Statistical modeling of extracellular vesicle cargo to predict clinical trial outcomes for hypoplastic left heart syndrome
Jessica R. Hoffman,
Hyun-Ji Park,
Sruti Bheri,
Manu O. Platt,
Joshua M. Hare,
Sunjay Kaushal,
Judith L. Bettencourt,
Dejian Lai,
Timothy C. Slesnick,
William T. Mahle,
Michael E. Davis
Affiliations
Jessica R. Hoffman
Wallace H. Coulter Department of Biomedical Engineering, Emory University School of Medicine & Georgia Institute of Technology, Atlanta, GA 30322, USA; Molecular & Systems Pharmacology Graduate Training Program, Laney Graduate School, Emory University, Atlanta, GA 30322, USA
Hyun-Ji Park
Wallace H. Coulter Department of Biomedical Engineering, Emory University School of Medicine & Georgia Institute of Technology, Atlanta, GA 30322, USA
Sruti Bheri
Wallace H. Coulter Department of Biomedical Engineering, Emory University School of Medicine & Georgia Institute of Technology, Atlanta, GA 30322, USA
Manu O. Platt
Wallace H. Coulter Department of Biomedical Engineering, Emory University School of Medicine & Georgia Institute of Technology, Atlanta, GA 30322, USA
Joshua M. Hare
Miller School of Medicine, University of Miami, Miami, FL 33136, USA
Sunjay Kaushal
Departments of Surgery and Pediatrics, Ann and Robert H. Lurie Children’s Hospital of Chicago, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
Judith L. Bettencourt
Coordinating Center for Clinical Trials, Department of Biostatistics and Data Science, University of Texas Health Science Center School of Public Health, Houston, TX 77030, USA
Dejian Lai
Coordinating Center for Clinical Trials, Department of Biostatistics and Data Science, University of Texas Health Science Center School of Public Health, Houston, TX 77030, USA
Timothy C. Slesnick
Division of Pediatric Cardiology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA; Children’s Heart Research & Outcomes (HeRO) Center, Children’s Healthcare of Atlanta & Emory University, Atlanta, GA 30322, USA
William T. Mahle
Division of Pediatric Cardiology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA; Children’s Heart Research & Outcomes (HeRO) Center, Children’s Healthcare of Atlanta & Emory University, Atlanta, GA 30322, USA
Michael E. Davis
Wallace H. Coulter Department of Biomedical Engineering, Emory University School of Medicine & Georgia Institute of Technology, Atlanta, GA 30322, USA; Molecular & Systems Pharmacology Graduate Training Program, Laney Graduate School, Emory University, Atlanta, GA 30322, USA; Children’s Heart Research & Outcomes (HeRO) Center, Children’s Healthcare of Atlanta & Emory University, Atlanta, GA 30322, USA; Corresponding author
Summary: Cardiac-derived c-kit+ progenitor cells (CPCs) are under investigation in the CHILD phase I clinical trial (NCT03406884) for the treatment of hypoplastic left heart syndrome (HLHS). The therapeutic efficacy of CPCs can be attributed to the release of extracellular vesicles (EVs). To understand sources of cell therapy variability we took a machine learning approach: combining bulk CPC-derived EV (CPC-EV) RNA sequencing and cardiac-relevant in vitro experiments to build a predictive model. We isolated CPCs from cardiac biopsies of patients with congenital heart disease (n = 29) and the lead-in patients with HLHS in the CHILD trial (n = 5). We sequenced CPC-EVs, and measured EV inflammatory, fibrotic, angiogeneic, and migratory responses. Overall, CPC-EV RNAs involved in pro-reparative outcomes had a significant fit to cardiac development and signaling pathways. Using a model trained on previously collected CPC-EVs, we predicted in vitro outcomes for the CHILD clinical samples. Finally, CPC-EV angiogenic performance correlated to clinical improvements in right ventricle performance.
