Abstract Body: Abdominal aortic aneurysms (AAAs) are defined as an enlargement of the abdominal aorta by 50% and are, in case of rupture, often fatal. As of now, there is no medical treatment; patients must either undergo open surgical repair or endovascular stenting, both of which carry substantial risks. To address this unmet need, we are exploring drug-eluting ballons (DEBs) as a novel, minimally invasive treatment option in a porcine model.
Our study includes a total of 54 Yucatan minipigs divided into four cohorts. Of these, 49 carried a homozygous knockout of the LDLR (low-density lipoprotein receptor) gene, making them prone to hypercholesterolemia and atherosclerotic lesions when fed a high-fat diet. In the first cohort (n = 21), we demonstrate that LDLR-KO minipigs, unlike wild-type animals, reliably develop an AAA using the PPE- model (perfusion with porcine pancreatic elastase), showing an average aortic diameter increase to 158% (absolute +4.36 mm) within 28 days. The histological evaluation revealed intermediate atherosclerotic lesions, characterized by foam cells and accumulation of lipids. In addition, we performed bulk RNA sequencing and saw in both human and porcine AAAs an upregulation of the immune response and a downregulation of collagen fibril organization.
The remaining cohorts validate the proof-of-concept for using DEBs as local treatment of AAAs. After the initial establishment, we are now able to professionally coat balloon catheters with antisense oligonucleotides (ASOs). With this standardized setup, the final cohort of animals (n=12) was treated with anti-miR29b coated DEBs. Inhibiting microRNA-29b has previously been shown to stabilize aneurysms by increasing the collagen abundance within the aortic wall. Aneurysm size remained stable at 99% of the diameter measured before treatment, corresponding to an absolute mean change of -0.23mm.
Given that no systemic adverse reactions were observed in any of the animals, we can confirm the successful local application. Molecular, histochemical, and single-cell RNA sequencing analyses provided further mechanistic insights into the effect of local antisense oligonucleotide delivery.
Our study shows that inducing an aortic aneurysm by intraluminal PPE-perfusion in LDLR-/- minipigs is a reliable and highly translational model for AAA research. We also demonstrate that DEBs offer significant potential for the early, minimally invasive management of abdominal aneurysms.