Heart disease often causes scarring (fibrosis), which makes the heart stiff and weak. This happens when certain cells called fibroblasts become overactive and produce too much collagen.
This project aims to stop harmful scarring and overactivation by using tiny molecules (miRNAs) delivered with special carriers called lipid nanoparticles. These miRNAs will be used as treatments in heart attack model organisms to see if they reduce scar tissue and help the heart heal.
Challenges
Target discoveryOrganisations
- King's College London
In depth
Fibrosis underpins all forms of cardiac disease. Cardiac fibrosis ensues from an over-activation of cardiac fibroblasts upon cardiac injury and their differentiation into myofibroblasts. Fibroblast activation is initially of protective nature, but fibroblast over-activation and persistence trigger an exacerbated deposition of extracellular matrix proteins that stiffens the myocardium ultimately leading to pathological remodelling and heart failure. Devising novel strategies to fine-tune cardiac fibroblast responses towards a fully protective, pro-regenerative phenotype is instrumental.
We have performed a series of high-content microscopy functional screenings to investigate, at the genome scale, the role of miRNAs on key phenotypes relevant to cardiac fibrosis, specifically fibroblast proliferation, activation/differentiation, and deposition of fibrillar collagen. The top three miRNAs selected from these screens are being extensively validated for the ability to block fibroblast proliferation and collagen deposition, while exhibiting a differential effect on (myo)fibroblast differentiation.
In addition to identifying miRNAs with therapeutic potential, we are testing approaches to selectively target miRNAs to cardiac fibroblasts using lipid nanoparticles (LNPs). Lipid nanoparticles with varied lipid composition are being tested both in vitro and in vivo. Further evaluation of the therapeutic potential of the miRNAs combined with delivery approaches using LNPs will entail detailed functional and histological analysis, alongside MRI-based detection of collagen deposition and scar formation.