h03 — Mini-STRC Single-Vector AAV

🔒 LITERATURE AUDIT DEFERRED (2026-04-23, user directive). Do NOT run a parameter-provenance audit on this hypothesis without explicit re-authorization. Reason: fear of destabilizing the active S-tier path while Holt lab is independently working on the same architecture. If parameters need retrieval for a specific proof, ask Egor first.

mech. Ultra-Mini STRC (aa 1075-1775, 2.1 kb CDS) preserves TMEM145-binding pocket and fits single AAV with OHC-specific promoter (B8+WPRE3). delivery. Anc80L65 AAV; 60-100% cochlear transduction in OTOF trials precedent; single-vector. patient-fit. Null-compatible (works on paternal 98 kb Δ); Shanghai Shu Yilai c.4976 knock-in mouse active.

status

S-tier. next: order Ultra-Mini gBlock; clone pAAV B8-IgK-Ultra-Mini-WPRE3-bGH; Phase 4 HEK coIP.

Recent activity

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h03 log
strc
h03
Misha compound-het stack integration: S held, scores unchanged, endpoint framing clarified. h03 for Misha’s specific genotype is physically ceiling-capped at MILD (~30-40 dB ABR) — at realistic transduction ε ≤ 0.5, ≥50% of OHCs remain non-transduced and cannot be rescued by AAV (maternal E1659A sub-threshold + paternal null → f_OHC < θ). “Meaningful rescue” endpoint intact (20-30 dB ABR improvement vs 64 dB baseline is clinically huge and matches OTOF trial responder criteria). “Cure” endpoint (NORMAL ≤ 25 dB) requires h01 co-therapy. No compute work needed on h03; this is endpoint semantics. → Misha Compound-Het Therapy Stack Model
S-tier reinforced: AAV-LNP stack model formalises AAV as primary path → STRC AAV-LNP Stack PKPD

evidence

STRC Mini-STRC Single-Vector Hypothesis — main hypothesis; full-stack validated 2026-04-21
STRC Mini-STRC Truncation Interface Validation — sub-Å RMSD at TMEM145 pocket; Ultra-Mini = clinical 700-1775
STRC Ultra-Mini CpG Depletion — 0 CpG CDS at 3.65% CAI cost; clinical CDS ready
STRC Homodimer Interface From CIF — weak homodimer at ARM 1579-1581; real weak dimerization surface
STRC Ultra-Mini Promoter Shortlist — B8+WPRE3-compact winner; OHC-exclusive
STRC Ultra-Mini Full-Length TMEM145 AF3 — ipTM 0.43, 23/41 contacts in GOLD zone
STRC AF3 Ultra-Mini Multimer Validation — GOLD ipTM 0.68; homodimer weak-positive
STRC Gene Therapy Landscape 2026 — Iranfar 2026, Holt 2021, Regeneron AAV.104
STRC Dual-Vector vs Single-Vector Transduction — engineering choice rationale

scripts

models/ (legacy pool — see STRC Computational Scripts Inventory § Hypothesis 3)

mini_strc_interface_preservation.py, cpg_depletion_mini_strc.py, cpg_depletion_ultra_mini_strc.py
strc_homodimer_interface_from_cif.py, ultramini_homodimer_consensus.py
ultra_mini_promoter_shortlist.py, ultramini_vector_cpg_audit.py

log

h03 log

cross

STRC Engineered Homodimer Avidity — h26 upgrades this candidate’s Kd 100-1000× at zero payload cost
STRC Synthetic Peptide Hydrogel HTC — h09 is independent path; if both pass → stack

Connections

[part-of] STRC Hypothesis Ranking
[about] Misha

STRC Research

Explorer

H03 · Mini-STRC Single-Vector