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 .- 34 . (canceled) 
     
     
         35 . A method of treating familial chylomicronemia syndrome (FCS) comprising administering to an affected individual a therapeutically effective amount of a compound comprising a modified oligonucleotide having nucleobase sequence SEQ ID NO: 3, or a pharmaceutically acceptable salt thereof;
 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, each nucleoside of each wing segment comprises a 2′-O-methyoxyethyl sugar, each cytosine is a 5′-methylcytosine, and each internucleoside linkage is a phosphorothioate linkage; and   wherein fasting triglyceride levels are reduced by at least forty percent (40%) from baseline level in the individual; thereby treating familial chylomicronemia syndrome (FCS) in the affected individual.   
     
     
         36 . The method of  claim 35  wherein the compound is parenterally administered. 
     
     
         37 . The method of  claim 36 , wherein the administration is subcutaneous administration. 
     
     
         38 . The method of  claim 35 , wherein the compound is in the form of a sodium salt. 
     
     
         39 . The method of  claim 35 , wherein the compound is administered as a composition further comprising a pharmaceutically acceptable carrier or diluent. 
     
     
         40 . The method of  claim 35 , further comprising administering a second agent or therapy. 
     
     
         41 . The method of  claim 40 , wherein the second agent is selected from an ApoCIII lowering agent, a non-HDL lipid lowering agent, an LDL lowering agent, a TG lowering agent, a cholesterol lowering agent, an HDL raising agent, fish oil, niacin, a fibrate, a statin, DCCR (salt of diazoxide), a glucose-lowering agent or an anti-diabetic agent. 
     
     
         42 . The method of  claim 40 , wherein the second therapy is dietary fat restriction. 
     
     
         43 . The method of  claim 35 , wherein fasting triglyceride levels are reduced by at least forty five percent (45%), at least fifty percent (50%), at least sixty percent (60%), at least seventy percent (70%), or at least eighty percent (80%) from baseline level in the individual. 
     
     
         44 . The method of  claim 35 , wherein fasting triglyceride levels are reduced by at least seventy percent (70%) from baseline level in the individual. 
     
     
         45 . A method of treating familial chylomicronemia syndrome (FCS) comprising administering to an affected individual a therapeutically effective amount of a compound comprising a modified oligonucleotide having nucleobase sequence SEQ ID NO: 3, or a pharmaceutically acceptable salt thereof, 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, each nucleoside of each wing segment comprises a 2′-O-methyoxyethyl sugar, each cytosine is a 5′-methylcytosine, and each internucleoside linkage is a phosphorothioate linkage; and 
       wherein fasting triglyceride levels are reduced to less than or equal to seven hundred fifty mg per dL (≤750 mg/dL) in the individual; thereby treating familial chylomicronemia syndrome (FCS) in the affected individual. 
     
     
         46 . The method of  claim 45  wherein the compound is parenterally administered. 
     
     
         47 . The method of  claim 46 , wherein the administration is subcutaneous administration. 
     
     
         48 . The method of  claim 45 , wherein the compound is in the form of a sodium salt. 
     
     
         49 . The method of  claim 45 , wherein the compound is administered as a composition further comprising a pharmaceutically acceptable carrier or diluent. 
     
     
         50 . The method of  claim 45 , further comprising administering a second agent or therapy. 
     
     
         51 . The method of  claim 40 , wherein the second agent is selected from an ApoCIII lowering agent, a non-HDL lipid lowering agent, an LDL lowering agent, a TG lowering agent, a cholesterol lowering agent, an HDL raising agent, fish oil, niacin, a fibrate, a statin, DCCR (salt of diazoxide), a glucose-lowering agent or an anti-diabetic agent. 
     
     
         52 . The method of  claim 50 , wherein the second therapy is dietary fat restriction. 
     
     
         53 . The method of  claim 45 , wherein fasting triglyceride levels are reduced to ≤750 mg/dL, ≤700 mg/dL, ≤650 mg/dL, ≤600 mg/dL, ≤550 mg/dL, ≤500 mg/dL, ≤450 mg/dL, ≤400 mg/dL, ≤350 mg/dL, ≤300 mg/dL, ≤250 mg/dL, or ≤200 mg/dL in the individual. 
     
     
         54 . The method of  claim 45 , wherein fasting triglyceride levels are reduced to ≤400 mg/dL in the individual.