Compositions and methods for modulating pkk expression

Abstract

Disclosed herein are antisense compounds and methods for decreasing PKK mRNA and protein expression. Such methods, compounds, and compositions are useful to treat, prevent, or ameliorate PKK-associated diseases, disorders, and conditions.

1 .- 219 . (canceled) 
     
     
         220 . A compound comprising a modified oligonucleotide and a conjugate group, wherein the modified oligonucleotide consists of 12 to 30 linked nucleosides and has a nucleobase sequence comprising a portion of at least 15 contiguous nucleobases that is at least 90% complementary to an equal length portion of nucleobases 33183-33242 of SEQ ID NO: 10, and wherein the conjugate group comprises at least one N-Acetylgalactosamine (GalNAc). 
     
     
         221 . The compound of  claim 220 , wherein the portion of at least 15 contiguous nucleobases is 100% complementary to the equal length portion of nucleobases 33183-33242 of SEQ ID NO: 10. 
     
     
         222 . The compound of  claim 220 , wherein the sequence of the modified oligonucleotide is SEQ ID NO: 705. 
     
     
         223 . The compound of  claim 220 , wherein the conjugate group comprises three GalNAcs. 
     
     
         224 . The compound of  claim 220 , wherein the conjugate group consists of: 
       
         
           
           
               
               
           
         
       
     
     
         225 . The compound of  claim 224 , consisting of the modified oligonucleotide and the conjugate group. 
     
     
         226 . The compound of  claim 220 , wherein the modified oligonucleotide consists of 20 linked nucleosides. 
     
     
         227 . The compound of  claim 220 , wherein the modified oligonucleotide is at least 90% complementary to SEQ ID NO: 10. 
     
     
         228 . The compound of  claim 220 , wherein at least one internucleoside linkage of the modified oligonucleotide is a phosphorothioate linkage. 
     
     
         229 . The compound of  claim 220 , wherein each cytosine of the modified oligonucleotide is a 5′-methylcytosine. 
     
     
         230 . The compound of  claim 220 , wherein the modified oligonucleotide is single-stranded. 
     
     
         231 . The compound of  claim 220 , comprising at least one 2′-O-methoxyethyl nucleoside, 2′-O-methyl nucleoside, constrained ethyl nucleoside, LNA nucleoside, or 3′-fluoro-HNA nucleoside. 
     
     
         232 . The compound of  claim 220 , wherein the modified oligonucleotide is a gapmer. 
     
     
         233 . The compound of  claim 232 , wherein the modified oligonucleotide comprises:
 a gap segment consisting of 10 linked deoxynucleosides;   a 5′ wing segment consisting of 5 linked nucleosides; and   a 3′ wing segment consisting of 5 linked nucleosides;   
       wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar. 
     
     
         234 . The compound of  claim 220 , wherein the compound is in the form of a salt. 
     
     
         235 . A pharmaceutical composition comprising the compound of  claim 220  and a pharmaceutically acceptable carrier or diluent. 
     
     
         236 . The pharmaceutical composition of  claim 235 , wherein the pharmaceutically acceptable carrier or diluent is phosphate buffered saline (PBS). 
     
     
         237 . The pharmaceutical composition of  claim 235 , wherein the pharmaceutical composition consists essentially of the compound and PBS. 
     
     
         238 . A method comprising administering the compound of  claim 220  to a subject in need thereof. 
     
     
         239 . The method of  claim 238 , wherein administering the compound prevents, treats, or ameliorates a PKK associated disease, disorder or condition. 
     
     
         240 . A compound comprising a modified oligonucleotide and a conjugate group, wherein the modified oligonucleotide consists of 12 to 30 linked nucleosides and has a nucleobase sequence comprising a portion of at least 15 contiguous nucleobases that is at least 90% identical to an equal length portion of a sequence selected from SEQ ID NOs: 155, 156, 157, 158, 159, 160, 261, 702, 703, 704, 705, 706, and 707, and wherein the conjugate group comprises at least one N-Acetylgalactosamine (GalNAc). 
     
     
         241 . The compound of  claim 240 , wherein the portion of at least 15 contiguous nucleobases is 100% identical to the sequence selected from SEQ ID NOs: 155, 156, 157, 158, 159, 160, 261, 702, 703, 704, 705, 706, and 707. 
     
     
         242 . The compound of  claim 240 , wherein the sequence of the modified oligonucleotide is selected from SEQ ID NOs: 155, 156, 157, 158, 159, 160, 261, 702, 703, 704, 705, 706, and 707. 
     
     
         243 . The compound of  claim 240 , wherein the conjugate group comprises three GalNAcs. 
     
     
         244 . The compound of  claim 240 , wherein the conjugate group consists of: 
       
         
           
           
               
               
           
         
       
     
     
         245 . The compound of  claim 244 , consisting of the modified oligonucleotide and the conjugate group. 
     
     
         246 . The compound of  claim 240 , wherein the modified oligonucleotide consists of 20 linked nucleosides. 
     
     
         247 . The compound of  claim 240 , wherein the modified oligonucleotide is at least 90% complementary to SEQ ID NO: 10. 
     
     
         248 . The compound of  claim 240 , wherein at least one internucleoside linkage of the modified oligonucleotide is a phosphorothioate linkage. 
     
     
         249 . The compound of  claim 240 , wherein each cytosine of the modified oligonucleotide is a 5′-methylcytosine. 
     
     
         250 . The compound of  claim 240 , wherein the modified oligonucleotide is single-stranded. 
     
     
         251 . The compound of  claim 240 , comprising at least one 2′-O-methoxyethyl nucleoside, 2′-O-methyl nucleoside, constrained ethyl nucleoside, LNA nucleoside, or 3′-fluoro-HNA nucleoside. 
     
     
         252 . The compound of  claim 240 , wherein the modified oligonucleotide is a gapmer. 
     
     
         253 . The compound of  claim 252 , wherein the modified oligonucleotide comprises:
 a gap segment consisting of 10 linked deoxynucleosides;   a 5′ wing segment consisting of 5 linked nucleosides; and   a 3′ wing segment consisting of 5 linked nucleosides;   
       wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar. 
     
     
         254 . The compound of  claim 240 , wherein the compound is in the form of a salt. 
     
     
         255 . A pharmaceutical composition comprising the compound of  claim 240  and a pharmaceutically acceptable carrier or diluent. 
     
     
         256 . The pharmaceutical composition of  claim 255 , wherein the pharmaceutically acceptable carrier or diluent is phosphate buffered saline (PBS). 
     
     
         257 . The pharmaceutical composition of  claim 255 , wherein the pharmaceutical composition consists essentially of the compound and PBS. 
     
     
         258 . A method comprising administering the compound of  claim 240  to a subject in need thereof. 
     
     
         259 . The method of  claim 258 , wherein administering the compound prevents, treats, or ameliorates a PKK associated disease, disorder or condition. 
     
     
         260 . A compound consisting of a modified oligonucleotide and a conjugate group, wherein the modified oligonucleotide is described by the following chemical notation: mCes mCes mCes mCes mCes Tds Tds mCds Tds Tds Tds Ads Tds Ads Gds mCes mCes Aes Ges mCe; wherein,
 A=an adenine,   mC=a 5-methylcytosine;   G=a guanine,   T=a thymine,   e=a 2′-O-methoxyethyl modified nucleoside,   d=a 2′-deoxynucleoside, and   s=a phosphorothioate internucleoside linkage, and   
       wherein the conjugate moiety is described by the following chemical structure: 
       
         
           
           
               
               
           
         
       
       and 
       wherein the 5′ end of the modified oligonucleotide is directly linked to the conjugate moiety. 
     
     
         261 . A pharmaceutical composition comprising the compound of  claim 260  and at least one of a pharmaceutically acceptable carrier or diluent. 
     
     
         262 . The pharmaceutical composition of  claim 261 , wherein the pharmaceutically acceptable carrier or diluent is PBS. 
     
     
         263 . The pharmaceutical composition of  claim 261 , wherein the pharmaceutical composition consists essentially of the compound and PBS. 
     
     
         264 . A method comprising administering the compound of  claim 260  to a subject in need thereof. 
     
     
         265 . The method of  claim 264 , wherein administering the compound prevents, treats, or ameliorates a PKK associated disease, disorder or condition.