Abstract Body: Background: Sarcomeric dilated cardiomyopathy (DCM) is defined by diminished calcium-sensitivity, reduced force generation and progressive systolic dysfunction. Current therapies focus on neurohormonal blockade rather than the underlying sarcomeric defect. There is a critical need for targeted therapies that restore contractility without increasing pro-arrhythmic risks or diastolic calcium levels.
Hypothesis: FDA-approved drugs may be repurposed as troponin-activators to halt or reverse disease progression of sarcomeric DCM.
Methods: A multi-tier screening pipeline identified FDA-approved drugs capable of improving DCM-troponin function. Surface plasmon resonance (SPR) measured binding affinities between immobilized FDA-approved drugs and wild-type (WT) or the DCM K210del-TroponinT troponin complexes. 4 lead candidate drugs were validated using isolated murine K210del-TnnT papillary muscle assays. Relative force generation was measured at physiologically low (pCa5.7) and high (pCa4.5) calcium concentrations at the maximum plasma concentrations (Cmax) and 0.5 mM of each drug. 3-mo-old K210del-TnnT mice with established systolic dysfunction and littermates were treated daily by oral gavage with the human equivalent dose of Drug A, Drug B or vehicle for 12-weeks. Ejection fraction (EF) was monitored via serial echocardiography (ECHO).
Results: SPR identified high-affinity binders to the troponin complexes. Drug A bound to the troponin complex with a Kd of 150 nM and Drug B with a Kd of 180 nM, which are below the respective Cmax concentrations. At physiologically low calcium (pCa5.7), Drug A and Drug B significantly improved the relative force at the Cmax concentrations, compared to vehicle. In the longitudinal in vivo study, while littermate controls had healthy ejection fractions of 90.2 ± 1.1%, K210del-TnnT vehicle-treated mice demonstrated a depressed ejection fraction of 60.0 ± 1.4%, n=7 p<0.0001. Drug A improved the systolic function to 72.0 ± 1.1%, n=5-8 p<0.05 relative to vehicle. Drug B improved the systolic function to 78 ± 1.5%, n=7-8 p<0.01 relative to vehicle.
Conclusion: The FDA-approved Drug A and Drug B represent promising sarcomere-directed therapies that successfully rescue systolic function in the pathogenic dilated cardiomyopathy K210del-TroponinT murine model, even after the onset of systolic dysfunction. These repurposed troponin-activators have the potential to be rapidly transitioned into clinical use for patients with sarcomeric DCM.