Liver-targeted Angptl4 silencing by antisense oligonucleotide treatment attenuates hyperlipidemia and atherosclerosis development in APOE*3-Leiden.CETP mice.

Autor:	Modder M; Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands.; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands., Het Panhuis WI; Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands.; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands., Li M; Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands.; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands., Afkir S; Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands.; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands., Dorn AL; Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands.; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands., Pronk ACM; Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands.; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands., Streefland TCM; Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands.; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands., Lalai RA; Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands.; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands., Pierrou S; Lipigon Pharmaceuticals AB, Tvistevägen 48C, 907 36, Umeå, Sweden., Nilsson SK; Lipigon Pharmaceuticals AB, Tvistevägen 48C, 907 36, Umeå, Sweden., Olivecrona G; Lipigon Pharmaceuticals AB, Tvistevägen 48C, 907 36, Umeå, Sweden.; Department of Medical Biosciences, Umeå University, Umeå, Sweden., Kooijman S; Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands.; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands., Rensen PCN; Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands.; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands., Schönke M; Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands.; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
Jazyk:	angličtina
Zdroj:	Cardiovascular research [Cardiovasc Res] 2024 Sep 11. Date of Electronic Publication: 2024 Sep 11.
DOI:	10.1093/cvr/cvae195
Abstrakt:	Background and Aims: Angiopoietin-like 3 (ANGPTL3) and 4 (ANGPTL4) inhibit lipoprotein lipase to regulate tissue fatty acid uptake from triglyceride-rich lipoproteins such as VLDL. While pharmacological inhibition of ANGPTL3 is being evaluated as lipid-lowering strategy, systemic ANGPTL4 inhibition is not pursued due to adverse effects. This study aimed to compare the therapeutic potential of liver-specific Angptl3 and Angptl4 silencing to attenuate hyperlipidemia and atherosclerosis development in APOE*3-Leiden.CETP mice, a well-established humanized model for lipoprotein metabolism. Methods and Results: Mice were subcutaneously injected twice-weekly with saline or liver-targeted antisense oligonucleotides against Angptl3, Angptl4, 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 ANGPTL4-silencing oligonucleotides.Liver-targeted Angptl4 silencing reduced plasma triglycerides (-48%) and total cholesterol (-56%), explained by higher VLDL-derived fatty acid uptake by brown adipose tissue and lower VLDL production by the liver. Accordingly, Angptl4 silencing reduced atherosclerotic lesion size (-86%) and improved lesion stability. Hepatic Angptl3 silencing similarly attenuated hyperlipidemia and atherosclerosis development. While Angptl3 and Angptl4 silencing lowered plasma triglycerides in the refed and fasted state, respectively, combined Angptl3/4 silencing lowered plasma triglycerides independent of nutritional state. In cynomolgus monkeys, anti-ANGPTL4 ASO treatment was well tolerated without adverse effects. Conclusions: Liver-targeted Angptl4 silencing potently attenuates hyperlipidemia and atherosclerosis development in APOE*3-Leiden.CETP mice, and liver-targeted ANGPTL4 silencing is well-tolerated in non-human primates. These data warrant further clinical development of liver-targeted ANGPTL4 silencing. (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)
Databáze:	MEDLINE
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