Poster J8 - Evaluating plaque growth and lipid deposit after multiple dosing of miR-145 micelles for atherosclerosis

Thursday, October 24, 2024

2:45 PM – 3:45 PM EST

Location: Exhibit Hall E, F & G

Presenting Author(s)

Eddie Kim

Undergraduate
University of Southern California
Los Angeles, California, United States

Co-Author(s)

Isabella Suzuki, PhD (she/her/hers)

Postdoctoral Researcher
University of Southern California, California, United States
Brian J. Lam

Undergraduate
University of Southern California, United States

Primary Investigator(s)

EC

Eun Ji Chung

Associate Professor
University of Southern California, United States

Introduction: Atherosclerosis is one of the leading causes of death worldwide and is a chronic inflammatory disease of the arterial wall in which unstable atherosclerotic plaque rupture can lead to acute or chronic ischemic events. Treatments currently available to slow atherosclerosis progression have focused on lowering plasma cholesterol levels by inhibiting cholesterol synthesis using statins, but despite its wide distribution, statins do not benefit all patients. We previously reported on a successful therapeutic strategy based on peptide amphiphile micelle nanoparticles to deliver microRNA-145 (miR-145) and its ability to inhibit atherosclerosis by targeting vascular smooth muscle cells (VSMCs). Here we present a long-term in vivo study to evaluate plaque growth and lipid deposit in the aorta after multiple doses of miR-145 micelles in mid/late-stage atherosclerotic mice.

Materials and

Methods: miR-145 micelles were synthesized by self-assembling amphiphiles containing miR-145 and a peptide sequence that targets the C–C chemokine receptor-2 (CCR2), which is highly expressed on pathogenic VSMCs. Apoe -/- mice were fed a high-fat diet (HFD) for 20 weeks to represent mid/late-stage disease. After 8 weeks of HFD, mice were treated every 3 weeks (4 doses total) of miR-145 micelles for 12 weeks. PBS, Atorvastatin (statins), and empty micelles (MCP1 micelles without miR-145) served as control groups.

Results, Conclusions, and Discussions:

Results: The nanoparticles exhibited a small diameter of 15 nm and a neutral surface charge of -0.2 mV, as revealed by DLS and zeta potential, respectively. Micelles also protected miR-145 from degradation by nucleases. For plaque size and quantification, sections of the aorta roots were stained with hematoxylin and eosin (H&E), and lipid deposit was assessed with Oil Red O staining. miR-145 micelles inhibited plaque growth (32%) compared to PBS (44%) and decreased lipid deposition in the aorta root (3.2 %) compared to PBS (5.3 %).

Conclusions: Here we showed that the 3-week dosing regimen of miR-145 micelles can reduce atherosclerosis progression without adverse effects. Currently, we are evaluating higher doses of miR-145 micelles and its safety profile.

Acknowledgements (Optional):