A novel mRNA Lipid Nanoparticle Therapy Improves Heart Failure Phenotype and Suppresses Endothelial-Mesenchymal Transition In Vitro
Discuss this preprint
Start a discussion What are Sciety discussions?Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Objectives
To evaluate the therapeutic potential of BMP-7 mRNA-lipid nanoparticle formulation in attenuating cardiac fibrosis and improving function in non-ischemic heart failure, and to assess its impact on endothelial phenotype and function under pro endothelial-to-mesenchymal transition (EndMT) conditions.
Background
Despite advances in neurohormonal blockade, heart failure (HF) progression remains driven in part by fibrotic remodeling. Endothelial-to-mesenchymal transition (EndMT) has emerged as a contributor to myocardial fibrosis, while recent work suggests endothelial phenotypic plasticity may also participate in myocardial recovery. Bone morphogenetic protein-7 (BMP-7) is a known anti-fibrotic regulator, but effective therapeutic delivery strategies remain limited.
Methods
A patent pending, custom-designed BMP-7 mRNA formulated in lipid nanoparticles (AET-1978) was administered subcutaneously in a murine model of non-ischemic HF induced by L-NAME and angiotensin II. Cardiac function and fibrosis were assessed by echocardiography and histology. In an invitro EndMT model, human umbilical vascular endothelial cells (HUVECs) were treated with BMP-7 mRNA and endothelial and mesenchymal morphology, and markers were assessed along with endothelial functional tests.
Results
AET-1978 therapy significantly improved left ventricular systolic and diastolic function and reduced myocardial fibrosis compared with untreated HF mice, without evidence of renal or hepatic toxicity. In vitro, BMP-7 mRNA delivery restored endothelial morphology, suppressed EndMT-associated mesenchymal and profibrotic marker expression while preserving nitric oxide production, lipoprotein uptake, and angiogenic capacity of the HUVECs.
Conclusions
A novel formulation of BMP-7-mRNA-LNP called AET-1978 represents a novel, transient, non-integrating strategy to attenuate fibrotic remodeling and improve cardiac function in heart failure, with supportive evidence of being anti endothelial to mesenchymal transition.
Highlights
A novel BMP-7 mRNA-lipid nanoparticle formulation delivered as a subcutaneous injection attenuated myocardial fibrosis and improved systolic and diastolic function in a murine model of non-ischemic heart failure.
BMP-7 mRNA therapy preserved endothelial phenotype and suppressed endothelial-to-mesenchymal transition in an in vitro platform of human umbilical vascular endothelial cells.
BMP-7 mRNA therapy preserved endothelial function including restoration of nitric oxide production, lipoprotein uptake, and angiogenic capacity in vitro .
This study introduces AET-1978, a transient, non-integrating mRNA therapeutic platform, as a novel approach to target residual fibrotic pathways in heart failure using a clinically scalable delivery route.
