New drug strategy targets liver to lower heart disease risk without side effects
Researchers have identified a way to safely reduce dangerous blood fats linked to heart disease by silencing a single gene in the liver. The approach sidesteps problems seen with broader treatments, potentially opening a new market for lipid-lowering drugs that could compete with existing cholesterol therapies.
Originaltitel: Liver-targeted Angptl4 silencing by antisense oligonucleotide treatment attenuates hyperlipidaemia and atherosclerosis development in APOE*3-Leiden.CETP mice
<p>Aims: Angiopoietin-like 3 (ANGPTL3) and 4 (ANGPTL4) inhibit lipoprotein lipase to regulate tissue fatty acid (FA) uptake from triglyceride (TG)-rich lipoproteins such as very low density lipoproteins (VLDL). While pharmacological inhibition of ANGPTL3 is being evaluated as a lipid-lowering strategy, systemic ANGPTL4 inhibition is not pursued due to adverse effects. This study aims to compare the therapeutic potential of liver-specific <em>Angptl3</em> and <em>Angptl4</em> silencing to attenuate hyperlipidemia and atherosclerosis development in APOE*3-Leiden.CETP mice, a well-established humanized model for lipoprotein metabolism.</p><p>Methods and results: Mice were subcutaneously injected twice per week with saline or liver-targeted antisense oligonucleotides against <em>Angptl3</em>, <em>Angptl4</em>, both, or a scrambled oligonucleotide. Plasma lipid levels, VLDL clearance, and hepatic VLDL production were determined, and atherosclerosis development was assessed. For toxicological evaluation, cynomolgus monkeys were treated with three dosages of liver-targeted <em>ANGPTL4</em>-silencing oligonucleotides. Liver-targeted <em>Angptl4</em> silencing reduced plasma TGs (-48%) and total cholesterol (-56%), explained by higher VLDL-derived FA uptake by brown adipose tissue and lower VLDL production by the liver. Accordingly, <em>Angptl4 </em>silencing reduced atherosclerotic lesion size (-86%) and improved lesion stability. Hepatic <em>Angptl3</em> silencing similarly attenuated hyperlipidemia and atherosclerosis development. While <em>Angptl3</em> and <em>Angptl4</em> silencing lowered plasma TGs in the refed and fasted state, respectively, combined <em>Angptl3/4</em> silencing lowered plasma TGs independent of the nutritional state. In cynomolgus monkeys, anti-<em>ANGPTL4</em> ASO treatment was well tolerated without adverse effects.</p><p>Conclusion: Liver-targeted <em>Angptl4</em> silencing potently attenuates hyperlipidemia and atherosclerosis development in APOE*3-Leiden.CETP mice, and liver-targeted <em>ANGPTL4</em> silencing is well tolerated in non-human primates. These data warrant further clinical development of liver-targeted <em>ANGPTL4</em> silencing.</p>