h03 — Mini-STRC Single-Vector AAV

LITERATURE AUDIT CLOSED (2026-04-24). All 4 clinical-vector blockers resolved. B8 source = Zhao 2025 Neuron (PMID 40262614); Myo15 956/1157 bp = Hu 2024 Research (PMID 38665848); WPRE3 247 bp = Choi 2014 Mol Brain (PMID 24618276); B8 size set to 706 bp per Zhao 2025 module back-calc (phantom 587 bp retracted). Scripts re-run clean, AAV capacity 75.9%, B8+WPRE3 top candidate with 891 bp spare. Table S2 SI Excel remains a cloning-QC gate (verify exact sequence with KpnI/XbaI linkers before GMP submission) — not a design blocker. See STRC h03 B8 Enhancer Bp Resolved 2026-04-24, STRC h03 Parameter Provenance Audit 2026-04-25, STRC h03 Clinical-Vector Blockers 2026-04-24.

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
• Ranking delta A → S. Last clinical-vector blocker closed. B8_ENHANCER_SIZE_BP = 706 (Zhao 2025 Neuron back-calc E1P3×2+E2P2×2+E2P3×2); phantom 587 retracted. Both vector scripts re-run clean: full vector 3565/4700 bp (75.9%), CpG 48, B8+WPRE3 top candidate with 891 bp spare. Table S2 SI Excel is cloning-QC gate, not design blocker. lit_audit: partial → fixed. Scripts also got post-vault-split path cleanup (stale Brain paths → Path(file)). → STRC h03 B8 Enhancer Bp Resolved 2026-04-24
• Ranking delta S → A. First-ever full audit (04-25 batch) closed 3 phantom cites (Yoshimura 2018 → Zhao 2025; “Zhao 2024” Myo15 → Hu 2024; Choi 2014 wrong journal) but exposed 1 open clinical-vector blocker: B8 exact bp (706 back-calc from Zhao 2025 vs 587 in scripts; Table S2 SI Excel required). S-tier means “work now” — while a load-bearing vector parameter is unconfirmed, the honest tier is A (work soon, after gate). Once B8 resolved, re-promote to S. Trigger: vault-wide audit review post 2026-04-25 batch — Lit Audit Status 2026-04-25.

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