Targeting FADD for the treatment of heart failure – HFADD

Heart Failure (HF) is an epidemic of the 21st century. This chronic disease is a major public health problem due to its high prevalence (26 million patients worldwide), frequent hospitalizations and economic impact of associated direct and indirect costs. With the aging and industrialization of the population, this value will continue to increase. The clinical syndrome of HF represents the final stage of the continuum of cardiovascular diseases such as arterial hypertension or myocardial infarction (MI), which is a leading cause of cardiovascular mortality. Infarct size is a major determinant of mortality after MI and its limitation is required to prevent post-ischemic HF and to improve survival. Prompt revascularization by reperfusion (using primary coronary angioplasty or thrombolysis) has improved functional myocardial recovery and increased patient survival dramatically. However despite beneficial effects on ischemic lesions, reperfusion leads to ischemia-reperfusion (IR) injury due to abrupt restoration of blood flow and oxygen. Unfortunately, there is no treatment to specifically abolish IR-induced lesions leading to apoptosis of cardiomyocytes previously weakened by ischemia. Due to improved revascularization techniques, MI is a major provider of HF patients because decreased mortality results in increased morbidity leading to HF. Indeed, although most patients are doing well for the long term after reopening of the occluded artery, some patients undergo an adverse remodeling of the left ventricle leading to the chronic pathology of HF despite the implementation of secondary prevention therapies. A new concept has recently emerged: a large infarct is neither necessary nor sufficient for progressive adverse LV remodeling and HF to occur. Beside beneficial effects during cardiac healing, inflammation is a driver of post-MI remodeling leading to HF when overactivated for a longer time than required.
We have demonstrated the crucial role of the apoptotic pathway during myocardial IR mediated by the FAS receptor, which binds to the FADD protein to trigger the caspase-dependent apoptotic cascade. FADD is also described as a mediator of inflammation and its inactivation in transgenic animal models prevents the appearance of HF. Our working hypothesis is to specifically target the FAS:FADD interaction activated during MI in order to develop an innovative therapeutics to decrease IR lesions and the ventricular remodeling leading to HF.
Based on the long collaboration between both partners of the project, we have designed a specific inhibitor peptide (Tat-FADDp) of the FAS:FADD complex, which shows anti-apoptotic effect in vitro and a reduction in infarct size and apoptosis in an in vivo murine model of acute myocardial IR (EP2982685 A1).
The HFADD project will confirm the cardioprotective effects of the patented peptide and evaluate its vasculoprotective and anti-inflammatory properties involved in the pathology of HF. More specifically, we plan to:
(1) Investigate the anti-remodeling effect of Tat-FADDp in a mouse model of HF,
(2) Develop second-generation Tat-FADDp,
(3) And study in vivo the therapeutic time window, pharmacokinetics and biodistribution of the peptide.
Final products will be well-characterized cardio- and vasculoprotective peptides able to limit infarct size and the pro-inflammatory phase that is over-activated during HF.
This innovative strategy specifically targeting the FAS:FADD interaction involved in deleterious mechanisms such as apoptosis, inflammation, hypertrophy and fibrosis will enable the early inhibition of IR lesions and subsequent adverse LV remodeling, in order to reduce morbi-mortality and associated economic costs. The HFADD project will have a real strong impact by improving human health care, mortality and societal costs.
Our valorization plan includes the filling of new patents and the creation of our own start-up with the help of the SATT AxLR valorization structure of the CNRS.