US2020263179A1PendingUtilityA1

Compositions and methods for inhibiting gene expression of lpa

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Assignee: ARROWHEAD PHARMACEUTICALS INCPriority: Oct 1, 2015Filed: May 6, 2020Published: Aug 20, 2020
Est. expiryOct 1, 2035(~9.2 yrs left)· nominal 20-yr term from priority
Inventors:Stacey MelquistSteven B. KannerDavid B. RozemaDavid L. LewisLauren J. AlmeidaDarren H. WakefieldVladimir TrubetskoyTao PeiZhen LiAaron Almeida
C12N 2310/315C12N 2310/321C12N 2310/351C12N 2310/14A61K 31/7088A61P 9/00C12N 15/113C12N 15/1137C12Y 304/21C12N 2310/3517C12N 2310/31
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Claims

Abstract

RNA interference (RNAi) agents and RNAi agent conjugates for inhibiting the expression of the LPA (apo(a)) gene are described. Pharmaceutical compositions comprising one or more LPA RNAi agents optionally with one or more additional therapeutics are also described. Delivery of the described LPA RNAi agents to liver cells in vivo provides for inhibition of LPA gene expression and treatment of cardiovascular and cardiovascular-related diseases.

Claims

exact text as granted — not AI-modified
1 . An LPA RNA interference (RNAi) agent comprising a sense strand and an antisense strand, wherein said antisense strand comprises the nucleotide sequence of
 a) nucleotides 2-19 of any of SEQ ID NOs:1-108, or   b) any of the antisense strands of Table 1 or Table 2A.   
     
     
         2 . The LPA RNAi agent of  claim 1 , wherein the sense strand comprises the nucleotide sequence of
 a) nucleotides 1-19 of any of SEQ ID NOs:190-268, or   b) any of the sense strands of Table 1 or Table 2B.   
     
     
         3 . The LPA RNAi agent of  claim 1 , wherein the antisense strand comprises the nucleotide sequence of any of SEQ ID NO:1246, SEQ ID NO:1242, SEQ ID NO:1244, SEQ ID NO:1248, SEQ ID NO:1250, SEQ ID NO:1252, or SEQ ID NO:1254, SEQ ID NO:1280, SEQ ID NO:1281, SEQ ID NO:1282, OR SEQ ID NO:1283. 
     
     
         4 . The LPA RNAi agent of  claim 3 , wherein:
 a) the antisense strand comprises the nucleotide sequence of SEQ ID NO:1246 and the sense strand comprises the nucleotide sequence of SEQ ID NO:1247;   b) the antisense strand comprises the nucleotide sequence of SEQ ID NO:1242 and the sense strand comprises the nucleotide sequence of SEQ ID NO:1243;   c) the antisense strand comprises the nucleotide sequence of SEQ ID NO:1244 and the sense strand comprises the nucleotide sequence of SEQ ID NO:1245;   d) the antisense strand comprises the nucleotide sequence of SEQ ID NO:1248 and the sense strand comprises the nucleotide sequence of SEQ ID NO:1249;   e) the antisense strand comprises the nucleotide sequence of SEQ ID NO:1250 and the sense strand comprises the nucleotide sequence of SEQ ID NO:1251;   f) the antisense strand comprises the nucleotide sequence of SEQ ID NO:1252 and the sense strand comprises the nucleotide sequence of SEQ ID NO:1253; or   g) the antisense strand comprises the nucleotide sequence of SEQ ID NO:1254 and the sense strand comprises the nucleotide sequence of SEQ ID NO:1255; or   h) the antisense strand comprises the nucleotide sequence of SEQ ID NO:1280 and the sense strand comprises the nucleotide sequence of SEQ ID NO:1260; OR   i) the antisense strand comprises the nucleotide sequence of SEQ ID NO:1281 and the sense strand comprises the nucleotide sequence of SEQ ID NO:1258; or   j) the antisense strand comprises the nucleotide sequence of SEQ ID NO:1280 and the sense strand comprises the nucleotide sequence of SEQ ID NO:1284; or   k) the antisense strand comprises the nucleotide sequence of SEQ ID NO:1281 and the sense strand comprises the nucleotide sequence of SEQ ID NO:1285; or   l) the antisense strand comprises the nucleotide sequence of SEQ ID NO:1282 and the sense strand comprises the nucleotide sequence of SEQ ID NO:1259; or   m) the antisense strand comprises the nucleotide sequence of SEQ ID NO:1283 and the sense strand comprises the nucleotide sequence of SEQ ID NO:1249.   
     
     
         5 . The LPA RNAi agent of  claim 1 , wherein the sense strand and/or the antisense strand further comprises a 3′ and/or 5′ extension of 1-6 nucleotides in length. 
     
     
         6 . The LPA RNAi agent of  claim 1  wherein the antisense strand comprises a nucleotide sequence of any of SEQ ID NO:156, SEQ ID NO:164, or SEQ ID NO:188. 
     
     
         7 . The LPA RNAi agent of  claim 6 , wherein:
 a) the antisense strand comprises a nucleotide sequence of SEQ ID NO:156. and the sense strand comprises a nucleotide sequence of SEQ ID NO:310,   b) the antisense strand comprises a nucleotide sequence of SEQ ID NO:164. and the sense strand comprises a nucleotide sequence of SEQ ID NO:357,   c) the antisense strand comprises a nucleotide sequence of SEQ ID NO:188 and the sense strand comprises a nucleotide sequence of SEQ ID NO:384,   d) the antisense strand comprises a nucleotide sequence of SEQ ID NO:164 and the sense strand comprises a nucleotide sequence of SEQ ID NO:376, or   e) the antisense strand comprises a nucleotide sequence of SEQ ID NO:164 and the sense strand comprises a nucleotide sequence of SEQ ID NO:384.   
     
     
         8 . The LPA RNAi agent of  claim 1 , wherein the sense strand and/or antisense strand independently comprises one or more modified nucleotides. 
     
     
         9 . The LPA RNAi agent of  claim 8 , wherein the one or more modified nucleotides are independently selected from the group consisting of: 2′-O-methyl modified nucleotide, nucleotide comprising a 5′-phosphorothioate group, 2′-deoxy-2′-fluoro modified nucleotide, 2′-deoxy-modified nucleotide, locked nucleotide, abasic nucleotide, deoxythymidine, inverted deoxythymidine, 2′-amino-modified nucleotide, 2′-alkyl-modified nucleotide, morpholino nucleotide, and non-natural base comprising nucleotide. 
     
     
         10 . The LPA RNAi agent of  claim 1 , wherein the LPA RNAi agent comprises one or more phosphorothioate internucleoside linkages. 
     
     
         11 . The LPA RNAi agent of  claim 1 , wherein the LPA RNAi agent further comprises a targeting group. 
     
     
         12 . The LPA RNAi agent of  claim 11 , wherein the targeting group comprises an asialoglycoprotein receptor ligand. 
     
     
         13 . The LPA RNAi agent of  claim 12 , wherein the asialoglycoprotein receptor ligand comprises a galactose cluster. 
     
     
         14 . The LPA RNAi agent of  claim 13 , wherein the galactose cluster is selected from the group consisting of: (C11-PEG5-NAG5), (C11-PEG5-NAG5), (C6-PEG 4 -NAG3), (NAG 3), (NAG4), (NAG3-AA2), (NAG5-Palm), (NAG13), (NAG18), (NAG24), (NAG25), (NAG25)s, (NAG26), (NAG27), (NAG28), (NAG29), (NAG30), (NAG30)s, (NAG31), (NAG13), (NAG31s), (NAG32), (NAG33), (NAG34), (NAG35), (NAG36), and (NAG37). 
     
     
         15 . The LPA RNAi agent of  claim 11 , wherein the targeting group is conjugated to the sense strand. 
     
     
         16 . The LPA RNAi agent of  claim 15 , wherein the targeting group is conjugated to the 5′ end of the sense strand. 
     
     
         17 . The LPA RNAi agent of  claim 15 , wherein the targeting group is conjugated to the 3′ end of the sense strand. 
     
     
         18 . The LPA RNAi agent of  claim 1 , wherein the LPA RNAi agent further comprises a linking group. 
     
     
         19 . The LPA RNAi agent of  claim 1 , wherein the LPA RNAi agent comprises one or two overhangs. 
     
     
         20 . The LPA RNAi agent of  claim 1 , wherein the LPA RNAi agent comprises one or two frayed ends. 
     
     
         21 . The LPA RNAi agent of  claim 1 , wherein the LPA RNAi agent comprises one or two blunt ends. 
     
     
         22 . The LPA RNAi agent of  claim 1 , wherein the LPA RNAi agent comprises any of the duplex sequences in Table 3A or Table 3B. 
     
     
         23 . The LPA RNAi agent of  claim 22 , wherein the LPA RNAi agent comprises AD03460, AD03536, AD03581, AD03583, AD3847, or AD04110, 
     
     
         24 . Use of the LPA RNAi agent of  claim 1 , for the manufacture of a medicament. 
     
     
         25 . The LPA RNAi agent of  claim 1 , further comprising one or more additional therapeutics or treatments. 
     
     
         26 . The LPA RNAi agent  claim 1 , further comprising a pharmaceutically acceptable excipient. 
     
     
         27 . The LPA RNAi agent of  claim 1 , wherein said LPA RNAi agent is packaged in a kit, container, pack, dispenser, pre-filled syringes, or vials. 
     
     
         28 . A method for inhibiting LPA expression in a cell, tissue, or subject comprising:
 administering to said subject a therapeutically effective amount of an LPA RNAi agent of  claim 1 .   
     
     
         29 . The method of  claim 28 , wherein the composition is administered parenterally. 
     
     
         30 . The method of  claim 28 , wherein the cell is a hepatocyte. 
     
     
         31 . An LPA RNA interference (RNAi) agent comprising a sense sequence and an antisense sequence, wherein said antisense sequence comprises a nucleotide sequence of nucleotides 1-17, 2-18, 1-19, 2-19, 1-21, 1-23, or 1-26 of any of the antisense sequences of Table 1 or Table 2A.

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