Abstract 14717: Gene Therapy Mediated Rescue of Chronic Non-Ischemic Cardiomyopathy in Minipigs

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)-organizes transverse tubule microdomains which organize the calcium handling machinery important for cardiac function. In rodent models, adeno-associated virus 9 (AAV9)-cBIN1 effectively reconstitutes microdomains and rescues 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 continuous RVP for 5.7 ± 1.0 weeks (N=10), minipigs developed dilated cardiomyopathy with increased left ventricular (LV) end diastolic volume (EDV, 70.7 ± 4.5 vs. baseline 45.5 ± 1.6 mL) and reduced ejection fraction (EF, 36.5 ± 1.2 vs. baseline 71.3 ± 1.5 %). Once EF ≤ 40% over a week, pigs were randomized to receive intravenous AAV9-cBIN1 or control (AAV9-GFP or PBS). Pacing was continued throughout the study period. In control animals (N=5 with 4 PBS and 1 AAV9-GFP treatment), LV further dilated (78.0 ± 8.7 mL) with EF declining to 27.6 ± 6.7 % by four weeks post injection. The first three control animals already died of severe HF symptoms by 7 weeks post injection (Figure 1A) and the other two animals are currently at 4 weeks post injection with EF reduced to 27 and 33 %, respectively. Despite of continuous RVP, AAV9-cBIN1 rescued HF with EF recovered to 52.6 ± 4.0 % and EDV at 67.3 ± 6.6 mL at 4 weeks post injection. Three cBIN1-treated animals survived the full protocol of 6-month monitoring with EF maintained at 57.5 ± 15.5 % (Figure 1B-C), with two ongoing pigs currently surviving at 4 weeks post-injection with normal EF. Figure contains data of the animals who died or have already completed the 6-month protocol (N=3 per group). No toxicity was observed. In conclusion, intravenous cBIN1 gene therapy rescues non-ischemic HF and improves mortality in pigs.