Network-based screen in iPSC-derived cells reveals therapeutic candidate for heart valve disease

Science. 2021 Feb 12;371(6530):eabd0724. doi: 10.1126/science.abd0724. Epub 2020 Dec 10.


Mapping the gene-regulatory networks dysregulated in human disease would allow the design of network-correcting therapies that treat the core disease mechanism. However, small molecules are traditionally screened for their effects on one to several outputs at most, biasing discovery and limiting the likelihood of true disease-modifying drug candidates. Here, we developed a machine-learning approach to identify small molecules that broadly correct gene networks dysregulated in a human induced pluripotent stem cell (iPSC) disease model of a common form of heart disease involving the aortic valve (AV). Gene network correction by the most efficacious therapeutic candidate, XCT790, generalized to patient-derived primary AV cells and was sufficient to prevent and treat AV disease in vivo in a mouse model. This strategy, made feasible by human iPSC technology, network analysis, and machine learning, may represent an effective path for drug discovery.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Animals
  • Aortic Valve / drug effects
  • Aortic Valve / metabolism
  • Aortic Valve / pathology*
  • Aortic Valve / physiopathology
  • Aortic Valve Disease / drug therapy*
  • Aortic Valve Disease / genetics
  • Aortic Valve Disease / physiopathology
  • Aortic Valve Stenosis / drug therapy*
  • Aortic Valve Stenosis / genetics
  • Aortic Valve Stenosis / physiopathology
  • Calcinosis / drug therapy*
  • Calcinosis / genetics
  • Calcinosis / physiopathology
  • Disease Models, Animal
  • Drug Discovery
  • Drug Evaluation, Preclinical
  • Gene Expression Regulation / drug effects
  • Gene Regulatory Networks / drug effects*
  • Haploinsufficiency
  • Humans
  • Induced Pluripotent Stem Cells
  • Machine Learning*
  • Mice, Inbred C57BL
  • Nitriles / pharmacology*
  • Nitriles / therapeutic use*
  • RNA-Seq
  • Receptor, Notch1 / genetics
  • Small Molecule Libraries
  • Thiazoles / pharmacology*
  • Thiazoles / therapeutic use*


  • NOTCH1 protein, human
  • Nitriles
  • Notch1 protein, mouse
  • Receptor, Notch1
  • Small Molecule Libraries
  • Thiazoles
  • XCT790

Supplementary concepts

  • Aortic Valve, Calcification of