(W1145) REVERSAL OF CONTRACTILE DEFECTS IN ENGINEERED HUMAN TISSUE MODELS OF HEART FAILURE WITH PRESERVED EJECTION FRACTION (HFPEF) LEADS TO FIRST-IN-HUMAN GENE THERAPY CLINICAL TRIAL
Abstract: Heart failure with preserved ejection fraction (HFpEF), is a global health problem lacking disease-modifying therapeutic options, reflecting a lack of predictive models for preclinical drug testing. Aligned with FDA Modernization Act 2.0, we aimed to create the first in vitro human-specific mini-heart models of HFpEF, and to test the efficacy of a candidate gene therapy to improve cardiac kinetics and correct the disease phenotype. To achieve these aims, healthy human pluripotent stem cell-derived ventricular cardiomyocytes were used to bioengineer beating human ventricular cardiac tissue strips (hvCTS) and pumping cardiac organoid chambers (hvCOC), and contractile function of these mini-heart models was tested using commercial cardiac screening systems designed specifically for such applications. When conditioned with transforming growth factor-β1 and endothelin-1, these mini-heart models exhibited signature HFpEF disease phenotypes of significantly elevated diastolic force and tissue stiffness, and slowed contraction and relaxation kinetics, with no significant deficit in systolic force or ejection fraction versus unconditioned controls. Bioinformatic analysis of bulk RNA sequencing data from HFpEF mini-heart models and patient ventricular samples confirmed downregulation of SERCA2a of the calcium signalling pathway as a key differentially expressed gene, representing a novel therapeutic target for HFpEF. After dosage optimization in vitro, AAV-mediated expression of SERCA2a abrogated the disease phenotype and improved the cardiac kinetics in HFpEF mini-hearts. These findings contributed IND and FTD applications approved by the FDA for an ongoing first-in-human gene therapy clinical trial for HFpEF. We conclude that such human-based disease-specific mini-heart platforms, created from human pluripotent stem cells, are relevant for target discovery and validation that can facilitate clinical translation of novel cardiac therapies.
