STRC Research

STRC ASO Exon Skipping

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STRC ASO Exon Skipping

Core claim

Antisense oligonucleotides (ASOs) can force exon skipping during pre-mRNA splicing, potentially restoring a reading frame or skipping a disease-causing exon. Unlike AAV, ASOs don’t integrate and can be re-administered. Relevant if specific STRC exon structure allows in-frame skipping near E1659.

Key advantage over AAV

Repeatable. ASOs are transient — cleared over weeks/months. Re-dosing is straightforward. No immune memory to capsid proteins. Solves the one-shot AAV constraint that drives the entire STRC Anti-AAV Immune Response Model.

Feasibility for STRC/E1659A

  • E1659A is a missense mutation, not a frameshift — exon skipping may not restore function
  • Skipping the exon containing E1659 might produce truncated protein — unknown if functional
  • Need to map E1659 to STRC exon structure and evaluate frame consequences
  • Exon containing residue 1659: encoded somewhere in exons covering aa 1075–1775 (C-terminal half)

The exon-deletion AF3 sweep (29 jobs, one per STRC exon) listed in STRC Mini-STRC Single-Vector Hypothesis would directly answer whether any single-exon deletions are structurally tolerated. This feeds both this hypothesis and mini-STRC optimization. Do this AF3 sweep before further ASO design.

E1659A is in exon 27

Misha’s maternal mutation c.4976A>C p.(E1659A) falls in exon 27 of the 29-exon STRC gene. Could exon 27 be skipped entirely? If the resulting protein (missing one LRR module from the C-terminal) retains its ability to form horizontal top connectors and TM attachment crowns, this is a viable non-viral, repeatable therapy on the maternal allele.

The LRR modularity argument makes this plausible: stereocilin is composed largely of leucine-rich repeats. LRR proteins are inherently modular — removing one repeat often shifts the structure by one unit without catastrophic misfolding. This is the same principle behind micro-dystrophin (removing non-essential spectrin-like repeats). AF3 modeling of the exon-27-skipped variant would provide the first structural prediction.

Important limitation: the paternal allele is a 98 kb deletion. ASO exon skipping, like prime editing, only affects the maternal allele. It does not address the null allele. Any ASO strategy for Misha is adjunctive, not standalone.

DMD precedent specifics

Four FDA-approved exon-skipping ASOs for Duchenne muscular dystrophy:

  • Eteplirsen (Exondys 51) — exon 51
  • Golodirsen (Vyondys 53) — exon 53
  • Viltolarsen (Viltepso) — exon 53
  • Casimersen (Amondys 45) — exon 45

All use phosphorodiamidate morpholino oligomers (PMOs). Weekly IV dosing. Accelerated FDA approval based on dystrophin expression. STRC has 29 exons; DMD has 79 — similar class of large, multi-exon gene with modular structure.

Open questions

  • Would skipping exon 27 produce in-frame protein with some residual function?
  • Can ASOs reach OHCs efficiently? Intratympanic injection reaches the round window, but OHC uptake of naked ASOs is unknown.
  • What dosing schedule maintains therapeutic levels? DMD uses weekly IV; cochlear delivery would need depot or LNP-encapsulated ASO.
  • What ASO chemistry is preferred for cochlear delivery (PMO, 2’-MOE, LNA)?

Status

Phase 1 complete 2026-04-21 — see STRC ASO Phase1 Splice-Switch Design. Pivoted from skipping-E1659 (not an RBM24 cassette) to blocking RBM24-driven skipping at the four rMATS-validated cassette exons. 16 candidate ASOs designed; lead = E1 donor-blocker 5′-CCTTGCCACTCTCATACC-3′ (Tm 65.6 °C, GC 56%, zero hairpin). Still needs off-target BLAST (Phase 2) before lab. Genotype fit: acts on wild-type portion of maternal allele; paternal deletion and E1659A untouched.

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