Novel Anti-fibrotic Therapies

Abstract

Fibrosis is a major player in cardiovascular disease, both as a contributor to the development of disease, as well as a post-injury response that drives progression. Despite the identification of many mechanisms responsible for cardiovascular fibrosis, to date no treatments have emerged that have effectively reduced the excess deposition of extracellular matrix associated with fibrotic conditions. Novel treatments have recently been identified that hold promise as potential therapeutic agents for cardiovascular diseases associated with fibrosis, as well as other fibrotic conditions. The purpose of this review is to provide an overview of emerging antifibrotic agents that have shown encouraging results in preclinical or early clinical studies, but have not yet been approved for use in human disease. One of these agents is bone morphogenetic protein-7 (BMP7), which has beneficial effects in multiple models of fibrotic disease. Another approach discussed involves altering the levels of micro-RNA (miR) species, including miR-29 and miR-101, which regulate the expression of fibrosis-related gene targets. Further, the antifibrotic potential of agonists of the peroxisome proliferator-activated receptors will be discussed. Finally, evidence will be reviewed in support of the polypeptide hormone relaxin. Relaxin is long known for its extracellular remodeling properties in pregnancy, and is rapidly emerging as an effective antifibrotic agent in a number of organ systems. Moreover, relaxin has potent vascular and renal effects that make it a particularly attractive approach for the treatment of cardiovascular diseases. In each case, the mechanism of action and the applicability to various fibrotic diseases will be discussed.

Minoxidil decreases collagen I deposition and tissue-like contraction in clubfoot-derived cells: a way to improve conservative treatment of relapsed clubfoot?

“…Research on possible antifibrotic therapies for various fibroproliferative diseases is relatively widespread (for a review, see 22 ). For some therapies, licensed pharmacological agents are already available.…”

Which molecular targets do we need to focus on to improve lower urinary tract dysfunction? ICI‐RS 2017

“…Fibrosis has been described as “errant wound‐healing process,” and there may be many mechanisms involved in its development, but activation of myofibroblasts and consequent production of excess extracellular matrix components is fundamental. The myofibroblasts may be activated in for example chronic inflammation or by a repetitive exposure to initiating factors …”

“…Antifibrotic treatment may be an attractive approach to manage several LUT disorders, but has not been well studied. However, several novel agents with a potential to treat cardiovascular diseases associated with fibrosis have been described, and can potentially be used also in LUT disorders. A key factor in fibrosis is transforming growth factor‐beta (TGF‐β; Figure ), and TGF‐β antibodies and inhibitors of the TGF‐β1 receptor (ALK‐5) were shown to reduce cardiac fibrosis in animal models, for example mice with myocardial infarction or pressure overload .…”

“…Other agents that have been shown to have beneficial effects in models of fibrotic disease are bone morphogenetic protein‐7 (BMP7) and the polypeptide hormone, relaxin (Figure ). Recently, the ability of relaxin to reverse fibrosis in the rat bladder exposed to ionising radiation has been demonstrated…”

Cell Cycle Arrest-Driven Fibrosis

“…6) At the present time, clinical data on anti-fibrotic drugs is limited, despite promising data having been produced by experimental models. 7) Therefore, new targets for anti-fibrotic therapy should be addressed.…”