AU2011326034B2

AU2011326034B2 - Compositions and methods for treating androgen receptor dependent disorders including cancers

Info

Publication number: AU2011326034B2
Application number: AU2011326034A
Authority: AU
Inventors: Jesper Worm; Yixian Zhang
Original assignee: Santaris Pharma AS; Enzon Pharmaceuticals Inc
Current assignee: Roche Innovation Center Copenhagen AS
Priority date: 2010-11-12
Filing date: 2011-11-11
Publication date: 2016-02-04
Anticipated expiration: 2031-11-11
Also published as: WO2012065051A1; EP2646553A1; AU2011326034A1; EP2646553A4

Abstract

The invention provides the combination use of antisense oligomers targeting androgen receptor mRNA and androgen receptor binding inhibitors that reduce androgen receptor activity for the treatment of androgen receptor related medical disorders, such as cancers, particularly prostate cancers and breast cancers.

Description

WO 2012/065051 PCT/US2011/060352 COMPOSITIONS AND METHODS FOR TREATING ANDROGEN RECEPTOR DEPENDENT DISORDERS INCLUDING CANCERS 5 This application claims priority to United States patent application serial no. 12/945,551 filed November 12, 2010 and United Kingdom patent application no. 1101969.2 filed February 4, 2011. FIELD OF INVENTION 10 The invention relates to the field of androgen receptor targeted therapies and methods for treating androgen receptor dependent disorders including cancers. BACKGROUND The androgen receptor (AR) is a type of nuclear receptor which is activated by binding 15 either of the androgenic hormones testosterone or dihydrotestosterone. The main function of the androgen receptor is as a DNA binding transcription factor which regulates gene expression. However the androgen receptor also has additional functions independent of DNA binding. The androgen receptor is most closely related to the progesterone receptor, and progestins in higher dosages can block the androgen receptor. 20 Whilst in humans the AR gene is single copy and found on the X chromosome at position Xq l 1-12, the receptor itself exists in two iso-forms (A and B). AR-A is an 87kDa protein which lacks the first 187 amino acids (N-terminal truncation). Isoform AR-B is the full length 110 kDa version. The binding of androgen to the androgen receptor induces a conformational change to 25 the receptor, resulting in a dissociation of heat shock proteins, dimerization and transport from the cytosol to the cell nucleus where the androgen receptor dimer binds to specific DNA sequences - referred to as hormone response elements. Depending on the interaction with other nuclear proteins, the AR controls gene expression, either increasing or decreasing transcription of specific genes, such as insulin-like growth factor I (IGF-1). 30 Androgen receptors can also have cytoplasmic activities though with signal transduction proteins in the cytoplasm. Androgen binding to cytoplasmic androgen receptors. can cause rapid changes in cell function independent of gene transcription, for example ion WO 2012/065051 PCT/US2011/060352 transport, as well as indirect influence of gene transcription, for example via mediating other signal transduction pathways, thereby influencing the activity of other transcription factors. The over-expression of androgen receptor, or expression of mutated androgen receptor genes has been indicated in several diseases, such as cancer, including prostate cancer and 5 breast cancer, as well as other disorders such as polyglutamate disease (Monks et al., PNAS November 2 2007, published on line) alopecia, benign prostatic hyperplasia, spinal and muscular atrophy and Kennedy disease. W097/l 1170 reports on a method of treating a patient diagnosed as having benign prostatic hyperplasia or a prostate cancer comprising administering an antisense 10 oligonucleotide which selectively hybridises to the androgen receptor mRNA. Three antisense oligonucleotide sequences of between 27 - 29 nucleotides are disclosed. US 6,733,776 and EP 0 692 972 report on a method for treating androgenic alopecia by applying liposomes comprising an antisense nucleic acid that hybridises to an androgen receptor gene. No antisense molecules with specific sequences and targeting the androgen 15 receptor are provided. US 2005/0164970 reports on a method of treating prostate cancer using siRNA complexes targeting the androgen receptor mRNA. WO 2005/027833 reports on a method of treating prostate cancer comprising of administering a morpholino oligonucleotide of between 12-40 morpholino sub-units in length 20 to the patient. WO 2001/083740 reports on an antisense compound having an uncharged morpholino backbone of between 18 to 20 contiguous units which targets the human androgen receptor. Morpholino antisense compounds work via binding to the nucleic acid target to block access to the mRNA by other molecules, such as molecules involved in mRNA splicing or 25 translation initiation. US 7,067,256 reports on a ribozyme which apparently mediates inactivation of the androgen receptor. A 19 nucleotide RNA molecule antisense to a corresponding region of the androgen receptor mRNA is provided. However, despite the application of siRNA, morpholino antisense and ribozymes, none 30 of the above androgen receptor inhibitors have been successful in efficiently down-regulating the androgen-receptor in vivo and at pharmacologically acceptable dosages. 2 3 US 7,709,517 teaches diarylhydantoin compounds, including diarylthiohydantoins, which inhibit androgen receptor binding, methods for synthesizing the compounds and methods for using them in the treatment of hormone refractory prostate cancer. 5 What is needed and desirable are improved compositions and methods for the treatment of androgen receptor (AR) dependent medical disorders including AR-dependent cancers. SUMMARY OF INVENTION A first aspect of the invention provides for a pharmaceutical composition 10 comprising: an antisense oligomer comprising a contiguous nucleotide sequence of a total of 10-30 nucleoides, wherein the contiguous nucleotide sequence is at least 80% homologous to a region corresponding to i) SEQ ID NO 58 or SEQ ID NO 94, ii) SEQ 1) NO 77 or SEQ ID NO 105 or iii) a sequence selected from the group consisting of SEQ ID NC): 2 -- 22 and 86-106 or a conjugate thereof, or a pharmaceutically acceptable salt 15 thereof, and a diarylhydantoin type androgen receptor ligand binding inhibitor or a pharmaceutically acceptable salt thereof. A second aspect of the invention provides for a method for treating an androgen receptor dependent hyperproliferative disorder in a mammal, the method comprising administering to said mammal, therapeutically effective amounts, in combination: 20 (a) an antisense oligomer or conjugate thereof, or pharmaceutically acceptable salt thereof, as defined in the first aspect of the invention; and (b) a diarylhydantoin type androgen receptor ligand binding inhibitor or a pharmaceutically acceptable salt thereof. 25 In an exemplary aspect, the present invention provides the use in combination of a new class of LNA antisense oligomer androgen receptor antagonists and diarylhydantoin androgen receptor binding inhibitors, such as 4-(3-(4-cyano-3 (trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N methylbenzamide ("MDV31 00"), for the treatment of androgen receptor dependent 30 medical disorders in mammals such as humans.

3a The condition treated may, for example, be an androgen receptor-dependent cancer such as a breast cancer or a prostate cancer, for example, advanced prostate cancer, castration-resistant prostate cancer (CRPC), hormone refractory prostate cancer, alopecia, benign prostatic hyperplasia, spinal and muscular atrophy, Kennedy disease and 5 polyglutamate disease. The present inventors have discovered that antisense oligomers targeting the androgen receptor strongly potentiate the effect of diarylhydantoin androgen receptor blockers. The present invention provides an antisense oligomer or conjugate thereof, or pharmaceutically acceptable salt thereof, that affects, preferably decreases, expression of 10 an androgen receptor for use in the treatment of an androgen receptor dependent hyperproliferative disorder in a mammal; wherein said oligomer is used in combination with a diarylhydantoin type androgen receptor ligand binding inhibitor or a pharmaceutically acceptable salt thereof. The present invention provides an antisense oligomer or conjugate thereof, or 15 pharmaceutically acceptable salt thereof, for use in the treatment of an androgen receptor dependent hyperproliferative disorder in a mammal; wherein said oligomer is used in combination with a diarylhydantoin type androgen receptor ligand binding inhibitor or a pharmaceutically acceptable salt thereof; and/or bicalutamide or a pharmaceutically acceptable salt thereof. Thus, in one embodiment the invention provides the use in 20 combination of a (i) diarylhydantoin type androgen receptor ligand binding inhibitor or a pharmaceutically acceptable salt thereof and (ii) an antisense androgen receptor oligomer or a pharmaceutically acceptable salt thereof or a conjugate of the oligomer or a pharmaceutically WO 2012/065051 PCT/US2011/060352 acceptable salt of the conjugate, such as those described herein, that decreases androgen receptor expression, for the treatment and/or prevention of androgen-dependent medical conditions and disorders including but not limited to hyperproliferative disorders. In a further aspect, the present invention provides a kit comprising: 5 (a) an antisense oligomer or conjugate thereof, or pharmaceutically acceptable salt thereof, as defined herein and (b) a diarylhydantoin type androgen receptor ligand binding inhibitor or a pharmaceutically acceptable salt thereof; and/or bicalutamide or a pharmaceutically acceptable salt thereof; 10 and pharmaceutically acceptable salts thereof. The component parts of a kit as described herein can be administered to a mammal as a single component or as different component parts. For example, component (a) may be delivered simultaneously with component (b) [wherein component (a) is the antisense oligomer and component (b) is the diarylhydantoin type androgen receptor ligand binding 15 inhibitor or a pharmaceutically acceptable salt thereof, and/or bicalutamide or a pharmaceutically acceptable salt thereof]. In another example, component (a) - may be delivered before and/or after component (b) [wherein component (a) is the antisense oligomer and component (b) is the diarylhydantoin type androgen receptor ligand binding inhibitor or a pharmaceutically acceptable salt thereof, and/or bicalutamide or a pharmaceutically 20 acceptable salt thereof]; in other words components (a) and (b) are administered sequentially. In a further example, component (b) - may be delivered before and/or after component (a) [wherein component (a) is the antisense oligomer and component (b) is the diarylhydantoin type androgen receptor ligand binding inhibitor or a pharmaceutically acceptable salt thereof, and/or bicalutamide or a pharmaceutically acceptable salt thereof]; in other words 25 components (b) and (a) are administered sequentially. In some embodiments, components (a) and (b) are in the same composition. In another aspect, the present invention provides the use of an antisense oligomer or conjugate thereof, or pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of an androgen receptor dependent hyperproliferative disorder 30 in a mammal;-wherein said medicament is for use in combination with either i) a diarylhydantoin type androgen receptor ligand binding inhibitor or a pharmaceutically acceptable salt thereof; and/or ii) bicalutamide or a pharmaceutically acceptable salt thereof. 4 WO 2012/065051 PCT/US2011/060352 In some embodiments, the antisense oligomer and (i) the diarylhydantoin type androgen receptor ligand binding inhibitor or a pharmaceutically acceptable salt thereof and/or (ii) bicalutamide or a pharmaceutically acceptable salt thereof may be in the same composition. 5 The present invention provides in another aspect a method for treating an androgen receptor dependent hyperproliferative disorder in a mammal, comprising administering to said mammal, optionally in amounts therapeutically effective in combination: (a) an antisense oligomer or conjugate thereof, or pharmaceutically acceptable salt thereof as defined herein; and 10 (b) a diarylhydantoin type androgen receptor ligand binding inhibitor or a pharmaceutically acceptable salt thereof; and/or bicalutamide or a pharmaceutically acceptable salt thereof. In another aspect, the present invention provides the combination use of (i) an antisense oligomer or conjugate thereof, or pharmaceutically acceptable salt thereof, and 15 (ii) a diarylhydantoin type androgen receptor ligand binding inhibitor for the treatment of an androgen receptor dependent hyperproliferative disorder in a mammal. One embodiment provides a method for treating a disease or a medical disorder as disclosed herein, such as a hyperproliferative disorder, such as cancer, said method comprising administering to a mammal, such as a human, in need of treatment for the 20 disorder (1) an antisense oligomer, a conjugate or a pharmaceutical composition according to the invention, in an amount effective to decrease expression of AR in the mammal and (2) a diarylhydantoin androgen receptor binding inhibitor, such as 4-(3-(4-cyano-3 (trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin- I -yl)-2-fluoro-N methylbenzamide, in an amount effective to decrease the activity of AR in the mammal, such 25 that the effect of the oligomer, conjugate thereof or composition is temporally overlapping with the effect of the diarylhydantoin AR inhibitor. A related embodiment provides a method for decreasing AR activity in a cell, such as a mammalian cell, such as a human cell, said method comprising contacting the cell with (1) an antisense oligomer, a conjugate or a pharmaceutical composition according to the invention 30 in an amount effective to decrease expression of AR and (2) a diarylhydantoin androgen receptor binding inhibitor, such as 4-(3-(4-cyano-3-(triflu6romethyl)phenyl)-5,5-dimethyl-4 oxo-2-thioxoimidazolidin- I -yl)-2-fluoro-N-methylbenzamide, in an'amount effective to decrease the activity of AR in the mammal, such that the effect of the oligomer, conjugate 5 WO 2012/065051 PCT/US2011/060352 thereof or composition is temporally overlapping with the effect of the diarylhydantoin AR inhibitor. The oligomer used may, for example, be 10 - 50, such as 10 - 30 nucleotides in length which comprises a contiguous nucleotide sequence of.a total of 10 - 50, such as 10 - 30 5 nucleotides, wherein said contiguous nucleotide sequence is at least 80% (e.g., 85%, 90%, 95%, 98%, or 99%) homologous to a region corresponding to the reverse complement of a nucleic acid which encodes a mammalian androgen receptor, such as a mammalian Androgen Receptor gene or mRNA, such as SEQ ID NO: I or naturally occurring variants thereof. Thus, for example, the oligomer hybridizes to a single stranded nucleic acid molecule having 10 the sequence of a (corresponding) portion of SEQ ID NO: 1. The oligomer used may, for example, be 10-50 nucleobases in length which comprises a contiguous nucleobase sequence of a total of 10-50 nucleobases, wherein said contiguous nucleobase sequence is at least 80% homologous to a corresponding region of a nucleic acid which encodes a mammalian androgen receptor. 15 The oligomer used may, for example, be 10-50 nucleobases in length which comprises a contiguous nucleobase sequence of a total of 10-50 nucleobases, wherein said contiguous nucleobase sequence is at least 80% identical to the reverse complement of a target region of a nucleic acid which encodes a mammalian androgen receptor. The oligomer used may, for example, consist of 10 to 30 contiguous monomers 20 wherein adjacent monomers are covalently linked by a phosphate group or a phosphorothioate group, wherein said oligomer comprises a first region of at least 10 contiguous monomers; wherein at least one monomer of said first region is a nucleoside analogue; wherein the sequence of said first region is at least 80% identical to the reverse complement of the best-aligned target region of a mammalian androgen receptor gene or a 25 mammalian androgen receptor mRNA. In one preferred variation, an antisense oligomer selected from the group consisting of: 5'-As *Cs*C sasasgstststscststscAsGs "C-3' (SEQ ID NO: 58); and 5'-MeCsMeCsMeCsasasgsgscsascstsgscsAsGA-3' (SEQ ID NO: 77), wherein uppercase letters denote beta-D-oxy-LNA monomers and lowercase letters 30 denote DNA monomers, the subscript "s" denotes a phosphorothioate linkage, and m'C denotes a beta-D-oxy-LNA monomer containing a 5-methyleytosine base, 6 WO 2012/065051 PCT/US2011/060352 or a conjugate thereof or a pharmaceutically acceptable salt of said compound or said conjugate, is used. Additional features, advantages, and embodiments of the invention may be set forth or apparent from consideration of the following detailed description, drawings, and claims. 5 Moreover, it is to be understood that both the foregoing summary of the invention and the following detailed description are exemplary and intended to provide further explanation without limiting the scope of the invention as claimed. BRIEF DESCRIPTION OF FIGURES 10 Figure 1. Oligonucleotides presented in Table 3 were evaluated for their potential to knockdown the androgen receptor mRNA at concentrations of 1, 4 and 16 nM in MCF7 cells 24 hours after transfection using Real-time PCR. All results were normalised to GAPDH and inhibition of AR mRNA is shown as percent of untreated control. Results shown are an average of three independent experiments. 15 Figure 2. Oligonucleotides presented in Table 3 were evaluated for their potential to knockdown the androgen receptor mRNA at concentrations of 1, 4 and 16 nM in A549 cells 24 hours after transfection using Real-time PCR. All results were normalised to GAPDH and inhibition of AR.mRNA is shown as percent of untreated control. Results shown are an average of three independent experiments. 20 Figure 3. Sequence alignment of the human Androgen receptor mRNA sequence (GenBank Accession No.: NM_000044; SEQ ID NO: 1) and the mouse Androgen receptor mRNA sequence (GenBank Accession No.: NM_013476; SEQ ID NO: 81). Figure 4. Location of preferred target regions of the human AR mRNA (cDNA ; SEQ ID NO: 1) targeted by oligomers according to the invention. Although 16mer target sites have 25 been shown, in some embodiments, these target regions may comprise an additional 4 bases 5' or 3' to the regions shown - i.e. are target regions of up to 24 contiguous nucleotides. Figure 5. SEQ ID NO: I Homo sapiens androgen receptor (dihydrotestosterone receptor; testicular feminization; spinal and bulbar muscular atrophy; Kennedy disease) (AR), transcript variant 1, mRNA. (Genbank Accession number NM_000044). 30 Figure 6. SEQ ID NO 81: Mouse androgen receptor mRNA sequence. Figure 7. SEQ ID NO 82: Rhesus monkey androgen receptor mRNA sequence. Figure 8. SEQ ID NO 83: Homo sapiens androgen receptor protein amino acid sequence. Figure 9. SEQ ID NO 84: Mouse androgen receptor protein amino acid sequence. 7 WO 2012/065051 PCT/US2011/060352 Figure 10. SEQ ID NO 85: Rhesus monkey androgen receptor protein amino acid sequence. Figure 11. AR mRNA in LNCaP, 24h post-transfection. Figure 12. AR mRNA in A549, 24h post-transfection. Figure 13. Cell proliferation assay - A549, time course post-transfection. 5 Figure 14. Cell proliferation assay - time course post-transfection. Figure 15. Caspase 3/7 activity in LNCaP cells, 24, 48 or 72 hours post-transfection. Figure 16. Caspase 3/7 activity in A549 cells, 24, 48 or 72 hours post-transfection. Figure 17. Average PSA in plasma after in vivo oligomer treatment. Figure 18. In vivo Inhibition of tumor growth. 10 Figure 19. Tumor volume measured over a 17-day period for antisense mismatch control, SEQ ID NO:58 alone, MDV3100 alone, SEQ ID NO:58 + MDV3100, and antisense mismatch + MDV3 100 treatment groups in the CWR-22 prostate tumor cell xenograft model. Figure 20. Tumor volume measured over a 31 day period for MDV3 100 alone versus MDV3 100 + SEQ ID NO: 58 combination treatment groups in the CWR-22 tumor cell tumor 15 xenograft model. Figure 21. SEQ ID NO: 58 potentiates the cell growth inhibitory effect of MDV3 100. Figure.22. SEQ ID NO: 58 potentiates MDV3 100 inhibition of AR transcriptional activity. Figure 23. SEQ ID NO: 58 potentiates the effect of MDV3 100 on AR transcriptional activity. SEQ ID NO: 58 (EZN-4176) and SEQ ID NO: 58 in combination with 4-(3-(4 20 cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin- I -yl)-2-fluoro N-methylbenzamide (MDV3 100) significantly down-modulate AR (androgen receptor) mRNA. Figure 24. SEQ ID NO: 58 potentiates the effect of MDV3 100 on PSA transcriptional activity. SEQ ID NO: 58 (EZN-4176) in combination with 4-(3-(4-cyano-3 25 (trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N methylbenzamide (MDV3 100) significantly down-modulate PSA (prostate specific antigen) mRNA. DETAILED DESCRIPTION OF INVENTION 30 The Oligomer The present invention employs oligomeric compounds (referred herein as oligomers), for use in modulating the function of nucleic acid molecules encoding mammalian Androgen Receptor, such as the Androgen Receptor nucleic acid shown in SEQ ID NO 1, and naturally 8 WO 2012/065051 PCT/US2011/060352 occurring variants of such nucleic acid molecules encoding mammalian Androgen Receptor. The term "oligomer" in the context of the present invention, refers to a molecule formed by covalent linkage of two or more nucleotides (i.e. an oligonucleotide). Herein, each single nucleotide, such as the nucleotides present in the oligomer of the invention, may also be 5 referred to as a "monomer" or "unit". In some embodiments, the oligomer consists or comprises of a contiguous nucleotide sequence of 10-50 nucleotides in length, such as 10 30 nucleotides in length (i.e. comprises or consists of from 10 - 30 covalently linked monomers). In various embodiments, the antisense oligomer targeting the androgen receptor does 10 not comprise RNA (units). In various embodiments, the antisense oligomers according to the invention are linear molecules or are synthesised as a linear molecule. The oligomer, in such embodiments, is a single stranded molecule, and typically does not comprise short regions of, for example, at least 3, 4 or 5 contiguous nucleotides, which are complementary to another region within the same oligomer (i.e. duplexes) In this regard, in some embodiments, the 15 oligomer is not (essentially) double stranded. In some embodiments, the oligomer is essentially not double stranded, such as is not a siRNA. In various embodiments, the oligomer of the invention may consist entirely of the contiguous nucleotide region. Thus, the oligomer is not substantially self-complementary. siRNAs comprise of 2 complementary short RNA (or equivalent nucleobase units) sequences, such as 21 and 23nts long, with, 20 typically a 2nt 3' overhang on either end. In order to enhance in vivo uptake, the siRNAs may be conjugated, such as conjugated to a sterol, such as a cholesterol group (typically at the 3' or 5' termini of one or both of the strands). The invention further provides target sequences in the AR mRNA or gene, or an allelic variant thereof, in particular those corresponding to SEQ ID NOS: 2 - 22, wherein antisense 25 oligonucleotides corresponding to said target sequences are capable of downregulating AR. For example, target sequences which correspond to the antisense oligonucleotide sequences SEQ ID NOS: 2 - 22, respectively, are shown in Figure 4 (bold and underlined, with the corresponding oligo SEQ ID NOS indicated above). Variant sequences, for example but not limited to allelic variants (such as a (AR) gene present at gene locus Xq 11-12) of such target 30 sequences are also within the scope of the invention. A variant sequence may have at least 60%, more preferably at least 70%, more preferably at least 80%, more preferably at least 85%, more preferably at least 90%, more preferably at least 91%, at least 92%, at least 93%, at least 94%, at least 95% sequence homology to a target sequence in AR. Typically, an 9 WO 2012/065051 PCT/US2011/060352 oligomer of the invention corresponding to said variant sequences is still capable of down regulating AR. Specific designs of LNA oligonucleotides are also disclosed, for example those shown in SEQ ID NOS 44 - 80. The oligomers of the invention are considered to be potent 5 inhibitors of androgen receptor mRNA and protein expression. In some embodiments, such as in relation to the use of an oligomer targeting the Androgen receptor (AR) in combination with a diarylhydantoin type androgen receptor ligand binding inhibitor or a pharmaceutically acceptable salt thereof; and/or bicalutamide or a pharmaceutically acceptable salt thereof, the oligomer may be an antisense oligonucleotide 10 may or may not comprise LNA. In this regard, the oligomer may be an oligomer, such as a gapmer oligomer, of 10 - 50 nucleotides in length, such as 10 - 30 nucleotides in length, which comprises a contiguous nucleotide sequence of a total of between 10 - 50, such as 10 30 nucleotides, wherein said contiguous nucleotide sequence is at least 80% (e.g., 85%, 90%, 95%, 98%, or 99%) homologous to a region corresponding to the reverse complement of a 15 nucleic acid which encodes a mammalian androgen receptor, such as a mammalian androgen Receptor gene or mRNA, such as SEQ ID NO: I or naturally occurring variants thereof. Thus, for example, the oligomer hybridizes to a single stranded nucleic acid molecule having the sequence of a (corresponding) portion of SEQ ID NO: 1 may be a gapmer. The Target 20 The mammalian androgen receptor is preferably selected from the group consisting of human or mouse androgen receptor. Preferably the mammalian androgen receptor is human androgen receptor, such as the Androgen receptor encoded by the nucleic acid as shown in SEQ ID NO 1. Further mammalian androgen receptor genes (targets) and their corresponding proteins are shown in the following table: Genbank Accession Numbers - Genbank Accession Numbers Nucleic acid (mRNA/cDNA - Polypeptide (deduced) sequence) Human NM_000044 NP_000035 Mouse NM_013476 NP_038504 Rhesus monkey NM_001032911 NP001028083 25 10 WO 2012/065051 PCT/US2011/060352 It should be recognised that the Androgen Receptor gene in humans does show a degree of allelic variation, and several of the polymorphisms are recognized. The above disclosed GenBank Accession numbers for nucleic acids refer to cDNA sequences and not to mRNA sequences per se. The sequence of a mature mRNA can be derived directly from the 5 corresponding cDNA sequence with thymine bases (T) being replaced by uracil bases (U). It should be recognised that the Androgen Receptor gene in humans does show a degree of allelic variation, and several of the polymorphisms are associated with disease phenotypes (Mooney et al, NAR 15; 31(8) 2003). For example, a CAG repeat expansion is associated with polyglutamine expansion disorder, other characterised allelic variants include 10 a (GGC)n trinucleotide repeat and R726L, T887A and L710H single nucleotide polymorphisms have been identified, and the latter two have been shown to be correlated to enhanced promiscuity of the AR receptor for other steroid ligands. In one embodiment n may range from 5 and 31. CAG repeats of less than 22 have been associated with an enhanced risk of prostate cancer in African American males, and this may therefore be a 15 preferred allelic variant. In some embodiments, the target nucleic acid is an AR allelic variant which comprises one or more single nucleotide polymorphisms, including R726L, T887A and L710H. Therefore, in some embodiments, the target is an AR allelic variant which comprises a (CAG)n trinucleotide repeat, or (GGC)n trinucleotide repeat. 20 The nucleic acid which encodes the mammalian androgen receptor is, in a preferable embodiment, the human androgen receptor cDNA sequence is shown as SEQ ID NO I and/or the mouse androgen receptor cDNA sequence is shown as SEQ ID NO 81, or allelic variants thereof. The oligomer according to the invention is an antisense oligonucleotide. Therefore, 'the target' of the oligomer according to the invention is the androgen 25 receptor mRNA. The oligoiner when introduced into the cell which is expressing the androgen receptor gene, results in reduction of the androgen receptor mRNA level, resulting in reduction in the level of expression of the androgen receptor in the cell. The androgen receptor is known to regulate the expression of several genes, such as a gene selected from the group consisting of Protein kinase C delta (PRKCD), Glutathione S 30 transferase theta 2 (GSTT2), transient receptor potential cation channel subfamily V member 3 (TRPV3), Pyrroline-5-carboxylate reductase I (PYCR I) or ornithine aminotransferase (OAT) - such genes are referred to as androgen receptor targets herein, and as such, in some embodiments, the oligomers according to the invention may be used to modulate the 11 WO 2012/065051 PCT/US2011/060352 expression of one or more androgen receptor targets in a cell which is expressing, or is capable of expressing (i.e. in the case of alleviation of repression (by the AR) of the androgen receptor target in a cell) said androgen receptor target. The oligomers which target the androgen receptor mRNA, may hybridize to any site 5 along the target mRNA nucleic acid, such as the 5' untranslated leader, exons, introns and 3'untranslated tail. However, it is preferred that the oligomers which target the androgen receptor mRNA hybridise to the mature mRNA form of the target nucleic acid. Suitably the oligomer of the invention is capable of down-regulating expression of the Androgen Receptor gene. In this regard, the oligomer of the invention can effect the 10 inhibition of Androgen Receptor, typically in a mammalian such as a human cell. In some embodiments, the oligomers of the invention bind to the target nucleic acid and effect inhibition of expression of at least 10% or 20% compared to the normal expression level, more preferably at least a 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95% inhibition as compared to the normal expression level (such as immediately prior to dosing of the 15 oligomer). In some embodiments, such modulation is seen when using between 0.04 and 25nM, such as between 0.8 and 20nM concentration of the compound of the invention. In the same or a different embodiment, the inhibition of expression is less than 100%, such as less than 98% inhibition, less than 95% inhibition, less than 90% inhibition, less than 80% inhibition, such as less than 70% inhibition. Modulation of expression level may be 20 determined by measuring protein levels, e.g. by the methods such as SDS-PAGE followed by western blotting using suitable antibodies raised against the target protein. Alternatively, modulation of expression levels can be determined by measuring levels of mRNA, e.g. by northern blotting or quantitative RT-PCR. When measuring via mRNA levels, the level of down-regulation when using an appropriate dosage, such as between 0.04 and 25nM, such as 25 between 0.8 and 20nM concentration, is, in some embodiments, typically to a level of between 10-20% the normal levels in the absence of the compound of the invention. The invention therefore provides a method of down-regulating or inhibiting the expression of the androgen receptor protein and/or mRNA in a cell which is expressing the androgen receptor protein and/or mRNA, said method comprising administering or 30 contacting the oligomer or conjugate according to the invention (suitably in an effective amount) to said cell to down-regulating or inhibiting the expression of the androgen receptor protein and/or mRNA in said cell. Suitably the cell is a mammalian cell such as a human 12 WO 2012/065051 PCT/US2011/060352 cell. The administration or contacting may occur, in some embodiments, in vitro. The administration or contacting may occur, in some embodiments, in vivo. The term "target nucleic acid", as used herein refers to the DNA or RNA encoding mammalian androgen receptor polypeptide, such as human androgen receptor, such as SEQ 5 ID NO: 1. Androgen receptor encoding nucleic acids or naturally occurring variants thereof, and RNA nucleic acids derived therefrom, preferably mRNA, such as pre-mRNA, although preferably mature mRNA. In some embodiments, for example when used in research or diagnostics the "target nucleic acid" may be a cDNA or a synthetic oligonucleotide derived from the above DNA or RNA nucleic acid targets. The oligomer according to the invention 10 is preferably capable of hybridising to the target nucleic acid. It will be recognised that SEQ ID NO: I is a cDNA sequences, and as such, corresponds to the mature mRNA target sequence, although uracil is replaced with thymidine in the cDNA sequences. The term "naturally occurring variant thereof' refers to variants of the androgen receptor polypeptide of nucleic acid sequence which exist naturally within the defined 15 taxonomic group, such as mammalian, such as mouse, monkey, and preferably human. Typically, when referring to "naturally occurring variants" of a polynucleotide the term also may encompass any allelic variant of the androgen receptor encoding genomic DNA which are found at the Chromosome X: 66.68 - 66.87 Mb by chromosomal translocation or duplication, and the RNA, such as mRNA derived therefrom. "Naturally occurring variants" 20 may also include variants derived from alternative splicing of the androgen receptor mRNA. When referenced to a specific polypeptide sequence, e.g., the term also includes naturally occurring forms of the protein which may therefore be processed, e.g. by co- or post translational modifications, such as signal peptide cleavage, proteolytic cleavage, glycosylation, etc. 25 Oligomer Sequences The oligomers comprise or consist of a contiguous nucleotide sequence which corresponds to the reverse complement of a nucleotide sequence present in SEQ ID NO: 1. Thus, the oligomer can comprise or consist of, or a sequence selected from the group 30 consisting of SEQ ID NOS: 2 - 22 and 86 - 106, wherein said oligomer (or contiguous nucleotide portion thereof) may optionally have one, two, or three mismatches against said selected sequence. 13 WO 2012/065051 PCT/US2011/060352 The oligomer may comprise or consist of a contiguous nucleotide sequence which is fully complementary (perfectly complementary) to the equivalent region of a nucleic acid which encodes a mammalian androgen receptor (e.g., SEQ ID NO: 1). Thus, the oligomer can comprise or consist of an antisense nucleotide sequence. 5 However, in some embodiments, the oligomer may tolerate 1, 2, 3, or 4 (or more) mismatches, when hybridising to the target sequence and still sufficiently bind to the target to show the desired effect, i.e. down-regulation of the target. Mismatches may, for example, be compensated by increased length of the oligomer nucleotide sequence and/or an increased number of nucleotide analogues, such as LNA, present within the nucleotide sequence. 10 In some embodiments, the contiguous nucleotide sequence comprises no more than 3, such as no more than 2 mismatches when hybridizing to the target sequence, such as to the corresponding region of a nucleic acid which encodes a mammalian androgen receptor. In some embodiments, the contiguous nucleotide sequence comprises no more than a single mismatch when hybridizing to the target sequence, such as the corresponding region of 15 a nucleic acid which encodes a mammalian androgen receptor. The nucleotide sequence of the oligomers of the invention or the contiguous nucleotide sequence is preferably at least 80% homologous to a corresponding sequence selected from the group consisting of SEQ ID NOS: 2 - 22 and 86 - 106, such as at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96% homologous, 20 such as 100% homologous (identical). The nucleotide sequence of the oligomers of the invention or the contiguous nucleotide sequence is preferably at least 80% homologous to the reverse complement of a corresponding sequence present in SEQ ID NO: 1, such as at least 85%, at least 90%, at least 91%, at least 92%at least 93%, at least 94%, at least 95%, at least 96% homologous, at least 25 97% homologous, at least 98% homologous, at least 99% homologous, such as 100% homologous (identical). The nucleotide sequence of the oligomers of the invention or the contiguous nucleotide sequence is preferably at least 80% complementary to a sub-sequence present in SEQ ID NO: 1, such as at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at 30 least 95%, at least 96% complementary, at least 97% complementary, at least 98% complementary, at least 99% complementary, such as 100% complementary (perfectly complementary). 14 WO 2012/065051 PCT/US2011/060352 In some embodiments, the oligomer (or contiguous nucleotide portion thereof) is selected from, or comprises, one of the sequences selected from the group consisting of SEQ ID NOS: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, and 22, or a sub sequence of at least 10 contiguous nucleotides thereof, wherein said oligomer (or contiguous 5 nucleotide portion thereof) may optionally comprise one, two, or three mismatches when compared to the sequence. In some embodiments, the oligomer (or contiguous nucleotide portion thereof) is selected from, or comprises, one of the sequences selected from the group consisting of SEQ ID NOS: 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105 10 and 106, or a sub-sequence of at least 10 contiguous nucleotides thereof, wherein said oligomer (or contiguous nucleotide portion thereof) may optionally comprise one, two, or three mismatches when compared to the sequence. Other preferred oligomers include a (contiguous) nucleotide sequence, such as a sequence of 12, 13, 14, 15 or 16 contiguous nucleotides in length, which have a nucleotide 15 sequence selected from a sequence from the group consisting of SEQ ID No 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, and 22, wherein said oligomer (or contiguous nucleotide portion thereof) may optionally comprise one, two, or three mismatches against said selected sequence. In some embodiments, the sub-sequence may consist of I1, 12, 13, 14, 15, 16, 17, 18, 20 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29 contiguous nucleotides, such as 12 -22, such as 12-18 nucleotides. Suitably, in some embodiments, the sub-sequence is of the same length as the contiguous nucleotide sequence of the oligomer of the invention. However, it is recognised that, in some embodiments the nucleotide sequence of the oligomer may comprise additional 5' or 3' nucleotides, such as, independently, 1, 2, 3, 4 or 5 25 additional nucleotides 5' and/or 3', which are non-complementary to the target sequence. In this respect the oligomer of the invention, may, in some embodiments, comprise a contiguous nucleotide sequence which is flanked 5' and or 3' by additional nucleotides. In some embodiments the additional 5' or 3' nucleotides are naturally occurring nucleotides, such as DNA or RNA. In some embodiments, the additional 5' or 3' nucleotides may represent 30 region D as referred to in the context of gapmer oligomers herein. In some embodiments, the oligomer according to the invention consists or comprises of a nucleotide sequence according to SEQ ID NO 2, such as SEQ ID NO 44, or a sub-sequence 15 WO 2012/065051 PCT/US2011/060352 of at least 10 contiguous nucleotides thereof, such as 1, 12, 13, 14, 15 or 16 contiguous nucleotides thereof. In some embodiments, the oligomer according to the invention consists or comprises of a nucleotide sequence according to SEQ ID 3, such as SEQ ID 45, or a sub-sequence of at 5 least 10 contiguous nucleotides thereof, such as 11, 12, 13, 14, 15 or 16 contiguous nucleotides thereof. In some embodiments, the oligomer according to the invention consists or comprises of a nucleotide sequence according to SEQ ID 4, such as SEQ ID NO 46, or a sub-sequence of at least 10 contiguous nucleotides thereof, such as 11, 12, 13, 14, 15 or 16 contiguous 10 nucleotides thereof. In some embodiments, the oligomer according to the invention consists or comprises of a nucleotide sequence according to SEQ ID 5, such as SEQ ID NO 47, or a sub-sequence of at least 10 contiguous nucleotides thereof, such as 1, 12, 13, 14, 15 or 16 contiguous nucleotides thereof. 15 In some embodiments, the oligomer according to the invention consists or comprises of a nucleotide sequence according to SEQ ID 6, such as SEQ ID NO 48,-49 or 50, or a sub sequence of at least 10 contiguous nucleotides thereof, such as 11, 12, 13, 14, 15 or 16 contiguous nucleotides thereof. In some embodiments, the oligomer according to the invention consists or comprises of 20 a nucleotide sequence according to SEQ ID 7, such as SEQ ID NO 51, 52, or 53, or a sub sequence of at least 10 contiguous nucleotides thereof, such as 11, 12, 13, 14, 15 or 16 contiguous nucleotides thereof. In some embodiments, the oligomer according to the invention consists or comprises of a nucleotide sequence according to SEQ ID 8, such as SEQ ID 54, 55 or 56, or a sub 25 sequence of at least 10 contiguous nucleotides thereof, such as 1, 12, 13, 14, 15 or 16 contiguous nucleotides thereof. In some embodiments, the oligomer according to the invention consists or comprises of a nucleotide sequence according to SEQ ID 9, such as SEQ ID 57, or a sub-sequence of at least 10 contiguous nucleotides thereof, such as 11, 12, 13, 14, 15 or 16 contiguous 30 .nucleotides thereof. In some embodiments, the oligomer according to the invention consists or comprises of a nucleotide sequence according to SEQ ID 10, such as SEQ ID 58, 59, or 60, or a sub 16 WO 2012/065051 PCT/US2011/060352 sequence of at least 10 contiguous nucleotides thereof, such as 11, 12, 13, 14, 15 or 16 contiguous nucleotides thereof. In some embodiments, the oligomer according to the invention consists or comprises of a nucleotide sequence according to SEQ ID 11, such as SEQ ID 61, or a sub-sequence of at 5 least 10 contiguous nucleotides thereof, such as 11, 12, 13, 14, 15 or 16 contiguous nucleotides thereof. In some embodiments, the oligomer according to the invention consists or comprises of a nucleotide sequence according to SEQ ID 12, such as SEQ ID 62, or a sub-sequence of at least 10 contiguous nucleotides thereof, such as 11, 12, 13, 14, 15 or 16 contiguous 10 nucleotides thereof. In some embodiments, the oligomer according to the invention consists or comprises of a nucleotide sequence according to SEQ ID 13, such as SEQ ID 63, 64 or 65 or a sub sequence of at least 10 contiguous nucleotides thereof, such as I1i, 12, 13, 14, 15 or 16 contiguous nucleotides thereof. 15 In some embodim'ents, the oligomer according to the invention consists or comprises of a nucleotide sequence according to SEQ ID 14, such as SEQ ID 66, or a sub-sequence of at least 10 contiguous nucleotides thereof, such as 11, 12, 13, 14, 15 or 16 contiguous nucleotides thereof. In some embodiments, the oligomer according to the invention consists or comprises of 20 a nucleotide sequence according to SEQ ID 15, such as SEQ ID 67, or a sub-sequence of at least 10 contiguous nucleotides thereof, such as 1, 12, 13, 14, 15 or 16 contiguous nucleotides thereof. In some embodiments, the oligomer according to the invention consists or comprises of a nucleotide sequence according to SEQ ID 16, such as SEQ ID 68, or a sub-sequence of at 25 least 10 contiguous nucleotides thereof, such as 11, 12, 13, 14, 15 or 16 contiguous nucleotides thereof. In some embodiments, the oligomer according to the invention consists or comprises of a nucleotide sequence according to SEQ ID 17, such as SEQ ID 69, 70 or 71, or a sub sequence of at least 10 contiguous nucleotides thereof, such as 11, 12, 13, 14, 15 or 16 30 contiguous nucleotides thereof. In some embodiments, the oligomer according to the invention consists or comprises of a nucleotide sequence according to SEQ ID 18, such as SEQ ID 72, or a sub-sequence of at 17 WO 2012/065051 PCT/US2011/060352 least 10 contiguous nucleotides thereof, such as 11, 12, 13, 14, 15 or 16 contiguous nucleotides thereof. In some embodiments, the oligomer according to the invention consists or comprises of a nucleotide sequence according to SEQ ID 19, such as SEQ ID 73, 74 or 75, or a sub 5 sequence of at least 10 contiguous nucleotides thereof, such as I1, 12, 13, 14, 15 or 16 contiguous nucleotides thereof. In some embodiments, the oligomer according to the invention consists or comprises of a nucleotide sequence according to SEQ ID 20, such as SEQ ID 76, or a sub-sequence of at least 10 contiguous nucleotides thereof, such as 11, 12, 13, 14, 15 or 16 contiguous 10 nucleotides thereof. In some embodiments, the oligomer according to the invention consists or comprises of a nucleotide sequence according to SEQ ID 21, such as SEQ ID 77, 78 or 79, or a sub sequence of at least 10 contiguous nucleotides thereof, such as I1, 12, 13, 14, 15 or 16 contiguous nucleotides thereof. 15 In some embodiments, the oligomer according to the invention consists or comprises of a nucleotide sequence according to SEQ ID 22, such as SEQ ID 80, or a sub-sequence of at least 10 contiguous nucleotides thereof, such as 11, 12, 13, 14, 15 or 16 contiguous nucleotides thereof. When determining "homology" between the oligomers of the invention (or contiguous 20 nucleotide sequence) and the nucleic acid which encodes the mammalian androgen receptor or the reverse complement thereof, such as those disclosed herein, the determination of homology may be made by a simple alignment with the corresponding nucleotide sequence of the compound of the invention and the corresponding region of the nucleic acid which encodes the mammalian androgen receptor (or target nucleic acid), or the reverse 25 complement thereof, and the homology is determined by counting the number of bases which align and dividing by the total number of contiguous nucleotides in the compound of the invention, and multiplying by 100. In such a comparison, if gaps exist, it is preferable that such gaps are merely mismatches rather than areas where the number of nucleotides within the gap differ between the nucleotide sequence of the invention and the target nucleic acid. 30 The terms "corresponding to" and "corresponds to" refer to the comparison between the nucleotide sequence of the oligomer or contiguous nucleotide sequence (a first sequence) and the equivalent contiguous nucleotide sequence of a further sequence selected from either i) a sub-sequence of the reverse complement of the nucleic acid target, such as the mRNA which 18 WO 2012/065051 PCT/US2011/060352 encodes the androgen receptor protein, such as SEQ ID NO: 1, and/or ii) the sequence of nucleotides provided herein such as the group consisting of SEQ ID NOS: 2 - 22 and 86 106, or sub-sequence thereof. Nucleotide analogues are compared directly to their equivalent or corresponding nucleotides. A first sequence which corresponds to a further sequence under 5 i) or ii) typically is identical to that sequence over the length of the first sequence (such as the contiguous nucleotide sequence) or, as described herein may, in some embodiments, is at least 80% homologous to a corresponding sequence, such as at least 85%, at least 90%, at least 91%, at least 92%at least 93%, at least 94%, at least 95%, at least 96% homologous, at least 97% homologous, at least 98% homologous, at least 99% homologous, such as 100% 10 homologous (identical). The terms "corresponding nucleotide analogue" and "corresponding nucleotide" are intended to indicate that the nucleotide in the nucleotide analogue and the naturally occurring nucleotide are identical. For example, when the 2-deoxyribose unit of the nucleotide is linked to an adenine, the "corresponding nucleotide analogue" contains a pentose unit (different 15 from 2-deoxyribose) linked to an adenine. Oligomer length The oligomers comprise or consist of a contiguous nucleotide sequence of a total of 10, I1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 contiguous 20 nucleotides in length. In some embodiments, the oligomers comprise or consist of a contiguous nucleotide sequence of a total of 10 - 22, such as 12 - 18, such as 13 - 17 or 12 - 16, such as 13, 14, 15, 16 contiguous nucleotides in length. In some embodiments, the oligomers comprise or consist of a contiguous nucleotide 25 sequence of a total of 10, H1, 12, 13, or 14 contiguous nucleotides in length. In some embodiments, the oligomer according to the invention consists of no more than 22 nucleotides, such as no more than 20 nucleotides, such as no more than 18 nucleotides, such as 15, 16 or 17 nucleotides. In some embodiments the oligomer of the invention comprises less than 20 nucleotides. 30 Nucleotide analogues The term "nucleotide" as used herein, refers to a glycoside comprising a sugar moiety, a base moiety and a covalently linked phosphate group and covers both naturally occurring 19 WO 2012/065051 PCT/US2011/060352 nucleotides, such as DNA or RNA, preferably DNA, and non-naturally occurring nucleotides comprising modified sugar and/or base moieties, which are also referred to as "nucleotide analogues" herein. Non-naturally occurring nucleotides include nucleotides which have modified sugar 5 moieties, such as bicyclic nucleotides or 2' modified nucleotides, such as 2' substituted nucleotides. "Nucleotide analogues" are variants of natural nucleotides, such as DNA or RNA nucleotides, by virtue of modifications in the sugar and/or base moieties. Analogues could in principle be merely "silent" or "equivalent" to the natural nucleotides in the context of the 10 oligonucleotide, i.e. have no functional effect on the way the oligonucleotide works to inhibit target gene expression. Such "equivalent" analogues may nevertheless be useful if, for example, they are easier or cheaper to manufacture, or are more stable to storage or manufacturing conditions, or represent a tag or label. Preferably, however, the analogues will have a functional effect on the way in which the oligomer works to inhibit expression; 15 for example by producing increased binding affinity to the target and/or increased resistance to intracellular nucleases and/or increased ease of transport'into the cell. Specific examples of nucleoside analogues are described by e.g. Freier & Altmann; Nucl. Acid Res., 1997, 25,4429-4443 and Uhlmann; Curr. Opinion in Drug Development, 2000, 3(2), 293-213, and in Scheme 1: 20 WO 2012/065051 PCT/US2011/060352 0 B O 0O 0 O O O F 0P-S~ o=- O4- OO=-o 4 4 4 4 Phosphorthioate 2-O-Methyl 2 -MOE 2-Fluoro 0 ~ ~ 0 N 4 H

NH

2 2'-AP HNA CeNA PNA 00TB O F B B 0 4 -N1o- 0 O= N\ O4- O O -O- O= -O' Morpholino 41OH 2-F-ANA 3-Phosphoramidate 2-(3-hydroxy)propyl O O=P-BH Boranophosphates Scheme 1 The oligomer may thus comprise or consist of a simple sequence of natural occurring 5 nucleotides - preferably 2'-deoxynucleotides (referred to here generally as "DNA"), but also possibly ribonucleotides (referred to here generally as "RNA"), or a combination of such naturally occurring nucleotides and one or more non-naturally occurring nucleotides, i.e. nucleotide analogues. Such nucleotide analogues may suitably enhance the affinity of the oligomer for the target sequence. 10 Examples of suitable and preferred nucleotide analogues are provided by International Pub. No. W02007/031091 (PCT[DK2006/000512) or are referenced therein. Incorporation of affinity-enhancing nucleotide analogues in the oligomer, such as LNA or 2'-substituted sugars, can allow the size of the specifically binding oligomer to be reduced, and may also reduce the upper limit to the size of the oligomer before non-specific or 15 aberrant binding takes place. In some embodiments the oligomer comprises at least 2 nucleotide analogues. In some embodiments, the oligomer comprises from 3-8 nucleotide analogues, e.g. 6 or 7 nucleotide 21 WO 2012/065051 PCT/US2011/060352 analogues. In the by far most preferred embodiments, at least one of said nucleotide analogues is a locked nucleic acid (LNA); for example at least 3 or at least 4, or at least 5, or at least 6, or at least 7, or 8, of the nucleotide analogues may be LNA. In some embodiments all the nucleotides analogues may be LNA. 5 It will be recognised that when referring to a preferred nucleotide sequence motif or nucleotide sequence, which consists of only nucleotides, the oligomers of the invention which are defined by that sequence may comprise a corresponding nucleotide analogue in place of one or more of the nucleotides present in said sequence, such as LNA units or other nucleotide analogues, which raise the duplex stability/Tm of the oligomer/target duplex (i.e. 10 affinity enhancing nucleotide analogues). In some embodiments, any mismatches between the nucleotide sequence of the oligomer and the target sequence are preferably found in regions outside the affinity enhancing nucleotide analogues, such as region B as referred to herein, and/or region D as referred to herein, and/or at the site of non modified such as DNA nucleotides in the 15 oligonucleotide, and/or in regions which are 5' or 3' to the contiguous nucleotide sequence. Examples of such modification of the nucleotide include modifying the sugar moiety to provide a 2'-substituent group or to produce a bridged (locked nucleic acid) structure which enhances binding affinity and may also provide increased nuclease resistance. A preferred nucleotide analogue is LNA, such as oxy-LNA (such as beta-D-oxy-LNA, 20 and alpha-L-oxy-LNA), and/or amino-LNA (such as beta-D-amino-LNA and alpha-L-amino LNA) and/or thio-LNA (such as beta-D-thio-LNA and alpha-L-thio-LNA) and/or ENA (such as beta-D-ENA and alpha-L-ENA). Most preferred is beta-D-oxy-LNA. In some embodiments the nucleotide analogues present within the oligomer of the invention (such as in regions A and C mentioned herein) are independently selected from, for 25 example: 2'-O-alkyl-RNA units, 2'-amino-DNA units, 2'-fluoro-DNA units, LNA units, arabino nucleic acid (ANA) units, 2'-fluoro-ANA units, HNA units, 3'fluoro hexitol nucleic acid (3'F-HNA). INA (intercalating nucleic acid -Christensen, 2002. Nucl. Acids. Res. 2002 30: 4918-4925, hereby incorporated by reference) units and 2'MOE units. In some embodiments there is only one of the above types of nucleotide analogues present in the 30 oligomer of the invention, or contiguous nucleotide sequence thereof. In some embodiments the nucleotide analogues are 2'-O-methoxyethyl-RNA (2'MOE), 2'-fluoro-DNA monomers or LNA nucleotide analogues, and as such the oligonucleotide of the invention may comprise nucleotide analogues which are independently selected from 22 WO 2012/065051 PCT/US2011/060352 these three types of analogue, or may comprise only one type of analogue selected from the three types. In some embodiments at least one of said nucleotide analogues is 2'-MOE-RNA, such as 2, 3, 4, 5, 6, 7, 8, 9 or 10 2'-MOE-RNA nucleotide units. In some embodiments at least one of said nucleotide analogues is 2'-fluoro DNA, such as 2, 3, 4, 5, 6, 7, 8, 9 or 10 2' 5 fluoro-DNA nucleotide units. In some embodiments, the oligomer according to the invention comprises at least one Locked Nucleic Acid (LNA) unit, such as 1, 2, 3, 4, 5, 6, 7, or 8 LNA units, such as 3 - 7 or. 4 to 8 LNA units, or 3, 4, 5, 6 or 7 LNA units. In some embodiments, all the nucleotide analogues are LNA. In some embodiments, the oligomer may comprise both beta-D-oxy 10 LNA, and one or more of the following LNA units: thio-LNA, amino-LNA, oxy-LNA, and/or ENA in either the beta-D or alpha-L configurations or combinations thereof. In some embodiments all LNA cytosine units are 5'methyl-Cytosine. In some embodiments of the invention, the oligomer may comprise both LNA and DNA units. Preferably the combined total of LNA and DNA units is 10-25, preferably 10-20, even more preferably 12-16. In 15 some embodiments of the invention, the nucleotide sequence of the oligomer, such as the contiguous nucleotide sequence consists of at least one LNA and the remaining nucleotide units are DNA units. In some embodiments the oligomer comprises only LNA nucleotide analogues and naturally occurring nucleotides (such as RNA or DNA, most preferably DNA nucleotides), optionally with modified internucleotide linkages such as phosphorothioate. 20 The term "nucleobase" refers to the base moiety of a nucleotide and covers both naturally occurring a well as non-naturally occurring variants. Thus, "nucleobase" covers not only the known purine and pyrimidine heterocycles but also heterocyclic analogues and tautomeres thereof. Examples of nucleobases include, but are not limited to adenine, guanine, cytosine, 25 thymidine, uracil, xanthine, hypoxanthine, 5-methylcytosine, isocytosine, pseudoisocytosine, 5-bromouracil, 5-propynyluracil, 6-aminopurine, 2-aminopurine, inosine, diaminopurine, and 2-chloro-6-aminopurine. In some embodiments, at least one of the nucleobases present in the oligomer is a modified nucleobase selected from the group consisting of 5-methylcytosine, isocytosine, 30 pseudoisocytosine, 5-bromouracil, 5-propynyluracil, 6-aminopurine, 2-aminopurine, inosine, diaminopurine, and 2-chloro-6-aminopurine. 23 WO 2012/065051 PCT/US2011/060352 LNA The term "LNA" refers to a bicyclic nucleotide analogue, known as "Locked Nucleic Acid". It may refer to an LNA monomer, or, when used in the context of an "LNA oligonucleotide" refers to an oligonucleotide containing one or more such bicyclic nucleotide 5 analogues. The LNA used in the oligonucleotide compounds of the invention preferably has the structure of the general formula I R5 B Rs* X R1 P R4 R2

R

2 R 3 wherein X is selected from -0-, -S-, -N(R N*)-, -C(R 6

R

6 *)-; 10 B is selected from hydrogen, optionally substituted C 4 -alkoxy, optionally substituted Cw- 4 -alkyl, optionally substituted CA-acyloxy, nucleobases, DNA intercalators, photochemically active groups, thermochemically active groups, chelating groups, reporter groups, and ligands; P designates the radical position for an internucleoside linkage to a succeeding 15 monomer, or a 5'-terminal group, such internucleoside linkage or 5'-terminal group optionally including the substituent R 5 or equally applicable the substituent R 5 ; P* designates an internucleoside linkage to a preceding monomer, or a 3-terminal group;

R

4 * and R 2 * together designate a biradical consisting of 1-4 groups/atoms selected from 20 -C(RaRb)-, -C(Ra)=C(Rb)-, -C(Ra)=N-, -O-, -Si(Ra) 2 -, -S-, -SO 2 -, -N(Ra)-, and >C=Z, wherein Z is selected from -0-, -S-, and -N(Ra)-, and Ra and Rb each is independently selected from hydrogen, optionally substituted CI - 12 -alkyl, optionally substituted C 21 2 alkenyl, optionally substituted C 2

-

12 -alkynyl, hydroxy, CI- 12 -alkoxy, C 2

-

12 -alkoxyalkyl, C 2

-

12 alkenyloxy, carboxy, CI- 1 2 -alkoxycarbonyl, CI- 1 2 -alkylcarbonyl, formyl, aryl, aryloxy 25 carbonyl, aryloxy, arylcarbonyl, heteroaryl, heteroaryloxy-carbonyl, heteroaryloxy, heteroarylcarbonyl, amino, mono- and di(CI- 6 -alkyl)amino, carbamoyl, mono- and di(CI- 6 alkyl)-amino-carbonyl, amino-CI.

6 -alkyl-aminocarbonyl, mono- and di(CI.

6 -alkyl)amino-C 6 -alkyl-aminocarbonyl, C - 6 -alkyl-carbonylamino, carbamido, C-alkanoyloxy, sulphono, 24 WO 2012/065051 PCT/US2011/060352

CI.

6 -alkylsulphonyloxy, nitro, azido, sulphanyl, C 1 .6-alkylthio, halogen, DNA intercalators, photochemically active groups, thermochemically active groups, chelating groups, reporter groups, and ligands, where aryl and heteroaryl may be optionally substituted and where two geminal substituents R' and R together may designate optionally substituted methylene 1* 2 3 * 6 6* 5 (=CH 2 ), and each of the substituents R *, R , R', R', R *, R and R , which are present is independently selected from hydrogen, optionally substituted Cr 12 -alkyl, optionally substituted C 2 r 12 -alkenyl, optionally substituted C 2 12 -alkynyl, hydroxy, Cr 12 -alkoxy, C 2 12 alkoxyalkyl, C 2 r 12 -alkenyloxy, carboxy, C- 1 2-alkoxycarbonyl, C 1 2-alkylcarbonyl, formyl, aryl, aryloxy-carbonyl, aryloxy, arylcarbonyl, heteroaryl, heteroaryloxy-carbonyl, heteroaryl 10 oxy, heteroarylcarbonyl, amino, mono- and di(CI- 6 -alkyl)amino, carbamoyl, mono- and di(C 6 -alkyl)-amino-carbonyl, amino-CI- 6 -alkyl-aminocarbonyl, mono- and di(C 6 -alkyl)amino CI-6-alkyl-aminocarbonyl, Cl.6-alkyl-carbonylamino, carbamido, C 1 6 -alkanoyloxy, sulphono, Ci- 6 -alkylsulphonyloxy, nitro, azido, sulphanyl, CI- 6 -alkylthio, halogen, DNA intercalators, photochemically active groups, thermochemically active groups, chelating groups, reporter 15 groups, and ligands, where aryl and heteroaryl may be optionally substituted, and where two geminal substituents together may designate oxo, thioxo, imino, or optionally substituted methylene, or together may form a spiro biradical consisting of a 1-5 carbon atom(s) alkylene chain which is optionally interrupted and/or terminated by one or more heteroatoms/groups selected from -0-, -S-, and -(NRN)- where RN is selected from hydrogen and CIA-alkyl, and 20 where two adjacent (non-geminal) substituents may designate an additional bond resulting in a double bond; and R , when present and not involved in a biradical, is selected from hydrogen and C 1 4 -alkyl; and basic salts and acid addition salts thereof; In some embodiments R * is selected from H, -CH 3 , -CH 2

-CH

3 ,- CH 2 -0-CH 3 , and CH=CH 2 . 25 In some embodiments, R* and R2* together designate a biradical selected from C(R"Rb)-O-, -C(RaRb)-C(RcRd)-O-, - -C(RaRb)-O-C(RcRd), C(RaRb)-O-C(RCRd)-O-, -C(RaRb)-C(RCRd)-, -C(RaRb)-C(RcRd)-C(R* R)-, C(Ra)=C(Rb)-C(RcRd)-, -C(RaRb)-N(Rc)-, -C(RaRb)-C(RcRd)- N(Re)-, -C(RaR b)-N(R')-O-, and -C(RaR )-S-, -C(RaRb)-C(RcRd)-S-, wherein Ra, Rb, Re, R', R , and R each is independently 30 selected from hydrogen, optionally substituted Ci 1 2-alkyl, optionally substituted C 2 r 12 alkenyl, optionally substituted C 2

.

2 -alkynyl, hydroxy, C 1 r 12 -alkoxy, C 2 12 -alkoxyalkyl, C 2 12 alkenyloxy, carboxy, Cr 12 -alkoxycarbonyl, Cr 12 -alkylcarbonyl, formyl, aryl, aryloxy carbonyl, aryloxy, arylcarbonyl, heteroaryl, heteroaryloxy-carbonyl, heteroaryloxy, 25 WO 2012/065051 PCT/US2011/060352 heteroarylcarbonyl, amino, mono- and di(CI.

6 -alkyl)amino, carbamoyl, mono- and di(CI.

6 alkyl)-amino-carbonyl, amino-CI.

6 -alkyl-aminocarbonyl, mono- and di(CI- 6 -alkyl)amino-Ci. 6 -alkyl-aminocarbonyl, C- 6 -alkyl-carbonylamino, carbamido, Cl-6-alkanoyloxy, sulphono,

CI.

6 -alkylsulphonyloxy, nitro, azido, sulphanyl, CI-,-alkylthio, halogen, DNA intercalators, 5 photochemically active groups, thermochemically active groups, chelating groups, reporter groups, and ligands, where aryl and heteroaryl may be optionally substituted and where two geminal substituents Ra and Rb together may designate optionally substituted methylene (=CH-2), In a further embodiment R 4 * and R 2 * together designate a biradical (bivalent group) 10 selected from -CH 2 -O-, -CH 2 -S-, -CH 2 -NH-, -CH 2

-N(CH

3 )-, -CH 2

-CH

2 -O-, -CH 2

-CH(CH

3 )-,

-CH

2

-CH

2 -S-, -CH 2

-CH

2 -NH-, -CH 2

-CH

2

-CH

2 -, -CH 2

-CH

2

-CH

2 -O-, -CH 2

-CH

2

-CH(CH

3 )-, CH=CH-CH 2 -, -CH 2

-O-CH

2 -O-, -CH 2 -NH-O-, -CH 2

-N(CH

3 )-O-, -CH 2

-O-CH

2 -, -CH(CH 3

)

0-, -CH(CH 2

-O-CH

3 )-O-. For all chiral centers, asymmetric groups may be found in either R or S orientation. 15 Preferably, the LNA used in the oligomer of the invention comprises at least one LNA unit according to any of the formulas z *Z Z* Y -O 0 -oL y B z B wherein Y is -0-, -O-CH 2 - ,-S-, -NH-, or N(R H); Z and Z* are independently selected among an internucleotide linkage, a terminal group or a protecting group; B constitutes a 20 natural or non-natural nucleotide base moiety, and RH is selected from hydrogen and C 1 4 alkyl. Specifically preferred LNA units are shown in scheme 2: ZZ* B [ o B 00 Z 0A-L-Oxy-LNA p-D-oxy-LNA 26 WO 2012/065051 PCT/US2011/060352 Z* B Z* B o 0 SC 0 p-D-thio-LNA B-D-ENA Z* B 0 z N R H p-D-amino-LNA Scheme 2 The term "thio-LNA" comprises a locked nucleotide in which Y in the general formula above is selected from S or -CH 2 -S-. Thio-LNA can be in either the beta-D and alpha-L 5 configuration. The term "amino-LNA" refers to a locked nucleotide in which Y in the general formula above is selected from -N(H)-, N(R)-, CH 2 -N(H)-, and -CH 2 -N(R)- where R is selected from hydrogen and CI.

4 -alkyl. Amino-LNA can be in either the beta-D and alpha-L-configuration. The term "oxy-LNA" refers to a locked nucleotide in which Y in the general formula 10 above represents -0- or -CH 2 -0-. Oxy-LNA can be in either the beta-D and alpha-L configuration. The term "ENA" refers to a locked nucleotide in which Y in the general formula above is -CH 2 -0- (where the oxygen atom of -CH 2 -0- is attached to the 2'-position relative to the base B). 15 In a preferred embodiment LNA is selected from beta-D-oxy-LNA, alpha-L-oxy-LNA, beta-D-amino-LNA and beta-D-thio-LNA, in particular beta-D-oxy-LNA. RNAse recruitment It is recognised that an oligomeric compound may function via non RNase mediated 20 degradation of target mRNA, such as by steric hindrance of translation, or other methods, 27 WO 2012/065051 PCT/US2011/060352 however, the preferred oligomers of the invention are capable of recruiting an endoribonuclease (RNase), such as RNase H. It is preferable that the oligomer, or contiguous nucleotide sequence, comprises of a region of at least 6, such as at least 7 consecutive nucleotide units, such as at least 8 or at 5 least 9 consecutive nucleotide units (residues), including 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 consecutive nucleotides, which, when formed in a duplex with the complementary target RNA is capable of recruiting RNase. The contiguous sequence which is capable of recruiting RNAse may be region B as referred to in the context of a gapmer as described herein. In some embodiments the size of the contiguous sequence which is capable of recruiting 10 RNAse, such as region B, may be higher, such as 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 nucleotide units. EP 1 222 309 provides in vitro methods for determining RNaseH activity, which may be used to determine the ability to recruit RNaseH. A oligomer is deemed capable of recruiting RNase H if, when provided with the complementary RNA target, it has an initial 15 rate, as measured in pmol/l/min, of at least I %, such as at least 5%, such as at least 10% or less than 20% of the equivalent DNA only oligonucleotide, with no 2' substitutions, with phosphorothioate linkage groups between all nucleotides in the oligonucleotide, using the methodology provided by Example 91 - 95 of EP 1 222 309. In some embodiments, an oligomer is deemed essentially incapable of recruiting 20 RNaseH if, when provided with the complementary RNA target, and RNaseH, the RNaseH initial rate, as measured in pmol/l/min, is less than 1%, such as less than 5%,such as less than 10% or less than 20% of the initial rate determined using the equivalent DNA only oligonucleotide, with no 2' substitutions, with phosphorothioate linkage groups between all nucleotides in the oligonucleotide, using the methodology provided by Example 91 - 95 of 25 EP 1 222 309. In other embodiments, an oligomer is deemed capable of recruiting RNaseH if, when provided with the complementary RNA target, and RNaseH, the RNaseH initial rate, as measured in pmol/l/min, is at least 20%, such as at least 40 %, such as at least 60 %, such as at least 80 % of the initial rate determined using the equivalent DNA only oligonucleotide, 30 with no 2' substitutions, with phosphorothioate linkage groups between all nucleotides in the oligonucleotide, using the methodology provided by Example 91 - 95 of EP 1 222 309. Typically the region of the oligomer which forms the consecutive nucleotide units which, when formed in a duplex with the complementary target RNA is capable of recruiting 28 WO 2012/065051 PCT/US2011/060352 RNase consists of nucleotide units which form a DNA/RNA like duplex with the RNA target - and include both DNA units and LNA units which are in the alpha-L configuration, particularly preferred being alpha-L-oxy LNA. The oligomer of the invention may comprise a nucleotide sequence which comprises 5 both nucleotides and nucleotide analogues, and may be in the form of a gapmer, a headmer or a mixmer. A headmer is defined by a contiguous stretch of non-RNase recruiting nucleotide analogues at the 5'-end followed by a contiguous stretch of DNA or modified nucleotide units recognizable and cleavable by the RNase towards the 3'-end (such as at least 7 such 10 nucleotides), and a tailmer is defined by a contiguous stretch of DNA or modified nucleotides recognizable and cleavable by the RNase at the 5'-end (such as at least 7 such nucleotides), followed by a contiguous stretch of non-RNase recruiting nucleotide analogues towards the 3'-end. Other chimeras according to the invention, called mixmers consisting of an alternate composition of DNA or modified nucleotides recognizable and cleavable by RNase and non 15 RNase recruiting nucleotide analogues. Some nucleotide analogues may also be able to mediate RNaseH binding and cleavage. Since a-L-LNA recruits RNaseH activity to a certain extent, smaller gaps of DNA or modified nucleotides recognizable and cleavable by the RNaseH for the gapmer construct might be required, and more flexibility in the mixmer construction might be introduced. 20 Gapmer Design Preferably, the oligomer of the invention is a gapmer. A gapmer oligomer is an oligomer which comprises a contiguous stretch of nucleotides which is capable of recruiting an RNAse, such as RNAseH, such as a region of at least 6 or 7 DNA nucleotides, referred to 25 herein in as region B, wherein region B is flanked both 5' and 3' by regions of affinity enhancing nucleotide analogues, such as I - 6 nucleotide analogues 5' and 3' to the contiguous stretch of nucleotides which is capable of recruiting RNAse - these regions are referred to as regions A and C respectively. Preferably the gapmer comprises a (poly)nucleotide sequence of formula (5' to 3'), A 30 B-C, or optionally A-B-C-D or D-A-B-C, wherein; region A (5' region) consists or comprises of at least one nucleotide analogue, such as at least one LNA unit, such as 1-6 nucleotide analogues, such as LNA units, and; region B consists or comprises of at least five consecutive nucleotides which are capable of recruiting RNAse (when formed in a duplex 29 WO 2012/065051 PCT/US2011/060352 with a complementary RNA molecule, such as the mRNA target), such as DNA nucleotides, and; region C (3'region) consists or comprises of at least one nucleotide analogue, such as at least one LNA unit, such as 1-6 nucleotide analogues, such as LNA units, and; region D, when present consists or comprises of 1, 2 or 3 nucleotide units, such as DNA nucleotides. 5 In some embodiments, region A consists of 1, 2, 3, 4, 5 or 6 nucleotide analogues, such as LNA units, such as 2-5 nucleotide analogues, such as 2-5 LNA units, such as 3 or 4 nucleotide analogues, such as 3 or 4 LNA units; and/or region C consists of 1, 2, 3, 4, 5 or 6 nucleotide analogues, such as LNA units, such as 2-5 nucleotide analogues, such as 2-5 LNA units, such as 3 or 4 nucleotide analogues, such as 3 or 4 LNA units. 10 In some embodiments B consists or comprises of 5, 6, 7, 8, 9, 10, 11 or 12 consecutive nucleotides which are capable of recruiting RNAse, or 6-10, or 7-9, such as 8 consecutive nucleotides which are capable of recruiting RNAse. In some embodiments region B consists or comprises at least one DNA nucleotide unit, such as 1-12 DNA units, preferably 4-12 DNA units, more preferably 6-10 DNA units, such as 7-10 DNA units, most preferably 8, 9 15 or 10 DNA units. In some embodiments region A consist of 3 or 4 nucleotide analogues, such as LNA, region B consists of 7, 8, 9 or 10 DNA units, and region C consists of 3 or 4 nucleotide analogues, such as LNA. Such designs include (A-B-C) 3-10-3, 3-10-4, 4-10-3, 3-9-3, 3-9-4, 4-9-3, 3-8-3, 3-8-4, 4-8-3, 3-7-3, 3-7-4, 4-7-3, and may further include region D, which may 20 have one or 2 nucleotide units, such as DNA units. Further gapmer designs are disclosed in W02004/046160 and are hereby incorporated by reference. US provisional application, 60/977409, hereby incorporated by reference, refers to 'shortmer' gapmer oligomers, which, in some embodiments may be the gapmer oligomer 25 according to the present invention. In some embodiments the oligomer is consisting of a contiguous nucleotide sequence of a total of 10, 11, 12, 13 or 14 nucleotide units, wherein the contiguous nucleotide sequence is of 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 nucleotide analogue units, such as LNA units; B consists of 7, 8 or 9 contiguous 30 nucleotide units which are capable of recruiting RNAse when formed in a duplex with a complementary RNA molecule (such as a mRNA target); and C consists of 1, 2 or 3 nucleotide analogue units, such as LNA units. When present, D consists of a single DNA unit. 30 WO 2012/065051 PCT/US2011/060352 In some embodiments A consists of I 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 I 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 nucleotide 5 units. In some embodiments B consists of 8 nucleotide units. In some embodiments B consists of 9 nucleotide units. In some embodiments B comprises of I - 9 DNA units, such as 2, 3, 4, 5, 6, 7 or 8 DNA units. In some embodiments B consists of DNA units. In some embodiments B comprises of at least one LNA unit which is in the alpha-L configuration, such as 2, 3, 4, 5, 6, 7, 8 or 9 LNA units in the alpha-L-configuration. In some embodiments 10 B comprises of at least one alpha-L-oxy LNA unit or wherein all the LNA units in the alpha L- configuration are alpha-L-oxy LNA units. In some embodiments the number of nucleotides present in A-B-C are selected from the group consisting of (nucleotide analogue units - region B - nucleotide analogue units): 1-8-1, 1-8-2, 2-8-1, 2-8-2, 3-8-3, 2-8-3, 3-8-2, 4-8-1, 4-8-2, 1-8-4, 2-8-4, or;I-9-1, 1-9-2, 2-9-1, 2-9-2, 2-9-3, 3-9-2, 1-9-3, 3-9-1, 4-9-1, 1-9 15 4, or; 1-10-1, 1-10-2, 2-10-1, 2-10-2, 1-10-3, 3-10-1. In some embodiments the number of nucleotides in A-B-C are selected from the group consisting of: 2-7-1, 1-7-2, 2-7-2, 3-7-3, 2 7-3, 3-7-2, 3-7-4, and 4-7-3. In some embodiments both A and C consists of two LNA units each, and B consists of 8 or 9 nucleotide units, preferably DNA units. 20 'Internucleotide Linkages The terms "linkage group" or "internucleotide linkage" are intended to mean a group capable of covalently coupling together two nucleotides, two nucleotide analogues, and a nucleotide and a nucleotide analogue, etc. Specific and preferred examples include phosphate groups and phosphorothioate groups. 25 The nucleotides of the oligomer of the invention or contiguous nucleotides sequence thereof are coupled together via linkage groups. Suitably each nucleotide is linked to the 3' adjacent nucleotide via a linkage group. Suitable intemucleotide linkages include those listed within PCT/DK2006/000512, for example the internucleotide linkages listed on the first paragraph of page 34 of 30 PCT/DK2006/000512 (hereby incorporated by reference). It is, in some embodiments, preferred to modify the internucleotide linkage from its normal phosphodiester to one that is more resistant to nuclease attack, such as 31 WO 2012/065051 PCT/US2011/060352 phosphorothioate or boranophosphate - these two, being cleavable by RNase H, also allow that route of antisense inhibition in reducing the expression of the target gene. Suitable sulphur (S) containing internucleotide linkages as provided herein may be preferred. Phosphorothioate internucleotide linkages are also preferred, particularly for the 5 gap region (B) of gapmers. Phosphorothioate linkages may also be used for the flanking regions (A and C, and for linking A or C to D, and within region D, as appropriate). Regions A, B and C, may however comprise internucleotide linkages other than phosphorothioate, such as phosphodiester linkages, particularly, for instance when the use of nucleotide analogues protects the internucleotide linkages within regions A and C from endo 10 nuclease degradation - such as when regions A and C comprise LNA nucleotides. The internucleotide linkages in the oligomer may be phosphodiester, phosphorothioate or boranophosphate so as to allow RNase H cleavage of targeted RNA. Phosphorothioate is preferred, for improved nuclease resistance and other reasons, such as ease of manufacture. In one aspect of the oligomer of the invention, the nucleotides and/or nucleotide 15 analogues are linked to each other by means of phosphorothioate groups. It is recognised that the inclusion of phosphodiester linkages, such as one or two linkages, into an otherwise phosphorothioate oligomer, particularly between or adjacent to nucleotide analogue units (typically in region A and or C) can modify the bioavailability and/or bio-distribution of an oligomer - see W02008/053314, hereby incorporated by 20 reference. In some embodiments, such as the embodiments referred to above, where suitable and not specifically indicated, all remaining linkage groups are either phosphodiester or phosphorothioate, or a mixture thereof. In some embodiments all the internucleotide linkage groups are phosphorothioate. 25 When referring to specific gapmer oligonucleotide sequences, such as those provided herein it will be understood that, in various embodiments, when the linkages are phosphorothioate linkages, alternative linkages, such as those disclosed herein may be used, for example phosphate (phosphodiester) linkages may be used, particularly for linkages between nucleotide analogues, such as LNA, units. Likewise, when referring to specific gapmer 30 oligonucleotide sequences, such as those provided herein, when the C residues are annotated as 5'methyl modified cytosine, in various embodiments, one or more of the Cs present in the oligomer may be unmodified C residues in some embodiments. 32 WO 2012/065051 PCT/US2011/060352 Oligomeric Compounds The oligomers of the invention may, for example, be selected from the group consisting of: 22 - 43 and 44 to 80. 5 Conjugates In the context of this disclosure, the term "conjugate" indicates a heterogenous molecule formed by the covalent attachment ("conjugation") of the oligomer as described herein to one or more non-nucleotide, or non-polynucleotide moieties. Examples of non nucleotide or non- polynucleotide moieties include macromolecular agents such as proteins, 10 fatty acid chains, sugar residues, glycoproteins, polymers, or combinations thereof. Typically proteins may be antibodies for a target protein. Typical polymers may be polyethylene glycol. Therefore, in various embodiments, the oligomer of the invention may comprise both a polynucleotide region which typically consists of a contiguous sequence of nucleotides, and a 15 further non-nucleotide region. When referring to the oligomer of the invention consisting of a contiguous nucleotide sequence, the compound may comprise non-nucleotide components, such as a conjugate component. In various embodiments of the invention the oligomeric compound is linked to ligands/conjugates, which may be used, e.g. to increase the cellular uptake of oligomeric 20 compounds. W02007/031091 provides suitable ligands and conjugates, which are hereby incorporated by reference. The invention also provides for a conjugate comprising the compound according to the invention as herein described, and at least one non-nucleotide or non-polynucleotide moiety covalently attached to said compound. Therefore, in various embodiments where the 25 compound of the invention consists of a specified nucleic acid or nucleotide sequence, as herein disclosed, the compound may also comprise at least one non-nucleotide or non polynucleotide moiety (e.g. not comprising one or more nucleotides or nucleotide analogues) covalently attached to said compound. Conjugation (to a conjugate moiety) may enhance the activity, cellular distribution or 30 cellular uptake of the oligomer of the invention. Such moieties include, but are not limited to, antibodies, polypeptides, lipid moieties such as a cholesterol moiety, cholic acid, a thioether, e.g. Hexyl-s-tritylthiol, a thiocholesterol, an aliphatic chain, e.g., dodecandiol or undecyl residues, a phospholipids, e.g., di-hexadecyl-rac-glycerol or triethylammonium 1,2 33 WO 2012/065051 PCT/US2011/060352 di-o-hexadecyl-rac-glycero-3-h-phosphonate, a polyamine or a polyethylene glycol chain, an adamantane acetic acid, a palmityl moiety, an octadecylamine or hexylamino-carbonyl oxycholesterol moiety. The oligomers of the invention may also be conjugated to active drug substances, for 5 example, aspirin, ibuprofen, a sulfa drug, an antidiabetic, an antibacterial or an antibiotic. In certain embodiments the conjugated moiety is a sterol, such as cholesterol. In various embodiments, the conjugated moiety comprises or consists of a positively charged polymer, such as a positively charged peptides of, for example 1 -50, such as 2 - 20 such as 3 - 10 amino acid residues in length, and/or polyalkylene oxide such as 10 polyethylglycol(PEG) or polypropylene glycol - see WO 2008/034123, hereby incorporated by reference. Suitably the positively charged polymer, such as a polyalkylene oxide may be attached to the oligomer of the invention via a linker such as the releasable inker described in WO 2008/034l23. By way of example, the following conjugate moieties may be used in the conjugates of 15 the invention: 0 Me 0 o-o1-5'- OLIGOMER 5 G R 00 0

-LK

0 5'- 0OL IGO0ME R-3 Activated oligomers The term "activated oligomer," as used herein, refers to an oligomer of the invention that is covalently linked (i.e., functionalized) to at least one functional moiety that permits 20 covalent linkage of the oligomer to one or more conjugated moieties, i.e., moieties that are not themselves nucleic acids or monomers, to form the conjugates herein described. Typically, a functional moiety will comprise a chemical group that is capable of covalently bonding to the oligomer via, e.g., a 3'-hydroxyl group or the exocyclic NH 2 group of the adenine base, a spacer that is preferably hydrophilic and a terminal group that is capable of 25 binding to a conjugated moiety (e.g., an amino, sulfhydryl or hydroxyl group). In some embodiments, this terminal group is not protected, e.g., is an NH 2 group. In other embodiments, the terminal group is protected, for example, by any suitable protecting group such as those described in "Protective Groups in Organic Synthesis" by Theodora W Greene 34 WO 2012/065051 PCT/US2011/060352 and Peter G M Wuts, 3rd edition (John Wiley & Sons, 1999). Examples of suitable hydroxyl protecting groups include esters such as acetate ester, aralkyl groups such as benzyl, diphenylmethyl, or triphenylmethyl, and tetrahydropyranyl. Examples of suitable amino protecting groups include benzyl, alpha-methylbenzyl, diphenylmethyl, triphenylmethyl, 5 benzyloxycarbonyl, tert-butoxycarbonyl, and acyl groups such as trichloroacetyl or trifluoroacetyl. In some embodiments, the functional moiety is self-cleaving. In other embodiments, the functional moiety is biodegradable. See e.g., U.S. Patent No. 7,087,229, which is incorporated by reference herein in its entirety. In some embodiments, oligomers of the invention are functionalized at the 5' end in 10 order to allow covalent attachment of the conjugated moiety to the 5' end of the oligomer. In other embodiments, oligomers of the invention can be functionalized at the 3' end. In still other embodiments, oligomers of the invention can be functionalized along the backbone or on the heterocyclic base moiety. In yet other embodiments, oligomers of the invention can be functionalized at more than one position independently selected from the 5' end, the 3' 15 end, the backbone and the base. In some embodiments, activated oligomers of the invention are synthesized by incorporating during the synthesis one or more monomers that is covalently attached to a functional moiety. In other embodiments, activated oligomers of the invention are synthesized with monomers that have not been functionalized, and the oligomer is 20 functionalized upon completion of synthesis. In some embodiments, the oligomers are functionalized with a hindered ester containing an aminoalkyl linker, wherein the alkyl portion has the formula (CH 2 )w, wherein w is an integer ranging from I to 10, preferably about 6, wherein the alkyl portion of the alkylamino group can be straight chain or branched chain, and wherein the functional group is attached to the oligomer via an ester group (-0 25 C(O)-(CH 2 )wNH). In other embodiments, the oligomers are functionalized with a hindered ester containing a (CH 2 ),-sulfhydryl (SH) linker, wherein w is an integer ranging from I to 10, preferably about 6, wherein the alkyl portion of the alkylamino group can be straight chain or branched chain, and wherein the functional group attached to the oligomer via an ester group 30 (-O-C(O)-(CH 2 )wSH) In some embodiments, sulfhydryl-activated oligonucleotides are conjugated with polymer moieties such as polyethylene glycol or peptides (via formation of a disulfide bond). 35 WO 2012/065051 PCT/US2011/060352 Activated oligomers containing hindered esters as described above can be synthesized by any method known in the art, and in particular by methods disclosed in International Pub. No. WO 2008/034122 and the examples therein, which is incorporated herein by reference in its entirety. 5 In still other embodiments, the oligomers of the invention are functionalized by introducing sulfhydryl, amino or hydroxyl groups into the oligomer by means of a functionalizing reagent substantially as described in U.S. Patent Nos. 4,962,029 and 4,914,210, i.e., a substantially linear reagent having a phosphoramidite at one end linked through a hydrophilic spacer chain to the opposing end which comprises a protected or 10 unprotected sulfhydryl, amino or hydroxyl group. Such reagents primarily react with hydroxyl groups of the oligomer. In some embodiments, such activated oligomers have a functionalizing reagent coupled to a 5'-hydroxyl group of the oligomer. In other embodiments, the activated oligomers have a functionalizing reagent coupled to a 3' hydroxyl group. In still other embodiments, the activated oligomers of the invention have a 15 functionalizing reagent coupled to a hydroxyl group on the backbone of the oligomer. In yet further embodiments, the oligomer of the invention is functionalized with more than one of the functionalizing reagents as described in U.S. Patent Nos. 4,962,029 and 4,914,210, incorporated herein by reference in their entirety. Methods of synthesizing such functionalizing reagents and incorporating them into monomers or oligomers are disclosed in 20 U.S. Patent Nos. 4,962,029 and 4,914,210. In some embodiments, the 5'-terminus of a solid-phase bound oligomer is functionalized with a dienyl phosphoramidite derivative, followed by conjugation of the deprotected oligomer with, e.g., an amino acid or peptide via a Diels-Alder cycloaddition reaction. 25 In various embodiments, the incorporation of monomers containing 2'-sugar modifications; such as a 2'-carbamate substituted sugar or a 2'-(O-pentyl-N-phthalimido) deoxyribose sugar into the oligomer facilitates covalent attachment of conjugated moieties to the sugars of the oligomer. In other embodiments, an oligomer with an amino-containing linker at the 2'-position of one or more monomers is prepared using a reagent such as, for 30 example, 5'-dimethoxytrityl-2'-O-(e-phthalimidylaminopentyl)-2'-deoxyadenosine-3'-- N,N diisopropyl-cyanoethoxy phosphoramidite. See, e.g., Manoharan, et al., Tetrahedron Letters, 1991, 34, 7171. 36 WO 2012/065051 PCT/US2011/060352 In still further embodiments, the oligomers of the invention may have amine-containing functional moieties on the nucleobase, including on the N6 purine amino groups, on the exocyclic N2 of guanine, or on the N4 or 5 positions of cytosine. In various embodiments, such functionalization may be achieved by using a commercial reagent that is already 5 functionalized in the oligomer synthesis. Some functional moieties are commercially available, for example, heterobifunctional and homobifunctional linking moieties are available from the Pierce Co. (Rockford, Ill.). Other commercially available linking groups are 5'-Amino-Modifier C6 and 3'-Amino Modifier reagents, both available from Glen Research Corporation (Sterling, Va.). 5'-Amino 10 Modifier C6 is also available from ABI (Applied Biosystems Inc., Foster City, Calif.) as Aminolink-2, and 3'-Amino-Modifier is also available from Clontech Laboratories Inc. (Palo Alto, Calif.). Compositions 15 The oligomer of the invention may be used in pharmaceutical formulations and compositions. Suitably, such compositions comprise a pharmaceutically acceptable diluent, carrier, salt or adjuvant. PCT/DK2006/00051 2 provides suitable and preferred pharmaceutically acceptable diluent, carrier and adjuvants - which are hereby incorporated by reference. Suitable dosages, formulations, administration routes, compositions, dosage 20 forms, combinations with other therapeutic agents, pro-drug formulations are also provided in PCT/DK2006/000512 - which are also hereby incorporated by reference. Applications The oligomers of the invention may be utilized as researchreagents for, for example, 25 diagnostics, therapeutics and prophylaxis. In research, such oligomers may be used to specifically inhibit the synthesis of androgen receptor protein (typically by degrading or inhibiting the mRNA and thereby prevent protein formation) in cells and experimental animals thereby facilitating functional analysis of the target or an appraisal of its usefulness as a target for therapeutic intervention. 30 In diagnostics the oligomers may be used to detect and quantitate androgen receptor expression in cell and tissues by Northern blotting, in-situ hybridisation or similar techniques. For therapeutics, an animal or a human, suspected of having a disease or disorder, which can be treated by modulating the expression of androgen receptor is treated by 37 WO 2012/065051 PCT/US2011/060352 administering antisense compounds in accordance with this invention, suitably in an effective amount. Further provided are methods of treating a mammal, such as treating a human, suspected of having or being prone to a disease or condition, associated with expression and/or activity of androgen receptor by administering a therapeutically or prophylactically 5 effective amount of one or more of the oligomers or compositions of the invention. The pharmaceutical composition according to the invention may be used for the treatment of conditions associated with abnormal levels of androgen receptor activity, such as cancer, such as prostate or breast cancer, The pharmaceutical composition according to the invention may be used for the 10 treatment of alopecia, benign prostatic hyperplasia, spinal and muscular atrophy and Kennedy disease. or polyglutamate disease. It will be recognised that treatment as referred to herein may be prophylactic. Suitable dosages, formulations, administration routes, compositions, dosage forms, combinations with other therapeutic agents, pro'drug formulations are also provided in 15 PCT/DK2006/000512 - which are hereby incorporated by reference., although it should be recognised that the aspects of PCT/DK2006/000512 which are only specifically applicable to the treatment of cancer may not be appropriate in the therapeutic/pharmaceutical compositions and methods of the present invention. The invention also provides for a pharmaceutical composition comprising a compound 20 or a conjugate as herein described or a conjugate, and a pharmaceutically acceptable diluent, carrier or adjuvant. PCT/DK2006/000512 provides suitable and preferred pharmaceutically acceptable diluent, carrier and adjuvants - which are hereby incorporated by reference. The oligomer, a conjugate or a pharmaceutical composition according to the invention is typically administered in an effective amount. 25 The invention also provides for the use of the compound or conjugate of the invention as described for the manufacture of a medicament for the treatment of a disorder as referred to herein, or for a method of the treatment of as a disorder as referred to herein. The invention also provides for a method for treating a disorder as referred to herein said method comprising administering a compound according to the invention as herein 30 described, and/or a conjugate according to the invention, and/or a pharmaceutical composition according to the invention to a patient in need thereof. 38 WO 2012/065051 PCT/US2011/060352 Pharmaceutical compositions comprising more than one active ingredient The pharmaceutical composition according to the invention may further comprise other active ingredients, including those which are indicated as being useful for the treatment of cancer such as prostate cancer or breast cancer, particularly agents used in conventional 5 antiandrogen therapy. One such class of compounds are Nonsteroidal antiandrogens (NSAAs), which block the binding of androgens at the receptor site. Diarylhydantoin type androgen receptor ligand binding inhibitors or pharmaceutically acceptable salts thereof including, for example, those disclosed in U.S. Patent No. 7,709,517 may be used. 10 Luteinizing hormone-releasing hormone analogs (LHRH-As) suppress testicular production of androgens to castrate levels. NSAAs, such as bicalutamide (CASODEX) when used with an LHRH-A as part of Combined Androgen Blockade therapy, help inhibit the growth of prostate cancer cells. In one embodiment, the present invention provides for a combined androgen blockade therapy, 15 characterised in that the therapy comprises administering an antisense oligomer composition according to the invention, and an NSAA and/or LHRH-A agent, which may be administered prior to, during or subsequent to the administering of an antisense oligomer composition of the invention, Generally, the antisense oligomer composition and one or more androgen blockade agents may be administered so that their effects are concurrent, i.e., temporally 20 overlapping in the subject. The invention also provides a kit of parts wherein a first part includes an antisense oligomer, conjugate thereof and/or oligomer pharmaceutical composition according to the invention and a further part comprises a Nonsteroidal antiandrogen (such as a diarylhydantoin type androgen receptor ligand binding inhibitor or pharmaceutically 25 acceptable salt thereof and/or bicalutamide) and/or a Luteinizing hormone-releasing hormone analog. One embodiment provides a kit that includes an antisense oligomer, pharmaceutically acceptable salt thereof, or conjugate thereof (or pharmaceutically acceptable salt of the conjugate) and a diarylhydantoin type androgen receptor ligand binding inhibitor or pharmaceutically acceptable salt thereof including, for example, those disclosed 30 in U.S. Patent No. 7,709,517. It is therefore envisaged that the kit of parts may be used in a method of treatment, as referred to herein, where the method comprises administering both the first part and the further part, either simultaneously or one after the other. 39 WO 2012/065051 PCT/US2011/060352 Oligomer Embodiments The following AR antisense oligomer embodiments of the present invention may, for example, be used in combination with the diaryihydantoin type AR ligand binding inhibitor embodiments described herein and/or bicalutamide and/or LHRH-As. 5 1. An oligomer of 10-50 nucleobases in length which comprises a contiguous nucleobase sequence of a total of 10-50 nucleobases, wherein said contiguous nucleobase sequence is at least 80% homologous to a corresponding region of a nucleic acid which encodes a mammalian androgen receptor. 2. The oligomer according to embodiment 1, wherein said oligomer comprises at least one 10 LNA unit. 3. The oligomer according to embodiment I or 2, wherein the contiguous nucleobase sequence comprises no more than 3, such as no more than 2 mismatches to the corresponding region of a nucleic acid which encodes a mammalian androgen receptor. 4. The oligomer according to embodiment 3, wherein said contiguous nucleobase sequence 15 comprises no more than a single mismatch to the corresponding region of a nucleic acid which encodes a mammalian androgen receptor. 5. The oligomer according to embodiment 4, wherein said contiguous nucleobase sequence comprises no mismatches, (i.e. is complementary to) the corresponding region of a nucleic acid which encodes a mammalian androgen receptor. 20 6. The oligomer according to any one of embodiments I - 5, wherein the nucleobase sequence of the oligomer consists of the contiguous nucleobase sequence. 7. The oligomer according to any one of embodiments 1- 6, wherein the nucleic acid which encodes a mammalian androgen receptor is the human androgen receptor nucleotide sequence such as SEQ ID No 1, or a naturally occurring allelic variant thereof. 25 8. The oligomer according to any one of embodiments 1 - 7, wherein the contiguous nucleobase sequence is complementary to a corresponding region of both the human androgen receptor nucleic acid sequence and a non-human mammalian androgen receptor nucleic acid sequence, such as the mouse androgen receptor nucleic acid sequence. 30 9. The oligomer according to any one of embodiments I to 8, wherein the contiguous nucleobase sequence comprises a contiguous subsequence of at least 7, nucleobase residues which, when formed in a duplex with the complementary androgen receptor target RNA is capable of recruiting RNaseH. 40 WO 2012/065051 PCT/US2011/060352 10. The oligomer according to embodiment 9, wherein the contiguous nucleobase sequence comprises of a contiguous subsequence of at least 8, at least 9 or at least 10 nucleobase residues which, when formed in a duplex with the complementary androgen receptor target RNA is capable of recruiting RNaseH. 5 11. The oligomer according to any one of embodiments 9 or 10 wherein said contiguous subsequence is at least 9 or at least 10 nucleobases in length, such as at least 12 nucleobases or at least 14 nucleobases in length, such as 14, 15 or 16 nucleobases residues which, when formed in a duplex with the complementary androgen receptor target RNA is capable of recruiting RNaseH. 10 12. The oligomer according to embodiment any one of embodiments I - 1 wherein said oligomer is conjugated with one or more non-nucleobase compounds. 13. The oligomer according to any one of embodiments I - 12, wherein said oligomer has a length of 10 - 22 nucleobases. 14. The oligomer according to any one of embodiments I - 13, wherein said oligomer has a 15 length of 12 - 18 nucleobases. 15. The oligomer according to any one of embodiments I - 14, wherein said oligomer has a length of 14, 15 or 16 nucleobases. 16. The oligomer according to any one of embodiments I - 15, wherein said continuous nucleobase sequence corresponds to a contiguous nucleotide sequence, present in a 20 nucleic acid sequence selected from the group consisting of SEQ ID NO 86 - 106. 17. The oligomer according to any one of embodiments 1-16, wherein the oligomer or contiguous nucleobase sequence comprises, or is selected from a corresponding nucleobase sequence present in a nucleotide sequence selected from the group consisting of SEQ ID NO 2 - 22. 25 18. The oligomer according to any one of embodiments I - 17, wherein said contiguous nucleobase sequence comprises at least one affinity enhancing nucleotide analogue. 19. The oligomer according to embodiment 18, wherein said contiguous nucleobase sequence comprises a total of 2, 3, 4, 5, 6, 7, 8, 9 or 10 affinity enhancing nucleotide analogues, such as 5 and 8 affinity enhancing nucleotide analogues. 30 20. The oligomer according to any one of embodiments I - 19 which comprises at least one affinity enhancing nucleotide analogue, wherein the remaining nucleobases are selected from the group consisting of DNA nucleotides and RNA nucleotides, preferably DNA nucleotides. 41 WO 2012/065051 PCT/US2011/060352 21. The oligomer according to any one of embodiments I - 20, wherein the oligomer comprises of a sequence of nucleobases of formula, in 5' to 3' direction, A-B-C, and optionally of formula A-B-C-D, wherein: A consists or comprises of at least one nucleotide analogue, such as 1, 2, 3, 4, 5 or 6 5 nucleotide analogues, preferably 2-5 nucleotide analogues, preferably 2, 3 or 4 nucleotide analogues, most preferably 2, 3 or 4 consecutive nucleotide analogues and; B consists or comprises at least five consecutive nucleobases which are capable of recruiting RNAseH (when formed in a duplex with a complementary RNA 10 molecule, such as the AR mRNA target), such as DNA nucleobases, such as 5, 6, 7, 8, 9, 10, 11 or 12 consecutive nucleobases which are capable of recruiting RNAseH, or 6-10, or 7-9, such as 8 consecutive nucleobases which are capable of recruiting RNAseH, and; C consists or comprises of at least one nucleotide analogue, such as 1, 2, 3, 4, 5, or 15 6 nucleotide analogues, preferably 2-5 nucleotide analogues, such as 2, 3 or 4 nucleotide analogues, most preferably 2, 3 or 4 consecutive nucleotide analogues, and; D when present, consists or comprises, preferably consists, of one or more DNA nucleotide, such as 1-3 or 1-2 DNA nucleotides. 20 22. The oligomer according to embodiment 21, wherein region A consists or comprises of 2, 3 or 4 consecutive nucleotide analogues. 23. The oligomer according to any one of embodiments 21 - 22, wherein region B consists or comprises of 7, 8, 9 or 10 consecutive DNA nucleotides or equivalent nucleobases which are capable of recruiting RNAseH when formed in a duplex with a 25 complementary RNA ,such as the androgen receptor mRNA target. 24. The oligomer according to any one of embodiments 21 - 23, wherein region C consists or comprises of 2, 3 or 4 consecutive nucleotide analogues. 25. The oligomer according to any one of embodiments 21 - 24, wherein region D consists, where present, of one or two DNA nucleotides. 30 26. The oligomer according to any one of embodiments 21 - 25, wherein: A Consists or comprises of 3 contiguous nucleotide analogues; B Consists or comprises of 7, 8, 9 or 10 contiguous DNA nucleotides or equivalent nucleobases which are capable of recruiting RNAseH when formed 42 WO 2012/065051 PCT/US2011/060352 in a duplex with a complementary RNA ,such as the androgen receptor mRNA target; C Consists or comprises of 3 contiguous nucleotide analogues; D Consists, where present, of one or two DNA nucleotides. 5 27. The oligomer according to embodiment 26, wherein the contiguous nucleobase sequence consists of 10, HI, 12, 13 or 14 nucleobases, and wherein; A Consists of 1 ,2 or 3 contiguous nucleotide analogues; B Consists of 7, 8, or 9 consecutive DNA nucleotides or equivalent nucleobases which are capable of recruiting RNAseH when formed in a duplex with a 10 complementary RNA ,such as the androgen receptor mRNA target; C Consists of 1 ,2 or 3 contiguous nucleotide analogues; D Consists, where present, of one DNA nucleotide. 28. The oligomer according to anyone of embodiments 21 - 27, wherein B comprises at least one LNA nucleobase which is in the alpha-L configuration, such as alpha-L-oxy LNA. 15 29. The oligomer according to any one of embodiments I - 28, wherein the nucleotide analogue(s) are independently or collectively selected from the group consisting of: Locked Nucleic Acid (LNA) units; 2'-O-alkyl-RNA units, 2'-OMe-RNA units, 2' amino-DNA units, 2'-fluoro-DNA units, PNA units, HNA units, and INA units. 30. The oligomer according to embodiment 29 wherein all the nucleotide analogues(s) are 20 LNA units. 31. The oligomer according to any one of embodiments I - 30, which comprises 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 LNA units such as 2 and 8 nucleotide LNA units. 32. The oligomer according to any one of the embodiments 29 - 31, wherein the LNAs are independently selected from oxy-LNA, thio-LNA, and amino-LNA, in either of the beta 25 D and alpha-L configurations or combinations thereof. 33. The oligomer according to embodiment 32, wherein the LNAs are all beta-D-oxy-LNA. 34. The oligomer according to any one of embodiments 21-33, wherein the nucleotide analogues or nucleobases of regions A and C are beta-D-oxy-LNA. 35. The oligomer according to any one of embodiments I - 34, wherein at least one of the 30 nucleobases present in the oligomer is a modified nucleobase selected from the group consisting of 5-methylcytosine, isocytosine, pseudoisocytosine, 5-bromouracil, 5 propynyluracil, 6-aminopurine, 2-aminopurine, inosine, diaminopurine, and 2-chloro-6 aminopurine. 43 WO 2012/065051 PCT/US2011/060352 36. The oligomer according to any one of embodiments I - 35, wherein said oligomer hybridises with a corresponding mammalian androgen receptor mRNA with a Tm of at least 50*C. 37. The oligomer according to any one of embodiments I - 36, wherein said oligomer 5 hybridises with a corresponding mammalian androgen receptor mRNA with a Tm of no greater than 80*C. 38, The oligomer according to any one of embodiments I - 37, wherein the internucleoside linkages are independently selected from the group consisting of: phosphodiester, phosphorothioate and boranophosphate. 10 39. The oligomer according to embodiment 38, wherein the oligomer comprises at least one phosphorothioate internucleoside linkage. 40. The oligomer according to embodiment 39, wherein the internucleoside linkages adjacent to or between DNA or RNA units, or within region B are phosphorothioate linkages. 15 41. The oligomer according to embodiment 39 or 40, wherein the linkages between at least one pair of consecutive nucleotide analogues is a phosphodiester linkage. 42. The oligomer according to embodiment 39 or 40, wherein all the linkages between consecutive nucleotide analogues are phosphodiester linkages. 43. The oligomer according to embodiment 42 wherein all the internucleoside linkages are 20 phosphorothioate linkages. 44. A conjugate comprising the oligomer according to any one of the embodiments 1-43 and at least one non-nucleotide or non-polynucleotide moiety covalently attached to said compound. 45. A pharmaceutical composition comprising an oligomer as defined in any of 25 embodiments 1-43 or a conjugate as defined in embodiment 44, and a pharmaceutically acceptable diluent, carrier, salt or adjuvant. 46. A pharmaceutical composition according to 45, wherein the oligomer is constituted as a pro-drug. 30 Diarylhydantoin type androgen receptor ligand binding inhibitor As used herein, the term "diarylhydantoin type androgen receptor ligand binding inhibitor" is synonymous with the term "diarylthiohydantoin androgen receptor ligand binding inhibitor". 44 WO 2012/065051 PCT/US2011/060352 It relates to a structure wherein the -N-C(O)-N- portion of the hydantoin ring is replaced with -N-C(S)-N-. As used herein, the diaryihydantoin type androgen receptor ligand binding inhibitor is a 5 compound of the formula (I): R Rs 10 4 R Formula (I) or a pharmaceutically acceptable salt thereof; 15 wherein R' is selected from the group consisting of trifluoromethyl and iodo; wherein R 2 and R 3 are each independently selected from C 1

-C

8 alkyl groups that are optionally substituted with one to three functional groups each independently selected from alkenyl, alkoxyl, alkyl, alkylthio, amido, amino, aryl, carbalkoyl, carboxyl, cyano, halogen, 20 heteroaryl, heterocyclyl, hydroxyl, mercapto, nitro and thio; or wherein R 2 and R 3 together with the carbon to which they are linked form a C 3

-C

1 cycloalkyl group that is optionally substituted with one to three functional groups each independently selected from acyl, alkenyl, alkoxyl, alkyl, alkanoylamino, alkylamido, 25 alkylthio, amido, amino, aryl, arylalkyl, arylcarbonylamino, aryloxy, carbalkoyl, carboxyl, cyano, cycloalkyl, halogen, heteroaryl, heterocyclyl, hydroxyl, mercapto, nitro, oxo, and thio; wherein R 4 is selected from the group consisting of hydrogen, halogen, alkyl, and haloalkyl, and 30 wherein R 5 is selected from the group consisting of hydrogen, halogen, methyl, CI-C 4 alkoxy, formyl, haloacetoxy, trifluoromethyl, cyano, nitro, hydroxyl, phenyl, amino, methylcarbamoyl, methoxycarbonyl, acetamido, methanesulfonamino, methanesulfonyl, 4 45 WO 2012/065051 PCT/US2011/060352 methanesulfonyl- I -piperazinyl, piperazinyl, and alkyl or alkenyl optionally substituted with hydroxyl, methoxycarbonyl, cyano, amino, amido, nitro, carbamoyl, methylcarbamoyl, dimethylcarbamoyl and hydroxyethylcarbamoyl. 5 Preferably, R' is trifluoromethyl. Preferably, R 2 and R 3 are independently selected from CI-C 8 alkyl groups, optionally substituted with one to three functional groups which are independently selected from bromo, fluoro, chloro, iodo; or R 2 and R 3 together with the carbon to which they are linked form a 10 C 3

-CI

7 cycloalkyl group optionally substituted with one to three functional groups which are independently selected from bromo, fluoro, chloro, iodo. More preferably, R 2 and R 3 are independently selected from CI-C 8 alkyl groups; or R 2 and R 3 together with the carbon to which they are linked form a C 3

-CI

7 cycloalkyl group. 15 More preferably, R 2 and R 3 are independently selected from CI-C 8 alkyl groups; or R 2 and R 3 together with the carbon to which they are linked form a C 3 -CIO cycloalkyl group. More preferably, R 2 and R 3 are methyl; or R 2 and R 3 together with the carbon to which they are linked form a C 4

-C

5 cycloalkyl group. 20 Preferably, R 4 is a halogen selected from bromo, fluoro, chloro, iodo. More preferably R 4 is fluoro. 25 Preferably, R 5 is selected from the group consisting of methylcarbamoyl, methoxycarbonyl, acetamido and methanesulfonamino. More preferably, R 5 is methylcarbamoyl. 30 Preferably, the diarylhydantoin type androgen receptor ligand binding inhibitor is a compound of the formula (II): 46 WO 2012/065051 PCT/US2011/060352 C N N 5 O Ra Formula (II) or a pharmaceutically acceptable salt thereof; 10 wherein R I, R 2 , R 3 , R 4 and R 5 have the same meanings as disclosed above in relation to Formula (I). 15 Preferably, the diarylhydantoin type androgen receptor ligand binding inhibitor is a compound of the formula (III): F 0 20 CN N N OR Formula (III) 25 wherein R 2 and R 3 have the same meanings as disclosed above in relation to Formula (I). In a preferred aspect, the diarylhydantoin type androgen receptor ligand binding inhibitor is a compound selected from the group consisting of: F O 30 CN N

F

3 C NItNN N 47 WO 2012/065051 PCT/US2011/060352 F 0 CN N 5 H F3C N N 10 F 0 CN N H

F

3 C N "N N 15 or a pharmaceutically acceptable salt thereof. Definitions 20 As used herein, the term "alkyl" denotes branched or unbranched hydrocarbon chains, preferably having about I to about 8 carbons, such as, methyl, ethyl, n-propyl, iso-propyl, n butyl, sec-butyl, iso-butyl, tert-butyl, 2-methylpentyl pentyl, hexyl, isohexyl, heptyl, 4,4 dimethyl pentyl, octyl, 2,2,4-trimethylpentyl and the like. 25 Unless otherwise indicated, the term "cycloalkyl" as employed herein alone or as part of another group includes saturated or partially unsaturated (containing I or more double bonds) cyclic hydrocarbon groups containing I to 3 rings, including monocyclicalkyl, bicyclicalkyl and tricyclicalkyl, containing a total of 3 to 20 carbons forming the rings, preferably 3 to 10 30 carbons, forming the ring and which may be fused to I or 2 aromatic rings as described for aryl, which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, cyclohexenyl. Preferably, the "cycloalkyl" is a 48 WO 2012/065051 PCT/US2011/060352 saturated or partially unsaturated (containing I or more double bonds) cyclic hydrocarbon groups containing I ring. Unless otherwise indicated, the term "alkenyl" as used herein by itself or as part of another 5 group refers to straight or branched chain radicals of 2 to 20 carbons, preferably 2 to 12 carbons, and more preferably 2 to 8 carbons in the normal chain, which include one or more double bonds in the normal chain, such as vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4 pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3 nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl, 4,8,12-tetradecatrienyl, and the like. 10 Unless otherwise indicated, the term "alkynyl" as used herein by itself or as part of another group refers to straight or branched chain radicals of 2 to 20 carbons, preferably 2 to 12 carbons and more preferably 2 to 8 carbons in the normal chain, which include one or more triple bonds in the normal chain, such as 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3 15 pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4 decynyl, 3-undecynyl, 4-dodecynyl and the like. The terms "arylalkyl", "arylalkenyl" and "arylalkynyl" as used alone or as part of another group refer to alkyl, alkenyl and alkynyl groups as described above having an aryl substituent. Representative examples of arylalkyl include, but are not limited to, benzyl, 2 20 phenylethyl, 3-phenylpropyl, phenethyl, benzhydryl and naphthylmethyl and the like. The terms "arylalkyl", "arylalkenyl" and "arylalkynyl" as used alone or as part of another group refer to alkyl, alkenyl, and alkynyl groups as described above having an aryl~ substituent. Representative examples of arylalkyl include, but are not limited to, benzyl, 2 25 phenylethyl, 3-phenylpropyl, phenethyl, benzhydryl and naphthylmethyl and the like. The term "halogen" or "halo" as used herein alone or as part of another group refers to chlorine, bromine, fluorine, and iodine. 30 The term "haloalkyl" refers to "alkyl" group which is substituted by one to three atoms selected from fluorine, chlorine, bromine, fluorine, and iodine. Unless otherwise indicated, the term "aryl" or "Ar" as employed herein alone or as part of 49 WO 2012/065051 PCT/US2011/060352 another group refers to monocyclic and polycyclic aromatic groups containing 6 to 10 carbons in the ring portion (such as phenyl or naphthyl including l-naphthyl and 2-naphthyl) and may optionally include one to three additional rings fused to a carbocyclic ring or a heterocyclic ring (such as aryl, cycloalkyl, heteroaryl or cycloheteroalkyl rings). 5 Unless otherwise indicated, the term "heterocyclic", "heterocyclyl" or "heterocycle", as used herein, represents an unsubstituted or substituted stable 5- to 10-membered monocyclic ring system which may be saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from N, 0 or S, and wherein the nitrogen and sulfur 10 heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic groups include, but is not limited to, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxopyrrolidinyl, oxoazepinyl, azepinyl, pyrrolyl, pyrrolidinyl, furanyl, thienyl, pyrazolyl, pyrazolidinyl, 15 imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyridazinyl, oxazolyl, oxazolidinyl, isooxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, thiadiazolyl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl. The term "heterocyclic aromatic" as used here in alone or as part of another group refers to a 5- or 7-membered aromatic ring which includes 1, 2, 3 or 4 hetero 20 atoms such as nitrogen, oxygen or sulfur and such rings fused to an aryl, cycloalkyl, heteroaryl or heterocycloalkyl ring (e.g. benzothiophenyl, indolyl), and includes possible N oxides. "Pharmaceutically acceptable" means that which is useful in preparing a pharmaceutical 25 composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use. "Pharmaceutically acceptable salts" means salts of compounds of the present invention which 30 are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic 50 WO 2012/065051 PCT/US2011/060352 acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)-benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, 5 benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-l-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic 10 acid and the like. Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, 15 aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like. US20100172975 and US20100210665 describe diarylhydantoin type androgen receptor 20 ligand binding inhibitors. These diarylhydantoin type androgen receptor ligand binding inhibitors are incorporated herein by reference and may be used in the present invention. Pharmacological Examination of the diarylhydantoin type compounds mentioned above using an in vitro reporter assay 25 Numerous assays for androgen receptor inhibition are known in the art and such assays are commercially available: For example the PolarScreen Androgen Receptor Competitor Assay (Invitrogen). In some aspects, AR inhibitor compounds may be screened using, for example, hormone refractory prostate cancer cells for antagonistic and agonistic activities against AR. 30 For example, see WO/2005/060661, US05/05529 and US applications US2010/0210665 and US20100172975, which are all, hereby incorporated by reference. 51 WO 2012/065051 PCT/US2011/060352 An in vitro assay. Potential AR inhibitor compounds may be subjected to tests using an artificial AR response reporter system in, for example, a hormone refractory prostate cancer cell line. In such a system, prostate cancer LNCaP cells, for instance, may be engineered to stably express exogenous AR such that it is at a higher level of than endogenous AR. The 5 exogenous AR has similar properties to endogenous AR in that both are stabilized by a synthetic androgen R1881. The AR-over expressed cells may also be engineered to stably incorporate an AR response reporter and the reporter activity of these cells shows features of hormone refractory prostate cancer. Said cells will respond to low concentrations of a synthetic androgen R 1881. 10 Engineered LNCaP cells (LNCaP-AR, also abbreviated LN-AR) can be maintained in Iscove's medium containing 10% fetal bovine serum (FBS). Two days prior to drug treatment, the cells are grown in Iscove's medium containing 10% charcoal-stripped FBS (CS-FBS) to deprive of androgens. The cells are split and grown in Iscove's medium 15 containing 10% CS-FBS with 100 pM of R1881 and increasing concentrations of test compounds. After two days of incubation, reporter activities were assayed. For example, bicalutamide will inhibit the AR response reporter and will not have agonistic activity in hormone sensitive prostate cancer cells. The antagonistic activity of the diaryihydantoin type compounds mentioned above can be determined using such a reporter 20 assay. Other suitable assays to determine the effect of compounds on AR include measuring secreted levels of prostate specific antigen (PSA) - US2010/0210665 and US20100172975 describe such an assay; this assay is incorporated herein by reference. 25 It is well established that PSA levels are indicators of AR activities in prostate cancer. To examine if the diarylhydantoin type compounds mentioned above affect AR function in a physiological environment, one can determine the secreted levels of endogenous PSA ' induced by R1881 in the AR-overexpressed LNCaP cells (LNCaP-AR, also abbreviated LN 30 AR). LNCaP-AR cells are a line of lymph node carcinoma of prostate cells transduced with a plasmid that expresses androgen receptors. LNCaP-AR cells can be maintained in Iscove's medium containing 10% FBS. Two days prior to drug treatment, the cells are grown in Iscove's medium containing 10% CS-FBS to deprive of androgens. The cells are split and 52 WO 2012/065051 PCT/US2011/060352 grown in Iscove's medium containing 10% CS-FBS with appropriate concentrations of R1881 and the test compounds. After four days incubation, secreted PSA levels may be assayed using PSA ELISA kits (American Qualex, San Clemente. Calif.). 5 Other suitable assays to determine theleffect of compounds on AR include in vivo assays US2010/0210665 and US20100172975 describe such an assay; this assay is incorporated herein by reference. One or more of the in vitro, in vivo and PSA assays described in US2010/0210665 and 10 US2010/0172975 may be used to show that the diarylhydantoin type compounds mentioned herein inhibit androgen receptor ligand binding. These assays may be used in addition to other assays. Diaryihydantoin Androgen Receptor Ligand Binding Inhibitors 15 Diarylhydantoin derivative androgen receptor ligand binding inhibitors that may be used in combination with AR antisense oligomers according to the invention include those disclosed in U.S. Patent No. 7,709,5 17 which is incorporated by reference in its entirety as if fully set forth herein. Preferred diarylhydantoin androgen receptor ligand binding inhibitors for use according 20 to the invention include, for example the following diarylthiohydantoin compounds: F 0 NCN "-% H '

F

3 C N N and 53 WO 2012/065051 PCT/US2011/060352 F NC 0 I S0 /N'

F

3 C N N H 01 F NC 0 ~. / N

F

3 C N N \ H 0 or a pharmaceutically acceptable salt thereof. The compounds of the invention are useful as pharmaceutical compositions prepared 5 with a therapeutically effective amount of a compound of the invention, as defined herein, and a pharmaceutically acceptable carrier or diluent. The diaryihydantoin compounds may, for example, be formulated as pharmaceutical compositions and administered to a subject in need of treatment, for example a mammal, such as a human patient, in a variety of forms adapted to the chosen route of administration, 10 for example, orally, nasally, intraperitoneally, or parenterally, by intravenous, intramuscular, topical or subcutaneous routes, or by injection into tissue. Thus, diarylhydantoin compounds used according to the invention may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier; or by inhalation or insufflation. They may be 15 enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet. For oral therapeutic administration, the diarylhydantoin compounds may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. The diarylhydantoin compounds may be combined with a fine inert 20 powdered carrier and inhaled by the subject or insufflated. Such compositions and preparations should contain at least 0.1% diarylhydantoin compounds. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2% to about 60% of the weight of a given unit dosage form. The amount of 54 WO 2012/065051 PCT/US2011/060352 diarylhydantoin compounds in such therapeutically useful compositions is such that an effective dosage level will be obtained. The tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium 5 phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as -magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene 10 glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material 15 used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the diarylhydantoin compounds may be incorporated into sustained-release preparations and devices. For example, the diarylhydantoin compounds may be incorporated into time release capsules, time release tablets, and time release pills. 20 The diarylhydantoin compounds may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the diarylhydantoin compounds can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions may also be prepared in glycerol, liquid polyethylene glycols, triacetin; and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative 25 to prevent the growth of microorganisms. The pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the diarylhydantoin compounds which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. The ultimate dosage 30 form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable 55 WO 2012/065051 PCT/US2011/060352 mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms may be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, 5 sorbic acid, thimerosal, and the like. It may be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions may be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatin. Sterile injectable solutions may be prepared by incorporating the diarylhydantoin 10 compounds in the required amount in the appropriate solvent with, for example, various of the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation include vacuum drying and freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the 15 previously sterile-filtered solutions. Useful dosages of the compounds of the diarylhydantoin compounds can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949, which is hereby incorporated by reference. 20 For example, the concentration of the diarylhydantoin compounds in a liquid composition, such as a lotion, can be from about 0.1-25% by weight, or from about 0.5-10% by weight. The concentration in a semi-solid or solid composition such as a gel or a powder can be about 0. 1-5% by weight, or about 0.5-2.5% by weight. The amount of the diarylhydantoin compounds and antisense AR oligomers required 25 for use in treatment may vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician. Effective dosages and routes of administration of agents of the diarylhydantoin compounds may, for example, be conventional. The exact amount (effective dose) of the 30 agent may vary from subject to subject, depending on, for example, the species, age, weight and general or clinical condition of the subject, the severity or mechanism of any disorder being treated, the particular agent or vehicle used, the method and scheduling of administration, and the like. A therapeutically effective dose can be determined empirically, 56 WO 2012/065051 PCT/US2011/060352 by conventional procedures known to those of skill in the art. See, e.g., The Pharmacological Basis of Therapeutics, Goodman and Gilman, eds., Macmillan Publishing Co., New York. For example, an effective dose can be estimated initially either in cell culture assays or in suitable animal models. The animal model may also be used to determine the appropriate 5 concentration ranges and routes of administration. Such information can then be used to determine useful doses and routes for administration in humans. A therapeutic dose can also be selected by analogy to dosages for comparable therapeutic agents. The particular mode of administration and the dosage regimen for the diarylhydantoin compounds may be selected by the attending clinician, taking into account the particulars of 10 the case (e.g., the subject, the disease, the disease state involved, and whether the treatment is prophylactic). Treatment may involve daily or multi-daily doses of compound(s) over a period of a few days to months, or even years. In general, however, a suitable dose will be in the range of from about 0.001 to about 100 mg/kg, e.g., from about 0.01 to about 100 mg/kg of body weight per day, such as above 15 about 0.1 mg per kilogram, or in a range of from about I to about 10 mg per kilogram body weight of the recipient per day. For example, a suitable dose may be about 1 mg/kg, 10 mg/kg, or 50 mg/kg of body weight per day. The diarylhydantoin compounds are conveniently administered in unit dosage form; for example, containing 0.05 to 10000 mg, 0.5 to 10000 mg, 5 to 1000 mg, or about 100 mg of 20 active ingredient per unit dosage form. The diarylhydantoin compounds may be administered to achieve peak plasma concentrations of, for example, from about 0.5 to about 75 pM, about I to 50 PM, about 2 to about 30 pM, or about 5 to about 25 pM. Exemplary desirable plasma concentrations include at least or no more than 0.25, 0.5, 1, 5, 10, 25, 50, 75, 100 or 200 pM. For example, plasma 25 levels may be from about I to 100 micromolar or from about 10 to about 25 micromolar. This may be achieved, for example, by the intravenous injection of a 0.05 to 5% solution of the diarylhydantoin compounds, optionally in saline, or orally administered as a bolus containing about 1-100 mg of the diarylhydantoin compounds. Desirable blood levels may be maintained by continuous infusion to provide about 0.00005-5 mg per kg body weight per 30 hour, for example at least or no more than 0.00005, 0.0005, 0.005, 0.05, 0.5, or 5 mg/kg/hr. Alternatively, such levels can be obtained by intermittent infusions containing about 0.0002 20 mg per kg body weight, for example, at least or no more than 0.0002, 0.002, 0.02, 0.2, 2, 20, or 50 mg of the diarylhydantoin compounds per kg of body weight. 57 WO 2012/065051 PCT/US20111/060352 The diarylhydantoin compounds may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator. 5 Medical indications Generally stated, one aspect of the invention is directed to a method of treating a mammal, such as a human, suffering from or susceptible to conditions associated with abnormal levels of androgen receptor activity, for example as.a result of overexpression of or 10 mutation of AR, that includes administering to the mammal and antisense oligomer targeted to AR, for example, one comprised solely of DNA rather than RNA and including one or more LNA DNA monomers, or a derivative thereof, such as those described herein, for example, in the form of a pharmaceutical composition, for example via intravenous administration, and a diarylhydantoin type androgen receptor ligand binding inhibitor or 15 pharmaceutically acceptable salt thereof including, for-example, those described herein and those disclosed in U.S. Patent No. 7,709,517, for example by oral administration or by intravenous administration or bolus injection. The disorder may, for example, be a cancer such as breast cancer or prostate cancer, for example, advanced prostate cancer, castration-resistant prostate cancer, LHRH-resistant 20 prostate cancer, androgen-sensitive prostate cancer, and androgen-insensitive prostate cancer, benign prostatic hyperplasia, AR-activity dependent breast cancer, alopecia, spinal and muscular atrophy, Kennedy disease and polyglutamate disease. The antisense oligomer may optionally be linked'to a ligand or conjugate. For example, in order to increase the cellular uptake of the oligomer. In some embodiments the 25 conjugate is a sterol, such as cholesterol. However, it has been found that the LNA antisense oligomers disclosed herein advantageously do not require conjugation for in vivo therapeutic use in mammals. Alternatively stated, the invention is furthermore directed to a method for treating abnormal levels of androgen receptor activity, said method comprising administering an 30 antisense oligomer of the invention, or a conjugate of the oligomer or a pharmaceutical composition of the oligomer or conjugate to a patient, such as a human or non-human mammal, in need thereof and further comprising the administration of and a diaryihydantoin type androgen receptor ligand binding inhibitor or pharmaceutically acceptable salt thereof 58 WO 2012/065051 PCT/US2011/060352 including, for example, those described herein and those disclosed in U.S. Patent No. 7,709,517. Said further administration may be such that the further chemotherapeutic agent is conjugated to the antisense oligomer, is present in the pharmaceutical composition, or is administered in a separate formulation. 5 The combination methods of treatment according to the invention may be employed, for example, for at least one week, such as one week, for at least two weeks, such as two weeks, for at least one month, such as one month, for at least two months, such as two, three, four, five or six months, or longer than six months, such as one year. The administration of antisense AR oligomer and antiandrogen compound may at least sometimes occur on the 10 same days or may not occur on the same days; what is important is that each of the agents is present at the same time in the mammal subject. Because of the relatively long duration of the antisense AR oligomers of the invention in mammals, one manner of dosing that may, for example, be employed, involves less frequent dosing of the antisense oligomer than the antiandrogen compound. For example, antisense AR oligomer may be administered to the 15 subject biweekly, weekly, every two weeks, or monthly, while the antiandrogen compound, such as MDV3 100, is administered daily or every two days. Those skilled in the art will recognize that many dosing regimens are possible for the combination therapy embodiments of the invention and that the use of depot formulations is also possible. Furthermore, the invention provides a method of regulating genes, and their respective 20 mRNA and protein products, which are modulated by the androgen receptor (i.e. androgen receptor-targets) such as genes, mRNA and/or proteins selected form the group consisting of: Protein kinase C delta (PRKCD), Glutathione S- tra.nsferase theta 2 (GSTT2), transient receptor potential cation channel subfamily V member 3 (TRPV3), Pyrroline-5-carboxylate reductase I (PYCR I) or ornithine aminotransferase (OAT), said methods including the step 25 of administering to a mammal subject such as a human, an antisense oligomer targeting AR and a diarylhydantoin type androgen receptor ligand binding inhibitor or pharmaceutically acceptable salt thereof including, for example, those described herein and those disclosed in U.S. Patent No. 7,709,517, in amounts effective together to regulate expression of one or more androgen receptor modulated genes, such as those described. 30 59 WO 2012/065051 PCT/US2011/060352 Antisense Oligomer Examples Example 1: Monomer synthesis The LNA monomer building blocks and derivatives were prepared following published procedures and references cited therein - see W007/031081 and the references cited therein. 5 Example 2: Oligonucleotide synthesis Oligonucleotides were synthesized according to the method described in W007/031081. Table I shows examples of antisense oligonucleotide sequences of the invention. Tables 2 and 3 show examples of antisense oligonucleotides (oligos) of the 10 invention. Example 3: Design of the oligonucleotides In accordance with the present invention, a series of different oligonucleotides were designed to target different regions of human Androgen receptor mRNA(GenBank accession 15 number NM_000044, SEQ ID NO: 1). Table I Antisense oligonucleotide sequences of the invention: SEQ ID NOS: 2-22 are oligo sequences designed to target human Androgen receptor mRNA. Length Target site SEQ ID NO Sequence (5'-3') (bases) NM_000044 SEQ ID NO: 2 GAGAACCATCCTCACC 16 1389-1404 SEQ ID NO: 3 GGACCAGGTAGCCTGT 16 1428-1443 SEQ ID NO: 4 CCCCTGGACTCAGATG 16 1881-1896 SEQ ID NO: 5 GCACAAGGAGTGGGAC 16 1954-1969 SEQ ID NO: 6 GCTGTGAAGAGAGTGT 16 2422-2437 SEQ ID NO: 7 T1TTGACACAAGTGGGA 16 2663-2678 SEQ ID NO: 8 GTGACACCCAGAAGCT 16 2813-2828 SEQ ID NO: 9 CATCCCTGCTFCATAA 16 2975-2990 SEQ ID NO: 10 ACCAAGTTTCTTCAGC 16 3008-3023 SEQ ID NO: I I CTTGGCCCACTTGACC 16 3263-3278 SEQ ID NO: 12 TCCTGGAGTTGACATT 16 3384-3399 SEQ ID NO: 13 CACTGGCTGTACATCC 16 3454-3469 60 WO 2012/065051 PCT/US2011/060352 SEQ ID NO Sequence (5'-3')Length Target site (bases) NM_000044 SEQ ID NO: 14 CATCCAAACTCTTGAG 16 3490-3505 SEQ ID NO: 15 GCTTTICATGCACAGGA 16 3529-3544 SEQ ID NO: 16 GAAGTTCATCAAAGAA 16 3594-3609 SEQ ID NO: 17 AGTTCCTTGATGTAGT 16 3616-3631 SEQ ID NO: 18 TTGCACAGAGATGATC 16 3809-3824 SEQ ID NO: 19 GATGGGCTTGACTTTC 16 3845-3860 SEQ ID NO: 20 CAGGCAGAAGACATCT 16 3924-3939 SEQ ID NO: 21 CCCAAGGCACTGCAGA 16 3960-3975 SEQ ID NO: 22 GCTGACATTCATAGCC 16 3114-3129 SEQ ID NO: 86 TGGGGAGAACCATCCTCACCCTGC 24 1385-1408 SEQ ID NO: 87 TCCAGGACCAGGTAGCCTGTGGGG 24 1424-1447 SEQ ID NO: 88 TGTTCCCCTGGACTCAGATGCTCC 24 1877-1990 TGGGGCACAAGGAGTGGGACGCA 1950-1973 SEQ ID NO: 89 24 C SEQ ID NO: 90 TICGGCTGTGAAGAGAGTGTGCCA 24 2418-2441 SEQ ID NO: 91 CGCTTTTGACACAAGTGGGACTGG 24 2659-2682 SEQ ID NO: 92 CATAGTGACACCCAGAAGCTTCAT 24 2809-2832 SEQ ID NO: 93 GAGTCATCCCTGCTTCATAACATT 24 2971-2994 SEQ ID NO: 94 GATTACCAAGTTTCTTCAGCTrCC - 24 3004-3027 SEQ ID NO: 95 AGGCCFTGGCCCACTTGACCACGT 24 3259-3282 SEQ ID NO: 96 AGCATCCTGGAGTTGACATTGGTG 24 3380-3403 SEQ ID NO: 97 GACACACTGGCTGTACATCCGGGA 24 3450-3473 SEQ ID NO: 98 GAGCCATCCAAACTCTTGAGAGAG 24 3486-3509 SEQ ID NO: 99 CAGTGCTTTCATGCACAGGAATC 24 3525-3548 SEQ ID NO: 100 ATTCGAAGTTCATCAAAGAATTIT 24 3590-3613 SEQ ID NO: 101 ATCGAGTTCCTTGATGTAGTTCAT 24 3612-3635 SEQ ID NO: 102 GCACTTGCACAGAGATGATCTCTG 24 3805-3828 SEQ ID NO: 103 AATAGATGGGCTTGACTTTCCCAG 24 3841-3864 SEQ ID NO: 104 ATAACAGGCAGAAGACATCTGAA 24 3920-3943 61 WO 2012/065051 PCT/US2011/060352 SEQ ID NO Sequence (5'-3') Length Target site (bases) NM_000044 A SEQ ID NO: 105 ATTCCCCAAGGCACTGCAGAGGAG 24 3956-3979 SEQ ID NO: 106 ATGGGCTGACATTCATAGCCTTCA 24 3110-3133 Table 2: Oligonucleotide designs of the invention - In SEQ ID NOs: 23-43 upper case letters indicates nucleotide analogue units and subscript "s" represents phosphorothiote linkage. Lower case letters represent nucleotide units. Absence of "s" (if any) indicates 5 phosphodiester linkage. Table 2 Oigonucleotide designs SEQ ID NO Sequence (5'-3') SEQ ID NO: 23 SEQ ID NO: 24 G-T-3 SEQ ID NO: 25 5'-CiCsChastsgsgsueastsasosgsA-Ti6-' SEQ ID NO: 26 5-GiCiAgesaa9s9aggssGiC-3' SEQ ID NO: 27 5-G-s'Tigstsa-SaggassT'G--3' SEQ ID NO: 28 5'-T6T 5 TigssassassassgstssGeG-sA-3' SEQ ID NO: 29 5'-GoTaGssascscsassa-aG C T-3' SEQ ID NO: 30 5'-'ATicsasastsgrcststsasagTiA A-3' SEQ ID NO: 31 5-A-CSCha-gasgstststscststscseGiC-3' SEQ ID NO: 32 5-C-gTgTsgs~scscss stsgsACeC-3' SEQ ID NO: 33 '-TiCiC-tsgsgsesgststsgsasosA'sTsT--3 SEQ ID NO: 34 5'-CiAgC'tsgsgscstsgstsa-scsersT4C-e-3' SEQ ID NO: 35 5'-C- %recscsa-sasa-scstscststsG'Ag6-3' SEQ ID NO: 36 '-GgC'T-istsasastsgscsrscsa'sG'G'A-3' SEQ ID NO: 37 ' 62 WO 2012/065051 PCT/US2011/060352 SEQ ID NO: 38 5'-A'sGg"etscsaststssstsistsAiGiT-3' SEQ ID NO: 39 5 SEQ ID NO: 40 5-G-A-T-agg sttgseesrtrTS TeC-3' SEQ ID NO: 41 5-CiAgGigscsasasaggcsa-sTiCiT-3' SEQ ID NO: 42 5-CiCiCeagaggaggesaacsis'susAiGiA-3' SEQIDNO:43 5'-GSCT gs 9 as os s ts t os as t a Gs CS C -3' Example 4: In vitro model: Cell culture The effect of antisense oligonucleotides on target nucleic acid expression can be tested 5 in any of a variety of cell types provided that the target nucleic acid is present at measurable levels. The target can be expressed endogenously or by transient or stable transfection of a nucleic acid encoding said target. The expression level of target nucleic acid can be routinely determined using, for example, Northern blot analysis, Real-Time PCR, Ribonuclease protection assays. The following cell types are provided for illustrative purposes, but other 10 cell types can be routinely used, provided that the target is expressed in the cell type chosen. Cells were cultured in the appropriate medium as described below and maintained at 37"C at 95-98% humidity and 5% CO 2 . Cells were routinely passaged 2-3 times weekly. A549 The human lung cancer cell line A5439 was cultured in DMEM (Sigma) + 10% fetal bovine serum (FBS) + 2 mM Glutamax I + gentamicin (25pg/ml). 15 MCF7 The human breast cancer cell line MCF7 was cultured in EagleMEM (Sigma) + 10% fetal bovine serum (FBS) + 2 mM Glutamax I + I xNEAA + gentamicin (25pg/ml). Example 5: In vitro model: Treatment with antisense oligonucleotide+ The cell lines listed in example 4 were treated with oligonucleotide using the cationic 20 liposome formulation LipofectAMINE 2000 (Gibco) as transfection vehicle. Cells were seeded in 6-well cell culture plates (NUNC) and treated when 80-90% confluent. Oligo concentrations used ranged from I nM to 16 nM final concentration. Formulation of oligo lipid complexes were carried out essentially as described by the manufacturer using serum free OptiMEM (Gibco) and a final lipid concentration of 5 pg/mL LipofectAMINE 2000. 25 Cells were incubated at 37*C for 4 hours and treatment was stopped by removal of oligo containing culture medium. Cells were washed and serum-containing media was added. After 63 WO 2012/065051 PCT/US2011/060352 oligo treatment cells were allowed to recover for 20 hours before they were harvested for RNA analysis. Example 6: In vitro model: Extraction of RNA and cDNA synthesis 5 Total RNA Isolation and first strand synthesis Total RNA was extracted from cells transfected as described above and using the Qiagen RNeasy kit (Qiagen cat. no. 74104) according to the manufacturer's instructions. First strand synthesis was performed using Reverse Transcriptase reagents from Ambion according to the manufacturer's instructions. 10 For each sample 0.5 pg total RNA was adjusted to (10.8 pl) with RNase free H 2 0 and mixed with 2 pl random decamers (50 pM) and 4 pl dNTP mix (2.5 mM each dNTP) and heated to 70 'C for 3 min after which the samples were rapidly cooled on ice. After cooling the samples on ice, 2 l lOx Buffer RT, I pl MMLV Reverse Transcriptase (100 U/pl) and 0.25 pl RNase inhibitor (10 U/pl) was added to each sample, followed by incubation at 42 *C 15 for 60 min, heat inactivation of the enzyme at 95*C for 10 min and then the sample was cooled to 4 *C. Example 7: In vitro model: Analysis of Oligonucleotide Inhibition of Androgen receptor Expression by Real-time PCR 20 Antisense modulation of Androgen receptor expression can be assayed in a variety of ways known in the art. For example, Androgen receptor mRNA levels can be quantitated by, e.g., Northern blot analysis, competitive polymerase chain reaction (PCR), or real-time PCR. Real-time quantitative PCR is presently preferred. RNA analysis can be performed on total cellular RNA or mRNA. 25 Methods of RNA isolation and RNA analysis such as Northern blot analysis is routine in the art and is taught in, for example, Current Protocols in Molecular Biology, John Wiley and Sons. Real-time quantitative (PCR) can be conveniently accomplished using the commercially available Multi-Color Real Time PCR Detection System, available from Applied Biosystem. 30 Real-time Quantitative PCR Analysis of Androgen receptor mRNA Levels The sample content of human Androgen receptor mRNA was quantified using the human Androgen receptor ABI Prism Pre-Developed TaqMan Assay Reagents (Applied Biosystems cat. no. HsOO171172_ml) according to the manufacturer's instructions. 64 WO 2012/065051 PCT/US2011/060352 Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA quantity was used as an endogenous control for normalizing any variance in sample preparation. The sample content of human GAPDH mRNA was quantified using the human GAPDH ABI Prism Pre-Developed TaqMan Assay Reagent (Applied Biosystems cat. no. 5 4310884E) according to the manufacturer's instructions. Real-time Quantitative PCR is a technique well known in the art and is taught in for example Heid et al. Real time quantitative PCR, Genome Research (1996), 6: 986-994. Real time PCR: The cDNA from the first strand synthesis performed as described in example 6 was diluted 2-20 times, and analyzed by real time quantitative PCR using Taqman 10. 7500 FAST or 7900 FAST from Applied Biosystems. The primers and probe were mixed with 2 x Taqman Fast Universal PCR master mix (2x) (Applied Biosystems Cat.# 4364103) and added to 4 pl cDNA to a final volume of 10 pl. Each sample was analysed in duplicate. Assaying 2 fold dilutions of a cDNA that had been prepared on material purified from a cell line expressing the RNA of interest generated standard curves for the assays. Sterile H 2 0 was 15 used instead of cDNA for the no template control. PCR program: 95* C for 30 seconds, followed by 40 cycles of 95* C, 3 seconds, 60* C, 20-30 seconds. Relative quantities of target mRNA sequence were determined from the calculated Threshold cycle using the Applied Biosystems Fast System SDS Software Version 1.3.1.21. or SDS Software Version 2.3. 20 Example 8: In vitro analysis: Antisense Inhibition of Human Androgen receptor mRNA Expression by oligonucleotide compounds Oligonucleotides presented in Table 3 were evaluated for their potential to knockdown of the androgen receptor mRNA at concentrations of 1, 4 and 16 nM (see Figures 1 and 2). 25 Table 3: Antisense Inhibition of Human Androgen receptor mRNA expression by oligonucleotides. The data in Table 3 are presented as percentage down-regulation relative to mock transfected cells at 16 nM. Lower case letters represent DNA units, bold upper case letters represent P-D-oxy-LNA units. All LNA C are 5'methyl C. Subscript "s" represents 30 phosphorothioate linkage. 65 WO 2012/065051 PCT/US2011/060352 Table 3 Inhibition of human androgen receptor mRNA expression >y oligonuleotides Percent Percent Inhibition Inhibition of Test substance Sequence (5-3') drogen renp receptor- A549 MCF7 SEQ ID NO: 44 5'-G'A'GiEasaGcsastscacttsaC C-3, 80.1 63.8 SEQ ID NO: 45 5'-GiG-sesss tgg 89.0 88.2 SEQ ID NO: 46 '-CsC'sC'gasssscsasgsAghG4' 89.4 82.8 SEQ ID NO: 47 5-GkC'sA'ssa sistsgsgsG'seC-3, 83.1 77.7 SEQ ID NO: 48 5'-C-ggtagsasggagasggT'gGif-3 93.8 96.7 SEQ ID NO: 49 -0'sgG-tsssassasgsTi-3 n.d. n.d. SEQ ID NO: 50 5-T-setssgggs (asT- n.d. n.d. SEQ ID NO: 51 gGGA- 96.9 95.5 SEQ ID NO: 52 5-T&TgGiascscsastagsgG'G4, n.d. n.d. SEQ ID NO: 53 5-TsGsa-sc s %rstsGiG-3' n.d. n.d. SEQ ID NO: 54 5-GirsG'ss~sscscsos%9's%G CiT-3, 95.4 98.3 SEQ ID NO: 55 5'-T'G-srsasss sa G's-S, n.d. n.d. SEQ ID NO: 56 5- G's 0sc6ogog n.d. n.d. SEQ ID NO: 57 5-C'AeT'scssstsssasTiA-3, 89.5 88.9 SEQ ID NO: 58 5'-A'sC'C-asagststsus G'C-3, 95.6 98.9 SEQ ID NO: 59 5T-C'CAasgtst 6 tscststscsA-sG-3, n.d. n.d. SEQ D NO: 60 5-C as n.d. n.d. SEQ I D NO: 61 5'-C'sT'sggssc-ssscsfstags'C'C-3, 86.7 93.3 SEQ lD NO: 62 5 81.3 93.0 66 WO 2012/065051 PCT/US2011/060352 Table 3 Inhibition of human androgen receptor mRNA expression y oligonucleotides Percent Percent Inhibition Inhibition of Test substance Sequence (5'-3) oge Androgen Andtrogen receptor. receptor- A549 MCF7 SEQ ID NO: 63 5'-C'gCStsgsgsostrstsissasT-C'C-3, 90.9 98.4 SEQ ID NO: 64 5'-A'sC-T'isgscstsgstsassasT-C-3, n.d. n.d. SEQ ID NO: 65 5-Cg'qgtggstsrsqsA'-3, n.d. n.d. SEQ ID NO: 66 5-C-%T'sccsrsasarcstsaststsG-AiG-3, 79.8 95.3 SEQ ID NO: 67 5'-GsC'T'tstscsastsosascsasG'G'A-3, 83.5 97.0 SEQ ID NO: 88 5 88.2 85.6 SEQ ID NO: 69 5 92.7 94.0 SEQ ID NO: 70 5-G'sTsTsccststsgsastsgs'rs , n.d. n.d. SEQ ID NO: 71 5-T'ssttssstssA-3 nd. n.d. SEQ ID NO: 72 5'-T-T-G-crsascsEsgsargsrstsgsA'T'C-3, 79.2 90.4 SEQ ID NO: 73 5'-G-A-gsgssscststsgsascstrT TiC-3, 91.1 97.3 SEQ ID NO: 74 5'- Ar~gs9s9SUsttsisaScsT--3, n.d. n.d. SEQ ID NO: 75 5'-T'G'ssscsstsgsescsTsT-3, n.d. n.d. SEQ ID NO: 76 .5'-C-AG-sscsasgsasgagsc-gs'sC'T-3, 85.9 94.3 SEQ ID NO: 77 5-Cs~OC'arsa-ggsssa~sctsgscsA G-A-3'. 93.0 98.5 SEQ ID NO: 78 9-'E'sCsaiasgsgscsascstsgscsAgG-3, n,d. n.d. SEQ ID NO: 79 5'-CjAsasg9s9sgcsWcsts9sC 6 A-3' n.d. n.d. SEQ ID NO: 80 5'- GsCsTs9saCsaststscsastsasGsCC-3' n.d. n.d. As shown in Table 3, oligonucleotides of SEQ ID NOs: 48, 51, 54, 58, 63, 69, 73 and 77 at 16 nM demonstrated greater than 90% inhibition of Androgen receptor mRNA expression in 67 WO 2012/065051 PCT/US2011/060352 A549 and MCF7 cells in these experiments and are therefore preferred. Also preferred are oligonucleotides based on the illustrated antisense oligo sequences, for example varying the length (shorter or longer) and/or nucleobase content (e.g. the type and/or proportion of analogue units), which also provide good inhibition of Androgen receptor expression. 5 Example 9: In vivo analysis: Antisense Inhibition of mouse Androgen receptor mRNA liver Expression by oligonucleotide compounds Nude mice were dosed i.v. q3dx4 with 100 mg/kg oligonucleotide (group size of 5 mice). The antisense oligonucleotides (SEQ ID:48, SEQ ID:51, SEQ ID:58, SEQ ID:63, SEQ 10 ID:77) were dissolved in 0.9% phosphate buffered saline. Animals were sacrificed 24h after last dosing and liver tissue was sampled and stored in RNA later until RNA extraction and QPCR analysis. Total RNA was extracted and AR mRNA expression in liver samples was measured by QPCR as described in example 7 using a mouse AR QPCR assay (cat. Mm01238475_ml, Applied Biosystems). Results were normalised to mouse GAPDH (cat. 15 no. 4352339E, Applied Biosystems) and Knockdown was quantitated relative to saline treated controls. The data in Table 4 are presented as percentage down-regulation relative to saline treated animals. Table 4 In vivo knock-down of AR mRNA expression Compound Liver (% KD) Saline 0 SEQ ID: 51 100 mg/kg 65.0+/-12.6 SEQ ID: 58 100 mg/kg 95.2+/-1.0 SEQ ID: 77 100 mg/kg 91.9+/-3.9 20 As shown in Table 4, oligonucleotides of SEQ ID NOs: 58 and 77 at 100 mg/kg demonstrated greater than 90% inhibition of Androgen receptor mRNA expression in mouse liver cells in these experiments and are therefore preferred. Example 10: In vitro analysis: Antisense Inhibition of Human Androgen receptor mRNA 25 Measurement of proliferating viable cells (MTS assay) LNCaP prostate cancer and A549 lung cancer cells were seeded to a density of 150000 cells per well in a 6-well plate the day prior to transfection. A549 cells were cultured in 68 WO 2012/065051 PCT/US2011/060352 DMEM (Sigma) + 10% fetal bovine serum (FBS) + 2 mM Glutamax I + gentamicin (25pg/ml) whereas LNCaP cells were cultured in RPMI 1640 Medium (Sigma) + 10% fetal bovine serum (FBS) + 2 mM Glutamax I + gentamicin (25pg/ml). The next day medium was removed followed by addition of 1.2 ml OptiMEM containing 5 pg/ml Lipofectamine2000 5 (Invitrogen). Cells were incubated for 7 min before adding 0.3 ml oligonucleotides diluted in OptiMEM. The final oligonucleotide concentrations were 4 and 16 nM. After 4 hours of treatment, media was removed and cells were trypsinized and seeded to a density of 5000 cells per well in clear 96 well plate (Scientific Orange no. 1472030100) in 100 p1 media. Viable cells were measured at the times indicated by adding 10 pl the tetrazolium compound 10 [3-(4,5-dimethyl-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt; MTS] and an electron coupling reagent (phenazine ethosulfate; PES) (CellTiter 96® AQueous One Solution Cell Proliferation Assay, Promega). Viable cells were measured at 490 nm in a Powerwave (Biotek Instruments). The OD490 nm were plotted against time/h. (See Figure 13 and Figure 14). As shown in figure 13 and figure 14, oligonucleotides of SEQ 15 ID NOs: 58 and 77 inhibits growth of both LNCaP prostate and A549 lung cancer cells, and are therefore preferred. Example 11: In vitro analysis: Caspase 3/7 activity by Antisense Inhibition of Human Androgen receptor mRNA 20 LNCaP prostate cancer and A549 lung cancer cells were seeded to a density of 150000 cells per well in a 6-well plate the day prior to transfection. A549 cells were cultured in DMEM (Sigma) + 10% fetal bovine serum (FBS) + 2 mM Glutamax I + gentamicin (25pg/ml) whereas LNCaP cells were cultured in RPMI 1640 Medium (Sigma) + 10% fetal bovine serum (FBS) + 2 mM Glutamax I + gentamicin (25pg/ml). The next day medium was 25 removed followed by addition of 1.2 ml OptiMEM containing 5 pg/ml Lipofectamine2000 (Invitrogen). Cells were incubated for 7 min before adding 0.3 ml oligonucleotides diluted in OptiMEM. The final oligonucleotide concentrations were 4 and 16 nM. After 4 hours of treatment, media was removed and cells were trypsinized and seeded to a density of 5000 cells per well in white 96 well plate (Nunc) in 100 pl media. Caspase 3/7 activity was 30 measured at the times indicated by adding 100 p1 Caspase-Glo 3/7 assay (promega). Caspase 3/7 activity was measured using a luminometer. The caspase 3/7 activities were measured at three different time points 14h, 48h and 72h (See Figure 15 and Figure 16). As shown in 69 WO 2012/065051 PCT/US2011/060352 figure 15 and figure 16, oligonucleotides of SEQ ID NOs: 58 and 77 induce caspase 3/7 activity in both LNCaP prostate and A549 lung cancer cells and are therefore preferred. Example 12: In vitro analysis: Antisense Inhibition of Human Androgen receptor mRNA Expression by oligonucleotide compounds in prostate cancer cells LNCaP and the lung 5 cancer cell line A549. Oligonucleotides were evaluated for their potential to knockdown of the androgen receptor mRNA at concentrations of 0.5, 1, 2, 4, 8 and 16 nM (see Figure II). LNCaP prostate cancer and A549 lung cancer cells were seeded to a density of 150000 cells per well in a 6-well plate the day prior to transfection. A549 cells were cultured in DMEM (Sigma) + 10 10% fetal bovine serum (FBS) + 2 mM Glutamax I + gentamicin (25pg/ml) whereas LNCaP cells were cultured in RPMI 1640 Medium (Sigma) + 10% fetal bovine serum (FBS) + 2 mM Glutamax I + gentamicin (25pg/ml). The next day medium was removed followed by addition of 1.2 ml OptiMEM containing 5 pg/ml Lipofectamine2000 (Invitrogen). Cells were incubated for 7 min before adding 0.3 ml oligonucleotides diluted in OptiMEM. The final 15 oligonucleotide concentrations were 0.5, 1, 2, 4, 8 and 16 nM. Cells were washed and serum containing media was added. After oligo treatment cells were allowed to recover for 20 hours before they were harvested for RNA analysis. The procedure for RNA isolation, cDNA synthesis and qPCR were as described in example 5, 6 and 7. As shown in Figures I I and 12 oligonucleotides of SEQ ID NOs: 58 and 77 were potent in knocking down AR mRNA 20 expression in both the lung cancer cell line A549 and in the androgen receptor-dependent 22RV I prostate cancer cell line. Example 13: Effect of antisense oligonucleotide on PSA (Figure 17): Six to seven week old male athymic nu/nu mice (Harlan Sprague Dawley) weighing an 25 average of 27.3±2.4g were used in the study. Ten million cells of 22RV I (androgen independent prostate cancer line) were suspended in PBS (Gibco#14190) and Matrigel (BD#356234) with a ratio of 1:1 were injected subcutaneously into each mouse. When tumors reach an average volume of 150-200 mm 3 , the mice were divided into nine experimental groups. Two hundred pl of oligo was injected intravenously when the average 30 tumor size reached 152.66±27.97 mm 3 . Oligos were given every 3 days for a total of 5 times. The control vehicles were given the same regime as the oligos. On day 16, mice were sacrificed and blood collected in EDTA laced tubes and spun for 5 min. 50 pl of the 70 WO 2012/065051 PCT/US2011/060352 supernatants were then subjected to PSA assay using the ELISA kit from ALPCO Diagnostics in Salem (PSAHU-LOI). Effect of antisense oligonucleotide on tumor growth (Figure 18): Six to seven week old male athymic nu/nu mice (Harlan Sprague Dawley) weighing an average of 27.3±2.4g were 5 used in the study. Ten million cells of 22RV1 (androgen-independent prostate cancer line) were suspended in PBS (Gibco#14190) and Matrigel (BD#356234) with a ratio of 1:1 were injected subcutaneously into each mouse. When tumors reach an average volume of 150-200 mm 3 , the mice were divided into nine experimental groups. Two hundred pl of oligo was injected intravenously when the average tumor size reached 152.66±27.97 mm . Oligos were 10 given every 3 days for a total of 5 times. The control vehicles were given the same regime as the oligos. The tumor volumes for each mouse were determined by measuring two dimensions with calipers and calculated using the formula: tumor volume = (length x width 2 )/2). 15 Example 14: Preparation of conjugates of oligomers with polyethylene glycol The oligomers having sequences shown as SEQ ID NO: 48 or SEQ ID NO: 63 are functionalized on the 5' terminus by attaching an aminoalkyl group, such as hexan-I-amine blocked with a blocking group such as Fmoc to the 5' phosphate groups of the oligomers using routine phosphoramidite chemistry, oxidizing the resultant compounds, deprotecting 20 them and purifying them to achieve the functionalized oligomers, respectively, having the formulas (IA) and (IB): 0 I (IA) o- - -- ceAs.s a s949Cs OteasCala C- -- OH (IB) wherein the bold uppercase letters represent nucleoside analogue monomers, lowercase letters represent DNA monomers, the subscript "s" represents a phosphorothioate linkage, 25 and M*C represents 5-methylcytosine. A solution of activated PEG, such as the one shown in formula (II): 71 WO 2012/065051 PCT/US2011/060352 o Me O O MPE O OO O-N Me 0 (II) wherein the PEG moiety has an average molecular weight of 12,000, and each of the compounds of formulas (IA) and (IB) in PBS buffer are stirred in separate vessels at room 5 temperature for 12 hours. The reaction solutions are extracted three times with methylene chloride and the combined organic layers are dried over magnesium sulphate and filtered and the solvent is evaporated under reduced pressure. The resulting residues are dissolved in double distilled water and loaded onto an anion exchange column. Unreacted PEG linker is eluted with water and the products are eluted with NH 4

HCO

3 solution. Fractions containing 10 pure products are pooled and lypophilized to yield the conjugates SEQ ID NOs: 48 and 63, respectively as show in formulas (IIIA) and (IIIB): o Me 0o Me (lllA) o Me M M /10-CA 0 L..~t %A T O Me (I1B) wherein each of the oligomers of SEQ ID NOs: 48 and 63 is attached to a PEG polymer 15 having average molecular weight of 12,000 via a releasable linker. Chemical structures of PEG polymer conjugates that can be made with oligomers having sequences shown in SEQ ID NOs: 51, 58 and 77 using the process described above are respectively shown in formulas (IVA), (IVB) and (IVC): 72 WO 2012/065051 PCT/US2011/060352 O O---TTTg~. acaAgtg... OH Me (IVA) Me mPEs O O O - -- A---C.M*C~aWa;.tfttt.c.A.G. C-OH H H Me (IVB) rnP~,N)~OMe~ Me (IVC) wherein bold uppercase letters represent beta-D-oxy-LNA monomers, lowercase letters represent DNA monomers, the subscript "s" represents a phosphorothioate linkage and m'C 5 represent 5-methylcytosine. Activated oligomers that can be used in this process to respectively make the conjugates shown in formulas (IVA), (IVB) and (IVC) have the chemical structures shown in formulas (VA), (VB) and (VC): 0 II H2N 0-- A--T.T.T~ga.CcNa. gtag.G..A--OH (VA) 0* H2_1 O-P-O--A.--,*..a~gt.ttckc..MC-OH (VB) 0 10 (VC) Example 15 - Combination therapy experiments In vivo therapeutic efficacy of combination treatment with antisense oligomers and diarylhydantoin type AR binding inhibitors was evaluated. A combination study with SEQ ID NO:58 and the diarylhydantoin type androgen receptor binding inhibitor 4-(3-(4-cyano-3 15 (trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin- I -yl)-2-fluoro-N methylbenzamide (MDV3100) was carried out in the androgen-dependent CWR-22 human prostate tumor cell line mouse xenograft model, as shown in FIGS. 19 and 20. A mismatch 73 WO 2012/065051 PCT/US2011/060352 oligomer control ("MM-oligo") having the sequence 5'-AsCsCsgsaststscsascstststsAsGsC-3' (SEQ ID NO: 107) was used as indicated (mismatched bases indicated in italics; this sequence does not have 100% match with any mRNA in the mouse or human database). Mice were purposely dosed with a low dose of SEQ ID NO:58 (40 mg/kg, q3dx4, i.v.), which showed 5 minimum or no significant tumor growth inhibition (TGI) by itself in this experiment. In contrast, 50 % TGI was observed with 50 mg/kg MDV3 100 (qdx 1, p.o.) on Day 17. In the combination treatment groups, SEQ ID NO:58 with 50 mg/kg MDV3 100, TGI increased to 76%. Since the tumor size exceeded the allowable limit (1690 mm 3 ) in the vehicle control group on day 17, animals in this group were euthanized, which precluded further meaningful 10 TGI calculations. Nevertheless, as shown in FIG. 20, animals were monitored for tumor growth until day 31 demonstrating 100% survival in the MDV3100 group and the SEQ ID NO:58 + MDV3100 combination group. FIG. 20 further shows that, in the combination group, a marked inhibition of tumor growth is observed when compared to animals treated only with MDV3100. This experiment was also been repeated in two independent studies, 15 yielding similar results. FIG. 21A shows effect of the combination of SEQ ID NO:58 and MDV3100 in a colony formation growth assay using the AR-positive, androgen-resistant human cell line, C4-2b-AR. SEQ ID NO:58 or MDV3100 alone showed dose-dependent growth inhibition. However, when combined, growth of colonies was inhibited more effectively than either 20 agent alone. As shown in FIG. 21B, a similar result was obtained when SEQ ID NO:58 was combined with bicalutamide, but only at a higher concentration. In the experiment, C4-2b cells were plated at 400 cells/well in a 24-well plate. 24 hours later, cells were treated with test compounds continuously for 12 days when MTT (100 laL of 5 mg/mL) was added to I mL of culture and incubated until a visible darker blue color became apparent. The 25 supernatant was removed to allow the colonies to dry, after which the .plate was scanned. FIG. 21A shows results for SEQ ID NO:58 (indicated EZN-4176) and MDV3100. FIG. 21B shows results for SEQ ID NO:58 (indicated EZN-4176) and bicalutamide. As shown in FIG. 22, the combination of SEQ ID NO:58 with MDV3 100 demonstrated better inhibition of AR transcriptional activity in an AR-positive, androgen-resistant human 30 cell line, C4-2b-AR-luc (luciferase marker of AR transcription), compared with either agent used alone. These results suggest that the demonstrated synergistic potentiation of in vivo tumor growth obtained when SEQ ID NO:58 was used in combination with MDV3100 results from a direct effect on the tumor cells. In the experiment, C4-2b-AR-luc cells were 74 WO 2012/065051 PCT/US2011/060352 plated in 96-well plate and treated with SEQ ID NO:58 or MM-oligo for 5 days followed with various concentrations of MDV3100 as marked and 10 nM DHT. Luciferase activity was determined after 24 hours. Each bar represents results in duplicates. MDV3100 has demonstrated antitumor effects in castration-resistant prostate cancer 5 (CRPC) patients since it decreased serum PSA by 50% or more in 56% of patients, induced responses in soft tissue in 22% of patients, stabilized bone disease in 56% of patients, and reduced circulating tumor cell counts in 49% of patients (Scher et al., Lancet 375, 1437 (April 24, 2010). Nevertheless, a certain population of patients failed initially to respond to MDV3100 and the median time to progression was approximately 47 weeks. Not only can 10 resistance to MDV3 100 occur, but MDV3 100, which competes with androgen for the ligand binding domain of the AR, may be less effective on AR variants devoid of the ligand-binding domain. Such variants have already been documented in prostate cancer patients. Therefore, in view of the findings presented here, it is believed that combination treatment with an antisense oligomer targeting AR, such as SEQ ID NO:58, and diarylhydantoin type AR 15 binding inhibitor, such as MDV3100, represents a significant advance in the treatment of prostate cancer, for both first line and salvage therapy, and other androgen receptor activity dependent disorders. Example 16: In vitro analysis: antisense inhibition of human androgen receptor mRNA 20 expression and prostate specific antigen (PSA) mRNA by oligonucleotide compounds in the prostate cancer cell line C4-2b. The inventors tested in the prostate cancer cells C4-2b the effect of treating said cells with (i) SEQ ID NO: 58 (EZN-4176), (ii) 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5 dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide (MDV3100), or 25 (iii) the combination of both MDV3100 and EZN-4176. C4-2b cells were plated at 5,000 cells/well in a 6-well plate. 24 hours later, the cells were treated with test compounds for 5 days when AR (Figure 23) and PSA (Figure 24) mRNA were measured by quantitative RT-PCR. Data are mean + SEM (n = 3). EZN-4176 at 5 mM resulted in significant down-modulation of AR mRNA (Figure 30 23). Interestingly, when prostate specific antigen (PSA) mRNA was examined, EZN-4176 or MDV3 100 each showed a moderate effect on PSA mRNA level. However, surprisingly when MDV3 100 and EZN-4176 were combined PSA mRNA was down-modulated 75 WO 2012/065051 PCT/US2011/060352 significantly (Figure 24). The effect of the combination was specific since MDV3100 in combination with the mismatch oligomer 'MM' did not demonstrate PSA mRNA down modulation (Figure 24). 5 For convenience, various embodiments and aspects of the present invention are presented herein by way of the following numbered paragraphs (para.s). 1. A method for treating an androgen receptor dependent hyperproliferative disorder in a mammal, comprising the steps of: 10 administering to a mammal in need of treatment for an androgen receptor dependent hyperproliferative disorder in amounts therapeutically effective in combination, (a) an antisense oligomer selected from the group consisting of: 5'-AsMeCs CsasasgstststscststscsAsG s C-3' (SEQ ID NO: 58); and 5 '-MCseCs eC sasasgsgscsascstsgscsAsGsA-3' (SEQ ID NO: 77), 15 wherein uppercase letters denote beta-D-oxy-LNA monomers and lowercase letters denote DNA monomers, the subscript "s" denotes a phosphorothioate linkage, and M"C denotes a beta-D-oxy-LNA monomer containing a 5-methylcytosine base, or a conjugate of said oligomer, or a pharmaceutically acceptable salt of said compound or said conjugate; and (b) a compound selected from the group consisting of: 76 WO 2012/065051 PCT/US2011/060352 F 0 NC H

F

3 C N N F NC 0 "/ N , and FC N N H F NC 0

F

3 C N N H 0 or a pharmaceutically acceptable salt of said compound. 5 2. The method of paragraph 1, wherein the mammal is a human. 3. The method of paragraph I or 2, wherein the androgen receptor dependent hyperproliferative disorder is selected from the group consisting of prostate cancer, benign 10 prostatic hyperplasia and breast cancer. 4. The method of paragraph 3, wherein the androgen receptor dependent hyperproliferative disorder is prostate cancer. 15 5. The method of paragraph 4, wherein the prostate cancer is castration-resistant prostate cancer. 6. The method of paragraph 4, wherein the prostate cancer is advanced prostate cancer. 77 WO 2012/065051 PCT/US2011/060352 7. The method of any one of paragraphs I to 6, wherein the compound is: F 0 NCa S N

F

3 C N& 5 8. The method of any one of paragraphs I to 6, wherein the compound is: F NC 0 / N F3C N N 6 H 9. The method of any one of paragraphs I to 6, wherein the compound is: F NC 0

F

3 C N N / 0 10 10. A kit comprising: (a) a pharmaceutical composition comprising an antisense oligomer selected from the group consisting of: 5'-A, M CSCsasasgstststscststscsAsG s C-3' (SEQ ID NO: 58); and 5'- MCSM*Cs**CsasasgsgscsascstsgscsAsGsA-3' (SEQ ID NO: 77), wherein uppercase letters denote beta-D-oxy-LNA monomers and lowercase letters denote DNA monomers, the subscript "s" denotes a phosphorothioate linkage, and m'C 78 WO 2012/065051 PCT/US2011/060352 denotes a beta-D-oxy-LNA monomer containing a 5-methylcytosine base, or a conjugate of said oligomer, or a pharmaceutically acceptable salt of said compound or said conjugate; and (b) a pharmaceutical composition comprising a compound selected from the group consisting of: F 0 NC

F

3 C )a N N 5 F NC 0 -AK 'N , and

F

3 C N N H F NC 0

F

3 C N N h V 0b or a pharmaceutically acceptable salt of said compound. 10 I1. A method for treating an androgen receptor dependent hyperproliferative disorder in a mammal, comprising the steps of: administering to a mammal in need of treatment for an androgen receptor dependent hyperproliferative disorder in amounts therapeutically effective in combination, (a) an antisense oligomer selected from the group consisting of: 15 5'- A, Cs**CsasasgstststseststscsAsGse C-3'(SEQ ID NO: 58); and 5' -MCs**Cs**CsasasgsgscsascstsgscsAGsA-3'(SEQ ID NO: 77), wherein uppercase letters denote beta-D-oxy-LNA monomers and lowercase letters denote DNA monomers, the subscript "s" denotes a phosphorothioate linkage, and mC 79 WO 2012/065051 PCT/US2011/060352 denotes a beta-D-oxy-LNA monomer containing a 5-methylcytosine base, or a conjugate of said oligomer, or a pharmaceutically acceptable salt of said compound or said conjugate; and (b) a non-steroidal antiandrogen compound or a pharmaceutically acceptable salt thereof. 5 12. The method of paragraph 11, wherein the mammal is a human. 13. The method of paragraph I I or 12, wherein the non-steroidal antiandrogen compound is bicalutamide. 10 14. The method of any one of paragraphs 1 to 13, wherein the androgen receptor dependent hyperproliferative disorder is selected from the group consisting of prostate cancer, benign prostatic hyperplasia and breast cancer. 15 15. The method of paragraph 14, wherein the androgen receptor dependent hyperproliferative disorder is prostate cancer. 16. The method of paragraph 15, wherein the prostate cancer is castration-resistant prostate cancer. 20 17. An oligomer of between 10 - 30 nucleotides in length which comprises a contiguous nucleotide sequence of a total of between 10 - 30 nucleotides, wherein said contiguous nucleotide sequence is at least 80% homologous to a region corresponding to a mammalian androgen receptor gene or the reverse complement of an mRNA, such as SEQ ID NO: I or 25 naturally occurring variant thereof, wherein said oligomer comprises at least one LNA unit. 18. The oligomer according to paragraph 17, wherein the contiguous nucleotide sequence is at least 80% homologous to a region corresponding to i) SEQ ID NO 94 or SEQ ID NO 58, ii) SEQ ID NO 105 or SEQ ID NO 77 or iii) a sequence selected from the group consisting of 30 SEQ ID NO: 2 - 22 and 86 - 106. 80 WO 2012/065051 PCT/US2011/060352 19. The oligomer according to paragraph 17 or 18, wherein the contiguous nucleotide sequence comprises no mismatches or no more than one or two mismatches with the reverse complement of the corresponding region of 1. 5 20. The oligomer according to any one of paragraphs 17 - 19, wherein the nucleotide sequence of the oligomer consists of the contiguous nucleotide sequence. 21. The oligomer according to any one of paragraphs 17 - 20, wherein the contiguous nucleotide sequence is between 10 - 18 nucleotides in length. 10 22. The oligomer according to any one of paragraphs 17 - 21, wherein the contiguous nucleotide sequence comprises nucleotide analogues. 23. The oligomer according to paragraph 22, wherein the nucleotide analogues are sugar 15 modified nucleotides, such as sugar modified nucleotides selected from the group consisting of: Locked Nucleic Acid (LNA) units; 2'-O-alkyl-RNA units, 2'-OMe-RNA units, 2'-amino DNA units, and 2'-fluoro-DNA units. 24. The oligomer according to paragraph 22, wherein the nucleotide analogues are LNA. 20 25. The oligomer according to any one of paragraphs 22 - 24 which is a gapmer. 26. The oligomer according to any one of paragraphs 17 - 25, which inhibits the expression of androgen receptor gene or mRNA in a cell which is expressing androgen receptor gene or 25 mRNA. 27. The oligomer according to any one of paragraphs 17 - 26, wherein the oligomer consists or comprises a contiguous nucleotide sequence selected from 5'-As**CsM*C asasgStStStScStStscSA s G eC-3' (SEQ ID NO: 58); and 30 5'- MCs**Cs*C sasasgsgscsascstsgscsAGA-3' (SEQ ID NO: 77), 81 WO 2012/065051 PCT/US2011/060352 wherein uppercase letters denote beta-D-oxy-LNA monomers and lowercase letters denote DNA monomers, the subscript "s" denotes a phosphorothioate linkage, and meC denotes a beta-D-oxy-LNA monomer containing a 5-methylcytosine base. 5 28. A conjugate comprising the oligomer according to any one of paragraphs 17 - 26, and at least one non-nucleotide or non-polynucleotide moiety covalently attached to said oligomer. 29. A pharmaceutical composition comprising the oligomer according to any one of paragraphs 17 - 27, or the conjugate according to paragraph 28, and a pharmaceutically 10 acceptable diluent, carrier, salt or adjuvant. 30. The oligomer according to any one of paragraphs 17 - 27 , or the conjugate according to paragraph 28, for use as a medicament, such as for the treatment of a.disease or a medical disorder as disclosed herein, such as a hyperproliferative disorder, such as cancer. 15 31. The use of an oligomer according to any one of paragraphs 17-27, or a corijugate as defined in paragraph 28, for the manufacture of a medicament for the treatment of a disease or a medical disorder as disclosed herein, such as a hyperproliferative disorder, such as cancer. 20 32. A method of treating a disease or a medical disorder as disclosed herein, such as a hyperproliferative disorder, such as cancer, said method comprising administering an effective amount of an oligomer according to any one of the paragraphs 17-27, or a conjugate according to paragraph 28, or a pharmaceutical composition according to paragraph 29, to a 25 patient suffering from, or likely to suffer from a disease or a medical disorder as disclosed herein, such as a hyperproliferative disorder, such as cancer. 33. A method for the inhibition of Androgen Receptor in a cell which is expressing the androgen receptor, said method comprising administering an oligomer according to any one 30 of the paragraphs 17-27, or a conjugate according to paragraph 28 to said cell so as to inhibit androgen receptor in said cell. 82 WO 2012/065051 PCT/US2011/060352 Each of the patents, patent applications and other publications cited in this disclosure is incorporated by reference in its entirety. ' Although the foregoing description is directed to the preferred embodiments of the invention, it is noted that other variations and modifications may be apparent to those skilled 5 in the art, and may be made without departing from the spirit or scope of the invention. Moreover, features described in connection with one embodiment of the invention may be used in conjunction with other embodiments, even if not explicitly stated above. 83

Claims

1. A pharmaceutical composition comprising: an antisense oligomer comprising a contiguous nucleotide sequence of a total of 10---30 nucleotides, wherein the contiguous nucleotide sequence is at least 80% homologous to a region 5 corresponding to i) SEQ ID NO 58 or SEQ ID NO 94, ii) SEQ ID NO 77 or SEQ ID NO 105 or iii) a sequence selected from the group consisting of SEQ ID NO:

2-22 and 86-106 or a conjugate thereof, or a pharmaceutically acceptable salt thereof, and a diarylhydantoin type androgen receptor ligand binding inhibitor or a pharmaceutically acceptable salt thereof. 10 2. The pharmaceutical composition of claim 1, wherein the continuous nucleotide sequence is at least 95% homologous to the region corresponding to i) SEQ ID NO 58 or SEQ ID NO 94, ii) SEQ ID NO 77 or SEQ ID NO 105 or iii) a sequence selected from the group consisting of SEQ ID NO: 2-22 and 86-106.

3. The pharmaceutical composition of any one of claims 1 to 2, wherein the 15 oligomer is 16-30 nucleotides in length.

4. The pharmaceutical composition of any one of claims 1 to 3, wherein said contiguous nucleotide sequence of the antisense oligomer comprises no mismatches or no more than one or two mismatches with the reverse complement of the corresponding region of SEQ ID NO: 1. 20

5. The pharmaceutical composition of any one of claims 1 to 4, wherein the nucleotide sequence of the antisense oligomer consists of the contiguous nucleotide sequence.

6. The pharmaceutical composition of any one of claims 1 to 5, wherein the contiguous nucleotide sequence of the antisense oligomer is less than or equal to 25 18 nucleotides in length.

7. The pharmaceutical composition of any one of claims 1 to 6, wherein the contiguous nucleotide sequence of the antisense oligomer comprises nucleotide analogues. 121

8. The pharmaceutical composition of claim 7, wherein the nucleotide analogues are sugar modified nucleotides, such as sugar modified nucleotides selected from the group consisting of: Locked Nucleic Acid (LNA) units; 2'-O-alkyl-RNA units, 2'-OMe-RNA units, 2'amino-DNA units, 3'fluoro hexitol nucleic acid, and 5 2'-fluoro-DNA units.

9. The pharmaceutical composition of claim 7 or claim 8, wherein the nucleotide analogues of the antisense oligomer include LNA.

10. The pharmaceutical composition of claim 9, wherein all the nucleotide analogues of the antisense oligomer are LNA. 10

11. The pharmaceutical composition of any one of claims 7 to 10 wherein said antisense oligomer is a gap mer.

12. The pharmaceutical composition of any one of claims 1 to 11, wherein said antisense oligomer is capable of inhibiting the expression of androgen receptor gene or mRNA, such as in a cell which is expressing androgen receptor gene or 15 mRNA.

13. The pharmaceutical composition of any one of claims 1 to 12, wherein said antisense oligomer comprises a contiguous nucleotide sequence selected from 5'-AsMeCsMeCsasasgstststsCststscsAsGsMeC-3' (SEQ ID NO: 58); and 5'-MeCsMeCsMeCsasasgsgscsasCstsgscsAsGsA-3' (SEQ ID NO: 77), wherein 20 uppercase letters denote beta-D-oxy-LNA monomers and lowercase letters denote DNA monomers, the subscript "s" denotes a phosphorothioate linkage, and Mec denotes a beta-D-oxy-LNA monomer containing a 5-methylcytosine base, or a conjugate of said oligomer, or a pharmaceutically acceptable salt of said compound or said conjugate. 122

14. The pharmaceutical composition of any one of claims 1 to 13, wherein the diarylhydantoin type androgen receptor ligand binding inhibitor is a compound selected from the group consisting of: N N I s

15. The pharmaceutical composition of any one of claims 1 to 14, wherein the diarylhydantoin type androgen receptor ligand binding inhibitor is the compound: Nt' /Q 123

16. The pharmaceutical composition of any one of claims 1 to 14, wherein the diarylhydantoin type androgen receptor ligand binding inhibitor is: F CN

17. The pharmaceutical composition of any one of claims 1 to 14, wherein the 5 diarylhydantoin type androgen receptor ligand binding inhibitor is: F "C N

18. A method for treating an androgen receptor dependent hyperproliferative disorder in a mammal, the method comprising administering to said mammal, therapeutically effective amounts, in combination: 10 (a) an antisense oligomer or conjugate thereof, or pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 13; and (b) a diarylhydantoin type androgen receptor ligand binding inhibitor or a pharmaceutically acceptable salt thereof.

19. The method according to claim 18, wherein the mammal is a human. 15

20. The method according to claim 18 or 19, wherein the androgen receptor dependent hyperproliferative disorder is selected from the group consisting of prostate cancer, benign prostatic hyperplasia and breast cancer.

21. The method according to any one of claims 18 to 20, wherein the androgen receptor dependent hyperproliferative disorder is prostate cancer. 124

22. The method according to claim 21, wherein the prostate cancer is castration resistant prostate cancer.

23. The method according claim 21, wherein the prostate cancer is advanced prostate cancer. 5

24. The method according to any one of claims 18 to 23, wherein the diarylhydantoin type androgen receptor ligand binding inhibitor is:

25. The method according to any one of claims 18 to 23, wherein the diarylhydantoin type androgen receptor ligand binding inhibitor is: N'' C' \1/

26. The method according to any one of claims 18 to 23, wherein the diarylhydantoin type androgen receptor ligand binding inhibitor is: SF Enzon Pharmaceuticals, Inc. is Santaris Pharma A/S Patent Attorneys for the Applicant/Nominated Person SPRUSON & FERGUSON