Liposomal azithromycin to reduce cardiac inflammation
Project Abstract:
Problem Description Inflammation is a major cause of secondary injury after a heart attack that results in poor patient prognosis Uncontrolled inflammation can cause a buildup of scar tissue and thickening of blood vessel walls Many therapies given after a heart attack myocardial infarction MI are used to restore blood flow and prevent clotting but none are designed to target inflammation There is a need for a potent medication that can be used to limit cardiac inflammatory damage Intended Customer Patients presenting to an emergency medical team with an acute MI Solution Azithromycin is capable of decreasing inflammation by shifting immune cells to a reparative state However the FDA issued a warning for azithromycin due to an increased risk of a fatal irregular heart rate To address this risk we have developed a formulation containing azithromycin that reduces cardiac cell death reduces cardiac scar size and has decreased offtarget toxicity Liposomal azithromycin LAZM serves as a vehicle for azithromycin to achieve rapid onset of azithromycins immune modulatory function while reducing the offtarget toxicity making this a viable treatment option for patients suffering from a MI Proposed work The proposed experiments are designed to address three critical aspects of the drug development process 1 in vitro and in vivo toxicity 2 timeframe to initiate therapy and 3 navigating the regulatory pathway This funding mechanism will support clearly defined objectives that will derisk the formulation and accelerate continued evaluation of LAZM toward IND application Milestones We propose four milestones evaluating LAZM M1 in vitro toxicity M2 in vivo cardiac toxicity in pigs M3 therapeutic treatment window M4 biodistribution in mice with guidance from a regulatory consultant Deliverables The data generated will include in vitro and in vivo toxicity data for LAZM M12 which stands as the most significant barrier to clinical translation We will establish the treatment window to initiate therapy in mice M3 to better identify the target market Preclinical biodistribution data for LAZM in consultation with a regulatory consultant M4 to navigate the drug approval process will also be generated Team We are the first team to evaluate LAZM as a formulation to modulate immune cell function after MI Our strong preliminary data places our team of experts in a unique position to leverage this finding to advance this formulation into a clinically relevant therapeutic Our team includes coPIs Vincent J Venditto PhD UK liposomes and Ahmed AbdelLatif MD PhD UK cardiologist and a supporting team of collaborators including Dave Feola PharmD PhD UK macrophages John Gensel PhD UK macrophages Brian Delisle PhD UK cardiac toxicity and John M Canty Jr MD U Buffalo pig model
