Title : Novel RNA-carbohydrate conjugates for modulation of LDLR and cholesterol by transcriptional silencing
The Low Density Lipoprotein receptor (LDLR) is a cell surface expressed protein that binds and internalizes low density lipoprotein (LDL), resulting in cholesterol being made available to the cell. A method to stably over-express LDLR could result in an increased removal of LDL from the blood and subsequent lowering of cholesterol. Previous studies have uncovered an antisense non-coding transcript that overlaps the LDLR promoter, EST BM450697. We investigated the role of this transcript on LDLR gene expression and screened several siRNAs targeted towards either BM450697 or its promoter in Hep 3B and Hep G2 hepatocellular carcinoma cell lines.
Chemically modified RNA have advantages of enzymatic stability, specificity and efficient uptake. In particular, carbohydrate modification such as GalNAC increases the therapeutic activity of RNA. Nevertheless, the synthesis of RNA derivatives remains being a challenge. This is mainly due to chemical instability of RNA and folding into stable 2D structures.
This talk will cover our recent results on the synthesis and tests of chemically modified RNA therapeutics. Our data suggests that small RNAs can functionally activate LDLR expression by the targeted inhibition of the LDLR regulatory lncRNA, BM450697. Notably, these small RNAs are amendable to liver targeted conjugations, such as GalNAC and target the repression of BM450697 in an epigenetic manner, suggesting that long-term activation of LDLR might be feasible by stable silencing of BM450697.
By describing a novel approach to therapeutically actionable RNA molecules, the presentation will provide the audience with new ideas and synthetic methods for developing effective gene therapeutics. The talk will cover both the conceptual novelty of transcriptional gene silencing using synthetic RNA, and practical solutions to preparing and testing this type of therapeutics.