Specificity, synergy, and mechanisms of splice-modifying drugs

Yuma Ishigami, Mandy S. Wong, Carlos Martí-Gómez, Andalus Ayaz, Mahdi Kooshkbaghi, Sonya M. Hanson, David M. McCandlish, Adrian R. Krainer () and Justin B. Kinney ()
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Yuma Ishigami: Cold Spring Harbor Laboratory
Mandy S. Wong: Cold Spring Harbor Laboratory
Carlos Martí-Gómez: Cold Spring Harbor Laboratory
Andalus Ayaz: Cold Spring Harbor Laboratory
Mahdi Kooshkbaghi: Cold Spring Harbor Laboratory
Sonya M. Hanson: Flatiron Institute
David M. McCandlish: Cold Spring Harbor Laboratory
Adrian R. Krainer: Cold Spring Harbor Laboratory
Justin B. Kinney: Cold Spring Harbor Laboratory

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract Drugs that target pre-mRNA splicing hold great therapeutic potential, but the quantitative understanding of how these drugs work is limited. Here we introduce mechanistically interpretable quantitative models for the sequence-specific and concentration-dependent behavior of splice-modifying drugs. Using massively parallel splicing assays, RNA-seq experiments, and precision dose-response curves, we obtain quantitative models for two small-molecule drugs, risdiplam and branaplam, developed for treating spinal muscular atrophy. The results quantitatively characterize the specificities of risdiplam and branaplam for 5’ splice site sequences, suggest that branaplam recognizes 5’ splice sites via two distinct interaction modes, and contradict the prevailing two-site hypothesis for risdiplam activity at SMN2 exon 7. The results also show that anomalous single-drug cooperativity, as well as multi-drug synergy, are widespread among small-molecule drugs and antisense-oligonucleotide drugs that promote exon inclusion. Our quantitative models thus clarify the mechanisms of existing treatments and provide a basis for the rational development of new therapies.

Date: 2024
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DOI: 10.1038/s41467-024-46090-5

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