Abstract 14026: Systemic Delivery of SOD2 mRNA to Experimental Abdominal Aortic Aneurysm Mitigates Expansion

Abstract

Rationale: Oxidative stress and the overproduction of reactive oxygen species are implicated in the pathogenesis of abdominal aortic aneurysm (AAA). Antioxidant delivery as a therapeutic for AAA is of substantial interest. Yet, despite promising experimental studies, clinical translation of antioxidant therapy has met with significant challenges due to limitations in achieving sufficient levels locally at the site of AAA. Herein, we explore a nanoparticle (NP)-based approach for the systemic delivery of antioxidants. Methods and Results: We employ a peptide-based NP that allows efficient in vivo delivery of mRNA to overexpress a key modulator of oxidative stress, superoxide dismutase 2 (SOD2). The SOD2 mRNA sequence containing the appropriate endcaps, poly-A tail, and base modifications (~1,000 nt) to enhance translation was mixed with p5RHH (an amphipathic peptide capable of efficiently delivering nucleic acids in vivo ) at a ratio of 3,200:1 (peptide:mRNA) to form a self-assembled NP of ~50-55 nm in diameter. The NP was further stabilized by a coating of hyaluronic acid (HA), which binds to CD44 expressed on a wide range of cells, enhancing targeting and uptake. Delivery of SOD2 mRNA suppresses expansion of small AAA. Mitigation of AAA following SOD2 mRNA delivery was accompanied by enhanced SOD2 protein expression in aortic wall tissue, decreased inducible nitric oxide synthase expression, lower nitric oxide production and cell death. Conclusions: The results will serve as proof-of-concept that the delivery of mRNA using the p5RHH-based NP holds promise to overcome challenges associated with systemic delivery of antioxidants in AAA medical management. Figure 1. Mice were perfused with elastase and administered NP iv (1 μg mRNA) on days 5, 8, 11. (A) Increase in (AD), measured on day 14 as increase in mm or %. Day 14 aortic sections (n = 5-6 aortas) were stained for SOD2 (red) and nitrotyrosine (green, NO) and expressed as relative ratios. * P <0.05, ** P <0.01, *** P <0.01.