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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\n                    <jats:italic>ELP1<\/jats:italic>\n                    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\n                    <jats:italic>CFTR<\/jats:italic>\n                    ,\n                    <jats:italic>LIPA<\/jats:italic>\n                    ,\n                    <jats:italic>MLH1<\/jats:italic>\n                    and\n                    <jats:italic>MAPT<\/jats:italic>\n                    . Subsequent validations in two disease-relevant cellular models demonstrate that BPN-15477 increases functional protein, confirming the clinical potential of our predictions.\n                  <\/jats:p>","DOI":"10.1038\/s41467-021-23663-2","type":"journal-article","created":{"date-parts":[[2021,6,7]],"date-time":"2021-06-07T06:20:51Z","timestamp":1623046851000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["A deep learning approach to identify gene targets of a therapeutic for human splicing disorders"],"prefix":"10.1038","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3638-8479","authenticated-orcid":false,"given":"Dadi","family":"Gao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1658-5213","authenticated-orcid":false,"given":"Elisabetta","family":"Morini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Salani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7948-5730","authenticated-orcid":false,"given":"Aram J.","family":"Krauson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0652-2630","authenticated-orcid":false,"given":"Anil","family":"Chekuri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neeraj","family":"Sharma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashok","family":"Ragavendran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6587-2625","authenticated-orcid":false,"given":"Serkan","family":"Erdin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily M.","family":"Logan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wencheng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amal","family":"Dakka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jana","family":"Narasimhan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolai","family":"Naryshkin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher R.","family":"Trotta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerstin A.","family":"Effenberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew G.","family":"Woll","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vijayalakshmi","family":"Gabbeta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary","family":"Karp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graham","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8427-7231","authenticated-orcid":false,"given":"William D.","family":"Paquette","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8250-8590","authenticated-orcid":false,"given":"Garry R.","family":"Cutting","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael E.","family":"Talkowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7958-6494","authenticated-orcid":false,"given":"Susan A.","family":"Slaugenhaupt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,6,7]]},"reference":[{"key":"23663_CR1","doi-asserted-by":"publisher","first-page":"777","DOI":"10.1016\/j.cell.2009.02.011","volume":"136","author":"TA Cooper","year":"2009","unstructured":"Cooper, T. 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In connection with such employment, the authors receive salary, benefits and stock-based compensation, including stock options, restricted stock, other stock-related grants, and the right to purchase discounted stock through PTC\u2019s employee stock purchase plan. Personal financial interests: S.A.S. is a paid consultant to PTC Therapeutics and is an inventor on several U.S. and foreign patents and patent applications assigned to the Massachusetts General Hospital, including U.S. Patents 8,729,025 and 9,265,766, both entitled \u201cMethods for altering mRNA splicing and treating familial dysautonomia by administering benzyladenine,\u201d filed on August 31, 2012 and May 19, 2014 and related to use of kinetin. S.A.S., G.J., and W.D.P. are inventors on U.S. Patent 10,675,475, assigned to Massachusetts General Hospital and entitled \u201cCompounds for improving mRNA splicing\u201d filed on July 14, 2017 and related to use of BPN-15477. 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