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