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

Vanessa Zancanella; Astrid Vallès; Jolanda M P Liefhebber; Lieke Paerels; Carlos Vendrell Tornero; Hendrina Wattimury; Tom van der Zon; Kristel van Rooijen; Monika Golinska; Tamar Grevelink; Erich Ehlert; Elsbet Jantine Pieterman; Nanda Keijzer; Hans Marinus Gerardus Princen; Geurt Stokman; Ying Poi Liu

doi:10.1016/j.omtn.2023.04.004

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

Mol Ther Nucleic Acids. 2023 Apr 7:32:454-467. doi: 10.1016/j.omtn.2023.04.004. eCollection 2023 Jun 13.

Authors

Vanessa Zancanella¹, Astrid Vallès¹, Jolanda M P Liefhebber¹, Lieke Paerels¹, Carlos Vendrell Tornero¹, Hendrina Wattimury¹, Tom van der Zon¹, Kristel van Rooijen¹, Monika Golinska¹, Tamar Grevelink¹, Erich Ehlert¹, Elsbet Jantine Pieterman², Nanda Keijzer², Hans Marinus Gerardus Princen², Geurt Stokman², Ying Poi Liu¹

Affiliations

¹ uniQure biopharma B.V., Department of Research and Development, 1105 BP, Amsterdam, The Netherlands.
² TNO Metabolic Health Research, Sylviusweg 71 2333 BE Leiden, The Netherlands.

Abstract

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.

Keywords: AAV; MT: Non-coding RNAs; RNA interference; angiopoietin-like 3 (ANGPTL3); gene therapy; gene-silencing; lipid-lowering; miRNA.