Heart-targeting agents for therapeutic delivery in failing cardiomyocytes – CardioTarget

Heart failure (HF) is one of the main cardiovascular diseases and is defined as the inability of the heart to meet the body’s circulatory demand. HF constitutes a major health problem, affecting about 1-2% of the adult industrialized-countries population. In spite of huge progress in its treatment over the last decades, no definite cure exists for HF and 5-years mortality remains as high as ~50%. Regardless the causes of HF, a common feature is the persistent activation of the ß-adrenergic/cAMP signaling cascade that leads to chronic Protein Kinase-A (PKA) activation responsible for adverse cardiac remodeling, cardiac myocyte death and fibrosis replacement. Therefore, ß-blockers are a cornerstone therapy for HF. However, they cause severe side effects and are ineffective in ~50% of HF patients. Thus, it becomes imperative to improve and/or to propose novel therapeutics to treat HF. Ideally, these medicines should deliver therapeutic molecules efficiently and rapidly directly to the myocardium in a tissue-specific manner. Such strategy would improve the treatment of cardiovascular diseases (i.e. hypertrophic cardiomyopathies, acute or chronic HF, rhythm disorders) and abolish or minimize undesirable side effects.
Heart homing peptides CTP and PCM have been previously described to preferentially bind to and to internalize cardiomyocytes. However, the characterization of these targeting agents is limited and the targeting efficacy remains modest. Therefore, we have designed, engineered over 100 optimized variants from original peptide sequences and selected new optimized-preferential cardiac targeting peptides (PCTP). We believe that our PCTP will offer a new class of therapeutic when coupled to a medicine-cargo to treat HF.
CardioTarget aims at developing an efficient heart-targeted drug delivery platform. For that, liposomal platforms will encapsulate PKA-inhibitor (i.e. PKI) as therapeutic and will be grafted with our optimized-PCTP, thus allowing rapid and efficient delivery of PKI specifically to cardiomyocytes for the treatment of HF. Therefore, in the course of this project, we propose: 1/ To characterize efficacy and specificity of PKI-coupled PCTP in pharmacological models (i.e. in vitro & ex vivo); 2/ To develop original delivery systems conjugated with PCPT to improve their plasmatic stability and cardiac delivery in vivo; 3/ To assess the efficiency of specific cardiac therapeutic vectors (i.e. PCTP targeted-liposomes) in the delivery of PKI as therapeutic in a pathophysiological model of HF.
CardioTarget will identify new specific cardiac targeting platforms to favor effective and preferential delivery of medicines. These plaftforms will promote development of new therapeutic approaches (peptides or nucleic acids) for the treatment of cardiac diseases with an improvement of the therapeutic index.