Modulation of apolipoprotein c-iii (apociii) expression in lipoprotein lipase deficient (lpld) populations

Abstract

Provided herein are methods, compounds, and compositions for reducing expression of ApoCIII mRNA and protein in a patient with Fredrickson Type I dyslipidemia, FCS, LPLD. Also provided herein are methods, compounds, and compositions for treating, preventing, delaying, or ameliorating Fredrickson Type I dyslipidemia, FCS, LPLD, in a patient. Further 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 a patient with Fredrickson Type I dyslipidemia, FCS, LPLD. Such methods, compounds, and compositions are useful to treat, prevent, delay, or ameliorate any one or more of pancreatitis, cardiovascular disease or metabolic disorder, or a symptom thereof.

1 . A method of treating or ameliorating pancreatitis or a symptom thereof in an animal having Fredrickson Type 1 dyslipidemia, FCS or LPLD, comprising administering a therapeutically effective amount of a compound comprising an ApoCIII specific inhibitor to the animal, thereby treating or ameliorating pancreatitis. 
     
     
         2 . The method of  claim 1 , wherein triglyceride levels are reduced in the animal. 
     
     
         3 . The method of  claim 1 , wherein HDL levels and/or the ratio of TG to HDL in an animal is improved. 
     
     
         4 .- 8 . (canceled) 
     
     
         9 . The method of  claim 1 , wherein the ApoCIII specific inhibitor is a modified oligonucleotide having a nucleobase sequence complementary to SEQ ID NO: 1, SEQ ID NO: 2 or SEQ ID NO: 4. 
     
     
         10 .- 11 . (canceled) 
     
     
         12 . The method of  claim 9 , wherein the modified oligonucleotide has a nucleobase sequence comprising at least 8 contiguous nucleobases of the nucleobase sequence of SEQ ID NO: 3. 
     
     
         13 . The method of  claim 9 , wherein the nucleobase sequence of the modified oligonucleotide is at least 80%, at least 90% or 100% complementary to the nucleobase sequence of SEQ ID NO: 1, SEQ ID NO: 2 or SEQ ID NO: 4. 
     
     
         14 . The method of  claim 9 , wherein the modified oligonucleotide is single-stranded. 
     
     
         15 . The method of  claim 9 , wherein the modified oligonucleotide consists of 12 to 30 linked nucleosides. 
     
     
         16 . The method of  claim 9 , wherein the modified oligonucleotide consists of 20 linked nucleosides. 
     
     
         17 . The method of  claim 9 , wherein the modified oligonucleotide has at least one modified internucleoside linkage, sugar moiety or nucleobase. 
     
     
         18 . The method of  claim 17 , wherein the modified internucleoside linkage of the modified oligonucleotide is a phosphorothioate internucleoside linkage, the modified sugar is a bicyclic sugar or 2′-O-methyoxyethyl and the modified nucleobase is a 5-methylcytosine. 
     
     
         19 . The method of  claim 9 , wherein the modified oligonucleotide comprises:
 (a) a gap segment consisting of linked deoxynucleosides;   (b) a 5′ wing segment consisting of linked nucleosides;   (c) a 3′ wing segment consisting 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 modified sugar. 
     
     
         20 . The method of  claim 9 , 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-methyoxyethyl sugar, wherein each cytosine is a 5′-methylcytosine, and wherein each internucleoside linkage is a phosphorothioate linkage. 
     
     
         21 . A method of treating or ameliorating pancreatitis or a symptom thereof in an animal having Fredrickson Type 1 dyslipidemia, FCS or LPLD, comprising administering to the animal a therapeutically effective amount of a compound comprising a modified oligonucleotide consisting of the nucleobase sequence of SEQ ID NO: 3 and 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-methyoxyethyl sugar, wherein each cytosine is a 5′-methylcytosine, wherein each internucleoside linkage is a phosphorothioate linkage, and wherein pancreatitis is treated or ameliorated. 
     
     
         22 .- 26 . (canceled) 
     
     
         27 . The method of  claim 1 , wherein the compound is parenterally administered. 
     
     
         28 .- 34 . (canceled)