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

Journal: Nature communications
PMID: 34099697

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.

Authors

  • Dadi Gao
    Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA.
  • Elisabetta Morini
    Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA.
  • Monica Salani
    Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA.
  • Aram J Krauson
    Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA.
  • Anil Chekuri
    Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA.
  • Neeraj Sharma
    School of Biomedical Engineering, Indian Institute of Technology (BHU), Varanasi, Uttar Pradesh, India.
  • Ashok Ragavendran
    Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA.
  • Serkan Erdin
    Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA.
  • Emily M Logan
    Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA.
  • Wencheng Li
    Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
  • Amal Dakka
    PTC Therapeutics, Inc., South Plainfield, NJ, USA.
  • Jana Narasimhan
    PTC Therapeutics, Inc., South Plainfield, NJ, USA.
  • Xin Zhao
    Florida International University.
  • Nikolai Naryshkin
    PTC Therapeutics, Inc., South Plainfield, NJ, USA.
  • Christopher R Trotta
    PTC Therapeutics, Inc., South Plainfield, NJ, USA.
  • Kerstin A Effenberger
    PTC Therapeutics, Inc., South Plainfield, NJ, USA.
  • Matthew G Woll
    PTC Therapeutics, Inc., South Plainfield, NJ, USA.
  • Vijayalakshmi Gabbeta
    PTC Therapeutics, Inc., South Plainfield, NJ, USA.
  • Gary Karp
    PTC Therapeutics, Inc., South Plainfield, NJ, USA.
  • Yong Yu
    Department of Automation, Xi'an Institute of High-Technology, Xi'an 710025, China, and Institute No. 25, Second Academy of China, Aerospace Science and Industry Corporation, Beijing 100854, China yuyongep@163.com.
  • Graham Johnson
    NuPharmAdvise LLC, Sanbornton, NH, USA.
  • William D Paquette
    Albany Molecular Research Inc., Albany, NY, USA.
  • Garry R Cutting
    McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Michael E Talkowski
    Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA. MTALKOWSKI@mgh.harvard.edu.
  • Susan A Slaugenhaupt
    Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA. slaugenhaupt@mgh.harvard.edu.

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