Improved Small Interfering RNA Therapy Targeting the Long, Non-Coding RNA SMILR For Therapeutic Intervention in Coronary Artery Bypass Graft Failure

Excessive vascular smooth muscle cell (vSMC) proliferation in the grafted tissue is recognised as central to late CABG failure. We previously showed that siRNA-mediated silencing of SMILR, a human-specific SMC-enriched lncRNA, blocks vSMC proliferation, suggesting that targeting SMILR expression could be a novel way to prevent neointima formation, and thus CABG failure.

Here, we describe the design and synthesis of a library of 76 chemically-enhanced SMILR-targeting siRNA. From this library, we identify a lead siRNA, BHF7, which demonstrates potent and reproducible silencing of SMILR expression and which robustly blocks vascular smooth muscle cell proliferation, both in vitro and up to 14 days in the ex vivo human saphenous vein model. We further demonstrate using RNA-sequencing that BHF7 down-regulates the expression of genes associated with proliferation and does not induce the expression of interferon or apoptosis genes, suggesting it has an acceptable safety profile both on and off-target.