Instead of replacing the entire STRC gene, what if we could make the cell skip the broken part? Antisense oligonucleotides (ASOs) bind to pre-mRNA and force the splicing machinery to skip specific exons, producing a shorter but potentially functional protein. This approach has 4 FDA-approved drugs for Duchenne muscular dystrophy.
Dystrophin (DMD gene, 79 exons) is the closest analogue to STRC's situation. Too large for AAV, with many patients having exon-specific mutations. The solution: ASOs that skip mutant exons, producing a shorter "Becker-like" dystrophin that still works. Four drugs are FDA-approved, treating exons 51, 53, 45, and 44.
Eteplirsen (exon 51), Golodirsen (exon 53), Viltolarsen (exon 53), Casimersen (exon 45). All use phosphorodiamidate morpholino oligomers (PMOs). Accelerated approval based on dystrophin expression; clinical benefit debated but mechanism validated.
STRC has 29 exons. Many DFNB16 patients carry mutations in specific exons. If we can identify which exons are dispensable for stereocilin function, ASOs could skip the mutant exon, producing a functional truncated protein.
Key principle: Stereocilin is a large extracellular protein composed mainly of leucine-rich repeats (LRRs). LRR proteins are inherently modular: removing one repeat often shifts the structure by one unit without catastrophic misfolding. This is exactly the principle behind micro-dystrophin.
For Misha's mutation (c.4976A>C / p.E1659A in exon 27): Could exon 27 be skipped entirely? If the resulting protein (missing one LRR module) retains its ability to form horizontal top connectors and TM attachment crowns, this could be a viable non-viral, repeatable therapy. AF3 modeling of the exon-27-skipped variant would provide the first structural prediction.
1. Which STRC exons are dispensable? Need systematic AF3 modeling of each single-exon deletion.
2. Can ASOs be delivered to OHCs efficiently? Intratympanic injection reaches the round window, but OHC uptake of naked ASOs is unknown.
3. What dosing schedule maintains therapeutic levels? DMD uses weekly IV infusions; cochlear delivery would need a different approach (depot, sustained release, or LNP-encapsulated ASO).
Eteplirsen (Exondys 51), Golodirsen (Vyondys 53), Viltolarsen (Viltepso), Casimersen (Amondys 45) - FDA-approved exon-skipping ASOs for DMD.
Leclere et al. (2024) "Gene therapy for hearing loss: Advances and prospects of non-viral vectors." Hear Res.