Key result
AAV9-cBIN1 gene therapy improves heart failure-free survival by ~29 points in pressure-overloaded mice.
Why the study?
Heart failure is a growing cause of morbidity and mortality, and half of patients have preserved ejection fraction, for whom therapeutic options are limited.
Does exogenous cBIN1 gene therapy preserve calcium-handling machinery and diastolic function in mice subjected to chronic stress?
Does exogenous cBIN1 gene therapy preserve calcium-handling machinery and diastolic function in mice subjected to chronic stress?
Exogenous cBIN1 gene therapy preserves diastolic function and calcium-handling machinery in a mouse model of chronic stress, suggesting a potential future therapeutic pathway for heart failure with preserved ejection fraction.
AAV9-cBIN1 improves survival in pressure-overloaded mice; leaves open translation to human HFpEF.
Heart failure is an important, and growing, cause of morbidity and mortality. Half of patients with heart failure have preserved ejection fraction, for whom therapeutic options are limited. Here we report that cardiac bridging integrator 1 gene therapy to maintain subcellular membrane compartments within cardiomyocytes can stabilize intracellular distribution of calcium-handling machinery, preserving diastolic function in hearts stressed by chronic beta agonist stimulation and pressure overload. This study identifies that maintenance of intracellular architecture and, in particular, membrane microdomains at t-tubules, is important in the setting of sympathetic stress. Stabilization of membrane microdomains may be a pathway for future therapeutic development.
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Liu et al. (2020) studied Heart failure and cardiac hypertrophy (n=170). AAV9-cBIN1 gene therapy vs. AAV9-GFP (green fluorescent protein) vector was evaluated on Heart failure-free survival (ejection fraction ≥35% or survival) at 8 weeks post-transverse aortic constriction (p=0.020). In mice subjected to pressure overload, AAV9-cBIN1 gene therapy significantly improved heart failure-free survival to 93.7% compared to 64.3% in AAV9-GFP control mice (p=0.020), while preserving cardiac systolic and diastolic function.
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