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Papers In Press, published online ahead of print February 16, 2005
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ISIS Pharmaceuticals, Carlsbad, CA 92008
Corresponding Author: rcrooke{at}isisph.com
High levels of plasma apolipoprotein (apo)B-100, the principal apolipoprotein of LDL, are associated with cardiovascular disease. We hypothesized that suppression of apoB-100 mRNA by an antisense oligonucleotide would reduce LDL cholesterol. 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 antisense oligonucleotide 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 cholesterol 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, 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.
Revised on February 7, 2005
Accepted on February 9, 2005
An apolipoprotein B antisense oligonucleotide lowers LDL cholesterol in hyperlipidemic mice without causing hepatic steatosis
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