TY - JOUR
T1 - A deep learning approach to identify gene targets of a therapeutic for human splicing disorders
AU - Gao, Dadi
AU - Morini, Elisabetta
AU - Salani, Monica
AU - Krauson, Aram J.
AU - Chekuri, Anil
AU - Sharma, Neeraj
AU - Ragavendran, Ashok
AU - Erdin, Serkan
AU - Logan, Emily M.
AU - Li, Wencheng
AU - Dakka, Amal
AU - Narasimhan, Jana
AU - Zhao, Xin
AU - Naryshkin, Nikolai
AU - Trotta, Christopher R.
AU - Effenberger, Kerstin A.
AU - Woll, Matthew G.
AU - Gabbeta, Vijayalakshmi
AU - Karp, Gary
AU - Yu, Yong
AU - Johnson, Graham
AU - Paquette, William D.
AU - Cutting, Garry R.
AU - Talkowski, Michael E.
AU - Slaugenhaupt, Susan A.
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-021-23663-2
DO - 10.1038/s41467-021-23663-2
M3 - Article
C2 - 34099697
AN - SCOPUS:85107527363
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 3332
ER -