Abstract 19086: Reducing Infarct Size by Protection of Ischemic Myocardium With Targeted Growth Factors
Introduction/Hypothesis: After AMI, patients suffer irreversible loss of heart function due to cardiomyocyte (CM) death and tissue scarring that may lead to heart failure. Growth factors can reduce CM apoptosis and scar size in preclinical studies but have poor drug-like qualities. Silver Creek Pharmaceuticals is developing Smart Growth Factors (SGFs), a new class of targeted therapies that are engineered to have optimized PK/PD and safety profiles. We determined the in vitro and in vivo properties of our first generation of SGFs for cardioprotection.
Methods/Results: We used computational modeling to design SGFs that activate prosurvival AKT signaling with an IGF-1-based signaling arm along with selectively targeting apoptotic CMs through an Annexin V-based targeting arm that binds to phosphatidylserine exposed on the apoptotic cell surface. These bispecific proteins were constructed with half-life modulators and linkers and screened for their ability to selectively increase pAKT levels in apoptotic iPSC-derived human CMs. We identified SGFs that were able to selectively signal in apoptotic CMs in vitro and tested the ability of our lead SGF to selectively activate AKT in vivo and reduce infarct size in a rat ischemia/reperfusion model of AMI. Our lead SGF was able to prolong pAKT in the infarcted region of the left ventricle without activating AKT in remote healthy tissue out to 2 hours post-reperfusion (p<0.05, 1.7 ± 0.3 fold over control, n=3-6/group). A dose range finding efficacy study investigating single IV bolus doses of our lead SGF administered at the start of 24 hours of reperfusion following 60 minutes of ischemia revealed two doses that were able to significantly reduce infarct size relative to the left ventricle (p<0.05; 0.43 mg/kg=18.7 ± 3%, n=12; 2.47 mg/kg=17.3 ± 3%, n=11; and vehicle=29.3 ± 3%, n=15). Additionally, we observed a dose-dependent decrease in area-at-risk (p<0.05; 0.43 mg/kg=39.7 ± 4%, n=12; 2.47 mg/kg=36.4 ± 3%, n=11; and vehicle=52.4 ± 4%, n=15) that suggests SGF efficacy may involve a novel mechanism of cardioprotection.
Conclusions: Our data shows that our lead SGF can selectively activate prosurvival signaling in apoptotic CMs in vitro and lead to infarct size reduction in vivo without off-target effects.
Author Disclosures: H.H. Chang: None. Y. Zhang: None. T.R. Stowe: None. K.M. Kuchenbecker: None. B.L. Millard: None. A.D. Nickerson: None. B.M. Schoeberl: None. U.B. Nielson: None.
- © 2016 by American Heart Association, Inc.