CH2-C≡C-C3H7, -C≡C-C4H9, -C2H4-CH(CH3)-C≡CH, -CH2-CH(CH3)-CH2-C≡CH, -CH(CH3)-C2H4-C≡CH, -CH2-CH(CH3)-C≡C-CH3, -CH(CH3)-CH2-C≡C-CH3, -CH(CH3)-C≡C-C2H5, -CH2-C≡C-CH(CH3)2, -C≡C-CH(CH3)-C2H5, -C≡C-CH2-CH(CH3)2, -C≡C-C(CH3)3, -CH(C2H5)-C≡C-CH3, -C(CH3)2-C≡C-CH3, -CH(C2H5)-CH2-C≡CH, -CH2-CH(C2H5)-C≡CH, -C(CH3)2-CH2-C≡CH, -CH2-C(CH3)2-C≡CH, -CH(CH3)-CH(CH3)-C≡CH, -CH(C3H7)-C≡CH, -C(CH3)(C2H5)-C≡CH, -C≡C-C≡CH, -CH2-C≡C-C≡CH, -C≡C-C≡C-CH3, -CH(C≡CH)2, -C2H4-C≡C-C≡CH, -CH2-C≡C-CH2-C≡CH, -C≡C-C2H4-C≡CH, -CH2-C≡C-C≡C-CH3, -C≡C-CH2-C≡C-CH3, -C≡C-C≡C-C2H5, -C≡C-CH(CH3)-C≡CH, -CH(CH3)-C≡C-C≡CH, -CH(C≡CH)-CH2-C≡CH, -C(C≡CH)2-CH3, -CH2-CH(C≡CH)2, -CH(C≡CH)-C≡C-CH3. Preferably, -C≡CH and -C≡C-CH3.

[0566] The term "C 1-6 -alkoxy" refers to "C1-C6-alkyl-O-".

[0567] The term "C 1-12"-alkoxy" means "C 1-12 -alkyl-O-".

[0568] The term "C 1-6 -aminoalkyl" means "H2N-C1-C6-alkyl-".

[0569] The term "C2-C6-alkenyloxy" means "C2-C6-alkenyl-O-".

[0570] The term "C 1-6 -alkylcarbonyl" means "C1-C6-alkyl-CO-". Also referred to as "acyl".

[0571] The term "C 1-12 -alkylcarbonyl" means "C 1-12 -alkyl-CO-". Also referred to as "acyl".

[0572] The term "C 1-6 -alkoxycarbonyl" means "C1-C6-alkyl-O-CO-".

[0573] The term "C 1-12 -alkoxycarbonyl" means "C 1-12 -alkyl-O-CO-".

[0574] The term "C1-C6-alkanoyloxy" means "C1-C6-alkyl-CO-O-".

[0575] The term "C 1-6 -alkylthio" means "C1-C6-alkyl-S".

[0576] The term "C 1-6 -alkylsulfonyloxy" means "C1-C6-alkyl-SO2-O-".

[0577] The term "C 1-6 -alkylcarbonylamino" means "C1-C6-alkyl-CO-NH-".

[0578] The term "C 1-6 -alkylamino" means "C1-C6-alkyl-NH-".

[0579] The term "(C 1-6 -)2alkylamino" means a dialkylamino such as "[C1-C6-alkyl][C1-C6-alkyl]N-".

[0580] The term "C 1-6 -alkylaminocarbonyl" means "C1-C6-alkyl-NH-CO-"

[0581] The term "(C 1-6-)2-alkylaminocarbonyl" means a dialkylaminocarbonyl such as "[C1-C6-alkyl][C1-C6-alkyl]N-CO-".

[0582] The term "amino-C 1-6 -alkylaminocarbonyl" means "H2N-[C1-C6-alkylene]-NH-CO-".

[0583] The term "C 1-6 -alkyl-amino-C 1-6 -alkylaminocarbonyl" means "C 1-6 -alkyl-NH-(C1-C6-alkylene)-NH-CO-".

[0584] The term "(C 1-6 -)2-alkyl-amino-C 1-6 -alkylaminocarbonyl" means "[C1-C6-alkyl][C1-C6-alkyl]N-[C1-C6-alkylene]-NH-CO-".

[0585] The term "aryl" means phenyl, toluoyl, substituted phenyl and substituted toluoyl.

[0586] The term "aryloxy" means "aryl-O-".

[0587] The term "arylcarbonyl" means "aryl-CO-".

[0588] The term "aryloxycarbonyl" means "aryl-O-CO-".

[0589] The term "heteroaryl" means a substituted or unsubstituted heteroaryl having 4 to 9 ring atoms, where 1 to 4 are selected from O, N and / or S. Preferred "heteroaryl" groups have 1 or 2 heteroatoms in a 5- or 6-membered aromatic ring. Monocyclic and bicyclic systems are included. Typical "heteroaryl" groups are pyridyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, indolizinyl, indolyl, isoindolyl, benzofuryl, benzothienyl, indazolyl, benzimidazolyl, benzothiazolyl, purinyl, quinazolinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, tetrahydroquinolinyl, benzoxazolyl, 2-chromonyl, indazolyl, etc.

[0590] The term "heteroaryloxy" means "heteroaryl-O-".

[0591] The term "heteroarylcarbonyl" means "heteroaryl-CO-".

[0592] The term "heteroaryloxycarbonyl" means "heteroaryl - O - CO -".

[0593] The term "substituted" means a group in which one or more hydrogen atoms are replaced by one or more of the following substituents: -OH, -OCH3, -OC2H5, -OC3H7, -O - cyclo - C3H5, -OCH(CH3)2, -OCH2Ph, -F, -Cl, -COCH3, -COC2H5, -COC3H7, -CO - cyclo - C3H5, -COCH(CH3)2, -COOH, -CONH2, -NH2, -NHCH3, -NHC2H5, -NHC3H7, -NH - cyclo - C3H5, -NHCH(CH3)2, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N(cyclo - C3H5)2, -N[CH(CH3)2]2, -SO3H, -OCF3, -OC2F5, cyclo - C3H5, -CH3, -C2H5, -C3H7, -CH(CH3)2, -CH=CH2, -CH2 - CH=CH2, -C≡CH and / or -C≡C - CH3.

[0594] When the general formula (I) represents a monomer or structural unit for synthesizing the antisense oligonucleotides of the present invention, the terminal groups Y and IL′ are independently selected from hydrogen, azide, halogen, cyano, nitro, hydroxy, PG - O -, AG - O -, mercapto, PG - S -, AG - S -, C 1-6 -alkylthio, amino, PG - N(R H ) -, AG - N(R H ) -, mono - or di(C 1-6 -alkyl)amino, optionally substituted C 1-6 -alkoxy, optionally substituted C 1-6 -alkyl, optionally substituted C 2-6 -alkenyl, optionally substituted C 2-6 -alkenyloxy, optionally substituted C 2-6 -alkynyl, optionally substituted C 2-6 -alkynyloxy, monophosphate, monothiophosphate, diphosphate, dithiophosphate, triphosphate, trithiophosphate, carboxyl, sulfonyl, hydroxymethyl, PG - O - CH2 -, AG - O - CH2 -, aminomethyl, PG - N(R H ) - CH2 -, AG - N(R H ) - CH2 -, carboxymethyl, sulfonylmethyl, where PG are protecting groups of -OH, -SH and -NH(R H ) respectively, AG are activating groups of -OH, -SH and -NH(R H ) and RH Selected from hydrogen and C 1-6 -alkyl groups.

[0595] Protecting groups PG for hydroxy substituents include substituted trityls such as 4,4'-dimethoxytrityl (DMT), 4-monomethoxytrityl (MMT), optionally substituted 9-(9-phenyl)xanthenyl (pixyl), optionally substituted methoxytetrahydropyranyl (mthp), silyls such as trimethylsilyl (TMS), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS), triethylsilyl and phenyldimethylsilyl, tert-butyl ethers, acetals (including two hydroxyl groups), acyl groups such as acetyl or halogen-substituted acetyl groups, such as chloroacetyl or fluoroacetyl, isobutyryl, pivaloyl, benzoyl and substituted benzoyl, methoxymethyl (MOM), benzyl ethers or substituted benzyl ethers such as 2,6-dichlorobenzyl (2,6-Cl2BzI). Alternatively, when Y or IL' is a hydroxyl group, they can be protected by optionally being attached to a solid support via a linker.

[0596] When Y or IL' is an amino group, exemplary examples of amino protecting groups are fluorenylmethoxycarbonyl (Fmoc), tert-butoxycarbonyl (BOC), trifluoroacetyl, allyloxycarbonyl (alloc or AOC), benzyloxycarbonyl (Z or Cbz), substituted benzyloxycarbonyl such as 2-chlorobenzyloxycarbonyl (2-ClZ), monomethoxytrityl (MMT), dimethoxytrityl (DMT), phthaloyl and 9-(9-phenyl)xanthenyl (pixyl).

[0597] Act represents activation groups for -OH, -SH, and -NH(R H ), respectively. Such activation groups are, for example, selected from optionally substituted O-phosphoramidites, optionally substituted O-phosphotriesters, optionally substituted O-phosphodiesters, optionally substituted H-phosphonates and optionally substituted O-phosphonates.

[0598] As used herein, the term "phosphoramidite" refers to a group of the formula -P(OR x )-N(R y )2, where R x represents an optionally substituted alkyl group, such as methyl, 2-cyanoethyl or benzyl, and each R y represents an optionally substituted alkyl group, such as ethyl or isopropyl, or the group -N(R y )2 forms a morpholino group (-N(CH2CH2)2O). R x preferably represents 2-cyanoethyl, and the two R yPreferably the same and represents isopropyl. Thus, a particularly relevant phosphoramidite is N,N - diisopropyl - O - (2 - cyanoethyl) - phosphoramidite.

[0599] LNA monomer or LNA structural unit

[0600] The LNA monomer or LNA structural unit used as a raw material in the synthesis of the antisense oligonucleotides of the present invention is preferably an LNA nucleoside of the following general formula:

[0601]

[0602] Generally, the LNA structural unit is provided as LNA phosphoramidites having four different nucleobases (adenine (A), guanine (G), 5 - methyl - cytosine (C*), and thymine (T)). The antisense oligonucleotides of the present invention containing LNA units are synthesized by standard phosphoramidite chemistry. In the LNA structural unit, the nucleobases are protected. The preferred protecting group for the amino group of the purine base is benzoyl (Bz), denoted as A Bz . The preferred protecting group for the amino group of the 5 - methylpyrimidinone base is benzoyl (Bz), denoted as C* Bz . The preferred protecting group for the amino group of the purinone base is a dimethylformamidine (DMF) group, diethylformamidine (DEF), dipropylformamidine (DPF), dibutylformamidine (DBF), or isobutyryl (-CO - CH(CH3)2) group, denoted as G DMF , G DEF , G DPF , G DBF , or G iBu . Thus, the -NDMF group means -N = CH - N(CH3)2. DMT means 4,4′ - dimethoxytriphenylmethyl.

[0603] Thus, LNA - T means 5′ - O - (4,4′ - dimethoxytriphenylmethyl) - 3′ - O - (2 - cyanoethyl - N,N - diisopropyl) - phosphoramidite - thymidine LNA. LNA - C* Bz means 5′ - O - (4,4′ - dimethoxytriphenylmethyl) - 3′ - O - (2 - cyanoethyl - N,N - diisopropyl) - phosphoramidite - 4 - N - benzoyl - 5 - methyl - 2′ - cytidine LNA. LNA - A Bz means 5′ - O - (4,4′ - dimethoxytriphenylmethyl) - 3′ - O - (2 - cyanoethyl - N,N - diisopropyl) - phosphoramidite - 6 - N - benzoyl - 2′ - adenosine LNA. LNA - G DMFRefers to 5'-O-(4,4'-dimethoxytrityl)-3'-O-(2-cyanoethyl-N,N-diisopropyl)-phosphoramidite-2-N-dimethylformamidine-2'-guanosine LNA. LNA-G iBu Refers to 5′-O-(4,4′-dimethoxy-trityl)-3′-O-(2-cyanoethyl-N,N-diisopropyl)-phosphoramidite-2-N-butyryl-2′-guanosine LNA.

[0604] Terminal group

[0605] When Y represents the 5'-terminal group of the antisense oligonucleotide of the present invention, the residue Y is also referred to as Y 5’ , and represents:

[0606] -OH, -O-C 1-6 -alkyl, -S-C 1-6 -alkyl, -O-C 6-9 -phenyl, -O-C 7-10 -benzyl, -NH-C 1-6 -alkyl, -N(C 1-6 -alkyl)2, -O-C 2-6 -alkenyl, -S-C 2-6 -alkenyl, -NH-C 2-6 -alkenyl, -N(C 2-6 -alkenyl)2, -O-C 2-6 -alkynyl, -S-C 2-6 -alkynyl, -NH-C 2-6 -alkynyl, -N(C 2-6 -alkynyl)2, -O-C 1-6 -alkylene -O-C 1-6 -alkyl, -O-[C 1-6 -alkylene-O] m -C 1-6 -alkyl, -O-CO-C 1-6 -alkyl, -O-CO-C 2-6 -alkenyl, -O-CO-C 2-6 -alkynyl, -O-S(O)-C 1-6 -alkyl, -O-SO2-C 1-6 -alkyl, -O-SO2-O-C 1-6 -alkyl, -O-P(O)(O - )2, -O-P(O)(O - )(O-C 1-6 -alkyl), -O-P(O)(O-C 1-6 -alkyl)2, -O-P(O)(S - )2, -O-P(O)(S-C1-6 -alkyl)2,-O-P(O)(S - )(O-C 1-6 -alkyl),-O-P(O)(O - )(NH-C 1-6 -alkyl),-O-P(O)(O-C 1-6 -alkyl)(NH-C 1-6 -alkyl), -O-P(O)(O - )[N(C 1-6 -alkyl)2],-O-P(O)(O-C 1-6 -alkyl)[N(C 1-6 -alkyl)2], -O-P(O)(O - )(BH3 - ),-O-P(O)(O-C 1-6 -alkyl)(BH3 - ), -O-P(O)(O - )(O-C 1-6 -alkylene-O-C 1-6 -alkyl),-O-P(O)(O-C 1-6 -alkylene-O-C 1-6 -alkyl)2,-O-P(O)(O - )(O-C 1-6 -alkylene-S-C 1-6 -alkyl), -O-P(O)(O-C 1-6 -alkylene-S-C 1-6 -alkyl)2,-O-P(O)(O - )(OCH2CH2O-C 1-6 -alkyl),-O-P(O)(OCH2CH2O-C 1-6 -alkyl)2,-O-P(O)(O - )(OCH2CH2S-C 1-6 -alkyl), -O-P(O)(OCH2CH2S-C 1-6 -alkyl)2,-O-P(O)(O - )OC3H6OH, -O-P(O)(S - )OC3H6OH,-O-P(S)(S - ),

[0607] wherein C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, -O-C 6-9 -phenyl or -O-C 7-10 -benzyl may be further substituted by -F, -OH, C1-4 -alkyl, C 2-4 -alkenyl and / or C 2-4 -alkynyl substituted, where m is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0608] More preferably: -OCH3, -OC2H5, -OC3H7, -O-cyclo-C3H5, -OCH(CH3)2, -OC(CH3)3, -OC4H9, -OPh, -OCH2-Ph, -O-COCH3, -O-COC2H5, -O-COC3H7, -O-CO-cyclo-C3H5, -O-COCH(CH3)2, -OCF3, -O-S(O)CH3, -O-S(O)C2H5, -O-S(O)C3H7, -O-S(O)-cyclo-C3H5, -O-SO2CH3, -O-SO2C2H5, -O-SO2C3H7, -O-SO2-cyclo-C3H5, -O-SO2-OCH3, -O-SO2-OC2H5, -O-SO2-OC3H7, -O-SO2-O-cyclo-C3H5, -O(CH2) n N[(CH2) n OH], -O(CH2) n N[(CH2) n -H], -O-P(O)(O - )OC3H6OH, -O-P(O)(S - )OC3H6OH,

[0609] Even more preferably:

[0610] -OCH3, -OC2H5, -OCH2CH2OCH3 (also known as MOE), -OCH2CH2-N(CH3)2 (also known as DMAOE), -O[(CH2) n O] m CH3, -O(CH2) n OCH3, -O(CH2) n NH2, -O(CH2) n N(CH3)2,, -O-P(O)(O - )OC3H6OH, -O-P(O)(S - )OC3H6OH,

[0611] where n is selected from 1, 2, 3, 4, 5 or 6; and

[0612] where m is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0613] When IL' represents the 3'-terminal group of the antisense oligonucleotide of the present invention, the residue IL' is also referred to as IL'. 3’ , representing:

[0614] -OH, -O-C 1-6 -alkyl, -S-C 1-6 -alkyl, -O-C 6-9 -phenyl, -O-C 7-10 -benzyl, -NH-C 1-6 -alkyl, -N(C 1-6 -alkyl)2, -O-C 2-6 -alkenyl, -S-C 2-6 -alkenyl, -NH-C 2-6 -alkenyl, -N(C 2-6 -alkenyl)2, -O-C 2-6 -alkynyl, -S-C 2-6 -alkynyl, -NH-C 2-6 -alkynyl, -N(C 2-6 -alkynyl)2, -O-C 1-6 -alkylene -O-C 1-6 -alkyl, -O-[C 1-6 -alkylene-O] m -C 1-6 -alkyl, -O-CO-C 1-6 -alkyl, -O-CO-C 2-6 -alkenyl, -O-CO-C 2-6 -alkynyl, -O-S(O)-C 1-6 -alkyl, -O-SO2-C 1-6 -alkyl, -O-SO2-O-C 1-6 -alkyl, -O-P(O)(O - )(O-P(O)(O - )(O-C 1-6 -alkyl), -O-P(O)(O-C 1-6 -alkyl)2, -O-P(O)(S - )(O-P(O)(S-C 1-6 -alkyl)2, -O-P(O)(S - )(O-C 1-6 -alkyl), -O-P(O)(O - )(NH-C 1-6 -alkyl), -O-P(O)(O-C 1-6 -alkyl)(NH-C 1-6 -alkyl), -O-P(O)(O - )(O)[N(C 1-6-alkyl)2], -O-P(O)(O-C 1-6 -alkyl)[N(C 1-6 -alkyl)2], -O-P(O)(O - )(BH3 - ), -O-P(O)(O-C 1-6 -alkyl)(BH3 - ), -O-P(O)(O - )(O-C 1-6 -alkylene-O-C 1-6 -alkyl), -O-P(O)(O-C 1-6 -alkylene-O-C 1-6 -alkyl)2, -O-P(O)(O - )(O-C 1-6 -alkylene-S-C 1-6 -alkyl), -O-P(O)(O-C 1-6 -alkylene-S-C 1-6 -alkyl)2, -O-P(O)(O - )(OCH2CH2O-C 1-6 -alkyl), -O-P(O)(OCH2CH2O-C 1-6 -alkyl)2, -O-P(O)(O - )(OCH2CH2S-C 1-6 -alkyl), -O-P(O)(OCH2CH2S-C 1-6 -alkyl)2, -O-P(O)(O - )OC3H6OH, -O-P(O)(S - )OC3H6OH,

[0615] wherein C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, -O-C 6-9 -phenyl or -O-C 7-10 -benzyl may be further substituted by -F, -OH, C 1-4 -alkyl, C 2-4 -alkenyl and / or C 2-4 -alkynyl, wherein m is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0616] More preferably: -OCH3, -OC2H5, -OC3H7, -O-cyclo-C3H5, -OCH(CH3)2, -OC(CH3)3, -OC4H9, -OPh, -OCH2-Ph, -O-COCH3, -O-COC2H5, -O-COC3H7, -O-CO-cyclo-C3H5, -O-COCH(CH3)2, -OCF3, -O-S(O)CH3, -O-S(O)C2H5, -O-S(O)C3H7, -O-S(O)-cyclo-C3H5, -O-SO2CH3, -O-SO2C2H5, -O-SO2C3H7, -O-SO2-cyclo-C3H5, -O-SO2-OCH3, -O-SO2-OC2H5, -O-SO2-OC3H7, -O-SO2-O-cyclo-C3H5, -O(CH2) n N[(CH2) n OH], -O(CH2) n N[(CH2) n -H],, -O-P(O)(O - )OC3H6OH, -O-P(O)(S - )OC3H6OH,

[0617] Even more preferably:

[0618] -OCH3, -OC2H5, -OCH2CH2OCH3 (also known as MOE), -OCH2CH2-N(CH3)2 (also known as DMAOE), -O[(CH2) n O] m CH3, -O(CH2) n OCH3, -O(CH2) n NH2, -O(CH2) n N(CH3)2, -O-P(O)(O - )OC3H6OH, -O-P(O)(S - )OC3H6OH,

[0619] wherein n is selected from 1, 2, 3, 4, 5 or 6; and

[0620] wherein m is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0621] Preferred LNA

[0622] In a preferred embodiment, the LNA unit of the antisense oligonucleotide for use in the present invention preferably has the structure of general formula (II):

[0623]

[0624] -C(R a R b )-X - moiety preferably represents -C(R a R b )-O-, -C(R a R b )-NR c -, -C(R a R b )-S-, and -C(R a R b )-C(R a R b )-O-, wherein the substituents R a 、R b and R c have the meanings as defined herein, preferably C 1-6 -alkyl, more preferably C 1-4 -alkyl. More preferably -C(R a R b )-X- is selected from -CH2-O-, -CH2-S-, -CH2-NH-, -CH2-N(CH3)-, -CH2-CH2-O-, or -CH2-CH2-S-, and more preferably -CH2-O-, -CH2-S-, -CH2-CH2-O-, or -CH2-CH2-S-, and more preferably -CH2-O-, -CH2-S-, or -CH2-CH2-O-, and more preferably -CH2-O- or -CH2-S-, and most preferably -CH2-O-.

[0625] All chiral centers and asymmetric substituents (if any) can be in the R or S orientation. For example, two exemplary stereoisomers are the β-D and α-L isotypes shown below:

[0626]

[0627] Preferred LNA units are selected from the general formulas (b 1 ) to (b 9 ):

[0628]

[0629]

[0630] The term "thio-LNA" encompasses locked nucleotides wherein X in the general formula (II) is selected from -S- or -CH2-S-. Thio-LNA can be in the β-D and α-L-configurations.

[0631] The term "amino-LNA" encompasses locked nucleotides in which X in formula (II) is selected from -NH-, -N(R)-, -CH2-NH- and -CH2-N(R)-, where R is selected from hydrogen and C 1-4 -alkyl. Amino-LNA can be in the β-D and α-L-configurations.

[0632] The term "oxy-LNA" encompasses locked nucleotides in which X in formula (II) is -O-. Oxy-LNA can be in the β-D and α-L-configurations.

[0633] The term "ENA" includes locked nucleotides in which X in formula (II) is -CH2-O- (where the oxygen atom of -CH2-O- is attached to the 2'-position relative to the base B). R a and R b are independently of each other hydrogen or methyl.

[0634] In a preferred exemplary embodiment, LNA is selected from β-D-oxy-LNA, α-L-oxy-LNA, β-D-amino-LNA and β-D-thio-LNA, especially β-D-oxy-LNA.

[0635] More preferably, the following antisense oligonucleotides (Table 1):

[0636]

[0637]

[0638]

[0639]

[0640]

[0641] SP: Starting position or starting nucleotide on Seq.ID No.2.

[0642] L: Sequence length

[0643] The antisense oligonucleotides disclosed herein, such as those in Tables 1-3, especially those in Tables 4 to 9, are composed of nucleotides that are not LNA units (also referred to as non-LNA nucleotides) and nucleotides that are LNA units (also referred to as LNA nucleotides), preferably DNA nucleotides.

[0644] Although not explicitly stated, the antisense oligonucleotides of SEQ ID NOs. 102a - 218a in Table 1 contain 2 to 4 LNA nucleotides (LNA units) at the 3'-end and 2 to 4 LNA nucleotides (LNA units) at the 5'-end. Although not explicitly stated, "C" in Table 2 indicates that the LNA unit preferably contains 5-methylcytosine (C*) as a nucleobase.

[0645] This means that, unless explicitly stated otherwise, the antisense oligonucleotides of the present invention or disclosed herein by the letter codes A, C, G, T, and U can contain any internucleotide linkage, any terminal group, and any nucleobase disclosed herein. In addition, the antisense oligonucleotides of the present invention or disclosed herein are gapmers of any gapmer structure having at least one LNA unit at the 3'-end and at least one LNA unit at the 5'-end as disclosed herein. Furthermore, any LNA unit disclosed herein can be used within the antisense oligonucleotides of the present invention or disclosed herein. Thus, for example, the antisense oligonucleotides GCTCGTCATAGACCGA (Seq. ID No. 13) or CGATACGCGTCCACAG (Seq. ID No. 14) or GTAGTGTTTAGGGAGC (Seq. ID No. 15) or GCTATTTGGTAGTGTT (Seq. ID No. 16) or CATGAATGGACCAGTA (Seq. ID No. 17) or AGGCATTAATAAAGTG (Seq. ID No. 18) contain at least one LNA unit at the 5'-end and at least one LNA unit at the 3'-end, any nucleobase, any 3'-terminal group, any 5'-terminal group, any gapmer structure, and any internucleotide linkage disclosed herein, and also encompass salts and optical isomers of the antisense oligonucleotides.

[0646] The use of LNA units, especially at the 3'-end and 5'-end, is preferred. Thus, it is preferred that if the last 1-5 nucleotides at the 3'-end and the last 1-5 nucleotides at the 5'-end of the sequences specifically disclosed herein, especially Seq. ID No. 102a–218a of Table 1, are LNA units (also referred to as LNA nucleotides), then there are 2-14, preferably 3-12, more preferably 4-10, even more preferably 5-9, still more preferably 6-8 non-LNA units (also referred to as non-LNA nucleotides) between the 1 to 5 LNA units at the 3' and 5’-ends. Such antisense oligonucleotides are referred to as gapmers and are disclosed in more detail below. More preferably, there are 2-5 LNA nucleotides at the 3'-end and 2-5 LNA nucleotides at the 5'-end, or 1-4 LNA nucleotides at the 3'-end and 1-4 LNA nucleotides at the 5'-end. More preferably, there are 2-4 LNA nucleotides at the 3'-end of the antisense oligonucleotide and 2-4 LNA nucleotides at the 5'-end, and preferably 4-10, more preferably 5-9, more preferably 6-8 non-LNA units are present between the LNA units at the 3' and 5’-ends.

[0647] Furthermore, as the internucleotide linkages between LNA units and between LNA units and non-LNA units, phosphorothioate or dithiophosphonate and preferably phosphorothioate are preferably used.

[0648] Thus, it is further preferred for the antisense oligonucleotide that more than 50%, preferably more than 60%, more preferably more than 70%, even more preferably more than 80%, most preferably more than 90% of the internucleotide linkages are phosphorothioate or phosphonate, more preferably phosphorothioate linkages, where the last 1-4 or 2-5 nucleotides at the 3'-end are LNA units, the last 1-4 or 2-5 nucleotides at the 5'-end are LNA units, and there are 6-14 nucleotides, preferably 7-12, preferably 8-11, more preferably 8-10 nucleotides between the terminal LNA units, which are non-LNA units, preferably DNA units. In addition, these antisense oligonucleotides in gapmer form preferably consist of a total of 12 to 20, preferably 12 to 18 nucleotides.

[0649] Gapmer

[0650] The antisense oligonucleotides of the present invention can consist of a nucleotide sequence comprising DNA nucleotides containing non-LNA units and LNA nucleotides, and can be arranged in the form of a spacer.

[0651] Accordingly, the antisense oligonucleotides of the present invention are preferably gapmers. A gapmer consists of a middle part of DNA nucleotide units that are not locked (thus they are non-LNA units). The DNA nucleotides of this middle part can be linked to each other through internucleotide linkages (ILs) as disclosed herein, which are preferably a phosphate group, a phosphorothioate group, or a phosphorodithioate group, and which can contain nucleobase analogs such as 5-propynylcytosine, 7-methylguanine, 7-methyladenine, 2-aminoadenine, 2-thiothymine, 2-thiocytosine, or 5-methylcytosine. The DNA units or DNA nucleotides are not bicyclic pentose structures. The middle part of non-LNA units is flanked at the 3'-end and 5'-end by sequences consisting of LNA units. Accordingly, a gapmer has the following general formula:

[0652] LNA sequence 1 - non-LNA sequence - LNA sequence 2

[0653] or

[0654] Region A - Region B - Region C

[0655] The middle part of the antisense oligonucleotide consisting of DNA nucleotide units of non-LNA units, when formed in a duplex with a complementary target RNA, is capable of recruiting ribonucleases. The 3'- and 5'-terminal nucleotide units are LNA units that are preferably in the α-L configuration, and particularly preferably β-D-oxy-LNA and α-L-oxy-LNA.

[0656] Accordingly, a gapmer is an antisense oligonucleotide that contains a continuous DNA nucleotide fragment capable of recruiting ribonucleases (such as ribonuclease H), for example, a region of at least 6 or 7 DNA nucleotides, which are non-LNA units and are referred to herein as the middle part or Region B, wherein Region B is flanked at the 5'- and 3'-sides by regions of affinity-enhanced nucleotide analogs, which are LNA units, such as 1 - 6 LNA units at the 5'- and 3'-sides of the continuous fragment of DNA nucleotides capable of recruiting ribonucleases, and these flanking regions are referred to as Region A and C, respectively.

[0657] Preferably, the gapmer comprises a (multi) nucleotide sequence of formula (5' to 3') A-B-C or optionally A-B-C-D or D-A-B-C, wherein; region A (5' region) consists of at least one nucleotide analogue, such as at least one LNA unit, such as 1-6 LNA units, and region B consists of at least five consecutive DNA nucleotides, which are non-LNA units and are capable of recruiting RNA enzymes (when forming a duplex with a complementary RNA molecule such as an mRNA target), and region C (3' region) consists of at least one nucleotide analogue (such as at least one LNA unit, such as 1 to 6 LNA units), and region D (when present) consists of 1, 2 or 3 DNA nucleotide units of non-LNA units.

[0658] In some embodiments, region A consists of 1, 2, 3, 4, 5 or 6 LNA units, such as 2-5 LNA units, such as 3 or 4 LNA units; and / or region C consists of 1, 2, 3, 4, 5 or 6 LNA units, such as 2-5 LNA units, such as 3 or 4 LNA units.

[0659] In some embodiments, region B consists of 5, 6, 7, 8, 9, 10, 11 or 12 consecutive DNA nucleotides capable of recruiting RNA enzymes or 6-10 or 7-9, such as 8 consecutive nucleotides capable of recruiting RNA enzymes. In some embodiments, region B consists of at least one DNA nucleotide unit, such as 1-12 DNA nucleotide units, preferably 4-12 DNA nucleotide units, more preferably 6-10 DNA nucleotide units, more preferably, such as 7-10 DNA nucleotide units, and most preferably 8, 9 or 10 DNA nucleotide units, which are non-LNA units.

[0660] In some embodiments, Region A consists of 3 or 4 LNAs, Region B consists of 7, 8, 9 or 10 DNA nucleotide units, and Region C consists of 3 or 4 LNA units. These designs include (A-B-C): 1-7-2, 2-7-1, 2-7-2, 3-7-1, 3-7-2, 1-7-3, 2-7-3, 3-7-3, 2-7-4, 3-7-4, 4-7-2, 4-7-3, 4-7-4, 1-8-1, 1-8-2, 2-8-1, 2-8-2, 1-8-3, 3-8-1, 3-8-3, 2-8-3, 3-8-2, 4-8-1, 4-8-2, 1-8-4, 2-8-4, 3-8-4, 4-8-3, 4-8-4, 1-9-1, 1-9-2, 2-9-1, 2-9-2, 2-9-3, 3-9-2, 3-9-3, 1-9-3, 3-9-1, 4-9-1, 1-9-4, 4-9-2, 2-9-4, 4-9-3, 3-9-4, 4-9-4, 1-10-1, 1-10-2, 2-10-1, 2-10-2, 1-10-3, 3-10-1, 2-10-2, 2-10-3, 3-10-2, 3-10-3, 2-10-4, 4-10-2, 3-10-4, 4-10-3, 4-10-4, 1-11-1, 1-11-2, 2-11-1, 2-11-2, 1-11-3, 3-11-1, 2-11-2, 2-11-3, 3-11-2, 3-11-3, 2-11-4, 4-11-2, 3-11-4, 4-11-3, 4-11-4, and may further include Region D which may have one or two non-LNA units of DNA nucleotide units.

[0661] Other gapmer designs are disclosed in WO2004 / 046160A and are incorporated herein by reference. U.S. Provisional Application 60 / 977409 (incorporated herein by reference) relates to "shortmer" gapmer antisense oligonucleotides that are also applicable to the present invention.

[0662] In some embodiments, the antisense oligonucleotide consists of a continuous nucleotide sequence of a total of 10, 11, 12, 13 or 14 nucleotide units (LNA units and non-LNA units together), wherein the continuous nucleotide sequence has the formula (5'-3') A-B-C or optionally A-B-C-D or D-A-B-C, wherein A consists of 1, 2 or 3 LNA units, B consists of 7, 8 or 9 consecutive non-LNA units and DNA nucleotide units capable of recruiting RNase when formed in a duplex with a complementary RNA molecule (e.g., mRNA target), and C consists of 1, 2 or 3 LNA units. When present, D consists of a DNA nucleotide unit of a single non-LNA unit.

[0663] In some embodiments, A consists of 1 LNA unit. In some embodiments, A consists of 2 LNA units. In some embodiments, A consists of 3 LNA units. In some embodiments, C consists of 1 LNA unit. In some embodiments, C consists of 2 LNA units. In some embodiments, C consists of 3 LNA units. In some embodiments, B consists of 7 DNA nucleotide units that are non-LNA units. In some embodiments, B consists of 8 DNA nucleotide units. In some embodiments, B consists of 9 DNA nucleotide units. In some embodiments, B consists of 1 - 9 DNA nucleotide units, such as 2, 3, 4, 5, 6, 7, or 8 DNA nucleotide units. The DNA nucleotide units are always non-LNA units. In some embodiments, B contains 1, 2, or 3 LNA units, which are preferably in the α-L configuration, more preferably α-L-oxy LNA units. In some embodiments, the number of nucleotides present in A - B - C is selected from (LNA unit - region B - LNA unit, more preferably α-L-oxy LNA unit (region A) - region B - (region C) α-L-oxy LNA unit): 1 - 8 - 1, 1 - 8 - 2, 2 - 8 - 1, 2 - 8 - 2, 1 - 8 - 3, 3 - 8 - 1, 3 - 8 - 3, 2 - 8 - 3, 3 - 8 - 2, 4 - 8 - 1, 4 - 8 - 2, 1 - 8 - 4, 2 - 8 - 4, 3 - 8 - 4, 4 - 8 - 3, 4 - 8 - 4, 1 - 9 - 1, 1 - 9 - 2, 2 - 9 - 1, 2 - 9 - 2, 2 - 9 - 3, 3 - 9 - 2, 3 - 9 - 3, 1 - 9 - 3, 3 - 9 - 1, 4 - 9 - 1, 1 - 9 - 4, 4 - 9 - 2, 2 - 9 - 4, 4 - 9 - 3, 3 - 9 - 4, 4 - 9 - 4, 1 - 10 - 1, 1 - 10 - 2, 2 - 10 - 1, 2 - 10 - 2, 1 - 10 - 3, 3 - 10 - 1, 2 - 10 - 2, 2 - 10 - 3, 3 - 10 - 2, 3 - 10 - 3, 2 - 10 - 4, 4 - 10 - 2, 3 - 10 - 4, 4 - 10 - 3, 4 - 10 - 4, 1 - 11 - 1, 1 - 11 - 2, 2 - 11 - 1, 2 - 11 - 2, 1 - 11 - 3, 3 - 11 - 1, 2 - 11 - 2, 2 - 11 - 3, 3 - 11 - 2, 3 - 11 - 3, 2 - 11 - 4, 4 - 11 - 2, 3 - 11 - 4, 4 - 11 - 3, 4 - 11 - 4.In a further preferred embodiment, the number of nucleotides in A - B - C is selected from: 3 - 8 - 3, 4 - 8 - 2, 2 - 8 - 4, 3 - 8 - 4, 4 - 8 - 3, 4 - 8 - 4, 3 - 9 - 3, 4 - 9 - 2, 2 - 9 - 4, 4 - 9 - 3, 3 - 9 - 4, 4 - 9 - 4, 3 - 10 - 3, 2 - 10 - 4, 4 - 10 - 2, 3 - 10 - 4, 4 - 10 - 3, 4 - 10 - 4, 2 - 11 - 4, 4 - 11 - 2, 3 - 11 - 4, 4 - 11 - 3, more preferably: 3 - 8 - 3, 3 - 8 - 4, 4 - 8 - 3, 4 - 8 - 4, 3 - 9 - 3, 4 - 9 - 3, 3 - 9 - 4, 4 - 9 - 4, 3 - 10 - 3, 3 - 10 - 4, 4 - 10 - 3, 4 - 10 - 4, 3 - 11 - 4, and 4 - 11 - 3.

[0664] Phosphorothioate, phosphate or phosphorodithioate, especially phosphorothioate internucleotide linkages are also preferred, especially for the gapmer region B. Phosphorothioate, phosphate or phosphorodithioate linkages, especially phosphorothioate internucleotide linkages can also be used in the flanking regions (A and C, and for linking A or C to D, and within region D if present).

[0665] However, regions A, B and C can include internucleotide linkages other than phosphorothioate or phosphorodithioate, such as phosphodiester linkages, especially for example when the use of nucleotide analogs protects the internucleotide linkages within regions A and C from endonuclease degradation, such as when regions A and C consist of LNA units.

[0666] The internucleotide linkages in the antisense oligonucleotide can be phosphodiester, phosphorothioate, phosphorodithioate or boranophosphate to allow RNase H cleavage of the targeted RNA. Phosphorothioate or phosphorodithioate is preferred for improving nuclease resistance and other reasons, such as ease of manufacture. In one aspect of the oligomers of the present invention, LNA units and / or non - LNA units are linked together by phosphorothioate groups.

[0667] It should be appreciated that including phosphodiester linkages (e.g., one or two linkages) in an antisense oligonucleotide that is otherwise phosphorothioate, especially between or adjacent to LNA units (usually in regions A and / or C), can alter the bioavailability and / or biodistribution of the antisense oligonucleotide (see WO2008 / 053314A, which is incorporated herein by reference).

[0668] In some embodiments, such as in the sequences of the antisense oligonucleotides disclosed herein, and where appropriate and not specifically indicated, all remaining internucleotide linkage groups are phosphodiester groups or phosphorothioate groups or mixtures thereof.

[0669] In some embodiments, all internucleotide linking groups are phosphorothioate groups. When referring to a specific gapmer antisense oligonucleotide sequence (such as those provided herein), it should be understood that in various embodiments, when the linkage is a phosphorothioate linkage, alternative linkages can be used, such as those disclosed herein, such as phosphate (also known as phosphodiester) linkages, particularly for linkages between nucleotide analogs (such as LNA units). Similarly, when referring to a specific gapmer antisense oligonucleotide sequence (such as those provided herein), when a C residue is annotated as a 5'-methyl-modified cytosine, in various embodiments, one or more Cs present in the oligomer can be unmodified C residues.

[0670] Text description

[0671] As used herein, the abbreviations b, d, s, ss have the following meanings:

[0672] b LNA unit or LNA nucleotide (selected from any of b 1 -b 7 )

[0673] b 1 β-D-oxy-LNA

[0674] b 2 β-D-thio-LNA

[0675] b 3 β-D-amino-LNA

[0676] b 4 α-L-oxy-LNA

[0677] b 5 β-D-ENA

[0678] b 6 β-D-(NH)-LNA

[0679] b 7 β-D-(NCH3)-LNA

[0680] d 2-deoxy, which means a 2-deoxyribose unit (such as formula B3 or B5 with R = -H)

[0681] C* methyl-C (5-methylcytosine); [thus dC* is 5-methyl-2'-deoxycytidine]

[0682] A* 2-aminoadenine [thus dA* is 2-amino-2'-deoxyadenosine]

[0683] The internucleotide linkage of s is a phosphorothioate group (-O-P(O)(S - )-O-)

[0684] The internucleotide linkage of ss is a phosphorodithioate group (-O-P(S)(S - )-O-)

[0685] / 5SpC3 / at the -O-P(O)(O of the 5'-terminal group of the antisense oligonucleotide - )OC3H6OH

[0686] / 3SpC3 / at the -O-P(O)(O of the 3'-terminal group of the antisense oligonucleotide - )OC3H6OH

[0687] / 5SpC3s / at the -O-P(O)(S of the 5'-terminal group of the antisense oligonucleotide - )OC3H6OH

[0688] / 3SpC3s / at the -O-P(O)(S of the 3'-terminal group of the antisense oligonucleotide - )OC3H6OH

[0689] The bold nucleotides are LNA nucleotides

[0690] The non-bold nucleotides are non-LNA nucleotides

[0691] Gapmer sequence

[0692] Among Tables 2 to 9, the following gapmer forms of antisense oligonucleotide forms listed in Tables 4 to 9 are more preferred, and those forms are particularly preferred.

[0693] Table 2

[0694]

[0695]

[0696]

[0697]

[0698]

[0699] Table 3

[0700]

[0701]

[0702]

[0703] Preferred antisense oligonucleotides

[0704] The preferred antisense oligonucleotides of the present invention are disclosed below.

[0705] Thus, the present invention preferably relates to antisense oligonucleotides in the form of gapmers consisting of 10 to 28 nucleotides, preferably 11 to 24 nucleotides, more preferably 12 to 20, more preferably 13 to 19 or 14 to 18 nucleotides, and salts and optical isomers of said antisense oligonucleotides, and 1 to 5 of these nucleotides at the 5'-end and 1 to 5 nucleotides at the 3'-end of the antisense oligonucleotide are LNA nucleotides, and there are at least 6, preferably 7, more preferably 8 DNA nucleotides between the LNA nucleotides at the 5'-end and the 3'-end, and the antisense oligonucleotide is capable of hybridizing to a region of the gene encoding TGF-R II or to a region of the mRNA encoding TGF-R II wherein the antisense oligonucleotide is represented by the following sequences 5'-N 1 -GTCATAGA-N 2 -3'(Seq.ID No.12) or 5'-N 3 -ACGCGTCC-N 4 -3'(Seq.ID No.98) or 5'-N 11 -TGTTTAGG-N 12 -3'(Seq.ID No.10) or 5'-N 5 -TTTGGTAG-N 6 -3'(Seq.ID No.11) or 5'-N 7 -AATGGACC-N 8 -3'(Seq.ID No.100) or 5'-N 9 -ATTAATAA-N 10 -3'(Seq.ID No.101), wherein

[0706] N 1Represent: CATGGCAGACCCCGCTGCTC-, ATGGCAGACCCCGCTGCTC-, TGGCAGACCCCGCTGCTC-, GGCAGACCCCGCTGCTC-, GCAGACCCCGCTGCTC-, CAGACCCCGCTGCTC-, AGACCCCGCTGCTC-, GACCCCGCTGCTC-, ACCCCGCTGCTC-, CCCCGCTGCTC-, CCCGCTGCTC-, CCGCTGCTC-, CGCTGCTC-, GCTGCTC-, CTGCTC-, TGCTC-, GCTC-, CTC-, TC-, or C-;

[0707] N 2 Represent: -C, -CC, -CCG, -CCGA, -CCGAG, -CCGAGC, -CCGAGCC, -CCGAGCCC, -CCGAGCCCC, -CCGAGCCCCC, -CCGAGCCCCCA, -CCGAGCCCCCAG, -CCGAGCCCCCAGC, -CCGAGCCCCCAGCG, -CCGAGCCCCCAGCGC, -CCGAGCCCCCAGCGCA, -CCGAGCCCCAGCGCAG, -CCGAGCCCCCAGCGCAGC, -CCGAGCCCCAGCGCAGCG, or –CCGAGCCCCCAGCGCAGCGG;

[0708] N 3 Represent: GGTGGGATCGTGCTGGCGAT-, GTGGGATCGTGCTGGCGAT-, TGGGATCGTGCTGGCGAT-, GGGATCGTGCTGGCGAT-, GGATCGTGCTGGCGAT-, GATCGTGCTGGCGAT-, ATCGTGCTGGCGAT-, TCGTGCTGGCGAT-, CGTGCTGGCGAT-, GTGCTGGCGAT-, TGCTGGCGAT-, GCTGGCGAT-, CTGGCGAT-, TGGCGAT-, GGCGAT-, GCGAT-, CGAT-, GAT-, AT-, or T-;

[0709] N 4Represent: -ACAGGACGATGTGCAGCGGC, -ACAGGACGATGTGCAG CGG, -ACAGGACGATGTGCAGCG, -ACAGGACGATGTGCAGC, -ACAGGACGATGTGCAG, -ACAGGACGATGTGCA, -ACAGGACGATGTGC, -ACAGGACGATGTG, -ACAGGACGATGT, -ACAGGA CGATG, -ACAGGACGAT, -ACAGGACGA, -ACAGGACG, -ACAG GAC, -ACAGGA, -ACAGG, -ACAG, -ACA, -AC, or -A;

[0710] N 5 Represent: GCCCAGCCTGCCCCAGAAGAGCTA-, CCCAGCCTGCCCCAGAAGAGCTA-, CCAGCCTGCCCCAGAAGAGCTA-, CAGCCTGCCCCAGAAGAGCTA-, AGCCTGCCCCAGAAGAGCTA-, GCCTGCCCCAGAAGAGCTA-, CCTGCCCCAGAAGAGCTA-, CTGCCCCAGAAGAGCTA-, TGCCCCAGAAGAGCTA-, GCCCCAGAAGAGCTA-, CCCCAGAAGAGCTA-, CCCAGAAGAGCTA-, CCAGAAGAGCTA-, CAGAAGAGCTA-, AGAAGAGCTA-, GAAGAGCTA-, AAGAGCTA-, AGAGCTA-, GAGCTA-, AGCTA-, GCTA-, CTA-, TA-, or A-;

[0711] N 6Represented by: -TGTTTAGGGAGCCGTCTTCAGGAA, -TGTTTAGGGAGCCGTCTTCAGGA, -TGTTTAGGGAGCCGTCTTCAGG, -TGTTTAGGGAGCCGTCTTCAG, -TGTTTAGGGAGCCGTCTTCA, -TGTTTAGGGAGCCGTCTTC, -TGTTTAGGGAGCCGTCTT, -TGTTTAGGGAGCCGTCT, -TGTTTAGGGAGCCGTC, -TGTTTAGGGAGCCGT, -TGTTTAGGGAGCCG, -TGTTTAGGGAGCC, -TGTTTAGGGAGC, -TGTTTAGGGAG, -TGTTTAGGGA, -TGTTTAGGG, -TGTTTAGG, -TGTTTAG, -TGTTTA, -TGTTT, -TGTT, -TGT, -TG, or –T;

[0712] N 7 Represented by: TGAATCTTGAATATCTCATG-, GAATCTTGAATATCTCATG-, AATCTTGAATATCTCATG-, ATCTTGAATATCTCATG-, TCTTGAATATCTCATG-, CTTGAATATCTCATG-, TTGAATATCTCATG-, TGAATATCTCATG-, GAATATCTCATG-, AATATCTCATG-, ATATCTCATG-, TATCTCATG-, ATCTCATG-, TCTCATG-, CTCATG-, TCATG-, CATG-, ATG-, TG-, or G-;

[0713] N 8 Represented by: -AGTATTCTAGAAACTCACCA, -AGTATTCTAGAAACTCA CC, -AGTATTCTAGAAACTCAC, -AGTATTCTAGAAACTCA, -AG TATTCTAGAAACTC, -AGTATTCTAGAAACT, -AGTATTCTAGAAAC, -AGTATTCTAGAAA, -AGTATTCTAGAA, -AGTATTCTAGA, -AGTATTCTAG, -AGTATTCTA, -AGTATTCT, -AGTATTC, -AG TATT, -AGTAT, -AGTA, -AGT, -AG, or -A;

[0714] N 9Represent: ATTCATATTTATATACAGGC-

[0715] TTCATATTTATATACAGGC-, TCATATTTATATACAGGC-, CATATTTATATACAGGC-, ATATTTATATACAGGC-, TATTTATATACAGGC-, ATTTATATACAGGC-

[0716] TTTATATACAGGC-, TTATATACAGGC-, TATATACAGGC-, ATATACAGGC-, TATACAGGC-, ATACAGGC-, TACAGGC-

[0717] ACAGGC-, CAGGC-, AGGC-, GGC-, GC-, or C-;

[0718] N 10 Represent: -AGTGCAAATGTTATTGGCTA, -AGTGCAAATGTTATTGGCT, -AGTGCAAATGTTATTGGC, -AGTGCAAATGTTATTGG, -AGTGCAAATGTTATTG, -AGTGCAAATGTTATT, -AGTGCAAATGTTAT, -AGTGCAAATGTTA, -AGTGCAAATGTT, -AGTGCAAATGT, -AGTGCAAATG, -AGTGCAAAT, -AGTGCAAA, -AGTGCAA, -AGTGCA, -AGTGC, -AGTG, -AGT, -AG, or -A;

[0719] N 11Represent: TGCCCCAGAAGAGCTATTTGGTAG-, GCCCCAGAAGAGCTATTTGGTAG-,CCCCAGAAGAGCTATTTGGTAG-, CCCAGAAGAGCTATTTGGTAG-,CCAGAAGAGCTATTTGGTAG-,CAGAAGAGCTATTTGGTAG-, AGAAGAGCTATTTGGTAG-,GAAGAGCTATTTGGTAG-,AAGAGCTATTTGGTAG-,AGAGCTATTTGGTAG-,GAGCTATTTGGTAG-,AGCTATTTGGTAG-,GCTATTTGGTAG-, CTATTTGGTAG-,TATTTGGTAG-,ATTTGGTAG-,TTTGGTAG-,TTGGTAG-,TGGTAG-,GGTAG-,GTAG-,TAG-,AG- or G-,

[0720] N 12 Represent: -GAGCCGTCTTCAGGAATCTTCTCC,

[0721] -GAGCCGTCTTCAGGAATCTTCTC, -GAGCCGTCTTCAGGAATCTTCT, -GAGCCGTCTTCAGGAATCTTC, -GAGCCGTCTTCAGGAATCTT, -GAGCCGTCTTCAGGAATCT,-GAGCCGTCTTCAGGAATC,-GAGCCGTCTTCAGGAAT,-GAGCCGTCTTCAGGAA, -GAGCCGTCTTCAGGA, -GAGCCGTCTTCAGG,-GAGCCGTCTTCAG,-GAGCCGTCTTCA, -GAGCCGTCTTC,-GAGCCGTCTT,-GAGCCGTCT, -GAGCCGTC,-GAGCCGT,-GAGCCG,-GAGCC,-GAGC,-GAG,-GA, or –G;

[0722] or where N 1 to N 12 Represent any list of restricted residues disclosed herein.

[0723] Furthermore, the present invention preferably relates to antisense oligonucleotides in the form of gapmers consisting of 10 to 28 nucleotides, preferably 11 to 24 nucleotides, more preferably 12 to 20 nucleotides, more preferably 13 to 19 nucleotides or 14 to 18 nucleotides, and salts and optical isomers of said antisense oligonucleotides, and 1 to 5 of these nucleotides at the 5'-end and 1 to 5 nucleotides at the 3'-end of the antisense oligonucleotide are LNA nucleotides, and there are at least 6, preferably 7, more preferably 8 DNA nucleotides between the LNA nucleotides at the 5'-end and 3'-end, and the antisense oligonucleotide is capable of hybridizing to a region of the gene encoding TGF-R II or to a region of the mRNA encoding TGF-R II wherein the antisense oligonucleotide is represented by the following sequence 5’-N 1 -GTCATAGA-N 2 -3’ (Seq.ID No.12), wherein

[0724] N 1 represents: GGCAGACCCCGCTGCTC-, GCAGACCCCGCTGCTC-, CAGACCCCGCTGCTC-, AGACCCCGCTGCTC-, GACCCCGCTGCTC-, ACCCCGCTGCTC-, CCCCGCTGCTC-, CCCGCTGCTC-, CCGCTGCTC-, CGCTGCTC-, GCTGCTC-, CTGCTC-, TGCTC-, GCTC-, CTC-, TC-, or C-;

[0725] N 2 represents: -C, -CC, -CCG, -CCGA, -CCGAG, -CCGAGC, -CCGAGCC, -CCGAGCCC, -CCGAGCCCC, -CCGAGCCCCC, -CCGAGCCCCCA, -CCGAGCCCCCAG, -CCGAGCCCCCAGC, -CCGAGCCCCCAGCG, -CCGAGCCCCCAGCGC, -CCGAGCCCCCAGCGCA, or -CCGAGCCCCCAGCGCAG.

[0726] N 1 and / or N 2 may also represent any one of the other restricted lists of 3' and 5' residues disclosed herein.

[0727] Gapmer antisense oligonucleotides falling within the general formula S1 are particularly preferred:

[0728] 5’-N 1-GTCATAGA-N 2 -3’(Seq.ID No.12)S1

[0729] Such gapmer antisense oligonucleotides are:

[0730] CCGCTGCTCGTCATAGAC(Seq.ID No.19)

[0731] CGCTGCTCGTCATAGACC(Seq.ID No.20)

[0732] GCTGCTCGTCATAGACCG(Seq.ID No.21)

[0733] CTGCTCGTCATAGACCGA(Seq.ID No.22)

[0734] TGCTCGTCATAGACCGAG(Seq.ID No.23)

[0735] GCTCGTCATAGACCGAGC(Seq.ID No.24)

[0736] CTCGTCATAGACCGAGCC(Seq.ID No.25)

[0737] TCGTCATAGACCGAGCCC(Seq.ID No.26)

[0738] CGTCATAGACCGAGCCCC(Seq.ID No.27)

[0739] CGCTGCTCGTCATAGAC(Seq.ID No.28)

[0740] GCTGCTCGTCATAGACC(Seq.ID No.29)

[0741] CTGCTCGTCATAGACCG(Seq.ID No.30)

[0742] TGCTCGTCATAGACCGA(Seq.ID No.31)

[0743] GCTCGTCATAGACCGAG(Seq.ID No.32)

[0744] CTCGTCATAGACCGAGC(Seq.ID No.33)

[0745] TCGTCATAGACCGAGCC(Seq.ID No.34)

[0746] CGTCATAGACCGAGCCC(Seq.ID No.35)

[0747] GCTGCTCGTCATAGAC(Seq.ID No.36)

[0748] CTGCTCGTCATAGACC(Seq.ID No.37)

[0749] TGCTCGTCATAGACCG(Seq.ID No.38)

[0750] GCTCGTCATAGACCGA(Seq.ID No.39)

[0751] CTCGTCATAGACCGAG(Seq.ID No.40)

[0752] TCGTCATAGACCGAGC(Seq.ID No.41)

[0753] CGTCATAGACCGAGCC(Seq.ID No.42)

[0754] CTGCTCGTCATAGAC(Seq.ID No.43)

[0755] TGCTCGTCATAGACC(Seq.ID No.44)

[0756] GCTCGTCATAGACCG(Seq.ID No.45)

[0757] CTCGTCATAGACCGA(Seq.ID No.46)

[0758] TCGTCATAGACCGAG(Seq.ID No.47)

[0759] CGTCATAGACCGAGC(Seq.ID No.48)

[0760] TGCTCGTCATAGAC(Seq.ID No.49)

[0761] GCTCGTCATAGACC(Seq.ID No.50)

[0762] CTCGTCATAGACCG(Seq.ID No.51)

[0763] TCGTCATAGACCGA(Seq.ID No.52)

[0764] CGTCATAGACCGAG(Seq.ID No.53)

[0765] The antisense oligonucleotides of formula S1 in gapmer form (LNA segment 1 - DNA segment - LNA segment 2) comprise an LNA segment at the 5'-end, which consists of 2 to 5, preferably 2 to 4 LNA units, and an LNA fragment at the 3'-end, which consists of 2 to 5, preferably 2 to 4 LNA units, and a DNA segment between the two LNA segments, which consists of 6 to 14, preferably 7 to 12, more preferably 8 to 11 DNA units.

[0766] The antisense oligonucleotides of formula S1 contain the LNA nucleotides (LNA units) disclosed herein, in particular those disclosed in the "Locked nucleic acids" section, preferably those disclosed in the "Preferred LNAs" section. The LNA units and DNA units may contain standard nucleobases, such as adenine (A), cytosine (C), guanine (G), thymine (T) and uracil (U), but may also contain modified nucleobases, as disclosed in the "Nucleobases" section. The antisense oligonucleotides of formula S1 or the LNA and DNA segments of the antisense oligonucleotides may contain any internucleotide linkages disclosed herein, in particular those disclosed in the "Internucleotide linkages (IL)" section. The antisense oligonucleotides of formula S1 may also optionally contain terminal groups at the 3'-end and / or 5'-end, in particular those disclosed in the "Terminal groups" section.

[0767] Experiments have shown that modified nucleobases do not significantly increase or alter the activity of the antisense oligonucleotides of the present invention in the tested neurological and oncology indications. It has been demonstrated that the modified nucleobases 5-methylcytosine or 2-aminoadenine further increase the activity of the antisense oligonucleotides of formula S1, in particular if 5-methylcytosine is used only in the LNA nucleotides or in the LNA and DNA nucleotides and / or if 2-aminoadenine is used in the DNA nucleotides rather than in the LNA nucleotides.

[0768] The preferred gapmer structures of the antisense oligonucleotide of formula S1 are as follows: 3-8-3, 4-8-2, 2-8-4, 3-8-4, 4-8-3, 4-8-4, 3-9-3, 4-9-2, 2-9-4, 4-9-3, 3-9-4, 4-9-4, 3-10-3, 2-10-4, 4-10-2, 3-10-4, 4-10-3, 4-10-4, 2-11-4, 4-11-2, 3-11-4, 4-11-3, more preferably 3-8-3, 3-8-4, 4-8-3, 4-8-4, 3-9-3, 4-9-3, 3-9-4, 4-9-4, 3-10-3, 3-10-4, 4-10-3, 4-10-4, 3-11-4, and 4-11-3.

[0769] The LNA unit of the antisense oligonucleotide of formula S1, in particular β-D-oxy-LNA (b 1 ), β-D-thio-LNA(b 2 ), α-L-oxy-LNA (b 4 ), β-D-ENA(b 5 ), β-D-(NH)-LNA (b 6 ), β-D-(NCH3)-LNA(b 7 ), β-D-(ONH)-LNA(b 8 ) and β-D-(ONCH3)-LNA(b 9 ) is preferred. Experiments have shown that all these LNA units b 1 , b 2 , b 4 , b 5 , b 6 , b 7 , b 8 and b 9 can be synthesized with the required effort and result in antisense oligonucleotides with comparable stability and activity. However, based on experiments, LNA units b are more preferred. 1 , b 2 , b 4 , b 5 , b 6 and b 7 More preferably, the LNA unit b 1 , b 2 , b 4 , b 6 and b 7 , even more preferably the LNA unit b 1 and b 4 , the most preferred one in terms of the complexity of chemical synthesis is β-D-oxy-LNA (b 1 ).

[0770] To date, no particular 3′-end group or 5′-end group has been found to significantly alter or increase stability or activity with respect to oncological or neurological indications such that 3′- and 5′-end groups are possible, but not clearly preferred.

[0771] A variety of internucleotide bridges or internucleotide linkages are possible. In the formulas disclosed herein, the internucleotide linkage IL is represented by -IL′-Y-. Thus, IL = -IL′-Y- = -X″-P(=X′)(X-)-Y-, where IL is preferably selected from:

[0772] -O-P(O)(O - )-O-, -O-P(O)(S - )-O-, -O-P(S)(S - )-O-, -S-P(O)(O - )-O-, -S-P(O)(S - )-O-, -O-P(O)(O - )-S-, -O-P(O)(S - )-S-, -S-P(O)(O - )-S-, -O-P(O)(CH3)-O-, -O-P(O)(OCH3)-O-, -O-P(O)(NH(CH3))-O-, -O-P(O)[N(CH3)2]-O-, -O-P(O)(BH3 - )-O-, -O-P(O)(OCH2CH2OCH3)-O-, -O-P(O)(OCH2CH2SCH3)-O-, -O-P(O)(O - )-N(CH3)-, -N(CH3)-P(O)(O - )-O-. Preferably selected from -O-P(O)(O - )-O-, -O-P(O)(S - )-O-, -O-P(S)(S - )-O-, -S-P(O)(O - )-O-, -S-P(O)(S - )-O-, -O-P(O)(O - )-S-, -O-P(O)(S - )-S-, -S-P(O)(O -)-S-, -O-P(O)(OCH3)-O-, -O-P(O)(NH(CH3))-O-, -O-P(O)[N(CH3)2]-O-, -O-P(O)(OCH2CH2OCH3)-O-, more preferably selected from -O-P(O)(O - )-O-, -O-P(O)(S - )-O-, -O-P(S)(S - )-O-, -S-P(O)(O - )-O-, -S-P(O)(S - )-O-, -O-P(O)(O - )-S-, -O-P(O)(S - )-S-, -S-P(O)(O - )-S-, more preferably selected from -O-P(O)(O - )-O-, -O-P(O)(S - )-O-, -O-P(S)(S - )-O-, most preferably selected from -O-P(O)(O - )-O- and -O-P(O)(S-)-O- internucleotide linkages IL.

[0773] Accordingly, the present invention preferably relates to antisense oligonucleotides in the form of gapmers composed of 10 to 28 nucleotides, preferably 11 to 24 nucleotides, more preferably 12 to 20, more preferably 13 to 19 or 14 to 18 nucleotides, and salts and optical isomers of said antisense oligonucleotides, wherein 1 to 5 of these nucleotides at the 5'-end and 1 to 5 nucleotides at the 3'-end of the antisense oligonucleotide are LNA nucleotides, and there are at least 6, preferably 7, more preferably 8 DNA nucleotides between the LNA nucleotides at the 5'-end and 3'-end, and the antisense oligonucleotide is capable of hybridizing to a region of the gene encoding TGF-R II or to a region of the mRNA encoding TGF-R II , wherein the antisense oligonucleotide is represented by the following sequence 5'-N 1 -GTCATAGA-N 2 -3' (Seq.ID No.12), wherein

[0774] N 1Represent: GGCAGACCCCGCTGCTC-, GCAGACCCCGCTGCTC-, CAGACCCCGCTGCTC-, AGACCCCGCTGCTC-, GACCCCGCTGCTC-, ACCCCGCTGCTC-, CCCCGCTGCTC-, CCCGCTGCTC-, CCGCTGCTC-, CGCTGCTC-, GCTGCTC-, CTGCTC-, TGCTC-, GCTC-, CTC-, TC-, or C-;

[0775] N 2 Represent: -C, -CC, -CCG, -CCGA, -CCGAG, -CCGAGC, -CCGAGCC, -CCGAGCCC, -CCGAGCCCC, -CCGAGCCCCC, -CCGAGCCCCCA, -CCGAGCCCCCAG, -CCGAGCCCCCAGC, -CCGAGCCCCCAGCG, -CCGAGCCCCCAGCGC, -CCGAGCCCCCAGCGCA, or -CCGAGCCCCCAGCGCAG; and

[0776] The LNA nucleotides are selected from β-D-oxy-LNA (b 1 ), β-D-thio-LNA (b 2 ), α-L-oxy-LNA (b 4 ), β-D-ENA (b 5 ), β-D-(NH)-LNA (b 6 ), β-D-(NCH3)-LNA (b 7 ), β-D-(ONH)-LNA (b 8 ), and β-D-(ONCH3)-LNA (b 9 ); and preferably selected from β-D-oxy-LNA (b 1 ), β-D-thio-LNA (b 2 ), α-L-oxy-LNA (b 4 ), β-D-(NH)-LNA (b 6 ), and β-D-(NCH3)-LNA (b 7 ); and

[0777] The internucleotide linkages are selected from

[0778] -O-P(O)(O - )-O-, -O-P(O)(S - )-O-, -O-P(S)(S - )-O-, -S-P(O)(O- )-O-,-S-P(O)(S - )-O-,-O-P(O)(O - )-S-,-O-P(O)(S - )-S-,-S-P(O)(O - )-S-,-O-P(O)(CH3)-O-,-O-P(O)(OCH3)-O-,-O-P(O)(NH(CH3))-O-,-O-P(O)[N(CH3)2]-O-,-O-P(O)(BH3 - )-O-,-O-P(O)(OCH2CH2OCH3)-O-,-O-P(O)(OCH2CH2SCH3)-O-,-O-P(O)(O - )-N(CH3)-,-N(CH3)-P(O)(O - )-O-;

[0779] and preferably selected from -O-P(O)(O - )-O-,-O-P(O)(S - )-O-,-O-P(S)(S - )-O-,-S-P(O)(O - )-O-,-S-P(O)(S - )-O-,-O-P(O)(O - )-S-,-O-P(O)(S - )-S-,-S-P(O)(O - )-S-. Such preferred antisense oligonucleotides may not contain any modified 3' and 5' ends, or may not contain any 3' and 5' end groups, and may contain 5-methylcytosine and / or 2-aminoadenine as modified nucleobases.

[0780] More preferably N 1 represents: CAGACCCCGCTGCTC-, AGACCCCGCTGCTC-, GACCCCGCTGCTC-, ACCCCGCTGCTC-, CCCCGCTGCTC-, CCCGCTGCTC-, CCGCTGCTC-, CGCTGCTC-, GCTGCTC-, CTGCTC-, TGCTC-, GCTC-, CTC-, TC-, or C-; and

[0781] N 2Represent: -C, -CC, -CCG, -CCGA, -CCGAG, -CCGAGC, -CCGAGCC, -CCGAGCCC, -CCGAGCCCC, -CCGAGCCCCC, -CCGAGCCCCCA, -CCGAGCCCCCAG, -CCGAGCCCCCAGC, -CCGAGCCCCCAGCG, or -CCGAGCCCCCAGCGC.

[0782] Further preferably, the present invention relates to antisense oligonucleotides in the form of gapmers consisting of 11 to 24 nucleotides, more preferably 12 to 20, more preferably 13 to 19 or 14 to 18 nucleotides, and salts and optical isomers of said antisense oligonucleotides, and 2 to 5 nucleotides among these nucleotides at the 5′ end and 2 to 5 nucleotides at the 3′ end of the antisense oligonucleotide are LNA nucleotides, and there is a sequence of preferably 7, more preferably 8 DNA nucleotides between the LNA nucleotides at the 5′ end and the 3′ end, and the antisense oligonucleotide is capable of hybridizing with a region of the gene encoding TGF-R II or a region of the mRNA encoding TGF-R II wherein the antisense oligonucleotide has the following sequence 5′-N 1 -GTCATAGA-N 2 -3′ (Seq. ID No. 12), wherein

[0783] N 1 represents: ACCCCGCTGCTC-, CCCCGCTGCTC-, CCCGCTGCTC-, CCGCTGCTC-, CGCTGCTC-, GCTGCTC-, CTGCTC-, TGCTC-, GCTC-, CTC-, TC-, or C-; preferably N 1 represents: CCCGCTGCTC-, CCGCTGCTC-, CGCTGCTC-, GCTGCTC-, CTGCTC-, TGCTC-, GCTC-, CTC-, TC-, or C-; and

[0784] N 2 represents: -C, -CC, -CCG, -CCGA, -CCGAG, -CCGAGC, -CCGAGCC, -CCGAGCCC, -CCGAGCCCC, or -CCGAGCCCCC, -CCGAGCCCCCA, or -CCGAGCCCCCAG; preferably N 2Represent: -C, -CC, -CCG, -CCGA, -CCGAG, -CCGAGC, -CCGAGCC, -CCGAGCCC, -CCGAGCCCC, or -CCGAGCCCCC;

[0785] and the LNA nucleotides are selected from β-D-oxy-LNA (b 1 ), β-D-thio-LNA (b 2 ), α-L-oxy-LNA (b 4 ), β-D-(NH)-LNA (b 6 ), and β-D-(NCH3)-LNA (b 7 ); and

[0786] the internucleotide linkages are selected from

[0787] -O-P(O)(O - )-O-, -O-P(O)(S - )-O-, -O-P(S)(S - )-O-, -S-P(O)(O - )-O-, -S-P(O)(S - )-O-, -P-P(O)(O - )-S-, -O-P(O)(S - )-S-, -S-P(O)(O - )-S-; preferably selected from phosphates, phosphorothioates and dithiophosphates. Such preferred antisense oligonucleotides may not contain any modified 3' and 5' termini, or may not contain any 3' and 5' terminal groups, and may contain 5-methylcytosine and / or 2-aminoadenine as modified nucleobases.

[0788] Particularly preferred are the gapmer antisense oligonucleotides of Seq.ID No.19 to Seq.ID No.53, which comprise a segment of 2 to 5, preferably 2 to 4, more preferably 3 to 4 LNA units at the 3' terminus, and a segment of 2 to 5, preferably 2 to 4, more preferably 3 to 4 LNA units at the 5' terminus, and a segment of at least 6, preferably 7, more preferably 8 DNA units between the two segments of LNA units, wherein the LNA units are selected from β-D-oxy-LNA (b 1 ), β-D-thio-LNA (b 2 ), α-L-oxy-LNA (b 4 ), β-D-(NH)-LNA (b 6 ), and β-D-(NCH3)-LNA (b 7), the internucleotide linkage is selected from phosphates, phosphorothioates, and phosphorodithioates. Such preferred antisense oligonucleotides may be free of any modified 3' and 5' ends, or free of any 3' and 5' end groups, and may contain 5-methylcytosine as a modified nucleobase in LNA units, preferably all LNA units, and / or 2-aminoadenine in some or all DNA units and / or 5-methylcytosine in some or all DNA units.

[0789] Particularly preferred are the gapmer antisense oligonucleotides of Table 4 (Seq.ID No.232a to 244b).

[0790] Furthermore, the present invention preferably relates to antisense oligonucleotides in the form of gapmers consisting of 10 to 28 nucleotides, preferably 11 to 24 nucleotides, more preferably 12 to 20, more preferably 13 to 19 or 14 to 18 nucleotides, and salts and optical isomers of said antisense oligonucleotides, and 1 to 5 of these nucleotides at the 5' end and 1 to 5 nucleotides at the 3' end of the antisense oligonucleotide are LNA nucleotides, and there are at least 6, preferably 7, more preferably 8 DNA nucleotides between the LNA nucleotides at the 5' end and the 3' end, and the antisense oligonucleotide is capable of hybridizing to a region of the gene encoding TGF-R II or to a region of the mRNA encoding TGF-R II and is represented by the following sequence 5'-N 3 -ACGCGTCC-N 4 -3' (Seq.ID No.98), where

[0791] N 3 represents: GGGATCGTGCTGGCGAT-, GGATCGTGCTGGCGAT-, GATCGTGCTGGCGAT-, ATCGTGCTGGCGAT-, TCGTGCTGGCGAT-, CGTGCTGGCGAT-, GTGCTGGCGAT-, TGCTGGCGAT-, GCTGGCGAT-, CTGGCGAT-, TGGCGAT-, GGCGAT-, GCGAT-, CGAT-, GAT-, AT-, or T-;

[0792] N 4Represent: -ACAGGACGATGTGCAGC, -ACAGGACGATGTGCAG, -ACAGGACGATGTGCA, -ACAGGACGATGTGC, -ACAGGACGATGTG, -ACAGGACGATGT, -ACAGGACGATG, -ACAGGACGAT, -ACAGGACGA, -ACAGGACG, -ACAGGAC, -ACAGGA, -ACAGG, -ACAG, -ACA, -AC, or -A.

[0793] N 3 and / or N 4 It can also represent any one of the additional restricted lists of 3' and 5' residues disclosed herein.

[0794] Gapmer antisense oligonucleotides falling within the general formula S2 are particularly preferred:

[0795] 5’-N 3 -ACGCGTCC-N 4 -3’(Seq.ID No.98)S2

[0796] Such gapmer antisense oligonucleotides are:

[0797] GCTGGCGATACGCGTCCA(Seq.ID No.54)

[0798] CTGGCGATACGCGTCCAC(Seq.ID No.55)

[0799] TGGCGATACGCGTCCACA(Seq.ID No.56)

[0800] GGCGATACGCGTCCACAG(Seq.ID No.57)

[0801] GCGATACGCGTCCACAGG(Seq.ID No.58)

[0802] CGATACGCGTCCACAGGA(Seq.ID No.59)

[0803] GATACGCGTCCACAGGAC(Seq.ID No.60)

[0804] ATACGCGTCCACAGGACG(Seq.ID No.61)

[0805] TACGCGTCCACAGGACGA(Seq.ID No.62)

[0806] CTGGCGATACGCGTCCA(Seq.ID No.63)

[0807] TGGCGATACGCGTCCAC(Seq.ID No.64)

[0808] GGCGATACGCGTCCACA(Seq.ID No.65)

[0809] GCGATACGCGTCCACAG(Seq.ID No.66)

[0810] CGATACGCGTCCACAGG(Seq.ID No.67)

[0811] GATACGCGTCCACAGGA(Seq.ID No.68)

[0812] ATACGCGTCCACAGGAC(Seq.ID No.349)

[0813] TACGCGTCCACAGGACG(Seq.ID No.350)

[0814] TGGCGATACGCGTCCA(Seq.ID No.351)

[0815] GGCGATACGCGTCCAC(Seq.ID No.352)

[0816] GCGATACGCGTCCACA(Seq.ID No.353)

[0817] CGATACGCGTCCACAG(Seq.ID No.354)

[0818] GATACGCGTCCACAGG(Seq.ID No.355)

[0819] ATACGCGTCCACAGGA(Seq.ID No.356)

[0820] TACGCGTCCACAGGAC(Seq.ID No.357)

[0821] GGCGATACGCGTCCA(Seq.ID No.358)

[0822] GCGATACGCGTCCAC(Seq.ID No.359)

[0823] CGATACGCGTCCACA(Seq.ID No.360)

[0824] GATACGCGTCCACAG(Seq.ID No.361)

[0825] ATACGCGTCCACAGG(Seq.ID No.362)

[0826] TACGCGTCCACAGGA(Seq.ID No.363)

[0827] GCGATACGCGTCCA(Seq.ID No.364)

[0828] CGATACGCGTCCAC(Seq.ID No.365)

[0829] GATACGCGTCCACA(Seq.ID No.366)

[0830] ATACGCGTCCACAG(Seq.ID No.367)

[0831] TACGCGTCCACAGG(Seq.ID No.368)

[0832] The antisense oligonucleotides of formula S2 in gapmer form (LNA segment 1 - DNA segment - LNA segment 2) comprise an LNA segment at the 5'-end, which consists of 2 to 5, preferably 2 to 4 LNA units, and an LNA fragment at the 3'-end, which consists of 2 to 5, preferably 2 to 4 LNA units, and a DNA segment between the two LNA segments, which consists of 6 to 14, preferably 7 to 12, more preferably 8 to 11 DNA units.

[0833] The antisense oligonucleotides of formula S2 contain the LNA nucleotides (LNA units) disclosed herein, in particular those disclosed in the "Locked nucleic acid" section, preferably those disclosed in the "Preferred LNA" section. The LNA units and DNA units may contain standard nucleobases such as adenine (A), cytosine (C), guanine (G), thymine (T) and uracil (U), but may also contain modified nucleobases as disclosed in the "Nucleobases" section. The antisense oligonucleotides of formula S2 or the LNA and DNA fragments of the antisense oligonucleotides may contain any internucleotide linkages disclosed herein, in particular those disclosed in the "Internucleotide linkages (IL)" section. The antisense oligonucleotides of formula S2 may also optionally contain terminal groups at the 3'-end and / or 5'-end, in particular those disclosed in the "Terminal groups" section.

[0834] Experiments have shown that modified nucleobases do not significantly increase or alter the activity of the antisense oligonucleotides of the present invention in the tested neurological and oncology indications. It has been demonstrated that the modified nucleobases 5-methylcytosine or 2-aminoadenine further increase the activity of the antisense oligonucleotides of formula S2, especially if 5-methylcytosine is used only in LNA nucleotides or in LNA nucleotides and DNA nucleotides and / or if 2-aminoadenine is used in DNA nucleotides rather than in LNA nucleotides.

[0835] Preferred gapmer structures of the antisense oligonucleotides of formula S2 are as follows: 3-8-3, 4-8-2, 2-8-4, 3-8-4, 4-8-3, 4-8-4, 3-9-3, 4-9-2, 2-9-4, 4-9-3, 3-9-4, 4-9-4, 3-10-3, 2-10-4, 4-10-2, 3-10-4, 4-10-3, 4-10-4, 2-11-4, 4-11-2, 3-11-4, 4-11-3, more preferably: 3-8-3, 3-8-4, 4-8-3, 4-8-4, 3-9-3, 4-9-3, 3-9-4, 4-9-4, 3-10-3, 3-10-4, 4-10-3, 4-10-4, 3-11-4, and 4-11-3.

[0836] The LNA units of the antisense oligonucleotides of formula S2, in particular β-D-oxy-LNA (b 1 ), β-D-thio-LNA (b 2 ), α-L-oxy-LNA (b 4 ), β-D-ENA (b 5 ), β-D-(NH)-LNA (b 6 ), β-D-(NCH3)-LNA (b 7 ), β-D-(ONH)-LNA (b 8 ) and β-D-(ONCH3)-LNA (b 9 ) are preferred. Experiments have shown that all these LNA units b 1 , b 2 , b 4 , b 5 , b 6 , b 7 , b 8 and b 9 can be synthesized with the required effort and lead to antisense oligonucleotides with comparable stability and activity. However, based on experiments, more preferred are the LNA units b 1 , b 2 , b4 , b 5 , b 6 and b 7 . More preferably, the LNA unit b 1 , b 2 , b 4 , b 6 and b 7 , and even more preferably, the LNA unit b 1 and b 4 , most preferably with respect to the complexity of chemical synthesis is β-D-oxy-LNA (b 1 ).

[0837] So far, no particular 3'-terminal group or 5'-terminal group has been found to significantly alter or increase the stability or activity with respect to oncological or neurological indications such that 3'- and 5'-terminal groups are possible but not clearly preferred.

[0838] Various internucleotide bridges or internucleotide linkages are possible. In the formulas disclosed herein, the internucleotide linkage IL is represented by -IL'-Y-. Thus, IL = -IL'-Y- = -X”-P(=X’)(X - ), -Y-, where IL is preferably selected from:

[0839] -O-P(O)(O - ), -O-P(O)(S - ), -O-P(S)(S - ), -O-, -S-P(O)(O - ), -O-P(O)(S - ), -O-P(O)(O - ), -O-P(O)(S - ), -S-P(O)(O - ), -O-P(O)(CH3)-O-, -O-P(O)(OCH3)-O-, -O-P(O)(NH(CH3))-O-, -O-P(O)[N(CH3)2]-O-, -O-P(O)(BH3 - ), -O-P(O)(OCH2CH2OCH3)-O-, -O-P(O)(OCH2CH2SCH3)-O-, -O-P(O)(O - ), -N(CH3)-, -N(CH3)-P(O)(O - ), -O-. Preferably selected from -O-P(O)(O - ), -O-P(O)(S - ), -O-P(S)(S- ) -O-, -S-P(O)(O - ) -O-, -S-P(O)(S - ) -O-, -O-P(O)(O - ) -S-, -O-P(O)(S - ) -S-, -S-P(O)(O - ) -S-, -O-P(O)(OCH3)-O-, -O-P(O)(NH(CH3))-O-, -P-P(O)[N(CH3)2]-O-, -O-P(O)(OCH2CH2OCH3)-O-, more preferably selected from -O-P(O)(O - ) -O-, -O-P(O)(S - ) -O-, -O-P(S)(S - ) -O-, -S-P(O)(O - ) -O-, -S-P(O)(S - ) -O-, -O-P(O)(O - ) -S-, -O-P(O)(S - ) -S-, -S-P(O)(O - ) -S-, more preferably selected from -O-P(O)(O - ) -O-, -O-P(O)(S - ) -O-, -O-P(S)(S - ) -O-, most preferably selected from -O-P(O)(O - ) -O- and -O-P(O)(S - ) -O- of the internucleotide linkage IL.

[0840] Therefore, the present invention preferably relates to antisense oligonucleotides in the form of gapmers composed of 10 to 28 nucleotides, preferably 11 to 24 nucleotides, more preferably 12 to 20, more preferably 13 to 19 or 14 to 18 nucleotides, and salts and optical isomers of said antisense oligonucleotides, and 1 to 5 of these nucleotides at the 5'-end and 1 to 5 nucleotides at the 3'-end of the antisense oligonucleotide are LNA nucleotides, and there are at least 6, preferably 7, more preferably 8 DNA nucleotides between the LNA nucleotides at the 5'-end and the 3'-end, and the antisense oligonucleotide is capable of hybridizing with the region of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II wherein the antisense oligonucleotide is represented by the following sequence 5'-N 3 -ACGCGTCC-N 4 -3' (Seq.ID No.98), wherein

[0841] N 3 represent: GGGATCGTGCTGGCGAT-, GGATCGTGCTGGCGAT-, GATCGTGCTGGCGAT-, ATCGTGCTGGCGAT-, TCGTGCTGGCGAT-, CGTGCTGGCGAT-, GTGCTGGCGAT-, TGCTGGCGAT-, GCTGGCGAT-, CTGGCGAT-, TGGCGAT-, GGCGAT-, GCGAT-, CGAT-, GAT-, AT-, or T-; and

[0842] N 4 represent: -ACAGGACGATGTGCAGC, -ACAGGACGATGTGCAG, -ACAGGACGATGTGCA, -ACAGGACGATGTGC, -ACAGGACGATGTG, -ACAGGACGATGT, -ACAGGACGATG, -ACAGGACGAT, -ACAGGACGA, -ACAGGACG, -ACAGGAC, -ACAGGA, -ACAGG, -ACAG, -ACA, -AC, or -A, and

[0843] The LNA nucleotides are selected from β-D-oxy-LNA (b 1 ), β-D-thio-LNA (b 2 ), α-L-oxy-LNA (b 4 ), β-D-ENA (b 5 ), β-D-(NH)-LNA (b 6 ), β-D-(NCH3)-LNA (b 7 ), β-D-(ONH)-LNA (b 8 ), and β-D-(ONCH3)-LNA (b 9 ); and preferably selected from β-D-oxy-LNA (b 1 ), β-D-thio-LNA (b 2 ), α-L-oxy-LNA (b 4 ), β-D-(NH)-LNA (b 6 ), and β-D-(NCH3)-LNA (b 7 ) and

[0844] The internucleotide linkages are selected from

[0845] -O-P(O)(O - )-O-, -O-P(O)(S - )-O-, -O-P(S)(S- ) -O-, -S-P(O)(O - ) -O-, -S-P(O)(S - ) -O-, -O-P(O)(O - ) -S-, -O-P(O)(S - ) -S-, -S-P(O)(O - ) -S-, -O-P(O)(CH3)-O-, -O-P(O)(OCH3)-O-, -O-P(O)(NH(CH3))-O-, -O-P(O)[N(CH3)2]-O-, -O-P(O)(BH3 - ) -O-, -O-P(O)(OCH2CH2OCH3)-O-, -O-P(O)(OCH2CH2SCH3)-O-, -O-P(O)(O - ) -N(CH3)-, -N(CH3)-P(O)(O - ) -O-;

[0846] and preferably selected from -O-P(O)(O - ) -O-, -O-P(O)(S - ) -O-, -O-P(S)(S - ) -O-, -S-P(O)(O - ) -O-, -S-P(O)(S - ) -O-, -O-P(O)(O - ) -S-, -O-P(O)(S - ) -S-, -S-P(O)(O - ) -S-. Such preferred antisense oligonucleotides may not contain any modified 3' and 5' ends, or may not contain any 3' and 5' end groups, and may contain 5-methylcytosine and / or 2-aminoadenine as modified nucleobases.

[0847] More preferably N 3 represents: GATCGTGCTGGCGAT-, ATCGTGCTGGCGAT-, TCGTGCTGGCGAT-, CGTGCTGGCGAT-, GTGCTGGCGAT-, TGCTGGCGAT-, GCTGGCGAT-, CTGGCGAT-, TGGCGAT-, GGCGAT-, GCGAT-, CGAT-, GAT-, AT-, or T-; and

[0848] N 4Represent: -ACAGGACGATGTGCA, -ACAGGACGATGTGC, -ACAGGA CGATGTG, -ACAGGACGATGT, -ACAGGACGATG, -ACAGGAC GAT, -ACAGGACGA, -ACAGGACG, -ACAGGAC, -ACAGGA, -AC AGG, -ACAG, -ACA, -AC, or -A.

[0849] Further preferably, the present invention relates to antisense oligonucleotides in the form of gapmers composed of 11 to 24 nucleotides, more preferably 12 to 20, more preferably 13 to 19 or 14 to 18 nucleotides, and salts and optical isomers of said antisense oligonucleotides, and 2 to 5 nucleotides among these nucleotides at the 5'-end and 2 to 5 nucleotides at the 3'-end of the antisense oligonucleotide are LNA nucleotides, and there is preferably a sequence of 7, more preferably 8 DNA nucleotides between the LNA nucleotides at the 5'-end and the 3'-end, and the antisense oligonucleotide can hybridize with the region of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II wherein the antisense oligonucleotide has the following sequence 5'-N 3 -ACGCGTCC-N 4 -3' (Seq. ID No. 98), wherein

[0850] N 3 represents: CGTGCTGGCGAT-, GTGCTGGCGAT-, TGCTGGCGAT-, GCTGGCGAT-, CTGGCGAT-, TGGCGAT-, GGCGAT-, GCGAT-, CGAT-, GAT-, AT-, or T-; preferably N 3 represents: TGCTGGCGAT-, GCTGGCGAT-, CTGGCGAT-, TGGCGAT-, GGCGAT-, GCGAT-, CGAT-, GAT-, AT-, or T-;

[0851] and

[0852] N 4 represents: -ACAGGACGATGT, -ACAGGACGATG, -ACAGGACGAT, -A CAGGACGA, -ACAGGACG, -ACAGGAC, -ACAGGA, -ACAGG, -A CAG, -ACA, -AC, or -A; preferably N 4Represent: -ACAGGACGAT, -ACAGGACGA, -ACAGGACG, -ACAGGAC, -ACAGGA, -ACAGG, -ACAG, -ACA, -AC, or -A; and

[0853] The LNA nucleotides are selected from β-D-oxy-LNA(b 1 ), β-D-thio-LNA(b 2 ), α-L-oxy-LNA(b 4 ), β-D-(NH)-LNA(b 6 ), and β-D-(NCH3)-LNA(b 7 ) and

[0854] The internucleotide linkages are selected from

[0855] -O-P(O)(O - )-O-, -O-P(O)(S - )-O-, -O-P(S)(S - )-O-, -S-P(O)(O - )-O-, -S-P(O)(S - )-O-, -O-P(O)(O - )-S-, -O-P(O)(S - )-S-, -S-P(O)(O - )-S-; preferably selected from phosphates, phosphorothioates and dithiophosphates. Such preferred antisense oligonucleotides may be free of any modified 3' and 5' termini, or free of any 3' and 5' terminal groups, and may contain 5-methylcytosine and / or 2-aminoadenine as modified nucleobases.

[0856] Particularly preferred are the gapmer antisense oligonucleotides of Seq.ID No.54 to Seq.ID No.68 and Seq.ID No.349 to Seq.ID No.368, which comprise a segment of 2 to 5, preferably 2 to 4, more preferably 3 to 4 LNA units at the 3' terminus, and a segment of 2 to 5, preferably 2 to 4, more preferably 3 to 4 LNA units at the 5' terminus, and a segment of at least 6, preferably 7, more preferably 8 DNA units between the two segments of LNA units, wherein the LNA units are selected from β-D-oxy-LNA(b 1 ), β-D-thio-LNA(b 2 ), α-L-oxy-LNA(b 4 ), β-D-(NH)-LNA(b 6 ), and β-D-(NCH3)-LNA(b 7), the internucleotide linkage is selected from phosphate esters, phosphorothioates, and dithiophosphates. Such a preferred antisense oligonucleotide may be free of any modified 3' and 5' ends, or free of any 3' and 5' end groups, and may contain 5-methylcytosine as a modified nucleobase in LNA units, preferably all LNA units, and / or 2-aminoadenine in some or all DNA units and / or 5-methylcytosine in some or all DNA units.

[0857] Also particularly preferred are the gapmer antisense oligonucleotides of Table 5 (Seq.ID No. 245a to 257b).

[0858] Furthermore, the present invention preferably relates to antisense oligonucleotides in the form of gapmers consisting of 10 to 28 nucleotides, preferably 11 to 24 nucleotides, more preferably 12 to 20, more preferably 13 to 19 or 14 to 18 nucleotides, and salts and optical isomers of said antisense oligonucleotides, and 1 to 5 of these nucleotides at the 5' end and 1 to 5 nucleotides at the 3' end of the antisense oligonucleotide are LNA nucleotides, and there are at least 6, preferably 7, more preferably 8 DNA nucleotides between the LNA nucleotides at the 5' end and the 3' end, and the antisense oligonucleotide is capable of hybridizing to a region of the gene encoding TGF-R II or to a region of the mRNA encoding TGF-R II and the antisense oligonucleotide is represented by the following sequence 5'-N 11 -TGTTTAGG-N 12 -3' (Seq.ID No. 10), where

[0859] N 11 represents: GAAGAGCTATTTGGTAG-, AAGAGCTATTTGGTAG-, AGAGCTATTTGGTAG-, GAGCTATTTGGTAG-, AGCTATTTGGTAG-, GCTATTTGGTAG-, CTATTTGGTAG-, TATTTGGTAG-, ATTTGGTAG-, TTTGGTAG-, TTGGTAG-, TGGTAG-, GGTAG-, GTAG-, TAG-, AG- or G-,

[0860] N 12Represented by: -GAGCCGTCTTCAGGAAT, -GAGCCGTCTTCAGGAA, -GAGCCGTCTTCAGGA, -GAGCCGTCTTCAGG, -GAGCCGTCTTCAG, -GAGCCGTCTTCA, -GAGCCGTCTTC, -GAGCCGTCTT, -GAGCCGTCT, -GAGCCGTC, -GAGCCGT, -GAGCCG, -GAGCC, -GAGC, -GAG, -GA, or –G.

[0861] N 11 and / or N 12 It can also represent any one in another restrictive list of 3' and 5' residues disclosed herein.

[0862] Gapmer antisense oligonucleotides falling within the general formula S3 are particularly preferred:

[0863] 5’-N 11 -TGTTTAGG-N 12 -3’(Seq.ID No.10)S3

[0864] Such gapmer antisense oligonucleotides are:

[0865] ATTTGGTAGTGTTTAGGG(Seq.ID No.369)

[0866] TTTGGTAGTGTTTAGGGA(Seq.ID No.370)

[0867] TTGGTAGTGTTTAGGGAG(Seq.ID No.371)

[0868] TGGTAGTGTTTAGGGAGC(Seq.ID No.372)

[0869] GGTAGTGTTTAGGGAGCC(Seq.ID No.373)

[0870] GTAGTGTTTAGGGAGCCG(Seq.ID No.374)

[0871] TAGTGTTTAGGGAGCCGT(Seq.ID No.375)

[0872] AGTGTTTAGGGAGCCGTC(Seq.ID No.376)

[0873] GTGTTTAGGGAGCCGTCT(Seq.ID No.377)

[0874] TTTGGTAGTGTTTAGGG(Seq.ID No.378)

[0875] TTGGTAGTGTTTAGGGA(Seq.ID No.379)

[0876] TGGTAGTGTTTAGGGAG(Seq.ID No.380)

[0877] GGTAGTGTTTAGGGAGC(Seq.ID No.381)

[0878] GTAGTGTTTAGGGAGCC(Seq.ID No.382)

[0879] TAGTGTTTAGGGAGCCG(Seq.ID No.383)

[0880] AGTGTTTAGGGAGCCGT(Seq.ID No.384)

[0881] GTGTTTAGGGAGCCGTC(Seq.ID No.385)

[0882] TTGGTAGTGTTTAGGG(Seq.ID No.386)

[0883] TGGTAGTGTTTAGGGA(Seq.ID No.387)

[0884] GGTAGTGTTTAGGGAG(Seq.ID No.388)

[0885] GTAGTGTTTAGGGAGC(Seq.ID No.389)

[0886] TAGTGTTTAGGGAGCC(Seq.ID No.390)

[0887] AGTGTTTAGGGAGCCG(Seq.ID No.391)

[0888] GTGTTTAGGGAGCCGT(Seq.ID No.392)

[0889] TGGTAGTGTTTAGGG(Seq.ID No.393)

[0890] GGTAGTGTTTAGGGA(Seq.ID No.394)

[0891] GTAGTGTTTAGGGAG(Seq.ID No.395)

[0892] TAGTGTTTAGGGAGC(Seq.ID No.396)

[0893] AGTGTTTAGGGAGCC(Seq.ID No.397)

[0894] GTGTTTAGGGAGCCG(Seq.ID No.398)

[0895] GGTAGTGTTTAGGG(Seq.ID No.399)

[0896] GTAGTGTTTAGGGA(Seq.ID No.400)

[0897] TAGTGTTTAGGGAG(Seq.ID No.401)

[0898] AGTGTTTAGGGAGC(Seq.ID No.402)

[0899] GTGTTTAGGGAGCC(Seq.ID No.403)

[0900] The antisense oligonucleotides of formula S3 in gapmer form (LNA segment 1 - DNA segment - LNA segment 2) comprise an LNA segment at the 5'-end, which consists of 2 to 5, preferably 2 to 4 LNA units, and an LNA fragment at the 3'-end, which consists of 2 to 5, preferably 2 to 4 LNA units, and a DNA segment between the two LNA segments, which consists of 6 to 14, preferably 7 to 12, more preferably 8 to 11 DNA units.

[0901] The antisense oligonucleotides of formula S3 contain LNA nucleotides (LNA units) disclosed herein, in particular those disclosed in the "Locked nucleic acid" section, preferably those disclosed in the "Preferred LNA" section. The LNA units and DNA units may contain standard nucleobases, such as adenine (A), cytosine (C), guanine (G), thymine (T) and uracil (U), but may also contain modified nucleobases, as disclosed in the "Nucleobases" section. The antisense oligonucleotides of formula S3 or the LNA and DNA segments of the antisense oligonucleotides may contain any internucleotide linkages disclosed herein, in particular those disclosed in the "Internucleotide Linkages (IL)" section. The antisense oligonucleotides of formula S3 may also optionally contain terminal groups at the 3'-end and / or 5'-end, in particular those disclosed in the "Terminal Groups" section.

[0902] Experiments have shown that, in the tested neurological and oncology indications, the modified nucleobases do not significantly increase or alter the activity of the antisense oligonucleotides of the present invention. It has been demonstrated that the modified nucleobases 5-methylcytosine or 2-aminoadenine further increase the activity of the antisense oligonucleotides of formula S3, especially if 5-methylcytosine is used only in LNA nucleotides or in LNA nucleotides and DNA nucleotides and / or if 2-aminoadenine is used in DNA nucleotides rather than in LNA nucleotides.

[0903] Preferred gapmer structures of the antisense oligonucleotides of formula S3 are as follows: 3-8-3, 4-8-2, 2-8-4, 3-8-4, 4-8-3, 4-8-4, 3-9-3, 4-9-2, 2-9-4, 4-9-3, 3-9-4, 4-9-4, 3-10-3, 2-10-4, 4-10-2, 3-10-4, 4-10-3, 4-10-4, 2-11-4, 4-11-2, 3-11-4, 4-11-3; more preferably: 3-8-3, 3-8-4, 4-8-3, 4-8-4, 3-9-3, 4-9-3, 3-9-4, 4-9-4, 3-10-3, 3-10-4, 4-10-3, 4-10-4, 3-11-4, and 4-11-3.

[0904] The LNA units of the antisense oligonucleotides of formula S3, in particular β-D-oxy-LNA (b 1 ), β-D-thio-LNA (b 2 ), α-L-oxy-LNA (b 4 ), β-D-ENA (b 5 ), β-D-(NH)-LNA (b 6 ), β-D-(NCH3)-LNA (b 7 ), β-D-(ONH)-LNA (b 8 ) and β-D-(ONCH3)-LNA (b 9 ) are preferred. Experiments have shown that all these LNA units b 1 , b 2 , b 4 , b 5 , b 6 , b 7 , b 8 and b 9 can be synthesized with the required effort and result in antisense oligonucleotides with comparable stability and activity. However, based on experiments, more preferred are the LNA units b 1 , b 2 , b4 and b 5 and b 6 and b 7 . More preferably, the LNA unit b 1 and b 2 and b 4 and b 6 and b 7 , even more preferably, the LNA unit b 1 and b 4 , most preferably with respect to the complexity of chemical synthesis is β-D-oxy-LNA (b 1 ).

[0905] So far, no particular 3'-terminal group or 5'-terminal group has been found to significantly alter or increase the stability or activity with respect to oncology or neurology indications such that 3'- and 5'-terminal groups are possible but not clearly preferred.

[0906] Various internucleotide bridges or internucleotide linkages are possible. In the formulas disclosed herein, the internucleotide linkage IL is represented by -IL'-Y-. Thus, IL = -IL'-Y- = -X''-P(=X')(X - )-Y-, where IL is preferably selected from:

[0907] -O-P(O)(O - )-O-, -O-P(O)(S - )-O-, -O-P(S)(S - )-O-, -S-P(O)(O - )-O-, -S-P(O)(S - )-O-, -O-P(O)(O - )-S-, -O-P(O)(S - )-S-, -S-P(O)(O-)-S-, -O-P(O)(CH3)-O-, -O-P(O)(OCH3)-O-, -O-P(O)(NH(CH3))-O-, -O-P(O)[N(CH3)2]-O-, -O-P(O)(BH3 - )-O-, -O-P(O)(OCH2CH2OCH3)-O-, -O-P(O)(OCH2CH2SCH3)-O-, -O-P(O)(O - )-N(CH3)-, -N(CH3)-P(O)(O - )-O-. Preferably selected from -O-P(O)(O - )-O-, -O-P(O)(S - )-O-, -O-P(S)(S -)-O-,-S-P(O)(O - )-O-,-S-P(O)(S - )-O-,-O-P(O)(O - )-S-,-O-P(O)(S - )-S-,-S-P(O)(O - )-S-,-O-P(O)(OCH3)-O-,-O-P(O)(NH(CH3))-O-,-O-P(O)[N(CH3)2]-O-,-O-P(O)(OCH2CH2OCH3)-O-,more preferably selected from -O-P(O)(O - )-O-,-O-P(O)(S - )-O-,-O-P(S)(S - )-O-,-S-P(O)(O - )-O-,-S-P(O)(S - )-O-,-O-P(O)(O - )-S-,-O-P(O)(S - )-S-,-S-P(O)(O - )-S-,more preferably selected from -O-P(O)(O - )-O-,-O-P(O)(S - )-O-,-O-P(S)(S - )-O-,most preferably selected from -O-P(O)(O - )-O- and -O-P(O)(S - )-O- of the internucleotide linkage IL.

[0908] Therefore, the present invention preferably relates to antisense oligonucleotides in the form of gapmers composed of 10 to 28 nucleotides, preferably 11 to 24 nucleotides, more preferably 12 to 20, more preferably 13 to 19 or 14 to 18 nucleotides, and salts and optical isomers of said antisense oligonucleotides, and 1 to 5 of these nucleotides at the 5'-end and 1 to 5 nucleotides at the 3'-end of the antisense oligonucleotide are LNA nucleotides, and there are at least 6, preferably 7, more preferably 8 DNA nucleotides between the LNA nucleotides at the 5'-end and the 3'-end, and the antisense oligonucleotide is capable of hybridizing with the region of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II and the antisense oligonucleotide is represented by the following sequence 5'-N 11 -TGTTTAGG-N 12 -3'(Seq.ID No.10), wherein

[0909] N11 Represented by: GAAGAGCTATTTGGTAG-, AAGAGCTATTTGGTAG-, AGAGCTATTTGGTAG-, GAGCTATTTGGTAG-, AGCTATTTGGTAG-, GCTATTTGGTAG-, CTATTTGGTAG-, TATTTGGTAG-, ATTTGGTAG-, TTTGGTAG-, TTGGTAG-, TGGTAG-, GGTAG-, GTAG-, TAG-, AG- or G-

[0910] N 12 Represented by: -GAGCCGTCTTCAGGAAT, -GAGCCGTCTTCAGGAA, -GAGCCGTCTTCAGGA, -GAGCCGTCTTCAGG, -GAGCCGTCTTCAG, -GAGCCGTCTTCA, -GAGCCGTCTTC, -GAGCCGTCTT, -GAGCCGTCT, -GAGCCGTC, -GAGCCGT, -GAGCCG, -GAGCC, -GAGC, -GAG, -GA, or -G;

[0911] The LNA nucleotides are selected from β-D-oxy-LNA (b 1 ), β-D-thio-LNA (b 2 ), α-L-oxy-LNA (b 4 ), β-D-ENA (b 5 ), β-D-(NH)-LNA (b 6 ), β-D-(NCH3)-LNA (b 7 ), β-D-(ONH)-LNA (b 8 ), and β-D-(ONCH3)-LNA (b 9 ); and preferably selected from β-D-oxy-LNA (b 1 ), β-D-thio-LNA (b 2 ), α-L-oxy-LNA (b 4 ), β-D-(NH)-LNA (b 6 ), and β-D-(NCH3)-LNA (b 7 ); and

[0912] The internucleotide linkages are selected from

[0913] -O-P(O)(O - )-O-, -O-P(O)(S - )-O-, -O-P(S)(S -)-O-,-S-P(O)(O - )-O-,-S-P(O)(S - )-O-,-O-P(O)(O - )-S-,-O-P(O)(S - )-S-,-S-P(O)(O - )-S-,-O-P(O)(CH3)-O-,-O-P(O)(OCH3)-O-,-O-P(O)(NH(CH3))-O-,-O-P(O)[N(CH3)2]-O-,-O-P(O)(BH3 - )-O-,-O-P(O)(OCH2CH2OCH3)-O-,-O-P(O)(OCH2CH2SCH3)-O-,-O-P(O)(O - )-N(CH3)-,-N(CH3)-P(O)(O - )-O-;

[0914] and preferably selected from -O-P(O)(O - )-O-,-O-P(O)(S - )-O-,-O-P(S)(S - )-O-,-S-P(O)(O - )-O-,-S-P(O)(S - )-O-,-O-P(O)(O - )-S-,-O-P(O)(S - )-S-,-S-P(O)(O - )-S-. Such preferred antisense oligonucleotides may be free of any modified 3' and 5' termini, or free of any 3' and 5' terminal groups, and may contain 5-methylcytosine and / or 2-aminoadenine as modified nucleobases.

[0915] More preferably N 11 denotes: AGAGCTATTTGGTAG-, GAGCTATTTGGTAG-, AGCTATTTGGTAG-, GCTATTTGGTAG-, CTATTTGGTAG-, TATTTGGTAG-, ATTTGGTAG-, TTTGGTAG-, TTGGTAG-, TGGTAG-, GGTAG-, GTAG-, TAG-, AG- or G-; and

[0916] N 12Represented by: -GAGCCGTCTTCAGGA, -GAGCCGTCTTCAGG, -GAGCCGTCTTCAG, -GAGCCGTCTTCA, -GAGCCGTCTTC, -GAGCCGTCTT, -GAGCCGTCT, -GAGCCGTC, -GAGCCGT, -GAGCCG, -GAGCC, -GAGC, -GAG, -GA, or –G.

[0917] Further preferably, the present invention relates to antisense oligonucleotides in the form of gapmers consisting of 11 to 24 nucleotides, more preferably 12 to 20, more preferably 13 to 19 or 14 to 18 nucleotides, and salts and optical isomers of said antisense oligonucleotides, and 2 to 5 nucleotides among these nucleotides at the 5'-end and 2 to 5 nucleotides at the 3'-end of the antisense oligonucleotide are LNA nucleotides, and there is preferably a sequence of 7, more preferably 8 DNA nucleotides between the LNA nucleotides at the 5'-end and 3'-end, and the antisense oligonucleotide is capable of hybridizing with the region of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II wherein the antisense oligonucleotide is represented by the following sequence 5'-N 11 -TGTTTAGG-N 12 -3' (Seq.ID No.10), wherein

[0918] N 11 is represented by: GCTATTTGGTAG-, CTATTTGGTAG-, TATTTGGTAG-, ATTTGGTAG-, TTTGGTAG-, TTGGTAG-, TGGTAG-, GGTAG-, GTAG-, TAG-, AG- or G-; preferably N 11 is represented by: TATTTGGTAG-, ATTTGGTAG-, TTTGGTAG-, TTGGTAG-, TGGTAG-, GGTAG-, GTAG-, TAG-, AG- or G-; and

[0919] N 12 is represented by: -GAGCCGTCTTCA, -GAGCCGTCTTC, -GAGCCGTCTT, -GAGCCGTCT, -GAGCCGTC, -GAGCCGT, -GAGCCG, -GAGCC, -GAGC, -GAG, -GA, or –G; preferably N 12Represented by: -GAGCCGTCTT, -GAGCCGTCT, -GAGCCGTC, -GAGCCGT, -GAGCCG, -GAGCC, -GAGC, -GAG, -GA, or –G; and

[0920] The LNA nucleotides are selected from β-D-oxy-LNA (b 1 ), β-D-thio-LNA (b 2 ), α-L-oxy-LNA (b 4 ), β-D-(NH)-LNA (b 6 ), and β-D-(NCH3)-LNA (b 7 ); and

[0921] The internucleotide linkages are selected from

[0922] -O-P(O)(O - )-O-, -O-P(O)(S - )-O-, -O-P(S)(S - )-O-, -S-P(O)(O - )-O-, -S-P(O)(S - )-O-, -O-P(O)(O - )-S-, -O-P(O)(S - )-S-, -S-P(O)(O - )-S-; and are preferably selected from phosphates, phosphorothioates, and dithiophosphates. Such preferred antisense oligonucleotides may be free of any modified 3' and 5' termini, or free of any 3' and 5' terminal groups, and may contain 5-methylcytosine and / or 2-aminoadenine as modified nucleobases.

[0923] Particularly preferred are the gapmer antisense oligonucleotides of Seq.ID No.369 to Seq.ID No.403, which comprise a segment of 2 to 5, preferably 2 to 4, more preferably 3 to 4 LNA units at the 3' terminus, and a segment of 2 to 5, preferably 2 to 4, more preferably 3 to 4 LNA units at the 5' terminus, and a segment of at least 6, preferably 7, more preferably 8 DNA units between the two segments of LNA units, wherein the LNA units are selected from β-D-oxy-LNA (b 1 ), β-D-thio-LNA (b 2 ), α-L-oxy-LNA (b 4 ), β-D-(NH)-LNA (b 6 ), and β-D-(NCH3)-LNA (b 7), the internucleotide linkage is selected from phosphate esters, phosphorothioates, and dithiophosphates. Such preferred antisense oligonucleotides may have unmodified 3' and 5' ends, or no 3' and 5' end groups, and may contain 5-methylcytosine as a modified nucleobase in LNA units, preferably all LNA units, and / or 2-aminoadenine in some or all DNA units and / or 5-methylcytosine in some or all DNA units.

[0924] Also particularly preferred are the gapmer antisense oligonucleotides of Table 6 (Seq.ID No. 258a to 270b).

[0925] Furthermore, the present invention preferably relates to antisense oligonucleotides in the form of gapmers composed of 10 to 28 nucleotides, preferably 11 to 24 nucleotides, more preferably 12 to 20, more preferably 13 to 19 or 14 to 18 nucleotides, and salts and optical isomers of said antisense oligonucleotides, and 1 to 5 of these nucleotides at the 5' end and 1 to 5 nucleotides at the 3' end of the antisense oligonucleotide are LNA nucleotides, and there are at least 6, preferably 7, more preferably 8 DNA nucleotides between the LNA nucleotides at the 5' end and the 3' end, and the antisense oligonucleotide is capable of hybridizing to a region of the gene encoding TGF-R II or to a region of the mRNA encoding TGF-R II and is represented by the following sequence 5'-N 5 -TTTGGTAG-N 6 -3' (Seq.ID No. 11), where

[0926] N 5 represents: CTGCCCCAGAAGAGCTA-, TGCCCCAGAAGAGCTA-, GCCCCAGAAGAGCTA-, CCCCAGAAGAGCTA-, CCCAGAAGAGCTA-, CCAGAAGAGCTA-, CAGAAGAGCTA-, AGAAGAGCTA-, GAAGAGCTA-, AAGAGCTA-, AGAGCTA-, GAGCTA-, AGCTA-, GCTA-, CTA-, TA-, or A-;

[0927] N 6Represented by: -TGTTTAGGGAGCCGTCT, -TGTTTAGGGAGCCGTC, -TGTTTAGGGAGCCGT, -TGTTTAGGGAGCCG, -TGTTTAGGGAGCC, -TGTTTAGGGAGC, -TGTTTAGGGAG, -TGTTTAGGGA, -TGTTTAGGG, -TGTTTAGG, -TGTTTAG, -TGTTTA, -TGTTT, -TGTT, -TGT, -TG, or –T.

[0928] N 5 and / or N 6 It can also represent any one of the additional restricted lists of 3' and 5' residues disclosed herein.

[0929] Gapmer antisense oligonucleotides falling within the general formula S4 are particularly preferred:

[0930] 5’-N 5 -TTTGGTAG-N 6 -3’(Seq.ID No.11)S4

[0931] Such gapmer antisense oligonucleotides are:

[0932] GAAGAGCTATTTGGTAGT(Seq.ID No.404)

[0933] AAGAGCTATTTGGTAGTG(Seq.ID No.405)

[0934] AGAGCTATTTGGTAGTGT(Seq.ID No.406)

[0935] GAGCTATTTGGTAGTGTT(Seq.ID No.407)

[0936] AGCTATTTGGTAGTGTTT(Seq.ID No.408)

[0937] GCTATTTGGTAGTGTTTA(Seq.ID No.409)

[0938] CTATTTGGTAGTGTTTAG(Seq.ID No.410)

[0939] TATTTGGTAGTGTTTAGG(Seq.ID No.411)

[0940] ATTTGGTAGTGTTTAGGG(Seq.ID No.412)

[0941] AAGAGCTATTTGGTAGT(Seq.ID No.413)

[0942] AGAGCTATTTGGTAGTG(Seq.ID No.414)

[0943] GAGCTATTTGGTAGTGT(Seq.ID No.415)

[0944] AGCTATTTGGTAGTGTT(Seq.ID No.416)

[0945] GCTATTTGGTAGTGTTT(Seq.ID No.417)

[0946] CTATTTGGTAGTGTTTA(Seq.ID No.418)

[0947] TATTTGGTAGTGTTTAG(Seq.ID No.419)

[0948] ATTTGGTAGTGTTTAGG(Seq.ID No.420)

[0949] AGAGCTATTTGGTAGT(Seq.ID No.421)

[0950] GAGCTATTTGGTAGTG(Seq.ID No.422)

[0951] AGCTATTTGGTAGTGT(Seq.ID No.423)

[0952] GCTATTTGGTAGTGTT(Seq.ID No.424)

[0953] CTATTTGGTAGTGTTT(Seq.ID No.425)

[0954] TATTTGGTAGTGTTTA(Seq.ID No.426)

[0955] ATTTGGTAGTGTTTAG(Seq.ID No.427)

[0956] GAGCTATTTGGTAGT(Seq.ID No.428)

[0957] AGCTATTTGGTAGTG(Seq.ID No.429)

[0958] GCTATTTGGTAGTGT(Seq.ID No.430)

[0959] CTATTTGGTAGTGTT(Seq.ID No.431)

[0960] TATTTGGTAGTGTTT(Seq.ID No.432)

[0961] ATTTGGTAGTGTTTA(Seq.ID No.433)

[0962] AGCTATTTGGTAGT(Seq.ID No.434)

[0963] GCTATTTGGTAGTG(Seq.ID No.435)

[0964] CTATTTGGTAGTGT(Seq.ID No.436)

[0965] TATTTGGTAGTGTT(Seq.ID No.437)

[0966] ATTTGGTAGTGTTT(Seq.ID No.438)

[0967] The antisense oligonucleotides of formula S4 in gapmer form (LNA segment 1 - DNA segment - LNA segment 2) comprise an LNA segment at the 5'-end, which consists of 2 to 5, preferably 2 to 4 LNA units, and an LNA fragment at the 3'-end, which consists of 2 to 5, preferably 2 to 4 LNA units, and a DNA segment between the two LNA segments, which consists of 6 to 14, preferably 7 to 12, more preferably 8 to 11 DNA units.

[0968] The antisense oligonucleotides of formula S4 contain the LNA nucleotides (LNA units) disclosed herein, in particular those disclosed in the "Locked nucleic acid" section, preferably those disclosed in the "Preferred LNA" section. The LNA units and DNA units may contain standard nucleobases such as adenine (A), cytosine (C), guanine (G), thymine (T) and uracil (U), but may also contain modified nucleobases as disclosed in the "Nucleobases" section. The antisense oligonucleotides of formula S4 or the LNA and DNA segments of the antisense oligonucleotides may contain any internucleotide linkages disclosed herein, in particular those disclosed in the "Internucleotide linkages (IL)" section. The antisense oligonucleotides of formula S4 may also optionally contain terminal groups at the 3'-end and / or 5'-end, in particular those disclosed in the "Terminal groups" section.

[0969] Experiments have shown that, with respect to the tested neurological and oncology indications, modified nucleobases do not significantly increase or alter the activity of the antisense oligonucleotides of the present invention. It has been demonstrated that the modified nucleobases 5-methylcytosine or 2-aminoadenine further increase the activity of the antisense oligonucleotides of formula S4, especially if 5-methylcytosine is used only in LNA nucleotides or in LNA and DNA nucleotides and / or if 2-aminoadenine is used in DNA nucleotides rather than in LNA nucleotides.

[0970] Preferred gapmer structures of the antisense oligonucleotides of formula S4 are as follows: 3-8-3, 4-8-2, 2-8-4, 3-8-4, 4-8-3, 4-8-4, 3-9-3, 4-9-2, 2-9-4, 4-9-3, 3-9-4, 4-9-4, 3-10-3, 2-10-4, 4-10-2, 3-10-4, 4-10-3, 4-10-4, 2-11-4, 4-11-2, 3-11-4, 4-11-3, more preferably: 3-8-3, 3-8-4, 4-8-3, 4-8-4, 3-9-3, 4-9-3, 3-9-4, 4-9-4, 3-10-3, 3-10-4, 4-10-3, 4-10-4, 3-11-4, and 4-11-3.

[0971] The LNA units of the antisense oligonucleotides of formula S4, in particular β-D-oxy-LNA (b 1 ), β-D-thio-LNA (b 2 ), α-L-oxy-LNA (b 4 ), β-D-ENA (b 5 ), β-D-(NH)-LNA (b 6 ), β-D-(NCH3)-LNA (b 7 ), β-D-(ONH)-LNA (b 8 ) and β-D-(ONCH3)-LNA (b 9 ) are preferred. Experiments have shown that all of these LNA units b 1 , b 2 , b 4 , b 5 , b 6 , b 7 , b 8 and b 9 can be synthesized with the required effort and result in antisense oligonucleotides with comparable stability and activity. However, based on experiments, more preferred are the LNA units b 1 , b 2 , b4 , b 5 , b 6 and b 7 . More preferably, the LNA unit b 1 , b 2 , b 4 , b 6 and b 7 , even more preferably, the LNA unit b 1 and b 4 , most preferably with respect to the complexity of chemical synthesis is β-D-oxy-LNA (b 1 ).

[0972] So far, no particular 3'-terminal group or 5'-terminal group has been found to significantly alter or increase the stability or activity with respect to oncology or neurology indications such that 3'- and 5'-terminal groups are possible but not clearly preferred.

[0973] Various internucleotide bridges or internucleotide linkages are possible. In the formulas disclosed herein, the internucleotide linkage IL is represented by -IL'-Y-. Thus, IL = -IL'-Y- = -X”-P(=X’)(X - ), -Y-, where IL is preferably selected from:[[]]

[0974] -O-P(O)(O - ), -O-P(O)(S - ), -O-P(S)(S - ), -S-P(O)(O - ), -S-P(O)(S - ), -O-P(O)(O - ), -O-P(O)(S - ), -S-P(O)(O - ), -S-P(O)(O - ), -O-P(O)(CH3)-O-, -O-P(O)(OCH3)-O-, -O-P(O)(NH(CH3))-O-, -O-P(O)[N(CH3)2]-O-, -O-P(O)(BH3 - ), -O-P(O)(OCH2CH2OCH3)-O-, -O-P(O)(OCH2CH2SCH3)-O-, -O-P(O)(O - ), -N(CH3)-, -N(CH3)-P(O)(O - ), -O-P(O)(S - ), -O-P(S)(S- )-O-,-S-P(O)(O - )-O-, -S-P(O)(S - )-O-,-O-P(O)(O - )-S-,-O-P(O)(S - )-S-,-S-P(O)(O - )-S-, -O-P(O)(OCH3)-O-,-O-P(O)(NH(CH3))-O-,-O-P(O)[N(CH3)2]-O-,-O-P(O)(OCH2CH2OCH3)-O-, and more preferably selected from -O-P(O)(O - )-O-, -O-P(O)(S - )-O-,-O-P(S)(S - )-O-,-S-P(O)(O - )-O-,-S-P(O)(S - )-O-, -O-P(O)(O - )-S-,-O-P(O)(S - )-S-,-S-P(O)(O - )-S-, and more preferably selected from -O-P(O)(O - )-O-,-O-P(O)(S - )-O-,-O-P(S)(S - )-O-, and most preferably selected from -O-P(O)(O - )-O- and -O-P(O)(S - )-O- nucleotide internucleoside linkage IL.

[0975] Thus, the present invention preferably relates to an antisense oligonucleotide in the form of a gapmer composed of 10 to 28 nucleotides, preferably 11 to 24 nucleotides, more preferably 12 to 20, more preferably 13 to 19 or 14 to 18 nucleotides, and salts and optical isomers of said antisense oligonucleotide, and 1 to 5 of these nucleotides at the 5'-end and 1 to 5 nucleotides at the 3'-end of the antisense oligonucleotide are LNA nucleotides, and there are at least 6, preferably 7, more preferably 8 DNA nucleotides between the LNA nucleotides at the 5'-end and 3'-end, and the antisense oligonucleotide is capable of hybridizing to a region of the gene encoding TGF-R II or to a region of the mRNA encoding TGF-R II and the antisense oligonucleotide is represented by the following sequence 5'-N 5 -TTTGGTAG-N 6 -3' (Seq.ID No.11), wherein

[0976] N 5 represent: CTGCCCCAGAAGAGCTA-, TGCCCCAGAAGAGCTA-, GCCCCAGAAGAGCTA-, CCCCAGAAGAGCTA-, CCCAGAAGAGCTA-, CCAGAAGAGCTA-, CAGAAGAGCTA-, AGAAGAGCTA-, GAAGAGCTA-, AAGAGCTA-, AGAGCTA-, GAGCTA-, AGCTA-, GCTA-, CTA-, TA-, or A-; and

[0977] N 6 represent: -TGTTTAGGGAGCCGTCT, -TGTTTAGGGAGCCGTC, -TGTTTAGGGAGCCGT, -TGTTTAGGGAGCCG, -TGTTTAGGGAGCC, -TGTTTAGGGAGC, -TGTTTAGGGAG, -TGTTTAGGGA, -TGTTTAGGG, -TGTTTAGG, -TGTTTAG, -TGTTTA, -TGTTT, -TGTT, -TGT, -TG, or –T; and

[0978] The LNA nucleotides are selected from β-D-oxy-LNA (b 1 ), β-D-thio-LNA (b 2 ), α-L-oxy-LNA (b 4 ), β-D-ENA (b 5 ), β-D-(NH)-LNA (b 6 ), β-D-(NCH3)-LNA (b 7 ), β-D-(ONH)-LNA (b 8 ), and β-D-(ONCH3)-LNA (b 9 ); and preferably selected from β-D-oxy-LNA (b 1 ), β-D-thio-LNA (b 2 ), α-L-oxy-LNA (b 4 ), β-D-(NH)-LNA (b 6 ), and β-D-(NCH3)-LNA (b 7 ); and

[0979] The internucleotide linkages are selected from

[0980] -O-P(O)(O - )-O-,-O-P(O)(S - )-O-,-O-P(S)(S- )-O-, -S-P(O)(O - )-O-,-S-P(O)(S - )-O-,-O-P(O)(O - )-S-,-O-P(O)(S - )-S-, -S-P(O)(O - )-S-,-O-P(O)(CH3)-O-,-O-P(O)(OCH3)-O-,-O-P(O)(NH(CH3))-O-,-O-P(O)[N(CH3)2]-O-,-O-P(O)(BH3 - )-O-,-O-P(O)(OCH2CH2OCH3)-O-,-O-P(O)(OCH2CH2SCH3)-O-,-O-P(O)(O - )-N(CH3)-,-N(CH3)-P(O)(O - )-O-;

[0981] and preferably selected from -O-P(O)(O - )-O-,-O-P(O)(S - )-O-,-O-P(S)(S - )-O-,-S-P(O)(O - )-O-,-S-P(O)(S - )-O-,-O-P(O)(O - )-S-,-O-P(O)(S - )-S-,-S-P(O)(O - )-S-. Such preferred antisense oligonucleotides may be free of any modified 3' and 5' ends, or free of any 3' and 5' end groups, and may contain 5-methylcytosine and / or 2-aminoadenine as modified nucleobases.

[0982] More preferably N 5 represents: GCCCCAGAAGAGCTA-, CCCCAGAAGAGCTA-, CCCAGAAGAGCTA-, CCAGAAGAGCTA-, CAGAAGAGCTA-, AGAAGAGCTA-, GAAGAGCTA-, AAGAGCTA-, AGAGCTA-, GAGCTA-, AGCTA-, GCTA-, CTA-, TA-, or A-; and

[0983] N 6Represented by: -TGTTTAGGGAGCCGT, -TGTTTAGGGAGCCG, -TGTTTAGGGAGCC, -TGTTTAGGGAGC, -TGTTTAGGGAG, -TGTTTAGGGA, -TGTTTAGGG, -TGTTTAGG, -TGTTTAG, -TGTTTA, -TGTTT, -TGTT, -TGT, -TG, or -T.

[0984] Further preferably, the present invention relates to antisense oligonucleotides in the form of gapmers consisting of 11 to 24 nucleotides, more preferably 12 to 20, more preferably 13 to 19 or 14 to 18 nucleotides, and salts and optical isomers of said antisense oligonucleotides, wherein 2 to 5 nucleotides among these nucleotides at the 5'-end and 2 to 5 nucleotides at the 3'-end of the antisense oligonucleotide are LNA nucleotides, and there is preferably a sequence of 7, more preferably 8 DNA nucleotides between the LNA nucleotides at the 5'-end and 3'-end, and the antisense oligonucleotide is capable of hybridizing with a region of the gene encoding TGF-R II or a region of the mRNA encoding TGF-R II wherein the antisense oligonucleotide is represented by the following sequence 5'-N 5 -TTTGGTAG-N 6 -3' (Seq. ID No. 11), wherein

[0985] N 5 is represented by: CCAGAAGAGCTA-, CAGAAGAGCTA-, AGAAGAGCTA-, GAAGAGCTA-, AAGAGCTA-, AGAGCTA-, GAGCTA-, AGCTA-, GCTA-, CTA-, TA-, or A-; preferably N 5 is represented by: AGAAGAGCTA-, GAAGAGCTA-, AAGAGCTA-, AGAGCTA-, GAGCTA-, AGCTA-, GCTA-, CTA-, TA-, or A-; and

[0986] N 6 is represented by: -TGTTTAGGGAGC, -TGTTTAGGGAG, -TGTTTAGGGA, -TGTTTAGGG, -TGTTTAGG, -TGTTTAG, -TGTTTA, -TGTTT, -TGTT, -TGT, -TG, or -T; preferably N 6Represented by: -TGTTTAGGGA, -TGTTTAGGG, -TGTTTAGG, -TGTTTAG, -TGTTTA, -TGTTT, -TGTT, -TGT, -TG, or –T; and

[0987] The LNA nucleotides are selected from β-D-oxy-LNA (b 1 ), β-D-thio-LNA (b 2 ), α-L-oxy-LNA (b 4 ), β-D-(NH)-LNA (b 6 ), and β-D-(NCH3)-LNA (b 7 ); and

[0988] The internucleotide linkages are selected from

[0989] -O-P(O)(O - )-O-, -O-P(O)(S - )-O-, -O-P(S)(S - )-O-, -S-P(O)(O - )-O-, -S-P(O)(S - )-O-, -O-P(O)(O - )-S-, -O-P(O)(S - )-S-, -S-P(O)(O - )-S-; and are preferably selected from phosphates, phosphorothioates, and dithiophosphates. Such preferred antisense oligonucleotides may be free of any modified 3' and 5' ends, or free of any 3' and 5' end groups, and may contain 5-methylcytosine and / or 2-aminoadenine as modified nucleobases.

[0990] Particularly preferred are the gapmer antisense oligonucleotides of Seq.ID No.404 to Seq.ID No.438, which comprise a segment of 2 to 5, preferably 2 to 4, more preferably 3 to 4 LNA units at the 3' end, and a segment of 2 to 5, preferably 2 to 4, more preferably 3 to 4 LNA units at the 5' end, and a segment of at least 6, preferably 7, more preferably 8 DNA units between the two segments of LNA units, wherein the LNA units are selected from β-D-oxy-LNA (b 1 ), β-D-thio-LNA (b 2 ), α-L-oxy-LNA (b 4 ), β-D-(NH)-LNA (b 6 ), and β-D-(NCH3)-LNA (b 7) The internucleotide linkage is selected from phosphate esters, phosphorothioates, and dithiophosphates. Such preferred antisense oligonucleotides can be free of any modified 3' and 5' ends, or free of any 3' and 5' end groups, and can contain 5-methylcytosine as a modified nucleobase in the LNA units, preferably all LNA units, and / or 2-aminoadenine in some or all of the DNA units and / or 5-methylcytosine in some or all of the DNA units.

[0991] Also particularly preferred are the gapmer antisense oligonucleotides of Table 7 (Seq.ID No.271a to 283b).

[0992] Furthermore, the present invention preferably relates to antisense oligonucleotides in the form of gapmers consisting of 10 to 28 nucleotides, preferably 11 to 24 nucleotides, more preferably 12 to 20, more preferably 13 to 19 or 14 to 18 nucleotides, and salts and optical isomers of said antisense oligonucleotides, and 1 to 5 of these nucleotides at the 5' end and 1 to 5 nucleotides at the 3' end of the antisense oligonucleotide are LNA nucleotides, and there are at least 6, preferably 7, more preferably 8 DNA nucleotides between the LNA nucleotides at the 5' end and the 3' end, and the antisense oligonucleotide is capable of hybridizing to a region of the gene encoding TGF-R II or to a region of the mRNA encoding TGF-R II and is represented by the following sequence 5'-N 7 -AATGGACC-N 8 -3' (Seq.ID No.100), where

[0993] N 7 represents: ATCTTGAATATCTCATG-, TCTTGAATATCTCATG-, CTTGAATATCTCATG-, TTGAATATCTCATG-, TGAATATCTCATG-, GAATATCTCATG-, AATATCTCATG-, ATATCTCATG-, TATCTCATG-, ATCTCATG-, TCTCATG-, CTCATG-, TCATG-, CATG-, ATG-, TG-, or G-;

[0994] N 8Represent: -AGTATTCTAGAAACTCA, -AGTATTCTAGAAACTC, -AGTATTCTAGAAACT, -AGTATTCTAGAAAC, -AGTATTCTAGAAA, -AGTATTCTAGAA, -AGTATTCTAGA, -AGTATTCTAG, -AGTATTCTA, -AGTATTCT, -AGTATTC, -AGTATT, -AGTAT, -AGTA, -AGT, or -A.

[0995] N 7 and / or N 8 It can also represent any one of the other restricted lists of 3' and 5' residues disclosed herein.

[0996] Gapmer antisense oligonucleotides falling within the general formula S6 are particularly preferred:

[0997] 5’-N 7 -AATGGACC-N 8 -3’(Seq.ID No.100)S6

[0998] Such gapmer antisense oligonucleotides are:

[0999] TATCTCATGAATGGACCA(Seq.ID No.439)

[1000] ATCTCATGAATGGACCAG(Seq.ID No.440)

[1001] TCTCATGAATGGACCAGT(Seq.ID No.441)

[1002] CTCATGAATGGACCAGTA(Seq.ID No.442)

[1003] TCATGAATGGACCAGTAT(Seq.ID No.443)

[1004] CATGAATGGACCAGTATT(Seq.ID No.444)

[1005] ATGAATGGACCAGTATTC(Seq.ID No.445)

[1006] TGAATGGACCAGTATTCT(Seq.ID No.446)

[1007] GAATGGACCAGTATTCTA(Seq.ID No.447)

[1008] ATCTCATGAATGGACCA (Seq.ID No.448)

[1009] TCTCATGAATGGACCAG (Seq.ID No.449)

[1010] CTCATGAATGGACCAGT (Seq.ID No.450)

[1011] TCATGAATGGACCAGTA (Seq.ID No.451)

[1012] CATGAATGGACCAGTAT (Seq.ID No.452)

[1013] ATGAATGGACCAGTATT (Seq.ID No.453)

[1014] TGAATGGACCAGTATTC (Seq.ID No.454)

[1015] GAATGGACCAGTATTCT (Seq.ID No.455)

[1016] TCTCATGAATGGACCA (Seq.ID No.456)

[1017] CTCATGAATGGACCAG (Seq.ID No.457)

[1018] TCATGAATGGACCAGT (Seq.ID No.458)

[1019] CATGAATGGACCAGTA (Seq.ID No.459)

[1020] ATGAATGGACCAGTAT (Seq.ID No.460)

[1021] TGAATGGACCAGTATT (Seq.ID No.461)

[1022] GAATGGACCAGTATTC (Seq.ID No.462)

[1023] CTCATGAATGGACCA (Seq.ID No.463)

[1024] TCATGAATGGACCAG (Seq.ID No.464)

[1025] CATGAATGGACCAGT(Seq.ID No.465)

[1026] ATGAATGGACCAGTA(Seq.ID No.466)

[1027] TGAATGGACCAGTAT(Seq.ID No.467)

[1028] GAATGGACCAGTATT(Seq.ID No.468)

[1029] TCATGAATGGACCA(Seq.ID No.469)

[1030] CATGAATGGACCAG(Seq.ID No.470)

[1031] ATGAATGGACCAGT(Seq.ID No.471)

[1032] TGAATGGACCAGTA(Seq.ID No.472)

[1033] GAATGGACCAGTAT(Seq.ID No.473)

[1034] The antisense oligonucleotides of formula S6 in gapmer form (LNA segment 1 - DNA segment - LNA segment 2) comprise an LNA segment at the 5'-end, which consists of 2 to 5, preferably 2 to 4 LNA units, and an LNA segment at the 3'-end, which consists of 2 to 5, preferably 2 to 4 LNA units, and a DNA segment between the two LNA segments, which consists of 6 to 14, preferably 7 to 12, more preferably 8 to 11 DNA units.

[1035] The antisense oligonucleotides of formula S6 contain the LNA nucleotides (LNA units) disclosed herein, in particular those disclosed in the "Locked nucleic acid" section, preferably those disclosed in the "Preferred LNA" section. The LNA units and DNA units may contain standard nucleobases, such as adenine (A), cytosine (C), guanine (G), thymine (T) and uracil (U), but may also contain modified nucleobases, as disclosed in the "Nucleobases" section. The antisense oligonucleotides of formula S6 or the LNA and DNA segments of the antisense oligonucleotides may contain any internucleotide linkages disclosed herein, in particular those disclosed in the "Internucleotide linkages (IL)" section. The antisense oligonucleotides of formula S6 may also optionally contain terminal groups at the 3'-end and / or 5'-end, in particular those disclosed in the "Terminal groups" section.

[1036] Experiments have shown that, in the tested neurological and oncology indications, modified nucleobases do not significantly increase or alter the activity of the antisense oligonucleotides of the present invention. It has been demonstrated that the modified nucleobases 5-methylcytosine or 2-aminoadenine further increase the activity of the antisense oligonucleotides of formula S6, especially if 5-methylcytosine is used only in LNA nucleotides or in LNA and DNA nucleotides and / or if 2-aminoadenine is used in DNA nucleotides rather than in LNA nucleotides.

[1037] Preferred gapmer structures of the antisense oligonucleotides of formula S6 are as follows: 3-8-3, 4-8-2, 2-8-4, 3-8-4, 4-8-3, 4-8-4, 3-9-3, 4-9-2, 2-9-4, 4-9-3, 3-9-4, 4-9-4, 3-10-3, 2-10-4, 4-10-2, 3-10-4, 4-10-3, 4-10-4, 2-11-4, 4-11-2, 3-11-4, 4-11-3, more preferably: 3-8-3, 3-8-4, 4-8-3, 4-8-4, 3-9-3, 4-9-3, 3-9-4, 4-9-4, 3-10-3, 3-10-4, 4-10-3, 4-10-4, 3-11-4, and 4-11-3.

[1038] The LNA units of the antisense oligonucleotides of formula S6, in particular β-D-oxy-LNA (b 1 ), β-D-thio-LNA (b 2 ), α-L-oxy-LNA (b 4 ), β-D-ENA (b 5 ), β-D-(NH)-LNA (b 6 ), β-D-(NCH3)-LNA (b 7 ), β-D-(ONH)-LNA (b 8 ) and β-D-(ONCH3)-LNA (b 9 ) are preferred. Experiments have shown that all these LNA units b 1 , b 2 , b 4 , b 5 , b 6 , b 7 , b 8 and b 9 can be synthesized with the required effort and result in antisense oligonucleotides with comparable stability and activity. However, based on experiments, more preferred are the LNA units b 1 , b 2 , b 4, b 5 , b 6 and b 7 . More preferably, the LNA unit b 1 , b 2 , b 4 , b 6 and b 7 , even more preferably the LNA unit b 1 and b 4 , most preferably with respect to the complexity of chemical synthesis is β-D-oxy-LNA (b 1 ).

[1039] So far, no particular 3'-terminal group or 5'-terminal group has been found to significantly alter or increase the stability or activity with respect to oncological or neurological indications such that 3'- and 5'-terminal groups are possible but not clearly preferred.

[1040] Various internucleotide bridges or internucleotide linkages are possible. In the formulas disclosed herein, the internucleotide linkage IL is represented by -IL'-Y-. Thus, IL = -IL'-Y- = -X”-P(=X’)(X - ), where IL is preferably selected from:

[1041] -O-P(O)(O - )-O-, -O-P(O)(S - )-O-, -O-P(S)(S - )-O-, -S-P(O)(O - )-O-, -S-P(O)(S - )-O-, -O-P(O)(O - )-S-, -O-P(O)(S - )-S-, -S-P(O)(O - )-S-, -O-P(O)(CH3)-O-, -O-P(O)(OCH3)-O-, -O-P(O)(NH(CH3))-O-, -O-P(O)[N(CH3)2]-O-, -O-P(O)(BH3 - )-O-, -O-P(O)(OCH2CH2OCH3)-O-, -O-P(O)(OCH2CH2SCH3)-O-, -O-P(O)(O - )-N(CH3)-, -N(CH3)-P(O)(O - )-O-. Preferably selected from -O-P(O)(O - )-O-, -O-P(O)(S - )-O-, -O-P(S)(S -)-O-,-S-P(O)(O - )-O-,-S-P(O)(S - )-O-,-O-P(O)(O - )-S-,-O-P(O)(S - )-S-,-S-P(O)(O - )-S-,-O-P(O)(OCH3)-O-,-O-P(O)(NH(CH3))-O-,-O-P(O)[N(CH3)2]-O-,-O-P(O)(OCH2CH2OCH3)-O-,more preferably selected from -O-P(O)(O - )-O-,-O-P(O)(S - )-O-,-O-P(S)(S - )-O-,-S-P(O)(O - )-O-,-S-P(O)(S - )-O-,-O-P(O)(O - )-S-,-O-P(O)(S - )-S-,-S-P(O)(O - )-S-,more preferably selected from -O-P(O)(O - )-O-,-O-P(O)(S - )-O-,-O-P(S)(S - )-O-,most preferably selected from -O-P(O)(O - )-P- and -P-P(O)(S - )-P- of the internucleotide linkage IL.

[1042] Accordingly, the present invention preferably relates to antisense oligonucleotides in the form of gapmers composed of 10 to 28 nucleotides, preferably 11 to 24 nucleotides, more preferably 12 to 20, more preferably 13 to 19 or 14 to 18 nucleotides, and salts and optical isomers of said antisense oligonucleotides, wherein 1 to 5 of these nucleotides at the 5'-end and 1 to 5 nucleotides at the 3'-end of the antisense oligonucleotide are LNA nucleotides, and there are at least 6, preferably 7, more preferably 8 DNA nucleotides between the LNA nucleotides at the 5'-end and 3'-end, and the antisense oligonucleotide is capable of hybridizing to a region of the gene encoding TGF-R II or to a region of the mRNA encoding TGF-R II and the antisense oligonucleotide...

Claims

1. An antisense oligonucleotide, its salt and optical isomers, characterized in that, The antisense oligonucleotide consists of 10 to 28 nucleotides, and the antisense oligonucleotide is an LNA gapmer that contains at least one LNA at the 3'-end and at least one LNA at the 5'-end, and the antisense oligonucleotide is capable of hybridizing with a region of the gene encoding TGF-R II or with a region of the mRNA encoding TGF-R II , wherein the region of the gene encoding TGF-R II or the region of the mRNA encoding TGF-R II contains the sequence CCCTAAACAC (Seq. ID No. 5), and the antisense oligonucleotide contains a sequence complementary to the sequence CCCTAAACAC (Seq. ID No. 5).

2. The antisense oligonucleotide, its salt and optical isomers according to claim 1, wherein the antisense oligonucleotide selectively hybridizes only with the region of the gene encoding TGF-R II or the sequence CCCTAAACAC (Seq. ID No. 5) of the region of the mRNA encoding TGF-R II .

3. The antisense oligonucleotide, its salt and optical isomers according to claim 1, wherein the antisense oligonucleotide has a length of 12 to 20 nucleotides and / or wherein the antisense oligonucleotide has a gapmer structure with 1 to 5 LNA units at the 3'-end and 1 to 5 LNA units at the 5'-end, and / or wherein the antisense oligonucleotide has phosphate, phosphorothioate and / or dithiophosphate as internucleotide linkages.

4. The antisense oligonucleotide, its salt and optical isomers according to claim 1, wherein the antisense oligonucleotide is represented by the following sequence: 5'-N 11 -TGTTTAGG-N 12 -3' wherein N 11 represents: CAGAAGAGCTATTTGGTAG-, AGAAGAGCTATTTGGTAG-, GAAGAGCTATTTGGTAG-, AAGAGCTATTTGGTAG-, AGAGCTATTTGGTAG-, GAGCTATTTGGTAG-, AGCTATTTGGTAG-, GCTATTTGGTAG-, CTATTTGGTAG-, TATTTGGTAG-, ATTTGGTAG-, TTTGGTAG-, TTGGTAG-, TGGTAG-, GGTAG-, GTAG-, TAG-, AG- or G-, N 12Represented by: -GAGCCGTCTTCAGGAATCT, -GAGCCGTCTTCAGGAATC, -GAGCCGTCTTCAGGAAT, -GAGCCGTCTTCAGGAA, -GAGCCGTCTTCAGGA, -GAGCCGTCTTCAGG, -GAGCCGTCTTCAG, -GAGCCGTCTTCA, -GAGCCGTCTTC, -GAGCCGTCTT, -GAGCCGTCT, -GAGCCGTC, -GAGCCGT, -GAGCCG, -GAGCC, -GAGC, -GAG, -GA, or -G.

5. The antisense oligonucleotide according to any one of claims 1 - 4, and its salts and optical isomers, wherein the last 2 to 4 nucleotides at the 5'-end are LNA nucleotides, and the last 2 to 4 nucleotides at the 3'-end are LNA nucleotides, and there are at least 6 consecutive nucleotides between the LNA nucleotides at the 5'-end and the LNA nucleotides at the 3'-end, which are non-LNA nucleotides or DNA nucleotides.

6. The antisense oligonucleotide according to any one of claims 1 - 4, and its salts and optical isomers, wherein the LNA nucleotides are linked to each other through a phosphorothioate group or a dithiophosphate group, or wherein all nucleotides are linked to each other through a phosphate group or a phosphorothioate group or a dithiophosphate group.

7. The antisense oligonucleotide according to any one of claims 1 - 4, and its salts and optical isomers, wherein the LNA nucleotides are selected from: wherein IL’ represents -X’’-P(=X’)(X - )-; X’ represents =O or =S; X - represents -O - , -OH, -OR H , -NHR H , -N(R H )2, -OCH2CH2OR H , -OCH2CH2SR H , -BH3 - , -R H , -SH, -SR H , or -S - ; X’’ represents -O-, -NH-, -NR H -, -CH2-, or -S-; Y is -O-, -NH-, -NR H -, -CH2- or -S-; R C and R H are each independently selected from hydrogen and C 1-4 -alkyl; B represents a nucleobase selected from: adenine, thymine, guanine, cytosine, uracil, 5-methylcytosine, 5-hydroxymethylcytosine, N 4 -methylcytosine, xanthine, hypoxanthine, 7-deazaxanthine, 2-aminoadenine, 6-methyladenine, 6-methylguanine, 6-ethyladenine, 6-ethylguanine, 2-propyladenine, 2-propylguanine, 6-carboxyuracil, 5,6-dihydrouracil, 5-propynyluracil, 5-propynylcytosine, 6-azauracil, 6-azacytosine, 6-azathymine, 5-uracil, 4-thiouracil, 8-fluoroadenine, 8-chloroadenine, 8-bromoadenine, 8-iodoadenine, 8-aminoadenine, 8-thioadenine, 8-thioalkyladenine, 8-hydroxyadenine, 8-fluoroguanine, 8-chloroguanine, 8-bromoguanine, 8-iodoguanine, 8-amino guanine, 8-thioguanine, 8-thioalkylguanine, 8-hydroxyguanine, 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, 5-trifluoromethyluracil, 5-fluorocytosine, 5-bromocytosine, 5-chlorocytosine, 5-iodocytosine, 5-trifluoromethylcytosine, 7-methylguanine, 7-methyladenine, 8-azaguanine, 8-azadenine, 7-deazaguanine, 7-deazaadenine, 7-deaza-8-azadenine, 3-deazaguanine, 3-deazaadenine, 2-thiouracil, 2-thiothymine and 2-thiocytosine.

8. The antisense oligonucleotide according to any one of claims 1-4, and salts and optical isomers thereof, wherein the antisense oligonucleotide has one of the following gapmer structures: 3-8-3, 4-8-2, 2-8-4, 3-8-4, 4-8-3, 4-8-4, 3-9-3, 4-9-2, 2-9-4, 4-9-3, 3-9-4, 4-9-4, 3-10-3, 2-10-4, 4-10-2, 3-10-4, 4-10-3, 4-10-4, 2-11-4, 4-11-2, 3-11-4, 4-11-3.

9. The antisense oligonucleotide according to any one of claims 1-4, and salts and optical isomers thereof, wherein the antisense oligonucleotide binds to the mRNA encoding TGF-RII with 100% complementarity and does not bind to any other region in the human transcriptome.

10. Antisense oligonucleotides selected from the following group: wherein b, d, C*, A*, s, ss have the following meanings: b 1 β-D-oxy-LNA b 2 β-D-thio-LNA b 3 β-D-amino-LNA b 4 α-L-oxy-LNA b 5 β-D-ENA b 6 β-D-(NH)-LNA b 7 β-D-(NCH3)-LNA d 2-deoxy C* methyl-C (5-methylcytosine) A* 2-aminoadenine s the internucleotide linkage is a phosphorothioate group (-O-P(O)(S - )-O-) ss the internucleotide linkage is a phosphorodithioate group (-O-P(S)(S - )-O-) / 5SpC3s / the -O-P(O)(S - )OC3H6OH at the 5'-terminal group of the antisense oligonucleotide / 3SpC3s / the -O-P(O)(S - )OC3H6OH at the 3'-terminal group of the antisense oligonucleotide The bold nucleotides are LNA nucleotides The non-bold nucleotides are non-LNA nucleotides.

11. Use of the antisense oligonucleotide of claim 10 in the preparation of a medicament for preventing and treating cancer or tumor selected from the following: lung cancer, pancreatic cancer, colorectal cancer, chronic myeloid leukemia, acute myeloid leukemia, gastric cancer, breast cancer and melanoma, wherein the antisense oligonucleotide has nucleotides selected from the following: SEQ ID No. 259e, 260d, 261b, 261e, 261g, 262d, 262e, 209s, 209v, 209w, 209x, 209ai, 209an, 209at, 209au and 209av.

12. A pharmaceutical composition comprising at least one antisense oligonucleotide according to any one of claims 1 - 4 or 10 and at least one pharmaceutically acceptable carrier, excipient, adjuvant, solvent or diluent.

Images