Advancing cBIN1 Therapy to Large Preclinical Animals

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Heart failure (HF) is a major cardiac syndrome with high mortality and morbidity which increases with age. For individuals 65 years of age and older, heart failure related hospitalization is the single greatest cost to the Medicare budget. In normal ventricular cardiomyocytes, beat-to-beat contraction and relaxation require coordinated systolic calcium release at dyads at transverse tubules (t-tubules, TT) and sarcoplasmic reticulum (SR) and diastolic calcium removal mainly through SR reuptake via Ca2+-ATPase (SERCA2a). A typical pathophysiology of failing cardiomyocytes is weakened calcium transients due to abnormal systolic calcium release from dyads as well as impaired diastolic removal due to altered SERCA2a activity. Central to the weakened transient is disorganization of TTs, their microdomains, and the calcium handling machinery. We recently identified that the calcium regulating cardiac bridging inte- grator 1 (cBIN1) forms TT microdomains and that cBIN1 is decreased in both systolic and diastolic HF. In rodent models, exogenous cBIN1 recovers failing myocardium. The overall objective here is to identify whether the cBIN1-microdomain targeting gene therapy can be translated from rodent studies to preclin- ical studies in a large animal model of HF. Our central hypothesis is that cBIN1-microdomains are dis- rupted in a canine model of chronic atrial pacing-induced HF, which can be rescued by exogenous cBIN1 gene therapy, allowing for recovery of failing myocardium. Two aims are proposed to first explore abnormal remodeling of subcellular microdomains in fail- ing cardiomyocytes from canine hearts subjected to tachy-pacing induced HF. Using biochemical and imaging tools, we will also determine the critical cellular point at which HF will require gene therapy. The second aim is proposed to study the efficacy of adeno associated virus 9 (AAV9)-transduced exog- enous cBIN1 in rescuing myocardial dysfunction and HF progression. A well-established canine model of chronic rapid atrial pacing-induced HF will be used to evaluate cardiomyocyte remodeling, functional deterioration, HF progression, as well as the therapeutic efficacy of intramyocardial injection of AAV9 transducing cBIN1 or a control protein GFP. Building on preliminary data, we will evaluate HF develop- ment by monitoring echocardiography recordings, hemodynamics, systemic symptoms, and blood available biomarkers. Our contribution here is expected to identify whether and how diminished cBIN1-microdomains are critical for reduced cardiac function in failing canine hearts, and whether exogenous cBIN1 can res- cue these hearts. The contribution is significant because it introduces a first in class HF therapeutic that targets the cellular remodeling of failing myocardium. Based on published and preliminary data, we ex- pect both a positive inotropic effect and lusitropic effect from exogenous cBIN1 therapy.