Enhanced splicing modulation by NMA-modified antisense oligonucleotides

Aberrant RNA splicing contributes to many human diseases, and splice‑switching antisense oligonucleotides (SSOs) are ideally suited as a therapeutic strategy to modulate splicing and restore normal gene expression. Nusinersen (Spinraza™) has revolutionized the treatment of spinal muscular atrophy. It is a splice-switching oligonucleotide (SSO) that is modified with 2′- O -methoxyethyl (MOE) modifications. Here, we introduce a next‑generation ribose modification, 2′‑ O ‑[2‑(methyl‑amino)‑2‑oxoethyl] (NMA), which enhances the pharmacological properties of SSOs. We identified a long-lasting NMA-modified human candidate SSO, salanersen, that is 3-4-fold more potent than nusinersen in human SMN2 transgenic mice. To evaluate the generality of the NMA chemistry, we applied it to modulation of SCN1A exon 20N splicing, a therapeutic strategy for Dravet syndrome. An NMA-modified SSO is 3.5-fold more potent than STK-001, a MOE-modified SSO currently in clinical trials. Our data establish the NMA chemistry as a broadly applicable ribose modification that markedly improves the pharmacological profile of SSOs, supporting its development as a next-generation platform for splicing modulation therapies.