STRC Ca Oscillation Maternal-Only PD

Maternal-allele-only pharmacodynamic sweep for STRC Calcium Oscillation Acoustic Therapy (#5 A-tier concrete next step). Answers: given Misha’s compound-het genotype (paternal 98 kb del = null + maternal c.4976A>C = E1659A missense), can acoustic-driven AC1-CREB induction of E1659A protein reach therapeutic occupancy when the protein has reduced TMEM145 binding affinity?

Answer: only if E1659A affinity penalty ≤ 3× AND chronic acoustic dose sustains maximum 2.6× fold induction. Realistically outside that window (3-30× penalty band typical for ARM-repeat missense), acoustic therapy does not reach partial rescue.

Model

functional_occupancy = allele_dosage × acoustic_fold × (1 / affinity_penalty)

• allele_dosage = 0.5 for Misha (only one functional allele, diploid scaling)
• acoustic_fold ∈ [1.0, 2.6] (AC1-CREB Phases 1-3 bound the max at 2.6× at 60 dB LAeq chronic)
• affinity_penalty ∈ [1x, 1000x] sweep; realistic ARM-repeat missense 3-30×

Thresholds:

• Partial rescue (≈22 dB ABR shift): occupancy ≥ 0.30 (from bundle mechanics f parameter)
• Full rescue (WT function): occupancy ≥ 1.0

Sweep result

	1×	2×	3×	5×	10×	30×	100×	300×	1000×
fold 1.0×	0.50 ᴾ	0.25	0.17	0.10	0.05	0.02	0.01	0.00	0.00
fold 1.3×	0.65 ᴾ	0.33 ᴾ	0.22	0.13	0.07	0.02	0.01	0.00	0.00
fold 1.6×	0.80 ᴾ	0.40 ᴾ	0.27	0.16	0.08	0.03	0.01	0.00	0.00
fold 1.9×	0.95 ᴾ	0.47 ᴾ	0.32 ᴾ	0.19	0.10	0.03	0.01	0.00	0.00
fold 2.2×	1.10 ᶠ	0.55 ᴾ	0.37 ᴾ	0.22	0.11	0.04	0.01	0.00	0.00
fold 2.6×	1.30 ᶠ	0.65 ᴾ	0.43 ᴾ	0.26	0.13	0.04	0.01	0.00	0.00

ᶠ = full rescue · ᴾ = partial rescue · unmarked = below partial threshold

Realistic affinity-penalty band (3-30×)

3 / 24 combos pass partial rescue, all at (penalty=3×, fold ≥1.9×). No combo passes full rescue.

Feasibility boundaries (max penalty that still passes, at each acoustic fold)

• Partial: 1.3×→2×, 1.9×→3×, 2.6×→3×. Ceiling: penalty 3×
• Full: 2.2×-2.6×→penalty 1× only. Ceiling: penalty 1×

Interpretation

Acoustic therapy cannot overcome ARM-repeat missense affinity penalties above ~3×. The single-allele dosage (0.5) is a fundamental ceiling — even WT-affinity E1659A (impossible; it’s by definition a penalty variant) at max acoustic fold only reaches 1.3× occupancy.

The missing piece is the true affinity penalty of E1659A. Published structural data on ARM-repeat missense variants suggests:

• Surface-exposed polar residue swap (Glu → Ala at internal interface position): 3-10×
• Buried hydrophobic disruption: 30-300×
• Salt-bridge disruption at critical contact: 10-100×

E1659A is internal to the STRC ARM repeat, at the TMEM145 interface. Glu→Ala removes a negative charge that in the Derstroff 2026 / our AF3 modeling sits in the K1141-D1140-D1173 pocket. This is likely salt-bridge-coupled → most plausible penalty 10-100×, i.e. outside the feasibility window for acoustic therapy as a primary rescue.

What would change this

1. Direct E1659A affinity measurement. SPR / BLI on purified WT-STRC vs E1659A vs TMEM145-GOLD. Wet-lab, ~$10-20k, weeks. If penalty turns out ≤3×, acoustic therapy becomes primary-viable.
2. Phase 5 computational FEP of E1659A vs WT binding ΔΔG. AMBER or GROMACS free-energy perturbation. Wall-clock 48-96h on GPU. Has ±1-2 kcal/mol error, could rule out or confirm the 10-100× penalty range.
3. Combination with AAV Mini-STRC. If AAV delivers WT-STRC to 60% of OHCs, acoustic therapy boosts endogenous E1659A expression in the AAV-untransduced 40%. Even at 30× penalty, 2.6× fold × 0.5 × (1/30) = 0.043 extra occupancy across the non-AAV fraction. Doesn’t save non-AAV cells, but the stack formalism from STRC AAV-LNP Stack PKPD says AAV does the real work. Acoustic on top is additive-not-dilutive but quantitatively small.

Ranking delta

STRC Calcium Oscillation Acoustic Therapy (#5): no tier change — stays A.

Scoring confirmed:

• Mechanism 3: unchanged (AC1-CREB pathway biology sound, Phases 1-3 Hill n=4.3 stable)
• Delivery 4: unchanged (hearing aid, non-invasive, zero risk)
• Misha-fit 2: unchanged (limited by allele dosage × affinity penalty ceiling)
• min(3, 4, 2) = 2 → A-tier confirmed

Next step refined from “maternal-allele-only; Touch Grass integration path” → “measure E1659A TMEM145 affinity penalty (SPR/BLI or Phase 5 FEP); if ≤3× → acoustic primary-viable, if 3-30× → acoustic as adjunct to AAV only, if >30× → deprioritise”.

Zero-risk-adjunct recommendation: chronic 45-60 dB LAeq via hearing aid / Touch Grass is still worth doing REGARDLESS of quantitative result — acoustic therapy has no downside, it’s the default “ambient therapeutic sound” posture already discussed with audiologist. Not a substitute for AAV; a free add-on that might contribute marginal lift.

Connections

• [part-of] index
• [applies] STRC Calcium Oscillation Acoustic Therapy
• [applies] STRC AC1-CREB Monotonic Sound Response (acoustic fold range)
• [applies] STRC AC1-CREB Parameter Robustness (robustness index 0.91)
• [applies] STRC Stereocilia Bundle Mechanics Model (f thresholds)
• STRC AAV-LNP Stack PKPD (stack adjunct logic)
• [see-also] STRC Electrostatic Analysis E1659A (affinity penalty prediction)
• [see-also] STRC Hypothesis Ranking