Therapeutic manipulation of IKBKAP mis-splicing with a small molecule to cure familial dysautonomia

Masahiko Ajiro, Tomonari Awaya, Young Jin Kim, Kei Iida, Masatsugu Denawa, Nobuo Tanaka, Ryo Kurosawa, Shingo Matsushima, Saiko Shibata, Tetsunori Sakamoto, Lorenz Studer, Adrian R. Krainer and Masatoshi Hagiwara ()
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Masahiko Ajiro: Kyoto University Graduate School of Medicine
Tomonari Awaya: Kyoto University Graduate School of Medicine
Young Jin Kim: Cold Spring Harbor Laboratory
Kei Iida: Kyoto University Graduate School of Medicine
Masatsugu Denawa: Kyoto University Graduate School of Medicine
Nobuo Tanaka: Kyoto University Graduate School of Medicine
Ryo Kurosawa: Kyoto University Graduate School of Medicine
Shingo Matsushima: Kyoto University Graduate School of Medicine
Saiko Shibata: Kyoto University Graduate School of Medicine
Tetsunori Sakamoto: Kyoto University Graduate School of Medicine
Lorenz Studer: Sloan Kettering Institute
Adrian R. Krainer: Cold Spring Harbor Laboratory
Masatoshi Hagiwara: Kyoto University Graduate School of Medicine

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

Abstract: Abstract Approximately half of genetic disease-associated mutations cause aberrant splicing. However, a widely applicable therapeutic strategy to splicing diseases is yet to be developed. Here, we analyze the mechanism whereby IKBKAP-familial dysautonomia (FD) exon 20 inclusion is specifically promoted by a small molecule splice modulator, RECTAS, even though IKBKAP-FD exon 20 has a suboptimal 5′ splice site due to the IVS20 + 6 T > C mutation. Knockdown experiments reveal that exon 20 inclusion is suppressed in the absence of serine/arginine-rich splicing factor 6 (SRSF6) binding to an intronic splicing enhancer in intron 20. We show that RECTAS directly interacts with CDC-like kinases (CLKs) and enhances SRSF6 phosphorylation. Consistently, exon 20 splicing is bidirectionally manipulated by targeting cellular CLK activity with RECTAS versus CLK inhibitors. The therapeutic potential of RECTAS is validated in multiple FD disease models. Our study indicates that small synthetic molecules affecting phosphorylation state of SRSFs is available as a new therapeutic modality for mechanism-oriented precision medicine of splicing diseases.

Date: 2021
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DOI: 10.1038/s41467-021-24705-5

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