Proof-of-concept study for liver-directed miQURE technology in a dyslipidemic mouse model

• Published in: Molecular therapy. Nucleic acids 2023-06, Vol.32, p.454-467
• Main Authors: Zancanella, Vanessa, Vallès, Astrid, Liefhebber, Jolanda M.P., Paerels, Lieke, Tornero, Carlos Vendrell, Wattimury, Hendrina, van der Zon, Tom, van Rooijen, Kristel, Golinska, Monika, Grevelink, Tamar, Ehlert, Erich, Pieterman, Elsbet Jantine, Keijzer, Nanda, Princen, Hans Marinus Gerardus, Stokman, Geurt, Liu, Ying Poi
• Format: Article
• Language: English
• Subjects: AAV; angiopoietin-like 3 (ANGPTL3); gene therapy; gene-silencing; lipid-lowering; miRNA; MT: Non-coding RNAs; Original; RNA interference
• ISSN: 2162-2531; 2162-2531
• DOI: 10.1016/j.omtn.2023.04.004

A gene-silencing platform (miQURE) has been developed and successfully used to deliver therapeutic microRNA (miRNA) to the brain, reducing levels of neurodegenerative disease-causing proteins/RNAs via RNA interference and improving the disease phenotype in animal models. This study evaluates the use of miQURE technology to deliver therapeutic miRNA for liver-specific indications. Angiopoietin-like 3 (ANGPTL3) was selected as the target mRNA because it is produced in the liver and because loss-of-function ANGPTL3 mutations and/or pharmacological inhibition of ANGPTL3 protein lowers lipid levels and reduces cardiovascular risk. Overall, 14 candidate miRNA constructs were tested in vitro, the most potent of which (miAngE) was further evaluated in mice. rAAV5-miAngE led to dose-dependent (≤−77%) decreases in Angptl3 mRNA in WT mice with ≤−90% reductions in plasma ANGPTL3 protein. In dyslipidemic APOE∗3-Leiden.CETP mice, AAV5-miAngE significantly reduced cholesterol and triglyceride levels vs. vehicle and scrambled (miSCR) controls when administrated alone, with greater reductions when co-administered with lipid-lowering therapy (atorvastatin). A significant decrease in total atherosclerotic lesion area (−58% vs. miSCR) was observed in AAV5-miAngE-treated dyslipidemic mice, which corresponded with the maintenance of a non-diseased plaque phenotype and reduced lesion severity. These results support the development of this technology for liver-directed indications. [Display omitted] Zancanella and colleagues have demonstrated that miQURE technology can be used to effectively transduce the liver. A one-time intravenous administration in mice with healthy and diseased livers led to dose-dependent reductions in target mRNA and protein knockdown with no safety concerns.