Modulators of irf5 expression

Abstract

The present embodiments provide methods, compounds, and compositions useful for inhibiting IRF5 expression, which may be useful for treating, preventing, or ameliorating a disease associated with IRF5.

What is claimed: 
     
         1 . A compound comprising a modified oligonucleotide consisting of 16 to 30 linked nucleosides, wherein the modified oligonucleotide has a nucleobase sequence comprising a 16 nucleobase portion that is at least 80% complementary to an equal length portion of any of the nucleobase sequences of SEQ ID NOs: 37-1356; and
 wherein the modified oligonucleotide comprises at least one modification selected from at least one modified internucleoside linkage, at least one modified sugar, and at least one modified nucleobase that is a 5-methylcytosine.   
     
     
         2 . The compound of  claim 1 , wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         3 . The compound of  claim 1 , wherein the modified sugar is a bicyclic sugar. 
     
     
         4 . The compound of  claim 4 , wherein the bicyclic sugar is selected from the group consisting of: 4′-(CH 2 )—O-2′ (LNA), 4′-(CH 2 ) 2 —O-2′ (ENA), and 4′-CH(CH 3 )—O-2′ (cEt). 
     
     
         5 . The compound of  claim 1 , wherein the modified sugar is 2′-O-methoxyethyl. 
     
     
         6 . The compound of  claim 1 , wherein the modified oligonucleotide comprises:
 a gap segment consisting of linked deoxynucleosides;   a 5′ wing segment consisting of linked nucleosides; and   a 3′ wing segment consisting of linked nucleosides;   wherein the gap segment is positioned immediately adjacent to and between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.   
     
     
         8 . The compound of claim  7 , wherein each internucleoside linkage is a phosphothiorate linkage, each cytosine is a 5-methylcytosine, and each nucleoside of each wing segment comprises a cEt sugar. 
     
     
         9 . A composition comprising the compound of  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         10 . A compound comprising a modified oligonucleotide consisting of 16 to 30 linked nucleosides, wherein the modified oligonucleotide has a nucleobase sequence comprising a 16 nucleobase portion that is at least 80% complementary to an equal length portion of nucleobases 4366-4381, 5141-5156, 5140-5160, 5179-5194, 5567-5642, 5644-5731, 5567-5731, 5567-5620, 11544-11559, 11542-11596, 11736-11751, 11720-11790, 11794-11809, 13697-13733, 20553-20676, 20664-20824, 20553-20824, or 25844-25912 of SEQ ID NO: 2; and
 wherein the modified oligonucleotide comprises at least one modification selected from at least one modified internucleoside linkage, at least one modified sugar, and at least one modified nucleobase that is a 5-methylcytosine.   
     
     
         11 . The compound of  claim 10 , wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         12 . The compound of  claim 10 , wherein the modified sugar is a bicyclic sugar. 
     
     
         13 . The compound of  claim 12 , wherein the bicyclic sugar is selected from the group consisting of: 4′-(CH 2 )—O-2′ (LNA), 4′-(CH 2 ) 2 —O-2′ (ENA), and 4′-CH(CH 3 )—O-2′ (cEt). 
     
     
         14 . The compound of  claim 10 , wherein the modified sugar is 2′-O-methoxyethyl. 
     
     
         15 . The compound of  claim 10 , wherein the modified oligonucleotide comprises:
 a gap segment consisting of linked deoxynucleosides;   a 5′ wing segment consisting of linked nucleosides; and   a 3′ wing segment consisting of linked nucleosides;   wherein the gap segment is positioned immediately adjacent to and between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.   
     
     
         16 . The compound of  claim 15 , wherein each internucleoside linkage is a phosphothiorate linkage, each cytosine is a 5-methylcytosine, and each nucleoside of each wing segment comprises a cEt sugar. 
     
     
         17 . A composition comprising the compound of  claim 10 , and a pharmaceutically acceptable carrier. 
     
     
         18 . A method of treating, preventing, or ameliorating a disease associated with IRF5 in an individual in need thereof, comprising administering to the individual the compound of  claim 10 , thereby treating, preventing, or ameliorating the disease. 
     
     
         19 . The method of  claim 18 , wherein the disease is an inflammatory bowel disease. 
     
     
         20 . The method of  claim 19 , wherein the inflammatory bowel disease is ulcerative colitis. 
     
     
         21 . The method of  claim 19 , wherein the inflammatory bowel disease is Crohn's disease. 
     
     
         22 . A method of inhibiting or reducing inflammation in the gastrointestinal tract, diarrhea, pain, fatigue, abdominal cramping, blood in the stool, intestinal inflammation, disruption of the epithelial barrier of the gastrointestinal tract, dysbiosis, increased bowel frequency, tenesmus or painful spasms of the anal sphincter, constipation, or unintended weight loss in an individual in need thereof, comprising administering to the individual the compound of  claim 10 , thereby inhibiting or reducing inflammation in the gastrointestinal tract, diarrhea, pain, fatigue, abdominal cramping, blood in the stool, intestinal inflammation, disruption of the epithelial barrier of the gastrointestinal tract, dysbiosis, increased bowel frequency, tenesmus or painful spasms of the anal sphincter, constipation, or unintended weight loss in the individual.