Oligonucleotide compositions and uses thereof

Abstract

The present invention provides oligonucleotide inhibitors of miR-155 and compositions thereof. The invention further provides methods for treating cancer such as a T cell lymphoma in a subject by administering to the subject an oligonucleotide inhibitor of miR-155. The invention also provides methods for reducing or inhibiting the proliferation of malignant T cells by administering an oligonucleotide inhibitor of miR-155.

1 - 71 . (canceled) 
     
     
         72 . An oligonucleotide inhibitor of miR-155, comprising the sequence of 5′-lCs.dAs.lCs.dGs.dAs.lTs.lTs.dAs.lGs.lCs.dAs.lTs.lTs.lA-3′ (SEQ ID NO: 53), wherein l stands for a locked nucleotide; d stands for a deoxyribonucleotide; and s stands for a phosphorothioate linkage. 
     
     
         73 . The oligonucleotide inhibitor of  claim 72 , wherein said oligonucleotide inhibitor consists of the sequence of 5′-lCs.dAs.lCs.dGs.dAs.lTs.lTs.dAs.lGs.lCs.dAs.lTs.lTs.lA-3′ (SEQ ID NO: 53). 
     
     
         74 . The oligonucleotide inhibitor of  claim 72 , wherein said oligonucleotide inhibitor reduces proliferation of cancer cells. 
     
     
         75 . The oligonucleotide inhibitor of  claim 74 , wherein said cancer cells are T cell lymphoma cells. 
     
     
         76 . The oligonucleotide inhibitor of  claim 74 , wherein the proliferation of cancer cells is reduced by about 30-90% compared to untreated cells. 
     
     
         77 . The oligonucleotide inhibitor of  claim 75 , wherein the proliferation of T cell lymphoma cells is reduced by about 30-90% compared to untreated cells. 
     
     
         78 . The oligonucleotide inhibitor of  claim 72 , wherein said oligonucleotide inhibitor induces apoptosis of cancer cells. 
     
     
         79 . The oligonucleotide inhibitor of  claim 78 , wherein said cancer cells are T cell lymphoma cells. 
     
     
         80 . The oligonucleotide inhibitor of  claim 78 , wherein the oligonucleotide inhibitor increases caspase activity in cancer cells by at least about 2-fold compared to untreated cells. 
     
     
         81 . The oligonucleotide inhibitor of  claim 72 , wherein said oligonucleotide inhibitor reduces proliferation of T cells. 
     
     
         82 . The oligonucleotide inhibitor of  claim 81 , wherein the reduction in T cell proliferation is dose-dependent. 
     
     
         83 . A composition comprising an oligonucleotide inhibitor of miR-155, comprising the sequence of 5′-lCs.dAs.lCs.dGs.dAs.lTs.lTs.dAs.lGs.lCs.dAs.lTs.lTs.lA-3′ (SEQ ID NO: 53), wherein l stands for a locked nucleotide; d stands for a deoxyribonucleotide; and s stands for a phosphorothioate linkage. 
     
     
         84 . The composition of  claim 83 , wherein said oligonucleotide inhibitor consists of the sequence of 5′-lCs.dAs.lCs.dGs.dAs.lTs.lTs.dAs.lGs.lCs.dAs.lTs.lTs.lA-3′ (SEQ ID NO: 53). 
     
     
         85 . The composition of  claim 83 , wherein the composition is a pharmaceutical composition and comprises a pharmaceutically acceptable carrier or excipient. 
     
     
         86 . A method for treating a T cell lymphoma in a subject in need thereof, comprising administering to the subject an oligonucleotide inhibitor of miR-155 comprising the sequence of 5′-lCs.dAs.lCs.dGs.dAs.lTs.lTs.dAs.lGs.lCs.dAs.lTs.lTs.lA-3′ (SEQ ID NO: 53), wherein l stands for a locked nucleotide; d stands for a deoxyribonucleotide; and s stands for a phosphorothioate linkage. 
     
     
         87 . The method of  claim 86 , wherein said oligonucleotide inhibitor consists of the sequence of 5′-lCs.dAs.lCs.dGs.dAs.lTs.lTs.dAs.lGs.lCs.dAs.lTs.lTs.lA-3′ (SEQ ID NO: 53). 
     
     
         88 . The method of  claim 86 , wherein the administration of said oligonucleotide inhibitor reduces proliferation of T cell lymphoma cells. 
     
     
         89 . The method of  claim 88 , wherein the proliferation of T cell lymphoma cells is reduced by about 30-90% compared to untreated cells. 
     
     
         90 . The method of  claim 86 , wherein the administration of said oligonucleotide inhibitor shows a dose-dependent inhibition of miR-155. 
     
     
         91 . The method of  claim 86 , wherein the administration of said oligonucleotide inhibitor induces apoptosis of T cell lymphoma cells. 
     
     
         92 . The method of  claim 91 , wherein the administration of said oligonucleotide inhibitor increases caspase activity in T cell lymphoma cells by at least about 2-fold compared to untreated cells. 
     
     
         93 . The method of  claim 86 , wherein said oligonucleotide inhibitor is administered to the subject via injection.