Abstract
Abstract Background and Aims Hypoplastic left heart syndrome (HLHS) survival relies on surgical reconstruction for the right ventricle (RV) to provide systemic circulation. This substantially increases the RV load, wall stress, maladaptive remodeling, and dysfunction, which in turn increases the risk of death or transplantation. Methods We conducted a phase 1 open-label multicenter trial to assess the safety and feasibility of Lomecel-B as an adjunct to second stage HLHS surgical palliation. Lomecel-B, an investigational cell therapy consisting of allogeneic medicinal signaling cells (MSCs), was delivered via intramyocardial injections. The primary endpoint was safety, and measures of RV function for potential efficacy were obtained. Results Ten patients were treated. None experienced major adverse cardiac events (MACE). All were alive and transplant-free at 1-year post-treatment, and experienced growth comparable to healthy historical data. Cardiac magnetic resonance imaging (CMR) suggested improved tricuspid regurgitant fraction (TR RF) via qualitative rater assessment, and via significant quantitative improvements from baseline at 6 and 12 months post-treatment (p < 0.05). Global longitudinal strain (GLS) and RV ejection fraction (EF) showed no declines. To understand potential mechanisms of action, circulating exosomes from intramyocardially transplanted MSCs were examined. Computational modeling identified 54 MSC-specific exosome RNAs corresponding to changes in TR RF, including miR-215-3p, miR-374b-3p, and RNAs related to cell metabolism and MAPK signaling. Conclusions Intramyocardially-delivered Lomecel-B appears safe in HLHS patients and may favorably affect RV performance. Circulating exosomes of transplanted MSC-specific provide novel insight into bioactivity. Conduct of a controlled phase trial is warranted and is underway.