STRC Research

STRC Engineered TECTA Chimera

3 min read

STRC Engineered TECTA Chimera

Instead of restoring STRC to the stereocilia bundle, re-engineer the tectorial membrane itself so it sticks to the bundle without STRC. A modified TECTA (α-tectorin) variant, bearing a “sticky” C-terminal extension that binds OHC surface markers directly, delivered to supporting cells via AAV, could anchor the TM to hair bundles via a STRC-independent pathway.

The hidden assumption this breaks

The field frames DFNB16 as an OHC disease — the bundle is broken, the bundle must be fixed. But the coupling failure is a two-body problem. Either body can be engineered. TM is a static, supporting-cell-derived matrix; its composition can be changed without touching OHCs.

Mechanism

Normal TM composition: α-tectorin (TECTA), β-tectorin (TECTB), otogelin (OTOG), otogelin-like (OTOGL), CEACAM16, otolin-1. Secreted by interdental cells and Kölliker’s organ; assembled into a meshed glycoprotein matrix.

Engineered construct: TECTA-EC = full-length TECTA with added C-terminal extension encoding:

  1. A glycan-binding domain (e.g., OHC prestin ectodomain binder, or an OHC-specific glycocalyx recognizer — prestin glycans OHC-restricted)
  2. OR a lectin-like module that grabs sialyl-Lewis or similar OHC-surface glycan pattern

Delivered as AAV with supporting-cell-specific promoter (e.g., Col9a1, Otog, or Kölliker-organ-restricted enhancer) — NOT the B8 OHC enhancer used in mini-STRC work. TECTA-EC is secreted, incorporated into existing TM, extends its adhesion surface to grab the hair bundle even when STRC is missing.

Computational proof path

  1. Bioinformatic scan of TECTA C-terminus — is there natural C-terminal flexibility permitting domain insertion without disrupting ZP-module-mediated TM assembly? Compare TECTA orthologs across mammals; identify tolerant regions.
  2. Target-ligand design — what OHC-surface handle is glycan-restricted enough to avoid TECTA-EC sticking to IHCs or supporting cells? Candidates: prestin N-glycans (primary: Matsuda 2004 PMID 15140192 — N163/N166 sites; Zheng 2009 JARO 10:373 — glycosylation regulates electromotility. Prior “Song 2021” citation was PHANTOM, replaced with verified Matsuda/Zheng references 2026-04-23); oncomodulin surface-displayed isoforms. Run AF3 / GlycoSHIELD to model glycan accessibility.
  3. AF3-Multimer of TECTA-EC + OHC surface protein(s) — confirm selective binding; ipTM > 0.6 on OHC handle, <0.3 on non-target.
  4. TM-mesh mechanical modeling — does added OHC-binding domain mechanically perturb TM? Finite-element model of TM with/without chimera protein incorporation.
  5. Supporting-cell promoter selection — browse ENCODE / cochlear single-cell atlases (Shield, Kelley lab data) for Kölliker-organ-restricted enhancers. Candidate list: Otog, Otogl, Col11a1.

Advantage over STRC-restoration approaches

  • Patient-genotype-agnostic: works whether the patient has deletion, missense, nonsense, or compound het STRC mutation. Doesn’t care what is wrong with STRC at all.
  • Compatible with stalled-stereocilia case: if bundle has partially collapsed, TECTA-EC still reaches whatever remains.
  • Does not compete with mini-STRC: could be stacked in a second AAV (dual-therapeutic).

Risks

  • AAV tropism for supporting cells vs OHCs is serotype-dependent; Anc80L65 hits both. Need stricter serotype (e.g., AAV-ie, AAV-PHP.B derivatives) or enhancer-only specificity.
  • TM is a fragile, highly organized matrix — modified TECTA may disrupt assembly even without reaching OHCs. Verpy 2008 shows TM can grossly form without STRC — so modification tolerance is partly demonstrated.
  • Coupling geometry may be wrong: stereocilia project into the TM at a specific angle. Engineered binding site geometry must match.

Connections

Graph View

Backlinks