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

Autor:	Zancanella V; uniQure biopharma B.V., Department of Research and Development, 1105 BP, Amsterdam, The Netherlands., Vallès A; uniQure biopharma B.V., Department of Research and Development, 1105 BP, Amsterdam, The Netherlands., Liefhebber JMP; uniQure biopharma B.V., Department of Research and Development, 1105 BP, Amsterdam, The Netherlands., Paerels L; uniQure biopharma B.V., Department of Research and Development, 1105 BP, Amsterdam, The Netherlands., Tornero CV; uniQure biopharma B.V., Department of Research and Development, 1105 BP, Amsterdam, The Netherlands., Wattimury H; uniQure biopharma B.V., Department of Research and Development, 1105 BP, Amsterdam, The Netherlands., van der Zon T; uniQure biopharma B.V., Department of Research and Development, 1105 BP, Amsterdam, The Netherlands., van Rooijen K; uniQure biopharma B.V., Department of Research and Development, 1105 BP, Amsterdam, The Netherlands., Golinska M; uniQure biopharma B.V., Department of Research and Development, 1105 BP, Amsterdam, The Netherlands., Grevelink T; uniQure biopharma B.V., Department of Research and Development, 1105 BP, Amsterdam, The Netherlands., Ehlert E; uniQure biopharma B.V., Department of Research and Development, 1105 BP, Amsterdam, The Netherlands., Pieterman EJ; TNO Metabolic Health Research, Sylviusweg 71 2333 BE Leiden, The Netherlands., Keijzer N; TNO Metabolic Health Research, Sylviusweg 71 2333 BE Leiden, The Netherlands., Princen HMG; TNO Metabolic Health Research, Sylviusweg 71 2333 BE Leiden, The Netherlands., Stokman G; TNO Metabolic Health Research, Sylviusweg 71 2333 BE Leiden, The Netherlands., Liu YP; uniQure biopharma B.V., Department of Research and Development, 1105 BP, Amsterdam, The Netherlands.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Nucleic acids [Mol Ther Nucleic Acids] 2023 Apr 07; Vol. 32, pp. 454-467. Date of Electronic Publication: 2023 Apr 07 (Print Publication: 2023).
DOI:	10.1016/j.omtn.2023.04.004
Abstrakt:	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. Competing Interests: V.Z. and Y.P.L. are uniQure employees, hold uniQure stocks, and are inventors on the corresponding patent application. A.V., J.M.P.L., L.P., C.V.T., H.W., T.V.Z., K.V.R., M.G., T.G., and E.E. are uniQure employees and hold uniQure stocks. E.J.P., N.K., H.M.G.P., and G.S. are employees of TNO and were employees of TNO during the time this work was conducted. (© 2023 The Author(s).)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu