STRC Stereocilia Bundle Mechanics Model
Computational model quantifying how HTC (horizontal top connector) spring coupling—maintained by stereocilin/STRC—determines OHC function and what gene therapy can restore.
The Core Question
Misha is ~5 years old with moderate SNHL from compound heterozygous STRC mutations. His OHCs are almost certainly alive (Verpy 2008 confirms survival in adult Strc-/- mice). But are they still rescuable? Does his bundle still have enough structural integrity to reform horizontal top connectors if STRC is delivered?
Two-Component Model
ABR threshold shift as a function of HTC coupling fraction f ∈ [0,1]:
ABR_shift = 9.5 dB × (1 - f) ← MET channel component
+ 34.5 dB × (1 - √f) ← cochlear amplification component
──────────────────────────
Total at f=0: 44 dB (matches Verpy 2008 Strc-/- data)
MET component (9.5 dB): Without HTCs, only the tallest stereocilia row (row 1) gets direct TM signal. Rows 2-3 receive signal via HTC transfer. Loss of HTCs = 1/3 of MET channels driven = -9.5 dB sensitivity.
Amplification component (34.5 dB): OHC cochlear amplification is a Hopf oscillator. Gain ∝ f^0.5 (square-root coupling, Camalet et al. 2000). This dominates. Without STRC, the feedback loop between OHC electromotility and TM is broken.
Results
| HTC coupling | ABR threshold | Category |
|---|---|---|
| 100% (normal) | 20 dB | Normal |
| 30% | 42 dB | Moderate |
| 10% | 52 dB | Moderate |
| 5% | 56 dB | Moderate-severe |
| 0% (full KO) | 64 dB | Moderate-severe |
Misha’s Position
From Sept 2025 audiometry (QMH):
- Right ear: ~50-65 dB → corresponds to ~0-10% HTC coupling
- Left ear: ~40-50 dB → corresponds to ~10-30% HTC coupling
His VUS allele (c.4976A>C) produces some stereocilin — enough for partial but reduced coupling. His moderate (not profound) loss is consistent with 10-30% residual coupling.
Gene Therapy Projection
At 67% OHC transduction (Anc80L65, clinical titer):
| Current coupling | Current ABR | Post-therapy ABR | Gain |
|---|---|---|---|
| 0% | 64 dB | 29 dB | 35 dB |
| 10% | 52 dB | 28 dB | 24 dB |
| 30% | 42 dB | 26 dB | 16 dB |
Post-therapy: 26-29 dB — mild hearing loss category, conversational speech without aids.
The Unknown Variable: Tectorial Membrane
The model assumes transduced OHCs can successfully reform HTCs AND TM attachment crowns. HTC reformation is structurally plausible (OHCs intact, stereocilia present, rootlets anchored). But the TM may have undergone structural remodeling after 5 years without proper OHC coupling.
If TM intact: model prediction holds, ~35 dB improvement If TM remodeled: internal HTCs can reform but TM-OHC link broken → partial gain only
No data exists for TM morphology in DFNB16 at age 5-equivalent in any model. This is the single most important experiment for STRC programs treating older patients.
Direct k_HTC measurement — Dulon et al. 2019
dulon-2019-htc-bundle-mechanics (Science Advances, PMC6382404) provides the first direct measurement of HTC spring contribution via non-contact acoustic FM-AFM:
- OHC bundle with HTCs: 5.12 ± 0.46 pN/nm
- OHC bundle without HTCs (Strc-/-): 2.05 ± 0.15 pN/nm
- 60% stiffness reduction from HTC loss — measured directly, not inferred
- IHC stiffness unchanged (HTCs are OHC-specific)
- Per-link k_HTC ≈ 0.16 mN/m (19 links in 20-stereocilia chain)
The model uses empirical 44 dB calibration from Verpy 2008. Dulon’s k_HTC values confirm the 60% coupling-loss magnitude used in the model.
Age progression — Verpy et al. 2011
verpy-2011-strc-tm-morphology (J Comp Neurol, PMC3375590) extended Strc-/- characterization across ages:
- P9: bundle structurally normal
- P15: tip links begin disappearing
- P60: almost all OHC stereocilia fully disconnected
- 5 months: basal — “scarce, shortened stereocilia”; apical — OHC loss NOT increased vs controls
TM imprints absent throughout — in full KO, TM-OHC attachment crowns never form. This is a developmental deficit, not age-related degradation.
Implication for Misha: his partial STRC (VUS allele) likely formed partial TM attachment crowns at birth. He starts from a better position than full KO mice. His apical OHCs (low frequencies) are likely better preserved than basal.
TM crown reformation — Tarchini et al. 2021
tarchini-2021-strc-dual-vector-neonatal (Science Advances, PMC8673757) — first STRC gene therapy in Strc-/- mice, P1 injection:
- Dual AAV PHP.B, split STRC
- 59% OHC transduction, 50–60 dB hearing improvement in best responders
- TM attachment crowns REFORMED even from full KO baseline
- Adult delivery: explicitly not tested — “remains to be determined”
Critical finding: TM retains structural capacity to embed stereocilia tips when STRC is provided, even after never having formed attachment crowns. Most encouraging data point for adult treatment viability.
The gap: no rescue experiment at P30+, P60+, or adult in STRC-null animals exists anywhere in the literature. This is what Misha’s program needs.
Model File
~/STRC/models/stereocilia_bundle_mechanics.py
Results: ~/STRC/models/bundle_mechanics_results.json
Connections
- Misha — direct clinical application
- DFNB16 Hearing Loss — disease context
- Adult Treatment Window STRC — therapeutic window analysis
- STRC Gene Therapy Landscape 2026 — treatment strategy
- STRC Mini-STRC Single-Vector Hypothesis — delivery vehicle, converging ABR estimate
[source]dulon-2019-htc-bundle-mechanics — direct k_HTC measurement[source]verpy-2011-strc-tm-morphology — age progression and TM imprints[source]tarchini-2021-strc-dual-vector-neonatal — P1 dual-AAV rescue, TM crown reformation