Article Impact Level: HIGH Data Quality: STRONG Summary of NPJ Regenerative Medicine, 9(1), 1–14. https://doi.org/10.1038/s41536-024-00380-0 Dr. Jing Li et al.
Points
- cBIN1 gene therapy targets heart failure with reduced ejection fraction (HFrEF) by reversing ventricular remodeling and improving heart function through better calcium handling in cardiomyocytes.
- In a minipig model, a single dose of AAV9-packaged cBIN1 significantly improved heart function by 30%, reduced fluid retention, and achieved six-month survival with no mortality despite ongoing cardiovascular stress.
- The therapy enhanced heart efficiency, reversed heart failure-related remodeling, and restored heart cell structure and protein organization, stabilizing the heart under stress.
- cBIN1 plays a critical scaffolding role in heart function, offering a novel therapeutic approach for heart failure and potentially reshaping treatment paradigms.
- Researchers aim for FDA approval and human trials by 2025, with ongoing assessments needed to address toxicology and immune response challenges.
Summary
This study explores the potential of cBIN1 gene therapy for heart failure with reduced ejection fraction (HFrEF), focusing on its ability to reverse ventricular remodeling and improve heart function. cBIN1, a protein that organizes the calcium-handling machinery in cardiomyocytes, is reduced in HFrEF. The study found that cBIN1 levels in human left ventricular tissue correlated with diastolic diameter, indicating its role in ventricular remodeling. Using a minipig model of non-ischemic dilated cardiomyopathy, the researchers delivered a single intravenous low dose (6 × 10^11 vg/kg) of adeno-associated virus 9 (AAV9)-packaged cBIN1. The therapy improved ventricular remodeling, reduced fluid retention, and increased survival in these animals. Notably, the treated pigs survived for six months, the study’s endpoint, with no mortality despite the continued cardiovascular stress from the model.
The cBIN1 gene therapy showed significant functional improvements in the heart. Over the six-month study period, heart function improved by 30%, compared to a typical 5-10% improvement seen in previous heart failure therapies. Treated hearts demonstrated enhanced efficiency in pumping blood, closer to healthy heart levels, and had less dilation and thinning, indicating a reversal of heart failure. This “reverse remodeling” was attributed to restoring heart cell structure and function, including better organizing heart cell proteins. The therapy also helped stabilize the heart despite ongoing stress, suggesting the possibility of repairing and preventing further damage.
The findings highlight cBIN1’s critical role in heart function as a scaffold for other proteins essential to heart cell function. This discovery opens the door for a novel approach to treating heart failure, with the potential for a paradigm shift in how heart muscle is targeted for therapy. In collaboration with TikkunLev Therapeutics, the research team is working towards adapting the therapy for human trials, with plans to apply for FDA approval in 2025. However, further testing, including toxicology and immune response assessments, will be necessary before clinical trials can proceed.
Link to the article: https://www.nature.com/articles/s41536-024-00380-0
References Li, J., Balmaceda, P., Ha, T., Visker, J. R., Maalouf, N., Kwan, E., Hoareau, G. L., Accad, M., Ranjan, R., Selzman, C. H., Drakos, S. G., Shaw, R. M., & Hong, T. (2024). Cardiac bridging integrator 1 gene therapy rescues chronic non-ischemic heart failure in minipigs. Npj Regenerative Medicine, 9(1), 1–14. https://doi.org/10.1038/s41536-024-00380-0
