Endothelialization of coronary stents after intra-luminal adenoviral VEGF-A gene transfer in a preclinical porcine restenosis model - Studies with optical coherence tomography, angioscopy, multiphoton and scanning electron microscopy

Jarkko P Hytönen; Juho Pajula; Paavo Halonen; Jouni Taavitsainen; Antti Kuivanen; Santeri Tarvainen; Minja Heikkilä; Petri Mäkinen; Arto Koistinen; Johanna P Laakkonen; Juha Hartikainen; Seppo Ylä-Herttuala

doi:10.1016/j.yjmcc.2024.12.007

Endothelialization of coronary stents after intra-luminal adenoviral VEGF-A gene transfer in a preclinical porcine restenosis model - Studies with optical coherence tomography, angioscopy, multiphoton and scanning electron microscopy

J Mol Cell Cardiol. 2024 Dec 18:S0022-2828(24)00212-8. doi: 10.1016/j.yjmcc.2024.12.007. Online ahead of print.

Affiliations

¹ A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland; Heart Centre and Gene Therapy Unit, Kuopio University Hospital, Kuopio, Finland.
² A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
³ Department of Technical Physics, University of Eastern Finland, Kuopio, Finland.
⁴ Heart Centre and Gene Therapy Unit, Kuopio University Hospital, Kuopio, Finland.
⁵ A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland; Heart Centre and Gene Therapy Unit, Kuopio University Hospital, Kuopio, Finland. Electronic address: seppo.ylaherttuala@uef.fi.

PMID: 39753392
DOI: 10.1016/j.yjmcc.2024.12.007

Abstract

Background: Coronary stenting operations have become the main option for the treatment of coronary heart disease. Vessel recovery after stenting has emerged as a critical factor in reducing possible complications. In this study, we evaluated the feasibility, safety and efficacy of locally administered intraluminal gene therapy delivered using a specialized infusion balloon catheter.

Methods: Sixteen pigs received bare metal stents (BMS) in the left circumflex coronary artery and drug-eluting stents (DES) in the right coronary artery. Adenoviral (Ad) gene transfers (dose 1,5e10 pfu) of VEGF-A and LacZ were performed with a ClearWay™ RX infusion balloon catheter on both stents. In vivo imaging included angiography, OCT and angioscopy. Tissue samples were collected for analyses at day 14 and studied using scanning electron microscopy and multiphoton microscopy.

Results: AdVEGF-A accelerated re-endothelialization in the BMS compared to the other groups. The highest restenosis was in the BMS AdLacZ group. DES groups had statistically significant reduced maximum stenosis compared to BMS AdLacZ. No major in-stent thrombosis events were detected. Ex vivo imaging showed that intraarterial imaging is not very accurate in the detection of endothelial layer. Biodistribution of the Ad vector and measured safety parameters (off-target tissues and blood tests) did not show any major safety concerns.

Conclusion: Adenoviral gene transfer using the ClearWay™ RX catheter was feasible and safe. AdVEGF-A accelerated re-endothelization in BMS. However, DES showed better outcomes in the short-term regarding restenosis and do not benefit from intraluminal AdVEGF-A gene transfer.

Keywords: Endothelialization; Gene therapy; Intra-vascular imaging; Restenosis.