Cardiac Bridging Integrator 1 Gene Therapy Rescues Heart Failure In Swine.

Heart failure (HF) is a major cause of morbidity and mortality worldwide, yet with limited therapeutic options. Recent evidence indicates that the cardiac bridging integrator 1 (cBIN1)-organized transverse tubule microdomain is key to calcium handling and cardiac function. In rodent models, adeno-associated virus 9 (AAV9)-cBIN1 effectively reconstitutes microdomains to rescue HF. Here we explored the therapeutic efficacy of AAV9-cBIN1 in a minipig model of non-ischemic HF. 6-7 months old Yucatan minipigs were subjected to continuous right ventricular rapid pacing (RVP) at 170 bpm. After 8-11 weeks of RVP, minipigs developed dilated cardiomyopathy with increased left ventricular (LV) end diastolic volume (EDV, 69.0 ± 5.3 vs. baseline 50.0 ± 3.8 mL) and reduced ejection fraction (EF, 36.3 ± 2.9 vs. baseline 68.7 ± 0.8 %). Once EF ≤ 40% over a week, pigs were randomized to receive AAV9-cBIN1 (6 x 10 11 vg/kg, intravenous, n = 3) or control (AAV9-GFP or PBS, n = 3). Weekly echocardiography, bloodwork, clinical assessment, and pacing interrogation were performed. In control animals, LV further dilated with EF declining and all three animals died of severe HF symptoms by 7 weeks post injection (terminal EF 18.3 ± 1.7, EDV 107.4 ± 25.0). Despite of continuous RVP, AAV9-cBIN1 limited LV dilation and rescued EF (58.0 ± 4.2, 59.0 ± 4.4 % at 4, 13 weeks post injection). Two cBIN1-treated animals survived to the end of protocol at 6 months post treatment (EF, 57.5 ± 15.5 %), with the third pig currently surviving at 13 weeks post treatment with a 60% EF. No significant toxicity was observed. In conclusion, low dose intravenous cBIN1 gene therapy rescues non-ischemic HF and improves mortality in pigs.