title: Comparison of the pharmacological profiles of murine antisense oligonucleotides targeting apolipoprotein B and microsomal triglyceride transfer protein.
abstract: Therapeutic agents that suppress apolipoprotein B (apoB) and microsomal triglyceride transfer protein (MTP) levels/activity are being developed in the clinic to benefit patients who are unable to reach target LDL-C levels with maximally tolerated lipid-lowering drugs. To compare and contrast the metabolic consequences of reducing these targets, murine-specific apoB or MTP antisense oligonucleotides (ASOs) were administered to chow-fed and high fat-fed C57BL/6 or to chow-fed and Western diet-fed LDLr⁻/⁻ mice for periods ranging from 2 to 12 weeks, and detailed analyses of various factors affecting fatty acid metabolism were performed. Administration of these drugs significantly reduced target hepatic mRNA and protein, leading to similar reductions in hepatic VLDL/triglyceride secretion. MTP ASO treatment consistently led to increases in hepatic triglyceride accumulation and biomarkers of hepatotoxicity relative to apoB ASO due in part to enhanced expression of peroxisome proliferator activated receptor γ target genes and the inability to reduce hepatic fatty acid synthesis. Thus, although both drugs effectively lowered LDL-C levels in mice, the apoB ASO produced a more positive liver safety profile.
authors.affiliation: Cardiovascular Antisense Drug Discovery Group, Isis Pharmaceuticals, Carlsbad, CA 92010.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Lee
authors.affiliation: Cardiovascular Antisense Drug Discovery Group, Isis Pharmaceuticals, Carlsbad, CA 92010.
authors.forename: Wuxia
authors.initials: W
authors.lastname: Fu
authors.affiliation: Cardiovascular Antisense Drug Discovery Group, Isis Pharmaceuticals, Carlsbad, CA 92010.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Graham
authors.affiliation: Cardiovascular Antisense Drug Discovery Group, Isis Pharmaceuticals, Carlsbad, CA 92010.
authors.forename: Adam E
authors.initials: AE
authors.lastname: Mullick
authors.affiliation: Cardiovascular Antisense Drug Discovery Group, Isis Pharmaceuticals, Carlsbad, CA 92010.
authors.forename: Donna
authors.initials: D
authors.lastname: Sipe
authors.affiliation: Cardiovascular Antisense Drug Discovery Group, Isis Pharmaceuticals, Carlsbad, CA 92010.
authors.forename: Danielle
authors.initials: D
authors.lastname: Gattis
authors.affiliation: Cardiovascular Antisense Drug Discovery Group, Isis Pharmaceuticals, Carlsbad, CA 92010.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Bell
authors.affiliation: Cardiovascular Antisense Drug Discovery Group, Isis Pharmaceuticals, Carlsbad, CA 92010.
authors.forename: Sheri
authors.initials: S
authors.lastname: Booten
authors.affiliation: Cardiovascular Antisense Drug Discovery Group, Isis Pharmaceuticals, Carlsbad, CA 92010.
authors.forename: Rosanne M
authors.initials: RM
authors.lastname: Crooke
mesh_terms: D000818:Animals; D001055:Apolipoproteins B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D014280:Triglycerides / Q000378:metabolism
chemical_list: D001055:Apolipoproteins B; D002352:Carrier Proteins; D016376:Oligonucleotides, Antisense; D014280:Triglycerides; C106092:microsomal triglyceride transfer protein; D002784:Cholesterol