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Published on: June 12, 2019
An apolipoprotein B antisense oligonucleotide lowers LDL cholesterol in hyperlipidemic mice without causing hepatic
Rosanne M Crooke1, Mark J Graham, Kristina M Lemonidis
1Cardiovascular Group, Antisense Drug Discovery, Isis Pharmaceuticals, Inc., 2292 Faraday Avenue, Carlsbad, CA 92008, USA. rcrooke@isisph.com
Abstract:
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.
Insights
Antisense oligonucleotides (ASOs) targeting apolipoprotein B-100 (apoB-100) mRNA effectively lowered LDL cholesterol in mouse models. This approach shows promise for treating hyperlipidemia safely and effectively.
Area of Science:
- Cardiovascular Science
- Genetics
- Pharmacology
Background:
- High levels of apolipoprotein B-100 (apoB-100), the main component of LDL, are linked to cardiovascular disease.
- Antisense oligonucleotides (ASOs) offer a potential strategy to reduce apoB-100 production by targeting its mRNA.
Purpose of the Study:
- To investigate the efficacy of an apoB-100 ASO in reducing LDL cholesterol (LDL-C) in hyperlipidemic mouse models.
- To evaluate the safety profile of the apoB-100 ASO, assessing effects on liver fat, fat absorption, and liver enzymes.
Main Methods:
- Tested a mouse-specific apoB-100 ASO (ISIS 147764) in C57BL/6 mice on a high-fat diet, Apoe-deficient mice, and Ldlr-deficient mice.
- Measured apoB-100 mRNA levels in the liver and serum apoB-100 levels.
- Assessed changes in total cholesterol and LDL-C, and monitored for hepatic/intestinal steatosis, fat absorption, and plasma transaminase levels.
Main Results:
- ISIS 147764 significantly reduced liver apoB-100 mRNA and serum apoB-100 levels in a dose- and time-dependent manner.
- Total cholesterol and LDL-C decreased by 25-55% and 40-88%, respectively.
- The ASO did not cause steatosis, affect fat absorption, or elevate transaminase levels, indicating a favorable safety profile.
Conclusions:
- Antisense inhibition of apoB-100 mRNA is an effective strategy for lowering LDL-C in hyperlipidemic models.
- The apoB-100 ASO demonstrated a good safety profile, without the adverse effects seen with other lipid-lowering agents.
- These findings, supported by early human trial data, suggest ASO therapy targeting apoB-100 is a promising treatment for human hyperlipidemia.
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