Wednesday, February 5, 2025
2/5/2025
PROJECT SUMMARY Heart failure (HF) is the major cardiac syndrome and treating chronic HFis an unmet need in the United States and worldwide. Therapeutic options for advanced heart failure target systemic stress pathways and sur- prisingly few therapies exist that directly target failing heart muscle. Our long-term goal is to use our under- standing of the biology of failing myocardium to develop muscle specific therapeutic solutions. The key patho- logical hallmark of HF is an abnormal calcium transient, impairing both contraction and relaxation. In small ani- mals and humans, cardiac bridging integrator 1 (cBIN1), which organizes calcium microdomains and the cal- cium handling machinery, is diminished in both systolic and diastolic heart failure. In these rodent models of HF, cBIN1-microdomains are disrupted and can be normalized by cBIN1 gene therapy for functional rescue and reduction in arrhythmogenic incidence. Whether the observed HF rescue by cBIN1 gene therapy in rodent models of HF can be translated to human patients requires a preclinical step in large animals. A validated ca- nine model of ischemia induced HF will be used to understand key regulators of T-tubules and sarcoplasmic reticulum microdomains, restore function, and improve mortlity in failing hearts. The overall objective of this application is to test a cBIN1 gene therapy in a preclinical large animal model of ischemic HF. Our central hypothesis is that in a canine model of ischemia induced HF, adeno asso- ciate virus 9 (AAV9)-transduced exogenous cBIN1 restores functional contractility and reduces arrhythmogenic substrate. The central hypothesis will be tested by accomplishing two aims: Specific Aim 1) Determine in a canine model of ischemic heart failure whether cBIN1 gene therapy provides a functional and mortality benefit. In vivo echocardiography, invasive hemodynamics, and serum biomarkers of cardiac stress and remodeling (NT-proBNP, cBIN1 score), will be monitored after cBIN1 therapy. Specific Aim 2) Determine in a canine model of ischemic heart failure whether cBIN1 gene therapy reduces arrhythmic events and substrate develop- ment. Continuous telemetrically recorded ECG monitoring, electroanatomical endocardial mapping and VT in- ducibility testing, and mapping of cardiac activation, intracellular calcium, and transmembrane voltage will be performed to determine the effectiveness of cBIN1 gene therapy in reducing the arrhythmogenic substrate. It is anticipated that this cBIN1 gene therapy will be the first therapy in medicine that directly targets and reverses the cellular remodeling in the myocytes of failing hearts, rescuing cardiac function, provides a mortal- ity benefit, and reduces arrhythmias prevalent in ischemic HF. This proposal will explore the effectiveness of this therapy in a highly relevant pre-clinical ischemic HF model and move this therapy from a promising lab finding closer to clinical realization.
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