A deep learning approach to identify gene targets of a therapeutic for human splicing disorders

Dadi Gao, Elisabetta Morini, Monica Salani, Aram J. Krauson, Anil Chekuri, Neeraj Sharma, Ashok Ragavendran, Serkan Erdin, Emily M. Logan, Wencheng Li, Amal Dakka, Jana Narasimhan, Xin Zhao, Nikolai Naryshkin, Christopher R. Trotta, Kerstin A. Effenberger, Matthew G. Woll, Vijayalakshmi Gabbeta, Gary Karp, Yong Yu, Graham Johnson, William D. Paquette, Garry R. Cutting, Michael E. Talkowski () and Susan A. Slaugenhaupt ()
Additional contact information
Dadi Gao: Center for Genomic Medicine, Massachusetts General Hospital Research Institute
Elisabetta Morini: Center for Genomic Medicine, Massachusetts General Hospital Research Institute
Monica Salani: Center for Genomic Medicine, Massachusetts General Hospital Research Institute
Aram J. Krauson: Center for Genomic Medicine, Massachusetts General Hospital Research Institute
Anil Chekuri: Center for Genomic Medicine, Massachusetts General Hospital Research Institute
Neeraj Sharma: McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine
Ashok Ragavendran: Center for Genomic Medicine, Massachusetts General Hospital Research Institute
Serkan Erdin: Center for Genomic Medicine, Massachusetts General Hospital Research Institute
Emily M. Logan: Center for Genomic Medicine, Massachusetts General Hospital Research Institute
Wencheng Li: PTC Therapeutics, Inc.
Amal Dakka: PTC Therapeutics, Inc.
Jana Narasimhan: PTC Therapeutics, Inc.
Xin Zhao: PTC Therapeutics, Inc.
Nikolai Naryshkin: PTC Therapeutics, Inc.
Christopher R. Trotta: PTC Therapeutics, Inc.
Kerstin A. Effenberger: PTC Therapeutics, Inc.
Matthew G. Woll: PTC Therapeutics, Inc.
Vijayalakshmi Gabbeta: PTC Therapeutics, Inc.
Gary Karp: PTC Therapeutics, Inc.
Yong Yu: PTC Therapeutics, Inc.
Graham Johnson: NuPharmAdvise LLC
William D. Paquette: Albany Molecular Research Inc.
Garry R. Cutting: McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine
Michael E. Talkowski: Center for Genomic Medicine, Massachusetts General Hospital Research Institute
Susan A. Slaugenhaupt: Center for Genomic Medicine, Massachusetts General Hospital Research Institute

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract Pre-mRNA splicing is a key controller of human gene expression. Disturbances in splicing due to mutation lead to dysregulated protein expression and contribute to a substantial fraction of human disease. Several classes of splicing modulator compounds (SMCs) have been recently identified and establish that pre-mRNA splicing represents a target for therapy. We describe herein the identification of BPN-15477, a SMC that restores correct splicing of ELP1 exon 20. Using transcriptome sequencing from treated fibroblast cells and a machine learning approach, we identify BPN-15477 responsive sequence signatures. We then leverage this model to discover 155 human disease genes harboring ClinVar mutations predicted to alter pre-mRNA splicing as targets for BPN-15477. Splicing assays confirm successful correction of splicing defects caused by mutations in CFTR, LIPA, MLH1 and MAPT. Subsequent validations in two disease-relevant cellular models demonstrate that BPN-15477 increases functional protein, confirming the clinical potential of our predictions.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23663-2

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DOI: 10.1038/s41467-021-23663-2

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