Antisense compounds and uses thereof

Abstract

The present invention provides compounds comprising oligonucleotides complementary to a pyruvate kinase M transcript. Certain such compounds are useful for hybridizing to a pyruvate kinase M transcript, including but not limited to a pyruvate kinase M transcript in a cell. In certain embodiments, such hybridization results in modulation of splicing of the pyruvate kinase M transcript. In certain embodiments, such compounds are used to treat one or more symptoms associated with cancer.

1 . A compound comprising a modified oligonucleotide consisting of 8 to 30 linked nucleosides and having a nucleobase sequence comprising a complementary region, wherein the complementary region comprises at least 8 contiguous nucleobases and is complementary to an equal-length portion of a target region of a PK-M transcript. 
     
     
         2 . The compound of  claim 1 , wherein the target region of the PK-M transcript comprises at least a portion of exon 10 of the PK-M transcript. 
     
     
         3 . (canceled) 
     
     
         4 . The compound of any of  claim 1 , wherein the complementary region of the modified oligonucleotide comprises at least 10 contiguous nucleobases, at least 15 contiguous nucleobases, or at least 20 contiguous nucleobases. 
     
     
         5 - 6 . (canceled) 
     
     
         7 . The compound of  claim 1 , wherein the nucleobase sequence of the oligonucleotide is at least 80%, at least 90%, or is 100% complementary to an equal-length region of the PK-M transcript, as measured over the entire length of the oligonucleotide. 
     
     
         8 - 9 . (canceled) 
     
     
         10 . The compound of  claim 1 , wherein the target region is within exon 10 of the PK-M transcript. 
     
     
         11 . The compound of  claim 1 , wherein the target region is within nucleobase 29153 and nucleobase 29281, nucleobase 29158 and nucleobase 29262, nucleobase 29164 and nucleobase 29188, nucleobase 29261 and nucleobase 29279, or nucleobase 29168 and nucleobase 29183 of SEQ ID NO.: 1. 
     
     
         12 - 15 . (canceled) 
     
     
         16 . The compound of  claim 1 , wherein the nucleobase sequence of the antisense oligonucleotide comprises any one of SEQ ID NOs: 4 to 36. 
     
     
         17 - 19 . (canceled) 
     
     
         20 . The compound of  claim 1 , wherein the modified oligonucleotide comprises at least one modified sugar moiety:
 wherein the at least one modified sugar moiety is one or more of a 2′-substituted sugar moiety, a bicyclic sugar moiety, and a sugar surrogate;   wherein the 2′-substitutent of at least one 2′-substituted sugar moiety is selected from among:   2′-OMe, 2′-F, and 2′-MOE;   wherein the bicyclic sugar moiety is LNA or cEt; and,   wherein the sugar surrogate is a morpholino or a modified morpholino.   
     
     
         21 - 26 . (canceled) 
     
     
         27 . The compound of  claim 1 , wherein the modified oligonucleotide comprises at least 5, at least 10, or at least 15 modified nucleosides or wherein each nucleoside of the modified oligonucleotide is a modified nucleoside, each independently comprising a modified sugar moiety. 
     
     
         28 - 30 . (canceled) 
     
     
         31 . The compound of  claim 1 , wherein the modified oligonucleotide comprises at least two modified nucleosides comprising modified sugar moieties that are the same as one another or different from one another. 
     
     
         32 . (canceled) 
     
     
         33 . The compound of  claim 1 , wherein the modified oligonucleotide comprises a modified region of at least 5, at least 10, at least 15, or at least 20 contiguous modified nucleosides. 
     
     
         34 - 36 . (canceled) 
     
     
         37 . The compound of  claim 33 , wherein each modified nucleoside of the modified region has a modified sugar moiety independently selected from among: 2′-F, 2′-OMe, 2′-MOE, cEt, LNA, morpholino, and modified morpholino. 
     
     
         38 . The compound of  claim 33 , wherein the modified nucleosides of the modified region each comprise the same modification as one another. 
     
     
         39 - 58 . (canceled) 
     
     
         59 . The compound of  claim 1 , wherein the modified oligonucleotide comprises at least one modified internucleoside linkage. 
     
     
         60 . The compound of  claim 59 , wherein each internucleoside linkage is a modified internucleoside linkage. 
     
     
         61 . The compound of  claim 59 , comprising at least one phosphorothioate internucleoside linkage. 
     
     
         62 . The compound of  claim 60 , wherein each internucleoside linkage is a modified internucleoside linkage and wherein each internucleoside linkage comprises the same modification. 
     
     
         63 . The compound of  claim 62 , wherein each internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         64 . The compound of  claim 1  comprising at least one conjugate. 
     
     
         65 - 66 . (canceled) 
     
     
         67 . The compound of  claim 1 , having a nucleobase sequence comprising any of the sequences as set forth in SEQ ID NOs. 4 to 36. 
     
     
         68 - 106 . (canceled)