STRC Research

aav-cochlear-delivery

5 min read

AAV Cochlear Delivery — Cross-Hypothesis Parameter Table

Parameters for AAV vector design and cochlear transduction. Primary consumer: h03 (Mini-STRC Single-Vector AAV). Also used by h04 (Strategy B dual-vector) and any future AAV-based hypotheses.

Created: 2026-04-25 from h03 parameter provenance audit (STRC h03 Parameter Provenance Audit 2026-04-25).

Parameter Table

ParameterValueUnitsPrimary sourcePDF in vaultNote
AAV packaging capacity (ITR-to-ITR)~4700bpIranfar 2026 (CTM 16, e70571) explicit text; Omichi 2020 says “no more than 5.0 kb”✅ Iranfar 2026 MinerU parsed4700 is consistent floor; 5000 is ceiling; use 4700 for conservative design
AAV2 ITR size~145bpSamulski 1987 J Virol (canonical)❌ no PDF in vaultStandard molecular biology; retrieval deferred
ITR overhead total~300bpDerived: 2 × 145 bp + linker; consistent with Iranfar 2026 vector diagrams⚠ inferred
bGH polyA signal size~225bppAAV-MCS canonical; no specific paper❌ no PDFStandard vector element
Human genome CpG density9.7CpG/kbLander et al. 2001 Nature (Human Genome Project) or equivalent — NOT cited in scripts❌ no PDFComparative denominator only
Anc80L65 OHC transduction~60–84%%Omichi 2020 (RWM+CF, adult C3H/FeJ): AAV2 = 83.9±2%; Anc80L65 OHC = 43% mean (apex 65.6%, middle 27.4%, base 36.1%); Iranfar 2026: PHP.eB dual-AAV = 60% STRC+ cells✅ Omichi 2020 MinerU parsed; ✅ Iranfar 2026NOTE: Omichi reports AAV2 as best OHC serotype in adult RWM+CF; Anc80 is lower in that study. h03 hub claims “Anc80L65 60–100% cochlear transduction in OTOF trials precedent” — this requires OTOF trial data (Lustig 2024 / Sun 2024), not Omichi.
Dual-AAV OHC co-transduction65.6±8.95%%Omichi 2020 dual AAV2-AAV2 at 3.75–3.80×10¹² GC/mL✅ Omichi 2020Co-transduction ≠ recombination efficiency
Recombination efficiency (dual-vector)~50%of co-transduction eventsInferred from Iranfar 2026 results: 60% STRC+ cells vs expected ~65–84% co-transduction → R ≈ 0.5–0.9. Not directly measured.⚠ inferredIranfar 2026 attributes reduced efficiency to “co-infection requirement and recombination constraint”
Clinical titer (DB-OTO trial)7.2×10¹²GC/earDB-OTO (Regeneron); Lustig et al. 2025 NEJM (10.1056/NEJMoa2400521) — published Oct 2025, 20 participants, 16/20 met primary endpoint❌ no PDF in vault yet; titer confirmed from public press releasesNote: DB-OTO NEJM paper is 2025 not 2024. Script “Lustig 2024 NEJM Evidence” citation is to the wrong year.
Clinical titer (Fudan/Lv 2024 dual-AAV OTOF)not confirmed from textGC/earLv et al. 2024, Lancet 403:2317-2325; PMID 38280389; DOI 10.1016/S0140-6736(23)02874-X⚠ paper note created 2026-04-24; titer requires full paperScript “Sun 2024 Lancet” = Lv 2024 Lancet (Fudan). First author is Lv, not Sun.
Human cochlear volume~50µLcochlear-pkpd topic file — sourced from Salt and Hale 2017 / Dhanasingh 2021✅ via cross-hypothesis library
B8 enhancer size706bpZhao et al. 2025, Neuron 113(10):1579-1596; PMID 40262614; B8 = E1P3×2+E2P2×2+E2P3×2; modules E1P3=93, E2P2=132, E2P3=128 bp → back-calc 2·93+2·132+2·128 = 706 bp✅ Zhao 2025 PDF + MinerU 2026-04-24; Table S2 remains cloning-QC gate for exact sequence with KpnI/XbaI linkersScripts updated 2026-04-24: 587 bp phantom retracted → 706 bp. Vector fit preserved (Ultra-Mini 75.9% of AAV capacity). NOTE: paper is Neuron not Cell.
B8 enhancer OHC specificity~100% OHC transduction%Zhao 2025 Fig 6C; zero IHC/vestibular/brain/heart/liver✅ Zhao 2025 confirmed
WPRE3-compact size247bpChoi et al. 2014, Mol Brain 7:17; PMID 24618276; DOI 10.1186/1756-6606-7-17✅ confirmed from PMC full text 2026-04-24Journal = Molecular Brain, NOT Cell 157. 83.4% of full WPRE (600 bp) expression.
Myo15 956 bp / 1157 bp promoter956 / 1157bpHu et al. 2024, Research (AAAS) 7:0341; PMID 38665848; DOI 10.34133/research.0341✅ confirmed from PMC 2026-04-24PHANTOM CITE FIXED: was “Zhao 2024” — correct source is Hu et al. 2024 (Shu lab). OHC efficiency: mini-Myo15 (956 bp) = 69-77% OHC.
Myo15 1611 bp native promoter1611bpWang et al. 2024, Mol Ther Nucleic Acids 35:102135; PMID 38404504; DOI 10.1016/j.omtn.2024.102135✅ confirmed from PMC 2026-04-24First author Wang H (not Liu).
Prestin native regulatory region~1800bpEstimated; no citation❌Not used in winning candidate; “estimated” noted in script

CpG Depletion Parameters

ParameterValueUnitsSourceStatus
Kazusa Homo sapiens codon usagePer-codon frequenciesper 1000 codonshttps://www.kazusa.or.jp/codon/cgi-bin/showcodon.cgi?species=9606✅ primary database
CAI methodSharp & Li 1987 geometric mean—Sharp PM, Li WH. Nucleic Acids Res. 1987;15:1281–1295❌ no PDF; foundational method
CAI optimization threshold≤5% penalty acceptable—No primary source❌ design choice, not literature-derived

Open Actions

Updated 2026-04-24 after clinical-vector blocker resolution pass:

  1. Myo15 956/1157 bp source — CLOSED. Source is Hu et al. 2024, Research (AAAS) 7:0341; PMID 38665848. Script phantom cite “Zhao 2024” corrected.
  2. WPRE3 247 bp source — CLOSED. Choi et al. 2014, Mol Brain 7:17; PMID 24618276 confirmed from PMC. Journal is Molecular Brain, not Cell 157.
  3. Myo15 1611 bp source — CLOSED. Wang et al. 2024, Mol Ther Nucleic Acids; PMID 38404504. First author Wang H, not Liu.
  4. B8 exact size from Zhao 2025 Table S2 — PARTIALLY CLOSED. Paper retrieved and MinerU parsed. Main text gives module sizes (E1P3=93, E2P2=132, E2P3=128 bp) → back-calc 706 bp. Table S2 (supplementary Excel) has exact cloned sequence. SI not extracted by MinerU. Remaining: retrieve Zhao 2025 SI Excel from Cell/Neuron journal supplementary to confirm 706 vs 587 bp. Script has WARNING flag; update to 706 bp pending confirmation.
  5. DB-OTO titer — PARTIALLY RESOLVED. NEJM paper identified (Lustig et al. 2025 NEJM, DOI 10.1056/NEJMoa2400521; titer = 7.2×10¹² GC/ear from press releases). PDF retrieval pending. Script “Lustig 2024 NEJM Evidence” needs year correction to 2025.
  6. Fudan trial titer — Lv 2024 Lancet identified (PMID 38280389). Exact titer per cohort requires full paper access.

Connections

Graph View

Backlinks