Emerging epigenetic therapies of cardiac fibrosis and remodelling in heart failure: from basic mechanisms to early clinical development

Abstract

Cardiovascular diseases and specifically heart failure (HF) impact global health and impose a significant economic burden on society. Despite current advances in standard of care, the risks for death and readmission of HF patients remain unacceptably high and new therapeutic strategies to limit HF progression are highly sought. In disease settings, persistent mechanical or neurohormonal stress to the myocardium triggers maladaptive cardiac remodelling, which alters cardiac function and structure at both the molecular and cellular levels. The progression and magnitude of maladaptive cardiac remodelling ultimately leads to the development of HF. Classical therapies for HF are largely protein-based and mostly are targeted to ameliorate the dysregulation of neuroendocrine pathways and halt adverse remodelling. More recently, investigation of novel molecular targets and the application of cellular therapies, epigenetic modifications, and regulatory RNAs has uncovered promising new avenues to address HF. In this review, we summarize the current knowledge on novel cellular and epigenetic therapies and focus on two non-coding RNA-based strategies that reached the phase of early clinical development to counteract cardiac remodelling and HF. The current status of the development of translating those novel therapies to clinical practice, limitations, and future perspectives are additionally discussed.

Keywords: Epigenetics; Fibrosis; Heart failure; MicroRNAs; Non-coding RNAs.

Figure 1

Immunological and epigenetic strategies to treat cardiac fibrosis. Activated CFs produce excess ECM, directly leading to pathological fibrosis. A: Chimeric antigen receptor T cells can be generated to specifically ablate activated CFs. Regulatory T cells and subsets of cardiac macrophages can also blunt CF activation partly through cytokine-mediated immunomodulation, and potentially through direct cell–cell interaction. B: Stress signalling triggers epigenetic reprogramming in CFs, resulting in activation of pro-fibrotic gene expression. C: Epigenetic writers, erasers, and readers are depicted. Targeting histone modifications through small molecule inhibitors of histone deacetylases (HDACi), histone acetyltransferases (HATi), BRD4 (BRD4i), lysine demethylases (KDMi), or by modulating other pro-fibrotic epigenetic targets yet to be uncovered, can rewire the fibroblast epigenome to selectively attenuate activation and subsequent fibrosis during cardiac stress. FAP, fibroblast activation protein; FAPCAR T, chimeric antigen receptor (CAR) T cells targeted against FAP; TCR, T-cell receptor; Me, methyl group; Ac, acetyl group.

Figure 2

miR-92a therapy improves vascularization in cardiac ischaemia. A: In-vitro miR-92a overexpression inhibits spout formation in human EC spheroids, vascular network formation, and EC migration. Implantation of HUVECs in matrigel plug in vivo inhibits vessel formation. B: Inhibition of miR-92a with antagomir-92ain ischaemic models in vivo in mouse hind-limb ischaemia model improves perfusion. Inhibition after AMI improves perfusion and reduces infarct size. Treatment regime for antagomir-92a injections in days (d) is indicated. Proposed targets of miR-92a modulation are shown. C: Large animal model of ischaemia/reperfusion for LNA-92a treatment is shown. Treatment regime is indicated in hours (h) or days (d). D. First-in-human study for MRG-110 is illustrated. Treatment regime in hours (h), days (d), and weeks (w) is indicated. ITGA5, integrin subunit α5; SIRT, sirtuin; Rap1, Ras-related protein-1; eNOS, endothelial nitric oxide synthase 3; ECV, extracellular vesicle.

Figure 3

Role of miR-132 in the cardiac remodelling process. Mechanisms of miR-132 in the cardiac remodelling process and development of anti-miR-132-based therapeutic strategies in mice, pigs, and humans with heart failure. A: Mice model with miR-212/132 overexpression. The proposed mechanism of miR-132 action. B: Inhibition of miR-212/132 in TG mice. Treatment regime in weeks (w) with anti-miR-132 is indicated. C: Large animal model of chronical heart failure after MI. Treatment regime in months (M) with CDR132L is indicated. D: First-in-human Phase 1b study in patients with stable chronic heart failure is illustrated. Inclusion criteria are given. Treatment regime in days (d) with CDR132L is indicated. FoxO3, Forkhead Box Protein O3; SERCA2, sarcoplasmic/endoplasmic reticulum calcium ATPase 2; NFAT, nuclear factor of activated T cells.