Communications medicine · 2025
AAV9-cBIN1 gene therapy rescues chronic heart failure due to ischemic cardiomyopathy in a canine model.
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Khan Muhammad S, Smego Douglas, Li Jing, Ishidoya Yuki, Offei Emmanuel, Ruiz Castillo Martha Sofia, Hirahara Annie M, Balmaceda Pia, Hunter Jennifer, Athavale Anand, Revelo Monica P, Palatinus Joseph A, Selzman Craig H, Ranjan Ravi, Hong TingTing, Dosdall Derek J, Shaw Robin M
Аннотация
BACKGROUND: Ischemic cardiomyopathy and resultant heart failure (HF) is a significant cause of morbidity and mortality worldwide. Downregulation of cardiac bridging integrator 1 (cBIN1), a membrane scaffolding protein responsible for organizing t-tubules and organizing the calcium handing apparatus, occurs in progressive HF. Therefore, gene therapy upregulating cBIN1 production may rescue failing muscle and clinical HF.
METHODS: Adult mongrel dogs underwent ligation of the left anterior descending artery and developed progressive dilated cardiomyopathy and chronic HF. When left ventricular ejection fraction (LVEF) dropped below 40%, the animals received a one-time series of endocardial injections of either of low dose gene therapy composed of either adeno-associated virus serotype 9 packaged cBIN1 (AAV9-cBIN1, n = 6) or AAV9-GFP (green fluorescent protein, n = 4). Animals were followed up to 7 weeks after therapy delivery with laboratory, echocardiography, and endocardial mapping assessment.
RESULTS: Post injection of the negative control, animals develop progressive symptomatic HF requiring early termination of all but one animal prior to the end of the study. In contrast, the AAV9-cBIN1-treated group reveals a significant improvement in LV function, with a noticeable improvement in LVEF (29 ± 3% vs. 42 ± 2%, p = 0.0095) and global longitudinal strain (-7.1 ± 0.9% vs. -12.5 ± 1.6%, p = 0.0095). Compared to the control animals, the AAV9-cBIN1-treated group displays improved T-tubule morphology, left ventricular chamber size, plasma biomarkers, and endocardial voltage, and survives the study period.
CONCLUSIONS: Chronic HF from ischemic cardiomyopathy can be successfully treated with low dose AAV9-cBIN1 gene therapy. This study indicates that myocardial specific therapy can dramatically reverse HF progression.
METHODS: Adult mongrel dogs underwent ligation of the left anterior descending artery and developed progressive dilated cardiomyopathy and chronic HF. When left ventricular ejection fraction (LVEF) dropped below 40%, the animals received a one-time series of endocardial injections of either of low dose gene therapy composed of either adeno-associated virus serotype 9 packaged cBIN1 (AAV9-cBIN1, n = 6) or AAV9-GFP (green fluorescent protein, n = 4). Animals were followed up to 7 weeks after therapy delivery with laboratory, echocardiography, and endocardial mapping assessment.
RESULTS: Post injection of the negative control, animals develop progressive symptomatic HF requiring early termination of all but one animal prior to the end of the study. In contrast, the AAV9-cBIN1-treated group reveals a significant improvement in LV function, with a noticeable improvement in LVEF (29 ± 3% vs. 42 ± 2%, p = 0.0095) and global longitudinal strain (-7.1 ± 0.9% vs. -12.5 ± 1.6%, p = 0.0095). Compared to the control animals, the AAV9-cBIN1-treated group displays improved T-tubule morphology, left ventricular chamber size, plasma biomarkers, and endocardial voltage, and survives the study period.
CONCLUSIONS: Chronic HF from ischemic cardiomyopathy can be successfully treated with low dose AAV9-cBIN1 gene therapy. This study indicates that myocardial specific therapy can dramatically reverse HF progression.