Local intraluminal delivery of a smooth muscle-targeted RNA ligand inhibits neointima growth in a porcine model of peripheral vascular disease

Saami K Yazdani; Beilei Lei; Claire V Cawthon; Kathryn Cooper; Clifton Huett; Paloma H Giangrande; Francis J Miller Jr

doi:10.1016/j.omtn.2022.08.007

Local intraluminal delivery of a smooth muscle-targeted RNA ligand inhibits neointima growth in a porcine model of peripheral vascular disease

Mol Ther Nucleic Acids. 2022 Aug 4:29:577-583. doi: 10.1016/j.omtn.2022.08.007. eCollection 2022 Sep 13.

Authors

Saami K Yazdani^{1

2}, Beilei Lei³, Claire V Cawthon², Kathryn Cooper², Clifton Huett², Paloma H Giangrande⁴, Francis J Miller Jr^{3

5}

Affiliations

¹ Department of Engineering, Wake Forest University, Winston-Salem, NC, USA.
² Department of Mechanical Engineering, University of South Alabama, Mobile, AL, USA.
³ Department of Medicine, Wake Forest School of Medicine, NC, USA.
⁴ Internal Medicine, University of Iowa, Iowa City, IA, USA.
⁵ Department of Medicine, Veterans Administration Medical Center, Salisbury, NC, USA.

Abstract

Anti-proliferative agents have been the primary therapeutic drug of choice to inhibit restenosis after endovascular treatment. However, recent safety and efficacy concerns for patients who underwent peripheral artery disease revascularization have demonstrated the need for alternative therapeutics. The aim of this investigation was to investigate the efficacy of a cell-specific RNA aptamer inhibiting vascular smooth muscle cell proliferation and migration. First, the impact of the RNA aptamer (Apt 14) on the wound healing of primary cultured porcine vascular smooth muscle cells (VSMCs) was examined in response to a scratch wound injury. We then evaluated the effect of local luminal delivery of Apt 14 on neointimal formation in a clinically relevant swine iliofemoral injury model. In contrast with a non-selected control aptamer (NSC) that had no impact on VSMC migration, Apt 14 attenuated the wound healing of primary cultured porcine VSMCs to platelet-derived growth factor-BB. Histological analysis of the Apt 14-treated arteries demonstrated a significant reduction in neointimal area percent diameter stenosis compared with arteries treated with saline and NSC controls. The findings of this study suggest that aptamers can function as selective inhibitors and thus provide more fine-tuning to inhibit selective pathways responsible for neointimal hyperplasia.

Keywords: MT: oligonucleotides, therapies and applications; RNA; aptamer; cell migration; cell-specific therapy; endovascular; injury model; in vitro; neointimal hyperplasia; perfusion catheter; swine; vascular smooth muscle cell.

Grants and funding

R01 EB028798/EB/NIBIB NIH HHS/United States