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.
2026-04-25
Clinical-vector blocker follow-up: 3/4 blockers closed. Phantom cites fixed in scripts: B8 → Zhao 2025 Neuron PMID 40262614 (706 bp back-calc, was “Yoshimura 2018”); Myo15 956/1157 bp → Hu 2024 Research PMID 38665848 (was “Zhao 2024”); WPRE3 247 bp → Choi 2014 Mol Brain PMID 24618276 (was “Choi 2014 Cell 157”). 4 paper notes created. One remaining blocker: B8 exact bp from Zhao 2025 Table S2 (SI Excel). Scripts flagged with WARNING. → STRC h03 Clinical-Vector Blockers 2026-04-24
Lit audit: lit_audit: deferred closed. 18 constants audited across 9 scripts: 8 ✅ sourced, 7 ⚠ partial (PDF present, value not explicit), 3 ❌ unsourced. 3 phantom cites flagged 🚨: “Yoshimura 2018” for B8/ARBITER (correct: Zhao 2025), “Zhao 2024” for Myo15 956/1157 bp (paper does not contain these values), B8 size 587 bp unconfirmed from SI. lit_audit: partial. → STRC h03 Parameter Provenance Audit 2026-04-25
2026-04-23
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
Misha compound-het stack integration: ref-entry added (Misha Compound-Het Therapy Stack Model) integrating #1 + #3 for Misha’s specific genotype (paternal 98 kb del + maternal E1659A). h03 AAV monotherapy physically cannot reach NORMAL hearing (≤ 25 dB) — ceiling-capped at MILD/MODERATE because non-transduced OHCs inherit 0 paternal + 0.5 × f_mat < θ from maternal, functional fraction capped at ε ≤ 0.5 → max 50% functional OHCs → ABR ~38 dB. h01 PC monotherapy CAN reach NORMAL at f_PC ≥ 0.50-0.75 (mild/moderate/severe E1659A); stack unlocks low-burden NORMAL at mild (9 combinations ε≤0.3 × f_PC≤0.5). Conclusion robust across θ ∈ {0.25, 0.35, 0.45}. Reframes h01 as the only monotherapy route to full cure for Misha; h03 remains S-tier as primary “meaningful rescue” path; clinical plan = parallel stack. Phase 5 MD on h01 priority strengthened (f_PC is the critical-path parameter). #1 + #3 scores unchanged; this is strategic framing. → Misha Compound-Het Therapy Stack Model
Misha compound-het stack integration: ref-entry added (Misha Compound-Het Therapy Stack Model) integrating #1 + #3 for Misha’s specific genotype (paternal 98 kb del + maternal E1659A). h03 AAV monotherapy physically cannot reach NORMAL hearing (≤ 25 dB) — ceiling-capped at MILD/MODERATE because non-transduced OHCs inherit 0 paternal + 0.5 × f_mat < θ from maternal, functional fraction capped at ε ≤ 0.5 → max 50% functional OHCs → ABR ~38 dB. h01 PC monotherapy CAN reach NORMAL at f_PC ≥ 0.50-0.75 (mild/moderate/severe E1659A); stack unlocks low-burden NORMAL at mild (9 combinations ε≤0.3 × f_PC≤0.5). Conclusion robust across θ ∈ {0.25, 0.35, 0.45}. Reframes h01 as the only monotherapy route to full cure for Misha; h03 remains S-tier as primary “meaningful rescue” path; clinical plan = parallel stack. Phase 5 MD on h01 priority strengthened (f_PC is the critical-path parameter). #1 + #3 scores unchanged; this is strategic framing. → Misha Compound-Het Therapy Stack Model