Validation of new therapeutic targets to prevent collagen accumulation in cardiac fibrosis: the procollagen C-proteinase enhancers – CardiActiV

Heart failure is a major cause of hospitalization worldwide, with 50% of the patients dying within 5 years of diagnosis. Its triggers (myocardial infarction, hypertension, coronary artery disease etc.) induce an active process of tissue response to injury often leading to aberrant tissue remodeling and cardiac fibrosis. The principal feature of cardiac fibrosis is an excessive accumulation of extracellular matrix (ECM) which results in myocardial stiffness, mechanical, electrical and vasomotor dysfunction and ultimately to irreversible ischemia. Among the main pathogenic factors leading to heart failure, fibrosis is considered to play a prominent role and to represent a promising target to delay the onset of the disease and limit its progression. While modulators of the renin-angiotensin-aldosterone system have shown beneficial effects in patients affected by cardiac fibrosis, there is currently no specific anti-fibrotic therapy despite a potential market of several billion euros.
Regardless of the etiology of fibrosis, fibrillar collagens are the major components of the interstitial ECM observed in the fibrotic myocardium. Though it has been recognized for a while that preventing their accumulation could be a valuable strategy to treat or prevent fibrosis, this approach has not been formally validated up to now.
In this project, we want to probe this concept through the evaluation of the diagnostic and therapeutic potential of two proteins acting as direct regulators of collagen fibrillogenesis. These proteins are the procollagen C-proteinase enhancers (PCPE-1 and -2) which are powerful and specific activators of the proteolytic maturation of soluble collagen precursors (procollagens) into insoluble collagen, the rate-limiting step in collagen fibrillogenesis. Our preliminary study already indicates correlation between PCPE expression levels and the extent of fibrosis in human atrial biopsies and in a rat model of cardiac fibrosis, thus confirming previous data reporting up-regulation of PCPEs in several fibrotic conditions. However, until now it has not been clear how this property could be translated into therapeutic application. Within the consortium, we have recently elucidated the molecular mechanism of action of PCPE-1, including the resolution of the 3D structure of its complex with procollagen III. We have also developed the very first high-affinity antagonists of PCPE activity (DARPins), thus opening the way to new highly specific therapeutic approaches.
We now propose to build on this unique knowledge to complete the validation of PCPEs as new therapeutic targets and demonstrate that the direct inhibition of collagen deposition is a valuable strategy to limit the deleterious effects of cardiac fibrosis and its progression towards heart failure. To achieve this, the project will be organized in 3 work packages with the following specific goals: (1) to fully characterize the expression patterns of PCPE-1 and -2 (and of related partners) in a new collection of heart biopsies and in a rat model of cardiac fibrosis, (2) to precisely define overlapping and specific functions of PCPEs and to analyze the effect of their inhibition in heart cells and (3) to evaluate anti-PCPE DARPins as diagnostic and therapeutic tools in a preclinical model of cardiac fibrosis.
The consortium includes four partners with complementary skills and expertise: one academic partner (LBTI-CNRS, Lyon, expert in PCPEs and collagens), one clinical partner (CHU-Dijon, expert in heart pathophysiology), one biotech (NVH Medicinal, Dijon, specialized in collagen-based therapies) and one preclinical imaging platform (CGFL, Dijon, expert in customized animal models and diagnostic tools). This project brings promising and innovative perspectives for the treatment of cardiac fibrosis in terms of target preclinical validation and therapeutic candidates and could also lead to novel developments related to fibrosis imaging techniques and biomarker discovery.