Rolling rubric for all STRC/DFNB16 hypotheses, Misha-centric. Each scored 1–5 on Mechanism (M), Delivery (D), Misha-fit (F).
Tier ≈ min(M, D, F). This page mirrors ~/STRC/hypotheses/index.md — the canonical register.
Summary: Truncated STRC (Ultra-Mini 1075-1775) packaged into single AAV for DFNB16 gene therapy — current S-tier lead strategy.
Next: Order Ultra-Mini gBlock + B8+WPRE3 cassette; clone pAAV B8-IgK-Ultra-Mini-WPRE3-bGH; Phase 4 HEK coIP. Verify B8 exact cloned sequence against Zhao 2025 Table S2 before GMP submission (cloning QC, not design blocker).
Summary: Self-assembling peptide ear drop forms synthetic horizontal top connectors without gene delivery (SAP hydrogel strategy).
Next: Reviewer-pack queue staged 2026-04-27 after Phase 4m S promotion. Next sessions should start at STRC h09 Reviewer Pack Queue 2026-04-27 and work in order: premortem -> precedent table -> orthogonal WH2 controls -> transfer memo. Phase 4m remains the gate-closing evidence (R2=0.690, Kd_F=1.48 mM); Phase 4k is a support…
Summary: mRNA encoding STRC delivered via cochlear LNP; intraductal dosing avoids AAV packaging limits and enables repeat administration.
Next: No fast compute-to-S path; keep as AAV maintenance/interim only unless new OHC-LNP tropism data reaches therapeutic population coverage
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Summary: Protein-replacement via direct mRNA to OHCs with OHC-tropic LNP formulation (variant of h04 emphasising tropism).
Next: No fast compute-to-S path; needs primary OHC RBM24 titration/Sun 2026 quantification before another model can change tier
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Summary: PVDF-TrFE nanofilm on OHC-apical membrane drives prestin via extracellular piezoelectric field; bypasses native STRC entirely.
Next: Blocked on literature — V_saturation, OHC membrane resistance, 210 kPa Young's modulus all unsourced; TM displacement 5–30 nm is in-house assumption. No compute advance until primary lit retrieved.
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Summary: Chronic 45-60 dB sound via hearing aid drives AC1-CREB signaling → endogenous STRC upregulation (Touch Grass as therapy).
Next: Blocked — 6 load-bearing parameters without primary lit (STRC mRNA t½, STRC protein t½, STRC copy #/OHC, CRE K_half, PDE4 Vmax OHC, CaMKII k_auto). Three require own wet-lab. No compute advance until own measurements or literature-absence explicitly documented in each script.
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Summary: PE3b allele-discriminating edit of maternal E1659A locus — killed 2026-04-22 by STRCP1 paralog cross-hybridization on 61/61 pegRNAs.
Next: Wet-lab ribosome-profiling STRCP1
Summary: Splice-switching ASO targeting cryptic exons E1-E4 — killed 2026-04-22 by STRCP1 paralog cross on 54/54 candidates.
Next: Phase 3a morpholino + 3b gapmer
Summary: Split-SpyCatcher/SpyTag peptide fragments covalently assemble a STRC-equivalent scaffold in perilymph after topical delivery.
Next: Wet-lab only if #3 fails
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Summary: Re-engineer the tectorial membrane to anchor to bundles without STRC, via AAV-delivered TECTA chimera to supporting cells.
Next: Alt scaffold deferred
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Summary: Sonogenetic stimulation of OHCs using acoustically-gated ion channels (MscL or TRP variants) to restore mechanotransduction.
Next: Speculative; no near-term path
Summary: Seamless recombinase-based editing for DFNB16 (Lilly 2026 cochlear recombinase framework adapted to STRC locus).
Next: Technology-watch only
Summary: Direct STRC protein delivery to perilymph via intratympanic injection; bypass genetic intervention entirely.
Next: No delivery route
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Summary: Single-point mutation (R1581Y/F, S1579W/F) stabilises weak Ultra-Mini homodimer interface → 100-1000× avidity on Mini-STRC with zero new AAV payload.
Next: Paused: Phase 1d A1078C/S1080C/S1579C/A1078W all fail AF3 G1; no further compute unless a new scaffold/interface appears
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Summary: Reframe STRCP1 paralog identity as asset — CRISPRa activates endogenous STRCP1 as STRC backup; Gate 1 = wet-lab ribosome profiling.
Next: Email Holt lab ribosome-profiling
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Summary: Upregulate OTOA (STRC paralog) to take over HTC/TM anchor function — chimera avenue killed on Cα RMSD 13.78 Å (ARM region).
Next: Chimera dead; upregulation weak
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Summary: Low-dose WT STRC templates Misha's folded E1659A monomers into mixed fibrils (prion-like cross-templating seeding therapy).
Next: Wrong patient (paternal 98kb Δ)
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