cBIN1 Gene Therapy Improves Left Ventricular Filling Pressure in a Canine Model of Ischemic Dilated Cardiomyopathy
Abstract Body: INTRODUCTION: In heart failure patients, increased left ventricular end diastolic pressure (LVEDP) is pathognomonic of myocardial dysfunction. Previously, we presented that gene therapy with exogeneous cardiac bridging integrator 1 (cBIN1), a membrane scaffolding protein that organizes T-tubule microdomains and is decreased in failing hearts, recovers systolic function in a canine model of chronic ischemic dilated cardiomyopathy (IDCM). The effect of catheter-based delivery of cBIN1 gene therapy on increased LVEDP is unclear.
HYPOTHESIS: We tested the hypothesis that cBIN1 gene therapy improves LVEDP in a canine model of IDCM.
METHODS: Twelve healthy dogs (30±2 kg) underwent left anterior descending artery ligation and developed IDCM with LVEF <40% and NT-proBNP >900 pmol/L over 3–4 months. Animals received a single application at 20 subendocardial LV sites of either AAV9-GFP (control, n=6) or AAV9-cBIN1 (n=6) using a MyoStar catheter-based injection. Pressure-volume loops were acquired in vivo, including measurement of LVEDP, end-systolic pressure-volume relation (ESPVR), isovolumic relaxation time (IVRT) and isovolumetric contraction time (IVCT). Measurements were performed on the day prior to administering the therapy (pre-therapy) and 5–8 weeks post-intramyocardial injection (post-therapy). For statistics, student t-test was used, and p<0.05 refers as significant. Results are reported as mean±SD.
RESULTS: In AAV9-GFP control-treated dogs, compared with pre-therapy, post-therapy LVEDP elevated significantly (13±1 vs. 17±1 mmHg, p=0.002, Figure A), whereas in the cBIN1-treated cohort, elevated LVEDP improved significantly (13±4 vs. 11±3 mmHg, p=0.042). With control therapy, ESPVR exhibited a significant decrease in contractility (1.40±0.44 vs. 1.81±0.49 mmHg/mL, p=0.001, Figure B), whereas cBIN1 therapy caused a substantial improvement in ESPVR (1.54±0.71 vs. 1.34±0.43 mmHg/mL, p=0.022, Figure B). At the post-therapy time-point, compared with control therapy, cBIN1 therapy improved IVRT (96±10 vs. 72±8 ms, p<0.001, Figure C) and IVCT (49±4 vs. 40±3 ms, p=0.009, Figure D).
CONCLUSION: cBIN1 gene therapy reduces elevated LV filling pressure and improves overall hemodynamics in a canine model of chronic IDCM.
Khan, Muhammad
( The University of Utah
, Salt Lake City
, Utah
, United States
)
Shaw, Robin
( The University of Utah
, Salt Lake City
, Utah
, United States
)
Dosdall, Derek
( The University of Utah
, Salt Lake City
, Utah
, United States
)
Yazaki, Kyoichiro
( The University of Utah
, Salt Lake City
, Utah
, United States
)
Ishidoya, Yuki
( The University of Utah
, Salt Lake City
, Utah
, United States
)
Offei, Emmanuel
( The University of Utah
, Salt Lake City
, Utah
, United States
)
Ruizcastillo, Sofia
( The University of Utah
, Salt Lake City
, Utah
, United States
)
Shah, Ankur
( The University of Utah
, Salt Lake City
, Utah
, United States
)
Li, Jing
( The University of Utah
, Salt Lake City
, Utah
, United States
)
Palatinus, Joseph
( The University of Utah
, Salt Lake City
, Utah
, United States
)
Hong, Tingting
( The University of Utah
, Salt Lake City
, Utah
, United States
)
Author Disclosures:
Muhammad Khan:DO NOT have relevant financial relationships
| Robin Shaw:DO have relevant financial relationships
;
Ownership Interest:TikkunLevTherapeutics:Active (exists now)
| Derek Dosdall:No Answer
| Kyoichiro Yazaki:DO NOT have relevant financial relationships
| Yuki Ishidoya:No Answer
| Emmanuel Offei:No Answer
| Sofia Ruizcastillo:No Answer
| Ankur Shah:DO NOT have relevant financial relationships
| Jing Li:DO NOT have relevant financial relationships
| Joseph palatinus:No Answer
| Tingting Hong:DO have relevant financial relationships
;
Research Funding (PI or named investigator):TikkunLev Inc.:Active (exists now)
; Individual Stocks/Stock Options:TikkunLev Inc.:Active (exists now)
