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

Autor: Theodoris CV; Gladstone Institute of Cardiovascular Disease, San Francisco, CA, USA.; Roddenberry Stem Cell Center, Gladstone Institutes, San Francisco, CA, USA.; Program in Developmental and Stem Cell Biology (DSCB), University of California, San Francisco (UCSF), San Francisco, CA, USA., Zhou P; Gladstone Institute of Cardiovascular Disease, San Francisco, CA, USA.; Roddenberry Stem Cell Center, Gladstone Institutes, San Francisco, CA, USA., Liu L; Gladstone Institute of Cardiovascular Disease, San Francisco, CA, USA.; Roddenberry Stem Cell Center, Gladstone Institutes, San Francisco, CA, USA., Zhang Y; Gladstone Institute of Cardiovascular Disease, San Francisco, CA, USA.; Roddenberry Stem Cell Center, Gladstone Institutes, San Francisco, CA, USA., Nishino T; Gladstone Institute of Cardiovascular Disease, San Francisco, CA, USA.; Roddenberry Stem Cell Center, Gladstone Institutes, San Francisco, CA, USA., Huang Y; Gladstone Institute of Cardiovascular Disease, San Francisco, CA, USA.; Roddenberry Stem Cell Center, Gladstone Institutes, San Francisco, CA, USA., Kostina A; Institute of Cytology, Russian Academy of Sciences, Saint Petersburg, Russia., Ranade SS; Gladstone Institute of Cardiovascular Disease, San Francisco, CA, USA.; Roddenberry Stem Cell Center, Gladstone Institutes, San Francisco, CA, USA., Gifford CA; Gladstone Institute of Cardiovascular Disease, San Francisco, CA, USA.; Roddenberry Stem Cell Center, Gladstone Institutes, San Francisco, CA, USA., Uspenskiy V; Almazov Federal Medical Research Centre, Saint Petersburg, Russia., Malashicheva A; Institute of Cytology, Russian Academy of Sciences, Saint Petersburg, Russia.; Almazov Federal Medical Research Centre, Saint Petersburg, Russia.; Saint Petersburg State University, Saint Petersburg, Russia., Ding S; Gladstone Institute of Cardiovascular Disease, San Francisco, CA, USA.; Roddenberry Stem Cell Center, Gladstone Institutes, San Francisco, CA, USA.; Department of Pharmaceutical Chemistry, UCSF, San Francisco, CA, USA., Srivastava D; Gladstone Institute of Cardiovascular Disease, San Francisco, CA, USA. dsrivastava@gladstone.ucsf.edu.; Roddenberry Stem Cell Center, Gladstone Institutes, San Francisco, CA, USA.; Department of Pediatrics, Department of Biochemistry and Biophysics, UCSF, San Francisco, CA, USA.
Jazyk: angličtina
Zdroj: Science (New York, N.Y.) [Science] 2021 Feb 12; Vol. 371 (6530). Date of Electronic Publication: 2020 Dec 10.
DOI: 10.1126/science.abd0724
Abstrakt: 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.
(Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
Databáze: MEDLINE
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