Compounds and methods for modulating angiotensinogen expression

Abstract

Disclosed herein are compositions and compounds comprising modified oligonucleotides for modulating AGT and modulating a RAAS pathway related disease, disorder and/or condition in an individual in need thereof. A RAAS pathway related disease, disorder and/or condition in an individual such as hypertension can be treated, ameliorated, delayed or prevented with the administration of antisense compounds targeted to AGT.

1 . An oligomeric compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides having a nucleobase sequence comprising a portion of at least 8 contiguous nucleobases complementary to an equal length portion of nucleobases 525 to 560 of SEQ ID NO: 1, wherein the nucleobase sequence of the modified oligonucleotide is at least 80% complementary to SEQ ID NO: 1. 
     
     
         2 . An oligomeric compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides having a nucleobase sequence comprising a portion of at least 8 contiguous nucleobases complementary to an equal length portion of nucleobases 643-691 of SEQ ID NO: 1, wherein the nucleobase sequence of the modified oligonucleotide is at least 80% complementary to SEQ ID NO: 1. 
     
     
         3 . The oligomeric compound of  claim 1 , wherein the modified oligonucleotide consists of 15 to 30 linked nucleosides. 
     
     
         4 - 6 . (canceled) 
     
     
         7 . An oligomeric compound comprising a modified oligonucleotide comprising 12 to 30 linked nucleosides and having a nucleobase sequence comprising at least 19 contiguous nucleobases of the nucleobase sequence of SEQ ID NOs: 46, 53-54, 61, 68, 76, 83, 85, 93, 96-97, 109, 134-135, 137-39, 142, 163-172, 180-184, 186, 189, 234, 236, 238-239, 267, 313, 411, 452, 463-470, 475-478, 480, 500-503, 512, 517-518, 524-526, 654, 689, 702, 725-726, 728, 738, 779, 786-787, 800, 808, 810-811, 825, 865, 868, 889, 894, 903, 905, 909, 954, 966, 1011, 1015, 1021, 1024, 1080, 1085, 1258-1259, 1261-1262, 1293-1294, 1299, 1325, 1470, 1472-1473, 1522, 1542, 1604, 1623-1624, 1667, 1670, 1682-1683, 1687, 1700, 1703-1704, 1708, 1714, 1716, 1719-1720, 1724-1726, 1729-1730, 1827, 1936, 1843-1844, 1846, 1886, 1893-1894, 1923, 1925, 1932, 1979, 1986, 1988, 1990, 2003, 2015, 2018, 2020, 2027-2028, 2035, 2037, 2039, 2044. 
     
     
         8 - 10 . (canceled) 
     
     
         11 . The oligomeric compound of  claim 1 , wherein the compound is double-stranded. 
     
     
         12 . The oligomeric compound of  claim 1 , wherein at least one internucleoside linkage is a modified internucleoside linkage. 
     
     
         13 . The oligomeric compound of  claim 12 , wherein at least one modified internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         14 . The oligomeric compound of  claim 12 , wherein each modified internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         15 . The oligomeric compound of  claim 1 , wherein the modified oligonucleotide comprises at least one modified sugar. 
     
     
         16 . The oligomeric compound of  claim 15 , wherein at least one modified sugar is a bicyclic sugar. 
     
     
         17 . The oligomeric compound of  claim 15 , wherein at least one modified sugar comprises a 2′-O-methoxyethyl, a constrained ethyl (cEt), a 3′-fluoro-HNA or a 4′-(CH 2 ) n —O-2′ bridge, wherein n is 1 or 2. 
     
     
         18 . The oligomeric compound of  claim 1 , wherein at least one nucleoside comprises a modified nucleobase. 
     
     
         19 . The oligomeric compound of  claim 18 , wherein the modified nucleobase is a 5-methylcytosine. 
     
     
         20 . The oligomeric compound of  claim 1 , wherein the modified oligonucleotide consists of 12 to 30 linked nucleosides and comprises:
 a. a gap segment consisting of linked deoxynucleosides;   b. a 5′ wing segment consisting of linked nucleosides; and   c. a 3′ wing segment consisting of 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.   
     
     
         21 - 23 . (canceled) 
     
     
         24 . The oligomeric compound of  claim 20 , wherein the modified oligonucleotide consists of 16 to 20 linked nucleosides comprising:
 a. a gap segment consisting of ten linked deoxynucleosides;   b. a 5′ wing segment consisting of three to five linked nucleosides; and   c. a 3′ wing segment consisting of three to five linked nucleosides;   wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar, wherein each internucleoside linkage is a phosphorothioate linkage and wherein each cytosine residue is a 5-methylcytosine.   
     
     
         25 . (canceled) 
     
     
         26 . The oligomeric compound of  claim 1 , further comprising a conjugate group. 
     
     
         27 . The oligomeric compound of 26, wherein the conjugate group is a GalNAc moiety. 
     
     
         28 - 29 . (canceled) 
     
     
         30 . A composition comprising the oligomeric compound of  claim 1 , or a salt thereof, and a pharmaceutically acceptable carrier or diluent. 
     
     
         31 - 33 . (canceled) 
     
     
         34 . A method of treating, preventing, ameliorating or slowing progression of a disease, disorder or condition related to a RAAS pathway related disease, disorder and/or condition in an animal comprising administering to the animal the composition of  claim 30 . 
     
     
         35 . The method of  claim 34 , wherein the disease, disorder or condition is hypertension.