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 lipoprotein lipase deficiency (LPLD) in an animal, comprising administering to the animal a modified oligonucleotide 20 nucleobases in length and having the sequence of SEQ ID NO: 3 wherein the modified oligonucleotide comprises:
 (a) a gap segment consisting of 10 linked deoxynucleosides;   (b) a 5′wing segment consisting of 5 linked nucleosides; and   (c) a 3′ wing segment consisting of 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-methoylcytosine and wherein each internucleoside linkage is a phosphorothioate linkage, thereby treating or ameliorating LPLD in the animal. 
     
     
         2 . The method of  claim 1 , wherein triglyceride levels are reduced in the animal. 
     
     
         3 . (canceled) 
     
     
         4 . The method of  claim 1 , wherein risk of pancreatitis is reduced in the animal. 
     
     
         5 .- 20 . (canceled) 
     
     
         21 . A method of treating or ameliorating Familial Chylomicronemia Syndrome FCS in an animal comprising administering to the animal a modified oligonucleotide 20 nucleobases in length having the sequence of SEQ ID NO: 3 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 the FCS is treated or ameliorated. 
     
     
         22 .- 26 . (canceled) 
     
     
         27 . The method of  claim 1  or  21 , wherein the compound is parenterally administered. 
     
     
         28 . The method of  claim 27 , wherein the parenteral administration is subcutaneous administration. 
     
     
         29 .- 31 . (canceled) 
     
     
         32 . The method of  claim 1  or  21 , wherein the modified oligonucleotide is a salt. 
     
     
         33 . The method of  claim 1  or  21 , further comprising a pharmaceutically acceptable carrier or diluent. 
     
     
         34 . The method of  claim 1  or  21 , wherein the FCS or LPLD, is identified by genetic screening. 
     
     
         35 . The method of  claim 32 , wherein the salt is a sodium salt or potassium salt.