Author:
Oostveen Reindert F.,Hovingh G. Kees,Stroes Erik S.G.
Abstract
Purpose of review
The aim of this study was to discuss the potential mechanisms and implications of the opposing liver safety results from recent angiopoietin-like 3 (ANGPTL3) inhibition studies.
Recent findings
The clinical development of vupanorsen, a N-acetylgalactosamine (GalNAc) antisense targeting hepatic ANGPTL3, was recently discontinued due to a significant signal of liver transaminase increase. Vupanorsen elicited a dose-dependent increase in hepatic fat fraction up to 75%, whereas the small interfering RNA (siRNA) ARO-ANG3, has reported preliminary evidence of a dose-dependent decrease in hepatic fat fraction up to 30%.
Summary
ANGPTL3 inhibition is an attractive therapeutic target to reduce all apoB-containing lipoproteins. The discrepancy in liver signal results between the antisense and siRNA approach may be explained by the level of target inhibition. An alternative explanation may relate to off-target effects of vupanorsen, which have a molecule- and/or platform-specific origin. For intrahepatic strategies, highly potent ANGPTL3 inhibition will for now require special attention for liver safety.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cell Biology,Cardiology and Cardiovascular Medicine,Nutrition and Dietetics,Genetics,Molecular Biology,Endocrinology, Diabetes and Metabolism
Cited by
1 articles.
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