Treating myocardial infarction using pH-sensitive nanoparticles for FADD silencing – NanoCard

Cardiovascular diseases (CVD) including myocardial infarction (MI) ranks first in worldwide mortality and according to WHO, they will stay at this rank until 2030. Prompt revascularization of the occluded artery to reperfuse the myocardium is the only recommended treatment (by angioplasty or thrombolysis) to decrease infarct size. However, despite beneficial effects on ischemic lesions, reperfusion leads to ischemia-reperfusion (IR) injury related mainly to apoptosis and inflammation. Improvement of revascularization techniques and patient care has decreased MI mortality but heart failure (HF) morbidity is increasing, contributing to the cost-intense worldwide HF epidemic. Currently, there is no treatment against reperfusion injury despite promising results in animal models. There is now an obvious need to develop new cardioprotective strategies to decrease morbidity/mortality of CVD, which is increasing due to the aging of the population and the rising prevalence of diabetes, a provider of MI patients.
In a previous study, we demonstrated the crucial role of the FAS receptor-dependent apoptotic pathway during myocardial IR. FAS ligand, released in the blood of patients during MI, activates FAS receptor. To complete its activation, FADD adaptor protein couples the intracellular part of the FAS receptor to the caspase-dependent apoptotic cascade in cardiac, cardiomyocytes and vascular, cells. Based on the long collaboration between Partners 1 & 3, we developed peptides targeting specifically the FAS:FADD interaction and leading to a potent decrease in infarct size in the mouse heart in vivo. Beside its role in apoptosis, FADD plays a pleiotropic role in necroptosis and in inflammation, which is responsible for post-MI anomalous cardiac remodeling leading to HF. Interestingly, FADD has been reported to be an apoptotic biomarker associated with increased incidence of coronary events in humans.
Our working hypothesis is to silence myocardial FADD protein globally to inhibit both acute IR injury as well as subsequent deleterious ventricular post-MI remodeling leading to HF in order to protect the heart on the long term.
Therefore, our main objective will be to develop an original therapeutic approach downregulating FADD signaling, specifically in the injured myocardium. Our innovative strategy is based on the use of small interfering RNA (siRNA-FADD) encapsulated in peptide-based nanoparticles (PBNs). Multi-grafted PBNs will result from grafting in PBN both (i) PEG units providing longer blood half-life of the therapeutic molecules after injection and (ii) targeting peptides allowing cardiac tissue addressing. To ensure the specific siRNA delivery at the site of injury (extracellular pH drop in ischemic and inflammatory tissue), pH sensitive linkers will be used between the grafted units and the PBNs, based on the expertise of Partner 2. This strategy will maximize local PBNs concentration at the site of injured cells and will offer specific siRNA delivery reducing then off-target and adverse side effects.
During the NanoCard project, we plan to:
- Develop and characterize the multi-grafted PBNs as therapeutic siRNA delivery system (Aim 1);
- Evaluate the multi-grafted PBNs target specificity and cargo release in cellulo (Aim 2);
- Evaluate the cardioprotective effects of the siRNA-FADD-loaded multi-grafted PBNs in a murine IR model (ex vivo and in vivo) as proof-of-concept (Aim 3).
Final products will be well-characterized cardioprotective siRNA-FADD-loaded multi-grafted PBNs able to limit infarct size and prevent post-MI cardiac remodeling. We are convinced that specifically targeting FADD signaling evidenced as a major player in myocardial apoptosis and inflammation will prevent the early inhibition of IR lesions and also the post-MI remodeling that leads to HF. The NanoCard project is expected to have a real strong impact by improving human health care and societal costs.