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Comparison of the pharmacological profiles of murine antisense oligonucleotides targeting apolipoprotein B and
Richard G Lee1, Wuxia Fu1, Mark J Graham1
1Cardiovascular Antisense Drug Discovery Group, Isis Pharmaceuticals, Carlsbad, CA 92010.
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.
Insights
Apolipoprotein B (apoB) and microsomal triglyceride transfer protein (MTP) antisense oligonucleotides (ASOs) effectively lower LDL-C. ApoB ASO demonstrated a superior liver safety profile compared to MTP ASO in preclinical models.
Area of Science:
- Pharmacology
- Metabolic Diseases
- Hepatology
Background:
- Lipid-lowering drugs are crucial for patients with hyperlipidemia.
- Apolipoprotein B (apoB) and microsomal triglyceride transfer protein (MTP) are key targets for reducing LDL-C.
- Novel therapeutic agents targeting apoB and MTP are under clinical development.
Purpose of the Study:
- To compare the metabolic consequences of targeting apoB versus MTP.
- To evaluate the liver safety profiles of apoB and MTP inhibition.
- To assess the efficacy of apoB and MTP antisense oligonucleotides (ASOs) in preclinical models.
Main Methods:
- Administration of murine-specific apoB or MTP ASOs to different mouse models (C57BL/6 and LDLr⁻/⁻) under various dietary conditions.
- Analysis of hepatic mRNA and protein levels for apoB and MTP.
- Assessment of hepatic VLDL/triglyceride secretion, hepatic triglyceride accumulation, and biomarkers of hepatotoxicity.
- Evaluation of peroxisome proliferator activated receptor γ (PPARγ) target gene expression and hepatic fatty acid synthesis.
Main Results:
- Both apoB and MTP ASO treatments significantly reduced hepatic target mRNA and protein, leading to decreased hepatic VLDL/triglyceride secretion.
- MTP ASO treatment resulted in increased hepatic triglyceride accumulation and elevated biomarkers of hepatotoxicity compared to apoB ASO.
- These effects in MTP ASO treatment were partly attributed to enhanced PPARγ target gene expression and unimpeded hepatic fatty acid synthesis.
Conclusions:
- Both apoB and MTP ASOs effectively lower LDL-C levels in preclinical models.
- ApoB ASO exhibits a more favorable liver safety profile than MTP ASO.
- Targeting apoB may offer a safer therapeutic strategy for managing hyperlipidemia compared to MTP inhibition.
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