Compositions and methods for modulating growth hormone receptor expression

Abstract

The present embodiments provide methods, compounds, and compositions for treating, preventing, or ameliorating a disease associated with excess growth hormone using antisense compounds or oligonucleotides targeted to growth hormone receptor (GHR).

1 .- 213 . (canceled) 
     
     
         214 . A compound comprising a modified oligonucleotide and a conjugate group, wherein the modified oligonucleotide has a nucleobase sequence selected from the group consisting of: SEQ ID NOs: 479, 918, 1800, 1904, 2127, and 2194. 
     
     
         215 . The compound of  claim 214 , wherein the modified oligonucleotide has a nucleobase sequence of SEQ ID NO: 1800, 1904, 2127, or 2194 and comprises of nucleosides that have either a MOE sugar modification, an (S)-cEt sugar modification, or a deoxy modification; wherein each internucleoside linkage is a phosphorothioate linkage; and wherein each cytosine is a 5-methylcytosine. 
     
     
         216 . The compound of  claim 214 , wherein the modified oligonucleotide has a nucleobase sequence of SEQ ID NO: 918 or 479 and comprises:
 a gap segment consisting of ten linked deoxynucleosides;   a 5′ wing segment consisting of five linked nucleosides; and   a 3′ wing segment consisting of five linked nucleosides;   wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment; wherein each nucleoside of the 5′ wing segment comprises a 2′-O-methoxyethyl sugar;   wherein each nucleoside of the 3′ wing segment comprises a 2′-O-methoxyethyl sugar; wherein each internucleoside linkage is a phosphorothioate linkage; and wherein each cytosine is a 5-methylcytosine.   
     
     
         217 . The compound of  claim 214 , wherein the conjugate group is linked to the modified oligonucleotide at the 5′ end of the modified oligonucleotide. 
     
     
         218 . The compound of  claim 214 , wherein the conjugate group comprises N-acetyl galactosamine. 
     
     
         219 . The compound of  claim 214 , wherein the conjugate group comprises: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         220 . The compound of  214 , wherein the conjugate group comprises at least one phosphorus linking group or neutral linking group 
     
     
         221 . A composition comprising the compound of  claim 214 , or salt thereof, and a pharmaceutically acceptable carrier or diluent. 
     
     
         222 . A prodrug comprising the compound of  claim 214 . 
     
     
         223 . A method, comprising:
 administering to an animal a compound of  claim 214 , or a composition comprising the compound or salt thereof and a pharmaceutically acceptable carrier or diluent.   
     
     
         224 . A method of treating a disease associated with excess growth hormone in a subject, comprising:
 administering to the subject a therapeutically effective amount of the compound of  claim 214  or salt thereof, or a composition comprising the compound and a pharmaceutically acceptable carrier or diluent, thereby treating the disease associated with excess growth hormone.   
     
     
         225 . The method of  claim 224 , wherein the subject is a human. 
     
     
         226 . The method of  claim 224 , wherein the disease associated with excess growth hormone is acromegaly. 
     
     
         227 . The method of  claim 224 , wherein the treatment reduces IGF-1 levels. 
     
     
         228 . The method of  claim 224 , comprising co-administering the compound or composition and a second agent. 
     
     
         229 . The method of  claim 228 , wherein the compound or composition and a second agent are administered concomitantly. 
     
     
         230 . A method of preventing a disease associated with excess growth hormone in a subject, comprising:
 administering to the subject a therapeutically effective amount of the compound of  claim 214  or salt thereof, or a composition comprising the compound and a pharmaceutically acceptable carrier and diluent, thereby preventing the disease associated with excess growth hormone.   
     
     
         231 . The method of  claim 230 , wherein disease associated with excess growth hormone is acromegaly. 
     
     
         232 . The method of  claim 230 , comprising co-administering the compound or composition and a second agent. 
     
     
         233 . A method of reducing growth hormone receptor (GHR) levels in a human, comprising:
 administering to the human a therapeutically effective amount of the compound of  claim 214  or salt thereof, or a composition comprising the compound and a pharmaceutically acceptable carrier and diluent, thereby reducing GHR levels in the human.