Treatment of post-infarction cardiac remodeling using image-guided delivery of microRNA-loaded microbubbles and ultrasound-mediated cavitation - Adverse left ventricular (LV) remodeling is a severe and common complication of acute myocardial infarction (AMI). It is characterized by acute infarct thinning and dilation, followed by chronic LV dilation, hypertrophy, and excess fibrosis in both infarct and remote non-infarct regions. This leads to globally reduced LV systolic function, heart failure (HF), frequent hospitalization, and death. Beyond daily agony from symptoms of ischemic HF, the financial burden is high, particularly since HF prevalence (~26 million worldwide) is rising as the population ages. Unfortunately, current drugs for remodeling merely delay progression and do not treat root causes. Thus, there is a vital, unmet need for treatments targeting newly identified pathways that cause post-AMI remodeling. MicroRNAs (miRs) are endogenous short RNAs that regulate normal gene expression by binding to target messenger RNAs (mRNAs), causing mRNA degradation or repression of mRNA translation into its target protein. However, miRs can be abnormally expressed in adverse remodeling. For example, miR-92a increases during AMI, suppressing specific mRNAs encoding for cardioprotective proteins. miR-92a has been causally implicated in adverse remodeling. Excitingly, miR-92a inhibition by antimiR-92a, an oligonucleotide (oligo) which binds to and inactivates miR-92a, attenuates remodeling in pre-clinical AMI models. However, antimiR-92a therapy is currently clinically unfeasible: Systemic delivery has poor efficacy and requires high doses, resulting in unwanted delivery to extra-cardiac organs and high cost. To advance clinical translation of antimiR- 92a therapy, we developed ultrasound-targeted microbubble cavitation (UTMC), a theranostic ultrasound-based approach for focal delivery of antimiR-92a. This comprises intravenous injection of antimiR-92a-loaded microbubbles (MBs) which expand and contract (cavitate) as they transit the coronary microcirculation in the presence of ultrasound (US) aimed at the heart. US imaging spatially guides delivery, and MB cavitation releases and concentrates payload in insonified heart by causing cell membrane pores and endothelial hyperpermeability. We have optimized MB and acoustic parameters for UTMC; proved UTMC oligo delivery to hypertensive murine heart; and generated preliminary data in rats with AMI suggesting superior efficacy and cardiac targeting of UTMC antimiR-92a delivery positioning UTMC for clinical translation. We hypothesize that UTMC-mediated cardiac antimiR-92a delivery will prevent adverse remodeling post-AMI and propose critical next steps for clinical translation: We will use a rat AMI model to define optimal antimiR-92a dose (Aim 1), then test UTMC cardiac antimiR-92a delivery for preventing remodeling in a clinically relevant porcine AMI model (Aim 2). Readouts will span whole organ function to gene expression and comprehensive safety and biodistribution measurements. Our data will, for the first time, establish the clinical feasibility and safety of UTMC and form the basis for future IND-enabling studies focused on clinical translation of UTMC-mediated cardiac delivery of antimiR-92a to treat adverse LV remodeling ultimately reducing suffering and death from HF post-AMI.
