BS-452758-2 RESCUE OF ISCHEMIC DILATED CARDIOMYOPATHY IN CANINES

Abstract

Ischemic cardiomyopathy and resultant heart failure (HF) are significant causes of morbidity and mortality worldwide. Mainstay therapeutic options are limited to the blockade of neurohormonal stress pathways. An unmet need in HF therapy is the development of targeted myocardium-specific therapies. Cardiac bridging integrator 1 (cBIN1), a membrane scaffolding protein in transverse-tubule microdomains, organizes the calcium handling apparatus proteins in cardiomyocytes. cBIN1 is transcriptionally reduced in failing hearts, impairing calcium transients and systolic and diastolic function. This study explored cBIN1 as a gene therapy-based rescue of ischemic cardiomyopathy. To investigate whether cBIN1 gene therapy rescues failing myocardium in a preclinical canine model of chronic ischemic HF. Nine healthy adult mongrel dogs (30±3 kg) underwent a lateral thoracotomy followed by left anterior descending artery ligation to induce myocardial infarctions. Animals developed progressive dilated cardiomyopathy and chronic ischemic HF over 10 – 16 weeks. When their left ventricular ejection fraction (LVEF) decreased below 40%, animals received a single intramyocardial injection of either adeno-associated virus serotype 9 (AAV9)-cBIN1 gene (n=6) or AAV9-green fluorescent protein (GFP) (Control, n=3) in the LV. Weekly echocardiography, laboratory testing and daily clinical examinations were performed up to 7 weeks post-therapy. From therapy to post-injection week 5, LV function in the GFP-treated cohort continued to decline. By week 5, all control animals developed progressive dilated cardiomyopathy and had to be euthanized due to worsening prognostic factors. In contrast, the cBIN1-treated cohort never developed HF symptoms, and LVEF statistically improved by 4% gain (Figure, p=0.003 – reclassifying the animals from HF with reduced ejection fraction to HF with mildly reduced ejection fraction), whereas the control cohort lost an additional 7% in LV function. In cBIN1-treated animals, there was no significant further LV dilation and positive remodeling to smaller dimensions. Cardiac biomarkers of HF continued to increase in the control cohort and decreased in the cBIN1-treated cohort. In a canine model of chronic ischemic HF, cBIN1 gene therapy significantly rescued and improved LV function. This work suggests that recovery of transverse-tubule microdomains and normalizing excitation-contraction coupling by cBIN1 gene therapy can restore contractility in ischemic HF.