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Originally published In Press as doi:10.1194/jlr.M400492-JLR200 on February 16, 2005

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Journal of Lipid Research, Vol. 46, 872-884, May 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

An apolipoprotein B antisense oligonucleotide lowers LDL cholesterol in hyperlipidemic mice without causing hepatic steatosis

Rosanne M. Crooke1, Mark J. Graham, Kristina M. Lemonidis, Charles P. Whipple, Seonjoon Koo and Ranjan J. Perera

Cardiovascular Group, Antisense Drug Discovery, Isis Pharmaceuticals, Inc., 2292 Faraday Avenue, Carlsbad, CA 92008

1 To whom correspondence should be addressed. e-mail: rcrooke{at}isisph.com

High levels of plasma apolipoprotein B-100 (apoB-100), the principal apolipoprotein of LDL, are associated with cardiovascular disease. We hypothesized that suppression of apoB-100 mRNA by an antisense oligonucleotide (ASO) would reduce LDL cholesterol (LDL-C). Because most of the plasma apoB is made in the liver, and antisense drugs distribute to that organ, we tested the effects of a mouse-specific apoB-100 ASO in several mouse models of hyperlipidemia, including C57BL/6 mice fed a high-fat diet, Apoe-deficient mice, and Ldlr-deficient mice. The lead apoB-100 antisense compound, ISIS 147764, reduced apoB-100 mRNA levels in the liver and serum apoB-100 levels in a dose- and time-dependent manner. Consistent with those findings, total cholesterol and LDL-C decreased by 25–55% and 40–88%, respectively.

Unlike small-molecule inhibitors of microsomal triglyceride transfer protein, ISIS 147764 did not produce hepatic or intestinal steatosis and did not affect dietary fat absorption or elevate plasma transaminase levels. These findings, as well as those derived from interim phase I data with a human apoB-100 antisense drug, suggest that antisense inhibition of this target may be a safe and effective approach for the treatment of humans with hyperlipidemia.

Abbreviations: AMPK, AMP-activated protein kinase; apoB, apolipoprotein B; ASO, antisense oligonucleotide; G3PDH, glyceraldehyde-3-phosphate dehydrogenase; HF, high fat; LDL-C, LDL cholesterol; 2'MOE, 2'-O-methoxyethyl; MTP, microsomal triglyceride transfer protein; SCD, stearoyl CoA desaturase; SREBP, sterol-responsive element binding protein; SSC, standard sodium citrate; TG, triglyceride

Supplementary key words lipid metabolism • hypercholesterolemia • apoB-100 • apoB-48 • fat malabsorption • MTP inhibitors


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