US2016060625A1PendingUtilityA1

Modulation of apolipoprotein ciii (apociii) expression

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Assignee: ISIS PHARMACEUTICALS INCPriority: Apr 27, 2011Filed: Aug 7, 2015Published: Mar 3, 2016
Est. expiryApr 27, 2031(~4.7 yrs left)· nominal 20-yr term from priority
Inventors:Adam MullickRosanne M. CrookeMark J. GrahamKenneth DobieThomas A. Bell, IiiRichard Lee
A61P 7/00A61P 3/06A61P 43/00A61P 9/04A61P 9/06A61P 9/10A61P 9/12A61P 9/00A61P 29/00A61P 1/00A61P 1/18A61P 25/00A61P 21/00C12N 2310/321A61K 45/06A61K 31/713C12N 2310/11A61K 31/7088A61K 48/0058C12N 15/113A61K 2121/00C12N 2310/341C12N 2310/315C12N 2310/346C12N 2310/351A61K 48/0066
51
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Claims

Abstract

Provided herein are methods, compounds, and compositions for reducing expression of ApoCIII mRNA and protein in an animal. Also provided herein are methods, compounds, and compositions for increasing HDL levels and/or improving the ratio of TG to HDL and reducing plasma lipids and plasma glucose in an animal. Such methods, compounds, and compositions are useful to treat, prevent, delay, or ameliorate any one or more of cardiovascular disease or metabolic disorder, or a symptom thereof.

Claims

exact text as granted — not AI-modified
1 . A method of increasing high density lipoprotein (HDL) levels in a human subject, comprising (a) selecting a human subject in need of treatment of cardiovascular disease, and (b) administering to the human subject a therapeutically effective amount of a compound comprising a modified oligonucleotide 12 to 30 nucleobases in length targeted to an apolipoprotein C-III (ApoCIII) nucleic acid as shown in SEQ ID NOs:1-2, wherein after (b) HDL levels are increased and the cardiovascular disease is treated in the human subject. 
     
     
         2 .- 14 . (canceled) 
     
     
         15 . The method of  claim 1 , wherein the cardiovascular disease is hypertriglyceridemia or dyslipidemia. 
     
     
         16 .- 23 . (canceled) 
     
     
         24 . The method of  claim 1 , wherein the modified oligonucleotide has a nucleobase sequence comprising at least 8 contiguous nucleobases of a nucleobase sequence of SEQ ID NO: 3. 
     
     
         25 . The method of  claim 1 , wherein the nucleobase sequence of the modified oligonucleotide is at least 80%, at least 90% or 100% complementary to a nucleobase sequence of SEQ ID NO: 1 or SEQ ID NO: 2. 
     
     
         26 .- 27 . (canceled) 
     
     
         28 . The method of  claim 1 , wherein the modified oligonucleotide consists of a single-stranded modified oligonucleotide. 
     
     
         29 . (canceled) 
     
     
         30 . The method of  claim 1 , wherein the modified oligonucleotide consists of 20 linked nucleosides. 
     
     
         31 . The method of  claim 1 , wherein at least one internucleoside linkage of the modified oligonucleotide is a modified internucleoside linkage. 
     
     
         32 . The method of  claim 31 , wherein at least one modified internucleoside linkage of the modified oligonucleotide is a phosphorothioate internucleoside linkage. 
     
     
         33 . The method of  claim 1 , wherein at least one nucleoside of the modified oligonucleotide comprises a modified sugar. 
     
     
         34 . The method of  claim 33 , wherein at least one modified sugar is a bicyclic sugar. 
     
     
         35 . The method of  claim 33 , wherein at least one modified sugar comprises a 2′-O-methoxyethyl. 
     
     
         36 . The method of  claim 1 , wherein at least one nucleoside of the modified oligonucleotide comprises a modified nucleobase. 
     
     
         37 . The method of  claim 36 , wherein the modified nucleobase is a 5-methylcytosine. 
     
     
         38 .- 39 . (canceled) 
     
     
         40 . The method of  claim 30 , wherein the modified oligonucleotide comprises:
 (a) a gap segment consisting of 10 linked deoxynucleosides;   (b) a 5′ wing segment consisting of 5 linked nucleosides;   (c) a 3′ wing segment consisting 5 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 2′O-methoxyethyl sugar, wherein each cytosine is a 5′-methylcytosine, and wherein each internucleoside linkage is a phosphorothioate linkage. 
     
     
         41 . The method of  claim 40 , wherein the modified oligonucleotide has a nucleobase sequence comprising at least 8 contiguous nucleobases of a nucleobase sequence of SEQ ID NO: 3. 
     
     
         42 .- 85 . (canceled) 
     
     
         86 . The method of  claim 1 , wherein the HDL levels are increased by at least 20% in the human subject. 
     
     
         87 . The method of  claim 1 , wherein the nucleobases of the modified oligonucleotide consist of the nucleobase sequence of SEQ ID NO: 3. 
     
     
         88 . The method of  claim 1 , wherein the compound comprises a conjugate. 
     
     
         89 . The method of  claim 1 , wherein the compound is in a salt form. 
     
     
         90 . A method for treating chylomicronemia in a human subject, comprising (i) selecting a human subject in need of treatment of chylomicronemia, and (ii) administering to the human subject a therapeutically effective amount of a compound comprising a modified oligonucleotide 12 to 30 nucleobases in length targeted to an apolipoprotein C-III (ApoCIII) nucleic acid as shown in SEQ ID NO: 1-2, wherein administration of the compound to the human subject treats the chylomicronemia. 
     
     
         91 . The method of  claim 90 , wherein the modified oligonucleotide consists of a single-stranded modified oligonucleotide. 
     
     
         92 . The method of  claim 90 , wherein the modified oligonucleotide has a nucleobase sequence comprising at least 8 nucleobases of the nucleobase sequence of SEQ ID NO: 3. 
     
     
         93 . The method of  claim 90 , wherein the modified oligonucleotide consists of 20 linked nucleosides. 
     
     
         94 . The method of  claim 93 , wherein the nucleobases of the modified oligonucleotide consist of the nucleobase sequence of SEQ ID NO: 3. 
     
     
         95 . The method of  claim 94 , wherein the modified oligonucleotide comprises:
 (a) a gap segment consisting of 10 linked deoxynucleosides;   (b) a 5′ wing segment consisting of 5 linked nucleosides;   (c) a 3′ wing segment consisting 5 linked nucleosides;   
       wherein the gap segment is positioned immediately adjacent to and 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 cytosine is a 5′-methylcytosine, and wherein each internucleoside linkage is a phosphorothioate linkage. 
     
     
         96 . The method of  claim 90 , wherein the compound comprises a conjugate. 
     
     
         97 . The method of  claim 90 , wherein the compound is in a salt form. 
     
     
         98 . A method for treating pancreatitis in a human subject, comprising (i) selecting a human subject in need of treatment of pancreatitis, and (ii) administering to the human subject a therapeutically effective amount of a compound comprising a modified oligonucleotide 12 to 30 nucleobases in length targeted to an apolipoprotein C-III (ApoCIII) nucleic acid as shown in SEQ ID NO: 1-2, wherein administration of the compound to the human subject treats the pancreatitis. 
     
     
         99 . The method of  claim 98 , wherein the modified oligonucleotide consists of a single-stranded modified oligonucleotide. 
     
     
         100 . The method of  claim 98 , wherein the modified oligonucleotide has a nucleobase sequence comprising at least 8 nucleobases of the nucleobase sequence of SEQ ID NO: 3. 
     
     
         101 . The method of  claim 98 , wherein the modified oligonucleotide consists of 20 linked nucleosides. 
     
     
         102 . The method of  claim 101 , wherein the nucleobases of the modified oligonucleotide consist of the nucleobase sequence of SEQ ID NO: 3. 
     
     
         103 . The method of  claim 102 , wherein the modified oligonucleotide comprises:
 (a) a gap segment consisting of 10 linked deoxynucleosides;   (b) a 5′ wing segment consisting of 5 linked nucleosides;   (c) a 3′ wing segment consisting 5 linked nucleosides;   
       wherein the gap segment is positioned immediately adjacent to and 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 cytosine is a 5′-methylcytosine, and wherein each internucleoside linkage is a phosphorothioate linkage. 
     
     
         104 . The method of  claim 98 , wherein the compound comprises a conjugate. 
     
     
         105 . The method of  claim 98 , wherein the compound is in a salt form.

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