Liposomal azithromycin to treat cardiac inflammation

Coronary artery disease is the leading cause of morbidity and mortality in the US leading to over 1 million myocardial infarctions (MI) annually. The inflammatory response associated with MI leads to an influx of circulating immune cells, particularly neutrophils, monocytes, and macrophages, into the myocardium. This response is crucial for removing dead tissue and initiating the healing process. However, exacerbated inflammation following MI and other cardiomyopathies can be detrimental and is associated with infarct expansion, poor cardiac remodeling, and adverse clinical outcomes. Modulating inflammation represents a paradigm shift in the treatment of MI, but clinical translation has not been realized. Therapeutic transition of macrophages to a reparative phenotype represents a promising strategy to reduce the damage responsible for heart failure after MI. To address this, we have prepared a liposomal formulation containing azithromycin (AZM), a clinically approved antibiotic, that has been shown to modulate immune responses to favor repair. The overall goal of this project is to advance the preclinical development of liposomal AZM (L-AZM) for clinical translation. The rationale for this proposed research is based on the need to identify treatments with improved therapeutic index to minimize the inflammation and fibrosis associated with adverse cardiomyopathies including MI. Encouraged by strong preliminary data, our goals are based on clear milestones that address current gaps in knowledge to further de-risk the technology and position it for clinical translation. The R61 phase will be completed through the following specific aims: 1) Determine the optimal dose initiation and formulation parameters that enhance the therapeutic index of AZM, and 2) Determine the optimal duration and dose of our lead L-AZM formulation to prevent myocardial fibrosis. The R33 phase will be completed through the following specific aims: 1) Determine the efficacy of the optimal L-AZM regimen in murine and porcine models of cardiac fibrosis, and 2) Determine the pharmacokinetic parameters in murine and porcine animal models. Completion of both milestone-driven phases of the award will result in the data necessary to advance the technology toward IND enabling studies for eventual clinical translation. The milestones of this proposal are well-defined to advance our pre-clinical development focused on identifying a treatment regimen that results in a survival benefit in animals. The approach is innovative and addresses an unmet need due to: 1) the repurposing of AZM in liposomes to polarize phagocytes toward a reparative phenotype to preserve cardiac muscle post-MI, and 2) our approach to assess formulations in an in vivo model with the goal of improving the therapeutic index of AZM. There are currently no therapies approved to treat the post-MI inflammatory response. This research is significant as the proposed aims are low risk, yet high impact and focus on improving our understanding of AZM in a liposomal formulation to reduce the pathological inflammation in patients post-MI.