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Nusinersen\/SPINRAZA, a splice-switching oligonucleotide that modulates <jats:italic>SMN2<\/jats:italic> (a paralog of <jats:italic>SMN1<\/jats:italic>) splicing and consequently increases SMN protein levels, has a therapeutic effect for SMA. Previously reported small-molecule <jats:italic>SMN2<\/jats:italic> splicing modulators such as risdiplam\/EVRYSDI and its analog SMN-C3 modulate not only the splicing of <jats:italic>SMN2<\/jats:italic> but also that of secondary splice targets, including forkhead box protein M1 (<jats:italic>FOXM1<\/jats:italic>). Through screening SMA patient-derived fibroblasts, a novel small molecule, designated TEC-1, was identified that selectively modulates <jats:italic>SMN2<\/jats:italic> splicing over three secondary splice targets. TEC-1 did not strongly affect the splicing of <jats:italic>FOXM1<\/jats:italic>, and unlike risdiplam, did not induce micronucleus formation. In addition, TEC-1 showed higher selectively on galactosylceramidase and huntingtin gene expression compared to previously reported compounds (e.g., SMN-C3) due to off-target effects on cryptic exon inclusion and nonsense-mediated mRNA decay. Moreover, TEC-1 significantly ameliorated the disease phenotype in an SMA murine model in vivo. Thus, TEC-1 may have promising therapeutic potential for SMA, and our study demonstrates the feasibility of RNA-targeting small-molecule drug development with an improved tolerability profile.<\/jats:p>","DOI":"10.1038\/s41598-020-74346-9","type":"journal-article","created":{"date-parts":[[2020,10,15]],"date-time":"2020-10-15T10:04:27Z","timestamp":1602756267000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Discovery of a CNS penetrant small molecule SMN2 splicing modulator with improved tolerability for spinal muscular atrophy"],"prefix":"10.1038","volume":"10","author":[{"given":"Shiori","family":"Ando","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunya","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shoichi","family":"Okubo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuki","family":"Ohuchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kei","family":"Takahashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinsuke","family":"Nakamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masamitsu","family":"Shimazawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koji","family":"Fuji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideaki","family":"Hara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,10,15]]},"reference":[{"key":"74346_CR1","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1086\/498853","volume":"1","author":"L Cartegni","year":"2006","unstructured":"Cartegni, L., Hastings, M. 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