Small Interfering RNA Therapy Targeting the Long Noncoding RNA SMILR for Therapeutic Intervention in Coronary Artery Bypass Graft Failure.
| Title: | Small Interfering RNA Therapy Targeting the Long Noncoding RNA SMILR for Therapeutic Intervention in Coronary Artery Bypass Graft Failure. |
|---|---|
| Authors: | Brown SD; BHF Centre for Cardiovascular Science, Queens Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.; Malinowska AL; MRC/UKRI Nucleic Acid Therapy Accelerator (NATA), Research Complex at Harwell (RCaH), Harwell, Oxford, United Kingdom.; Bennett M; BHF Centre for Cardiovascular Science, Queens Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.; Correa-Sánchez AF; MRC/UKRI Nucleic Acid Therapy Accelerator (NATA), Research Complex at Harwell (RCaH), Harwell, Oxford, United Kingdom.; Horcasitas Valencia LL; BHF Centre for Cardiovascular Science, Queens Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.; Lucignoli AP; School of Biosciences, Cardiff University, Cardiff, United Kingdom.; Barton AK; BHF Centre for Cardiovascular Science, Queens Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.; Clark L; BHF Centre for Cardiovascular Science, Queens Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.; Sluimer JC; BHF Centre for Cardiovascular Science, Queens Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom; Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, the Netherlands.; Webster SP; BHF Centre for Cardiovascular Science, Queens Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.; Rodor J; BHF Centre for Cardiovascular Science, Queens Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.; Newby DE; BHF Centre for Cardiovascular Science, Queens Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.; Cunningham M; MRC/UKRI Nucleic Acid Therapy Accelerator (NATA), Research Complex at Harwell (RCaH), Harwell, Oxford, United Kingdom.; Baker AH; BHF Centre for Cardiovascular Science, Queens Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom; Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, the Netherlands. Electronic address: andy.baker@ed.ac.uk. |
| Source: | JACC. Basic to translational science [JACC Basic Transl Sci] 2025 Nov; Vol. 10 (11), pp. 101364. Date of Electronic Publication: 2025 Sep 10. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Elsevier on behalf of the American College of Cardiology Foundation Country of Publication: United States NLM ID: 101677259 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2452-302X (Electronic) Linking ISSN: 2452302X NLM ISO Abbreviation: JACC Basic Transl Sci Subsets: PubMed not MEDLINE |
| Imprint Name(s): | Original Publication: [New York] : Elsevier on behalf of the American College of Cardiology Foundation, [2016]- |
| Abstract: | Coronary artery bypass graft (CABG) surgery remains the gold standard of care to prevent myocardial ischemia in patients with advanced atherosclerosis; however, poor long-term graft patency remains a considerable and long-standing problem. Excessive vascular smooth muscle cell (SMC) proliferation in the grafted tissue is recognized as central to late CABG failure. We previously identified SMILR, a human-specific SMC-enriched long noncoding RNA that drives SMC proliferation, suggesting that targeting SMILR expression could be a novel way to prevent neointima formation, and thus CABG failure. Here, we sought to identify a lead siRNA for clinical development. 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 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 a favorable safety profile, both on- and off-target. Finally, we performed TUNEL staining on BHF7-treated tissues and measured the levels of cleaved caspase-3 by enzyme-linked immunosorbent assay after BHF7 treatment. This demonstrated that BHF7 does not induce a cytotoxic response either in vitro or ex vivo. Collectively, these data represent a preclinical package into the function and specificity of BHF7 which warrants further investigation into the possibility of utilizing BHF7 as a novel, ex vivo RNA therapeutic for the prevention of CABG failure in humans.; (Copyright © 2025. Published by Elsevier Inc.) |
| Competing Interests: | Funding Support and Author Disclosures Dr Baker is funded by a British Heart Foundation Translational award (TA/F/20/210022), a British Heart Foundation Chair of Translational Cardiovascular Sciences (CH/11/2/28733), a British Heart Foundation programme grant (RG/20/5/34796), and Medical Research Council Confidence in Concept grant MC_PC_16043. The Nucleic Acid Therapy Accelerator is funded by MRC grant MC_PC_20061. Dr Newby is supported by the British Heart Foundation (CH/09/002, RG/23/F/22/110093, RE/24/130012), Medical Research Council (MR/Y008944/1, G0701127), and the joint Medical Research Council and British Heart Foundation Centre of Research Excellence in Advanced Cardiac Therapies (MR/Z504658/1, SI/F/24/21170016). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. |
| References: | Circulation. 1998 Dec 22-29;98(25):2883-90. (PMID: 9860791); Mol Ther Nucleic Acids. 2022 Jun 22;29:135-149. (PMID: 35847173); Nat Genet. 2000 May;25(1):25-9. (PMID: 10802651); Eur J Cardiothorac Surg. 2005 May;27(5):870-5. (PMID: 15848328); Cardiovasc Drug Rev. 2007 Fall;25(3):221-34. (PMID: 17919257); Mol Ther Nucleic Acids. 2015 Nov 03;4:e263. (PMID: 26528940); Mol Cancer Ther. 2024 Aug 1;23(8):1139-1143. (PMID: 38657233); Eur J Vasc Surg. 1991 Feb;5(1):5-12. (PMID: 2009985); Ann Thorac Surg. 2005 Feb;79(2):544-51; discussion 544-51. (PMID: 15680832); Biochem J. 1992 Nov 15;288 ( Pt 1):93-9. (PMID: 1445285); Circ Res. 2003 Jul 25;93(2):162-9. (PMID: 12829616); Circulation. 2008 Jun 3;117(22):2859-64. (PMID: 18506009); Korean J Anesthesiol. 2010 Dec;59(6):403-10. (PMID: 21253378); Bioorg Med Chem. 2018 Sep 1;26(16):4635-4643. (PMID: 30121212); Cardiovasc Res. 1993 Nov;27(11):1961-7. (PMID: 8287404); N Engl J Med. 2004 Nov 25;351(22):2302-9. (PMID: 15564545); Blood. 2024 May 30;143(22):2256-2269. (PMID: 38452197); Mol Ther. 2018 Mar 7;26(3):708-717. (PMID: 29456020); Circ Res. 2019 Aug 16;125(5):535-551. (PMID: 31339449); Eur Heart J. 2025 Jan 3;46(1):19-34. (PMID: 39412205); Lancet. 2023 Apr 29;401(10386):1427-1437. (PMID: 37003287); Nucleic Acids Res. 2025 Jan 6;53(D1):D672-D677. (PMID: 39417505); Amyloid. 2023 Mar;30(1):1-9. (PMID: 35875890); J Vasc Surg. 2006 Apr;43(4):742-751; discussion 751. (PMID: 16616230); Genome Biol. 2014;15(12):550. (PMID: 25516281); Methods Mol Biol. 2006;342:129-38. (PMID: 16957372); Physiol Rev. 2004 Jul;84(3):767-801. (PMID: 15269336); N Engl J Med. 2013 Aug 29;369(9):819-29. (PMID: 23984729); Am Heart J. 1992 Apr;123(4 Pt 1):1046-54. (PMID: 1549969); Circulation. 2004 Nov 30;110(22):3418-23. (PMID: 15557371); J Urol. 2014 Jun;191(6):1697-702. (PMID: 24342146); J Mol Cell Biol. 2019 Aug 19;11(8):703-718. (PMID: 30452682); J Immunol Methods. 2020 Jan;476:112674. (PMID: 31629740); Circulation. 1984 Sep;70(3 Pt 2):I208-12. (PMID: 6611220); J Am Coll Cardiol. 1996 Sep;28(3):616-26. (PMID: 8772748); N Engl J Med. 2024 Sep 12;391(10):899-912. (PMID: 38804517); Circulation. 1998 Mar 10;97(9):916-31. (PMID: 9521341); Am J Cardiol. 2016 Aug 15;118(4):473-6. (PMID: 27328951); JAMA Surg. 2014 Aug;149(8):798-805. (PMID: 25073921); Circulation. 2016 May 24;133(21):2050-65. (PMID: 27052414); Proc Natl Acad Sci U S A. 2003 May 27;100(11):6347-52. (PMID: 12746500); Lancet. 2004 Oct 23-29;364(9444):1519-21. (PMID: 15500897); Ann Surg. 2013 May;257(5):824-33. (PMID: 23574989); J Invest Dermatol. 2016 Nov;136(11):2305-2313. (PMID: 27427487); N Engl J Med. 2017 Jan 5;376(1):41-51. (PMID: 27959715); Proc Natl Acad Sci U S A. 1995 Jun 20;92(13):5855-9. (PMID: 7597041); Heart Lung Circ. 2020 Mar;29(3):384-389. (PMID: 30929990); Circulation. 2015 Mar 10;131(10):927-64. (PMID: 25679302); Nat Biotechnol. 2017 Mar;35(3):222-229. (PMID: 28244992); J Control Release. 2019 May 28;302:116-125. (PMID: 30940496); Circulation. 2002 Apr 9;105(14):1686-92. (PMID: 11940548); Nat Rev Cardiol. 2016 Aug;13(8):451-70. (PMID: 27194091); Drug Dev Res. 2014 Dec;75(8):489-96. (PMID: 25452110); JAMA. 2005 Nov 16;294(19):2446-54. (PMID: 16287955); Nucleic Acids Res. 2024 Jan 5;52(D1):D672-D678. (PMID: 37941124); BMC Bioinformatics. 2017 Mar 2;18(1):142. (PMID: 28249561); J Control Release. 2023 Oct;362:667-691. (PMID: 37666302); J Am Chem Soc. 2014 Dec 10;136(49):16958-61. (PMID: 25434769); N Engl J Med. 2025 Jan 9;392(2):127-137. (PMID: 39225259); J Clin Invest. 2005 Oct;115(10):2811-21. (PMID: 16200212); Proc Natl Acad Sci U S A. 2008 Aug 19;105(33):11915-20. (PMID: 18695239); N Engl J Med. 2016 May 19;374(20):1954-64. (PMID: 27192673); Front Pharmacol. 2022 Oct 19;13:1006304. (PMID: 36339619); Nat Protoc. 2024 Nov;19(11):3292-3320. (PMID: 39019974); Bioinformatics. 2011 Nov 1;27(21):2987-93. (PMID: 21903627); Proc Natl Acad Sci U S A. 2007 Aug 7;104(32):12988-93. (PMID: 17652516); Int J Mol Sci. 2025 Feb 15;26(4):. (PMID: 40004122); RNA. 2006 Jul;12(7):1179-87. (PMID: 16682560); Nature. 2011 Feb 10;470(7333):284-8. (PMID: 21307942); Circulation. 2004 May 4;109(17):2086-91. (PMID: 15123539); Ann Thorac Surg. 2017 Jun;103(6):1886-1892. (PMID: 28012643); Lancet. 2014 Jan 4;383(9911):60-68. (PMID: 24094767); Nucleic Acids Res. 2016 Aug 19;44(14):6518-48. (PMID: 27084936); Eur J Cardiothorac Surg. 2006 Apr;29(4):511-6. (PMID: 16439151); Circulation. 2000 Oct 3;102(14):1697-702. (PMID: 11015350); Am J Cardiol. 1994 Jan 15;73(2):103-12. (PMID: 8296729); Arch Intern Med. 2003 Oct 27;163(19):2306-14. (PMID: 14581250); J Card Surg. 2018 May;33(5):235-242. (PMID: 29687489); J Am Coll Cardiol. 2004 Dec 7;44(11):2149-56. (PMID: 15582312); Am J Pathol. 1990 Dec;137(6):1401-10. (PMID: 2260628); Kidney Int. 2023 Jan;103(1):207-217. (PMID: 36007597); Circulation. 2014 Oct 21;130(17):1445-51. (PMID: 25261549); Orphanet J Rare Dis. 2015 Sep 04;10:109. (PMID: 26338094); N Engl J Med. 2021 Apr 1;384(13):1216-1226. (PMID: 33789010); N Engl J Med. 2018 Jul 5;379(1):11-21. (PMID: 29972753); Methods. 2001 Dec;25(4):402-8. (PMID: 11846609); J Thorac Cardiovasc Surg. 2001 Apr;121(4):714-22. (PMID: 11279413); Proc Natl Acad Sci U S A. 2014 May 27;111(21):7777-82. (PMID: 24821812); Clin Pharmacol Ther. 2020 Jul;108(1):63-72. (PMID: 31994716); Genetics. 2023 May 4;224(1):. (PMID: 36866529); Cureus. 2020 Nov 16;12(11):e11496. (PMID: 33354442); Eur J Cardiothorac Surg. 2022 Jan 24;61(2):449-456. (PMID: 34448848); Nucleic Acids Res. 2010 Jan;38(1):e3. (PMID: 19854938); Br J Pharmacol. 2025 Jan;182(2):246-280. (PMID: 38773733); Nucleic Acids Res. 2000 Jan 1;28(1):27-30. (PMID: 10592173); Vasc Health Risk Manag. 2006;2(4):477-84. (PMID: 17323602); Lancet. 1999 Oct 30;354(9189):1493-8. (PMID: 10551494); J Cell Physiol. 2000 Mar;182(3):311-22. (PMID: 10653597); N Engl J Med. 2019 Feb 7;380(6):549-558. (PMID: 30726693); Clin Hemorheol Microcirc. 2013 Jan 1;55(4):445-55. (PMID: 24113503); Cardiovasc Res. 2012 Jul 15;95(2):156-64. (PMID: 22406749); Lancet Haematol. 2023 May;10(5):e322-e332. (PMID: 37003278); J Thorac Cardiovasc Surg. 1985 Feb;89(2):248-58. (PMID: 2857209); Signal Transduct Target Ther. 2020 Jun 19;5(1):101. (PMID: 32561705); Lancet. 2025 Jan 11;405(10473):127-136. (PMID: 39798981); Exp Cell Res. 2015 Aug 15;336(2):204-10. (PMID: 26160451); Nucleic Acids Res. 2019 Feb 20;47(3):1082-1096. (PMID: 30544191); Circulation. 2004 Mar 30;109(12):1489-96. (PMID: 15023868) |
| Contributed Indexing: | Keywords: RNA therapeutic; coronary artery bypass graft; long noncoding RNA; vascular smooth muscle cell |
| Entry Date(s): | Date Created: 20250910 Date Completed: 20251126 Latest Revision: 20260113 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC12790151 |
| DOI: | 10.1016/j.jacbts.2025.101364 |
| PMID: | 40928446 |
| Database: | MEDLINE |
Journal Article