New HDL-Cholesterol therapies for cardiovascular diseases – HDL-NEXT-THERAPEUTICS

Despite considerable progresses in their prevention and treatment, cardiovascular diseases (CVD) remain the most frequent cause of death worldwide (31% of deaths, WHO data) and are also one of the leading causes of long term sickness and loss to the labor market. Current preventive and therapeutic measures, including the lowering of low-density lipoprotein (LDL) and high blood pressure can reduce about 30%. For the remaining 70% there will only be hope if new therapies are identified. In this context, high-density lipoprotein (HDL), for which atheroprotective properties have been supported by epidemiological, clinical and basic research, is one of the more interesting targets for treatments that will further reduce cardiovascular morbidity and mortality.
Most of the atheroprotective effect of HDL is ascribed to its role in reverse cholesterol transport, a process whereby HDL removes cholesterol from atherosclerotic foam cells and delivers it to the liver for biliary excretion. In addition, HDL exerts various direct anti-inflammatory, anti-thrombotic, anti-oxidant and cytoprotective effects on the vasculature.
However, HDL is not easy to target, mainly because its atheroprotective functions are determined by the quality of HDL particles rather than the quantity of HDL-cholesterol (HDL-C level). Thus, HDL therapies that lower cardiovascular risk are NOT yet available. This lack of innovation for such a ??public health issue is paradoxical and can be illustrated by the failure of therapeutic strategies aiming to solely increase HDL-C levels, rather than treat functional status of HDL particles, i.e. by stimulating their atheroprotective functions.
Hence, major public health and economic and societal interest exists for the development of new drugs able to affect specific mechanisms rather than increasing HDL-C levels.
The groundbreaking strategy of this project is that the issue is approached with a different angle of view, by studying a novel target, namely ecto-F1-ATPase, previously described by the public laboratory as an HDL receptor involved in its atheroprotective effects.
The laboratory has developed an expertise and unique knowledge in biology, physiology and epidemiology of ecto-F1-ATPase. For his part, Lifesearch, which holds an expertise in molecular modelling and pharmacology, has developed activator peptides of ecto-F1-ATPase. To date, a pilot study, conducted jointly by the two entities, has demonstrated the specificity and efficacy of these peptides in vitro and ex-vivo.
This project aims to WP1) further evaluate the therapeutic efficacy of these activator peptides; WP2) better characterize a biomarker (IF1), previously patented by the laboratory, with the potential to be used as a companion diagnostic test.
In WP1, we will evaluate activator peptides on preclinical models, assessing their their pharmacological profile (pharmacokinetics, pharmacodynamics, biological activities) and therapeutic efficacy. Different delivery route and derivative peptides retaining equivalent pharmacological properties but with better pharmacokinetic properties will be considered. This will allow to identify therapeutic peptide(s) with the potential to be suitable for further clinical trials.
In WP2, we will better characterize the biomarker IF1, of which serum level reflects cellular ecto-F1-ATPase activity. Particularly, we will analyzed on cohorts whether IF1 is associated with other emerging HDL markers and will assess its ability to predict cardiovascular events. IF1 measurement could be used as a companion diagnostic test for identifying patients who will best respond to treatment.
Our objective is to achieve a preclinical proof of concept, which will look forward to clinical trials. Our project will permit a biologically and clinical based reassessment of the optimal therapeutic strategy for targeting HDL, with the ultimate goal of proposing a theranostic approach in the diagnosis/prognosis, prevention and treatment of CVD.