Gamma-secretase inhibition reduce apoc3 levels and plasma triglycerides

Abstract

A method of reducing a subject's plasma triglyceride level, comprising administering to a subject in need thereof a gamma-secretase inhibitor in an amount effective to reduce the subject's plasma triglyceride level.

What is claimed is: 
     
         1 . A method of reducing a subject's plasma triglyceride level, comprising administering to a subject in need thereof a gamma-secretase inhibitor in an amount effective to reduce the subject's plasma triglyceride level. 
     
     
         2 . A method of treating a subject afflicted with hypertriglyceridemia, comprising administering to the subject a gamma-secretase inhibitor in an amount effective to treat the subject. 
     
     
         3 . The method of  claim 1  or  claim 2 , wherein the administration reduces the subject's serum triglyceride level. 
     
     
         4 . The method of  claim 3 , wherein the administration reduces the triglyceride level in the subject's very low-density lipoprotein (VLDL) serum fraction. 
     
     
         5 . The method of  claim 3 , wherein the administration reduces the subject's serum triglyceride level and serum apolipoprotein C3 (ApoC3) level. 
     
     
         6 . A method of reducing a subject's plasma glucose level, comprising administering to a subject in need thereof a gamma-secretase inhibitor in an amount effective to reduce the subject's glucose level. 
     
     
         7 . The method of any one of  claims 1 - 6 , wherein administration of the gamma-secretase inhibitor inhibits whole-body gamma-secretase. 
     
     
         8 . The method of any one of  claims 1 - 6 , wherein administration of the gamma-secretase inhibitor inhibits liver gamma-secretase without significantly inhibiting gamma-secretase elsewhere in the subject. 
     
     
         9 . The method of any one of  claims 1 - 6 , wherein the administration of the gamma-secretase inhibitor targets the gamma-secretase inhibitor to the liver. 
     
     
         10 . The method of  claim 10 , wherein the administration of the gamma-secretase inhibitor targets the gamma-secretase inhibitor to hepatocytes. 
     
     
         11 . The method of any one of  claims 8 - 10 , wherein the gamma-secretase inhibitor is (i) coupled to a ligand molecule targeted to a receptor on a hepatic cell, or (ii) administered by a bio-nanocapsule. 
     
     
         12 . The method of any one of  claims 8 - 11 , wherein gastrointestinal Notch inhibition is substantially uninhibited. 
     
     
         13 . The method of any one of  claims 1 - 12 , wherein the gamma-secretase inhibitor is a small molecule inhibitor, an oligonucleotide or an adenoviral vector. 
     
     
         14 . The method of  claim 13 , wherein the gamma-secretase inhibitor is an oligonucleotide. 
     
     
         15 . The method of  claim 14 , wherein the oligonucleotide is an antisense oligonucleotide, an RNA-interference inducing compound, or a ribozyme. 
     
     
         16 . The method of  claim 14  or  claim 15 , wherein the oligonucleotide is targeted to hepatocytes. 
     
     
         17 . The method of any one of  claims 14 - 16 , wherein the oligonucleotide comprises 1, 2, 3, 4, or 5 or more stretches of nucleotides in a sequence that is complementary to nicastrin-encoding mRNA, presenilin 1-encoding mRNA and presenilin 2-encoding mRNA, or APH1A-encoding mRNA and API1B-encoding mRNA, wherein each stretch of complementary continguous nucleotides is at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more nucleotides in length. 
     
     
         18 . The method of any one of  claims 14 - 17 , wherein the oligonucleotide is modified to increase its stability in vivo. 
     
     
         19 . The method of  claim 13 , wherein the gamma-secretase inhibitor is a small molecule inhibitor. 
     
     
         20 . The method of  claim 19 , wherein the small molecule inhibitor is 2,2-dimethyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide, (S)-2-((S)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-3-ylamino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide, bis(fluoroalkyl)-1,4- benzodiazepinone, (2S)-2-hydroxy-3-methyl-N-((1S)-1-methyl-2-{[(1S)-3-methyl-2-oxo-2,3,4,5-tetrahydro-1H-3-benzazepin-1-yl]amino}-2- oxoethyl)butanamide, cis-3-[4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl] propanoic acid, dual anti-platelet study, bis(fluoroalkyl)-1,4-benzodiazepinone, or N-[(1S)-2-[[(7S)-6,7-dihydro-5-methyl-6-oxo-5H-dibenz[b, d]azepin-7-yl]amino]-1-methyl-2-oxoethyl]-3,5-difluoro-benzeneacetamide. 
     
     
         21 . The method of any one of  claims 1 - 20 , wherein the subject is obese. 
     
     
         22 . The method of any one of  claims 1 - 21 , wherein the subject has hypertriglyceridemia. 
     
     
         23 . The method of  claim 22 , wherein the hypertriglyceridemia is obesity-induced hypertriglyceridemia. 
     
     
         24 . The method of any one of  claims 1 - 23 , wherein the subject has fatty liver disease. 
     
     
         25 . The method of  claims 24 , wherein the subject has non-alcoholic fatty liver disease. 
     
     
         26 . The method of any one of  claims 1 - 25 , wherein the subject has atherosclerosis. 
     
     
         27 . The method of any one of  claims 1 - 26 , wherein the subject has coronary heart disease. 
     
     
         28 . The method of any one of  claims 1 - 27 , wherein the subject has diabetes. 
     
     
         29 . The method of  claim 28 , wherein the subject has Type 2 Diabetes. 
     
     
         30 . The method of any one of  claims 1 - 29 , wherein the subject is a human. 
     
     
         31 . The method of any one of  claims 1 - 30 , wherein the subject's plasma triglyceride level is >150 mg/dL. 
     
     
         32 . The method of any one of  claims 1 - 30 , wherein the subject's plasma triglyceride level is >500 mg/dL, about 200 to 499 mg/dL, or about 150 to 199 mg/dL. 
     
     
         33 . The method of any one of  claims 1 - 32 , wherein the subject's plasma triglyceride level is reduced by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, or at least 75%, relative to the level prior to administration of the gamma-secretase inhibior. 
     
     
         34 . The method of any one of  claims 1 - 33 , wherein the subject's glucose level while fasting is >100 mg/dl,. 
     
     
         35 . The method of any one of  claims 1 - 33 , wherein the subject's glucose level two hours after eating is >140 mg/dL. 
     
     
         36 . The method of any one of  claims 1 - 35 , wherein the subject's plasma triglyceride level is reduced by at least 5%, at least 10%, at least 15%, at least 20%, or at least 25%, relative to the level prior to administration of the gamma-secretase inhibitor.