CD44---targeted rosuvastatin delivery attenuates valvular fibrotic remodelling in calcific aortic valve disease

Background/Introduction

Calcific aortic valve disease (CAVD) is a progressive fibro-calcific disorder lacking effective pharmacotherapy. Despite strong lipid-related risk associations, systemic statins have failed to demonstrate disease-modifying benefit and may exert context-dependent pro-calcific effects, a phenomenon termed the “statin paradox”. A hyaluronic acid–guided cerasome formulation of rosuvastatin (YN001) has completed phase Ib/IIa clinical evaluation in atherosclerosis, but its therapeutic potential in CAVD remains unknown.

Purpose

To test whether CD44-guided cerasome delivery of rosuvastatin improves valve phenotype in experimental CAVD.

Methods

Human single-cell RNA sequencing data (GSE220774) were analysed to map CD44 expression across valve cell populations. Primary human valve interstitial cells (VICs) were cultured in osteogenic medium with graded rosuvastatin (0–20 μM) to evaluate fibrotic (FN1, α-SMA, CTGF, COL1A1) and osteogenic (ALP, RUNX2) responses. In a translational wire-injury mouse model of CAVD, the impact of the cerasome formulation (HA-CC–RST; YN001) on valvular fibrosis, calcification, and haemodynamics was assessed using high-resolution echocardiography and histology (Masson and Von Kossa staining). All animal procedures complied with the Principles of Laboratory Animal Care.

Results

Human single-cell profiling of stenotic valves (GSE220774) identified a prominent CD44-enriched myeloid niche in CAVD tissue, supporting a disease-relevant targeting landscape. In vitro, rosuvastatin dose-dependently attenuated osteogenic medium–induced fibrotic activation in human VICs, significantly reducing FN1, α-SMA, CTGF, and COL1A1 expression, while osteogenic markers ALP and RUNX2 remained largely unchanged at the tested concentrations.

In vivo, CD44-guided delivery using the YN001 formulation significantly improved transvalvular haemodynamics in the wire-injury model, with peak velocity decreasing from 136.37 ± 12.54 cm/s in controls to 99.32 ± 10.41 cm/s in the treatment group (p=0.00017), accompanied by a modest improvement in ejection fraction. Histological analysis showed reduced valvular fibrotic remodelling (Masson) with comparable calcification burden between groups (Von Kossa).

Conclusion(s)

CD44-guided cerasome delivery of rosuvastatin using the YN001 platform targets a myeloid-enriched niche in CAVD and is associated with reduced valvular fibrosis and improved haemodynamics without increased calcification. These findings support targeted augmentation of local statin exposure as a potential strategy to address the statin paradox in CAVD and warrant further translational evaluation.