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Vein graft failure: an ideal opportunity for gene therapy

Author: Aimee Lucignoli, Cardiff University


In the summer I received BSGCT’s undergraduate research bursary which enabled me to move from Cardiff to Edinburgh – experience the chaos of the Edinburgh Fringe Festival, see some beautiful Scottish landscapes, and, of course, do some exciting research! I joined Andy Baker’s lab in the Centre for Cardiovascular Science at the University of Edinburgh, developing RNA therapeutics for preventing vein graft failure. Here’s a bit more about the project:


When a patient has severe coronary artery disease, one of the most common surgical interventions is coronary artery bypass grafting (CABG). A vein is taken from the patient’s leg and used to bypass the blocked arteries in their heart. Veins or arteries from other locations can be used, but the leg is most common as it’s relatively easy to access and a long length of vein can be harvested. However, in up to 50% of cases, the graft will fail within 10 years – becoming blocked itself – and the patient’s symptoms will return (1). Due to a combination of surgical trauma and the high blood pressure environment in which the vein has to adapt, the tissue undergoes physiological remodelling. Unfortunately, this remodelling is often excessive and detrimental to the patient. Key players in this process are certain cells in the vein wall called smooth muscle cells. They adapt by dividing, but in up to 50% of cases, overcompensate and divide too quickly – drastically thickening the wall of the vessel and contributing to its blockage. [Figure 1] (2).



Currently there are no drugs for vein graft failure that actually target the process of a graft failing. However, during CABG surgeries there is a perfect opportunity to administer gene therapy! After the vein is removed from the patient’s leg, the surgeon has to access the heart before grafting. In the 30 minutes this takes, the vein just sits waiting in a dish. Simply adding a gene therapy to this dish wouldn’t change the surgeon’s routine much and would allow targeting the vein alone, outside the body – almost entirely removing worries of side-effects on the rest of the patient. With a well-designed therapy, there is potential for long-term vein graft failure prevention by just this one 30-minute treatment.


What would the gene therapy actually do? The Baker lab have studied the mechanisms of vein graft failure and identified a target: an RNA called SMILR (smooth muscle cell-induced lncRNA enhances replication). When vein graft failure is mimicked in the lab, the cells’ SMILR levels hugely increase. SMILR promotes cell division, leads to the vein thickening, and is only seen in the smooth muscle cells (3). This is ideal as there are other cells in the vein that do need to divide to repair damage. SMILR could be targeted without preventing beneficial remodelling in other vein layers. Crucially, the lab showed that it’s possible to use a commercially available siRNA (a short interfering RNA) to reduce SMILR levels and limit proliferation of the smooth muscle cells (4).


Commercial siRNAs work but are not optimal. This strategy can be improved with development of siRNAs that are better at ‘knocking down’ SMILR, that will remain inside cells for longer, and are formulated so they can get into cells better in the first place. Then we will be able to prevent excess proliferation specifically in the smooth muscle cells and prevent failure of the graft. This work is well underway in the Baker lab and is what I contributed to on my summer placement. Things look promising, so hopefully there’ll be a shiny new gene therapy coming soon!


Thank you to Simon Brown, Andy Baker and the rest of the Baker lab for welcoming me, British Heart Foundation for funding the SMILR project, and BSGCT for the bursary which let me be part of this.

 

References

  1. Xenogiannis I, Zenati M, Bhatt DL, Rao SV, Rodés-Cabau J, Goldman S, et al. Saphenous Vein Graft Failure: From Pathophysiology to Prevention and Treatment Strategies. Circulation. 2021 Aug 31;144(9):728–45.

  2. Alpers CE, Imrey PB, Hudkins KL, Wietecha TA, Radeva M, Allon M, et al. Histopathology of Veins Obtained at Hemodialysis Arteriovenous Fistula Creation Surgery. J Am Soc Nephrol JASN. 2017 Oct;28(10):3076–88.

  3. Ballantyne MD, Pinel K, Dakin R, Vesey AT, Diver L, Mackenzie R, et al. Smooth Muscle Enriched Long Noncoding RNA (SMILR) Regulates Cell Proliferation. Circulation. 2016 May 24;133(21):2050–65.

  4. Mahmoud AD, Ballantyne MD, Miscianinov V, Pinel K, Hung J, Scanlon JP, et al. The Human-Specific and Smooth Muscle Cell-Enriched LncRNA SMILR Promotes Proliferation by Regulating Mitotic CENPF mRNA and Drives Cell-Cycle Progression Which Can Be Targeted to Limit Vascular Remodeling. Circ Res. 2019 Aug 16;125(5):535–51.

 

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