Lna antagonists targeting the androgen receptor

Abstract

The invention relates to oligonucleotide compounds (oligomers), which target androgen receptor mRNA in a cell, leading to reduced expression of the androgen receptor. Reduction of the androgen receptor expression is beneficial for the treatment of certain disorders, such as a hyperproliferative disorders (e.g., cancer). The invention provides therapeutic compositions comprising oligomers and methods for modulating the expression of androgen receptor using said oligomers, including methods of treatment.

1 . An oligomer consisting of 10 to 30 contiguous monomers 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 mammalian androgen receptor mRNA.   
     
     
         2 . The oligomer according to  claim 1 , wherein the sequence of the first region is at least 80% identical to the sequence of a region of at least 10 contiguous monomers present in SEQ ID NOs: 2-22, 44-80 or 86-106. 
     
     
         3 . The oligomer according to  claim 1 , wherein the sequence of the first region is at least 80% identical to the sequence of a region of at least 10 contiguous monomers present in SEQ ID NO 94, or SEQ ID NO 105. 
     
     
         4 . The oligomer according to  claim 1  wherein the sequence of the first region comprises 0 to 2 mismatches when compared to the sequence of the best-aligned region of the reverse complement of a mammalian androgen receptor gene or a mammalian androgen receptor mRNA. 
     
     
         5 . The oligomer according to  claim 1 , wherein the first region of said oligomer consists of 10 to 18 contiguous monomers. 
     
     
         6 . The oligomer according to  claim 1 , wherein each nucleoside analogue is independently selected from the group consisting of an LNA monomer, a monomer containing a 2′-O-alkyl-ribose sugar, a monomer containing a 2′-O-methyl-ribose sugar, a monomer containing a 2′-amino-deoxyribose sugar, and a monomer containing a 2′fluoro-deoxyribose sugar. 
     
     
         7 . The oligomer according to  claim 1 , wherein the oligomer is a gapmer, and wherein said gapmer comprises from the 5′ end to the 3′ end:
 i. a region A consisting of 1-6 contiguous monomers, wherein at least one monomer is a nucleoside analogue, 
 ii. a region B, the 5′ end of which is covalently linked to the 3′ end of region A and consisting of 5-12 contiguous monomers, wherein at least one monomer is a nucleoside; and 
 iii. a region C, the 5′ end of which is covalently linked to the 3′ end of region B and consisting of 1-6 contiguous monomers, wherein at least one monomer s a nucleoside analogue. 
 
     
     
         8 . The oligomer according to  claim 7 , wherein the oligomer is a gapmer, and wherein said gapmer comprises from the 5′-end to the 3′-end:
 i. a region A consisting of 2-5 contiguous monomers, wherein all monomers are nucleoside analogues 
 ii. a region B, the 5′ end of which is covalently linked to the 3′ end of region A and consisting of 6-10 contiguous monomers, wherein all monomers are nucleosides; and 
 iii. a region C, the 5′ end of which is covalently linked to the 3′ end of region B and consisting of 2-5 contiguous monomers, wherein all monomers are nucleoside analogues. 
 
     
     
         9 . The oligomer according to  claim 7 , wherein all nucleoside analogues are LNA monomers. 
     
     
         10 . The oligomer according to  claim 1 , which inhibits the expression of a human androgen receptor gene or mRNA in a cell that expresses androgen receptor. 
     
     
         11 . A conjugate comprising an oligomer according to  claim 1  covalently attached to at least one moiety that is not a nucleic acid or a monomer. 
     
     
         12 . A pharmaceutical composition comprising the oligomer according to  claim 1  or the conjugate comprising the oligomer of  claim 1 , and a pharmaceutically acceptable diluent, carrier, salt or adjuvant. 
     
     
         13 . A method of (a) inhibiting the expression of androgen receptor or androgen receptor target gene in a cell or a tissue of a mammal; (b) treating cancer in a mammal; or (c) treating a disorder wherein the disorder is selected from the group consisting of alopecia, benign prostatic hyperplasia, spinal and muscular atrophy and Kennedy disease and polyglutamate disease, comprising contacting said cell or tissue of a mammal with; or administering to said mammal, an effective amount of an oligomer consisting of 10 to 30 contiguous monomers wherein adjacent monomers are covalently linked by a phosphate group or a phosphorothioate group or a conjugate comprising the oligomer,
 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 mammalian androgen receptor mRNA.   
     
     
         14 . The method of  claim 13 , wherein the androgen receptor target gene is selected from the group consisting of a protein kinase C delta gene, a glutathione S-transferase theta 2 gene, a transient receptor potential cation channel subfamily V member 3 gene, a pyrroline-5-carboxylate reductase 1 gene and an ornithine aminotransferase gene in a tissue of a mammal comprising contacting said tissue with an effective amount of a conjugate according to  claim 11 . 
     
     
         15 . The method of  claim 13 , wherein the cancer is breast cancer or prostate cancer.