Intravenous AAV8 Encoding Urocortin-2 Increases Function of the Failing Heart in Mice

Human Gene Therapy
N Chin LaiH Kirk Hammond

Abstract

Urocortin-2 (UCn2) peptide infusion increases cardiac function in patients with heart failure, but chronic peptide infusion is cumbersome, is costly, and provides only short-term benefits. Gene transfer would circumvent these shortcomings. We previously showed that a single intravenous (IV) injection of AAV8.UCn2 increases plasma UCn2 and left ventricular (LV) systolic and diastolic function for at least 7 months in normal mice. Here we test the hypothesis that IV delivery of AAV8.UCn2 increases function of the failing heart. Myocardial infarction (MI, by coronary ligation) was used to induce heart failure, which was assessed by echocardiography 3 weeks after MI. Mice with LV ejection fraction (EF) <25% received IV delivery of AAV8.UCn2 (5×10(11) gc) or saline, and 5 weeks later echocardiography showed increased LV EF in mice that received UCn2 gene transfer (p=0.01). In vivo physiological studies showed a 2-fold increase in peak rate of LV pressure development (LV +dP/dt; p<0.0001) and a 1.6-fold increase in peak rate of LV pressure decay (LV -dP/dt; p=0.0007), indicating increased LV systolic and diastolic function in treated mice. UCn2 gene transfer was associated with increased peak systolic Ca(2+) transient amplitude and r...Continue Reading

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Citations

Jul 14, 2017·Molecular Biology of the Cell·Burcu HasdemirAditi Bhargava
Jul 14, 2018·Human Gene Therapy·Dimosthenis GiamouridisH Kirk Hammond
Oct 4, 2018·Current Gene Therapy·Cen YanYing-Mei Feng
Sep 13, 2019·Cardiovascular Drugs and Therapy·Cláudia Monteiro-PintoCarmen Brás-Silva
Nov 8, 2018·Biology of Sex Differences·Sreenivasan ParuthiyilAditi Bhargava
Nov 5, 2019·Molecular Therapy : the Journal of the American Society of Gene Therapy·Dimosthenis GiamouridisH Kirk Hammond
Aug 1, 2018·JACC. Basic to Translational Science·Dimosthenis GiamouridisH Kirk Hammond
Mar 30, 2021·Advanced Drug Delivery Reviews·Matthew A BorrelliSteven R Little

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Methods Mentioned

BETA
transfection
column chromatography

Software Mentioned

NIS
Elements AR

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