STRC / DFNB16 — Problem Context for Research Routines
Agent context file. Every scheduled routine working in this vault reads this first to understand the current research state before acting. Mirrors
~/STRC/AGENTS.mdphilosophy and[[STRC Hypothesis Ranking]].Last synced: 2026-04-24
Core problem
STRC encodes stereocilin — an extracellular protein that maintains the structure of the hair bundle on outer hair cells (OHCs) of the cochlea. Stereocilin forms the horizontal top connectors between stereocilia and attaches the tallest stereocilia to the tectorial membrane. Without it, hair bundles collapse, OHCs lose mechanosensitivity, and hearing fails.
Mutations in STRC cause DFNB16 — autosomal recessive non-syndromic hearing loss. Target patient: Misha (compound heterozygote — paternal 98 kb deletion / maternal c.4976A>C E1659A).
Central engineering constraint
STRC CDS is ~5,320 bp. AAV payload limit ~4,700 bp. STRC doesn’t fit a single AAV. Every mechanism hypothesis addresses this: truncate, split, edit in situ, use a non-AAV chassis, or replace function via materials.
Active hypothesis register
Source of truth: ~/Brain/notes/STRC Hypothesis Ranking.md. Full table below.
Scoring: M = Mechanism, D = Delivery, F = Misha-fit (each 1-5). Tier ≈ min(M, D, F). Tiers: S (primary, active compute, top-5 max) / A (active backburner) / B (watch) / C (paused) / D (killed) / reference (supporting models).
Canonical view. To change a row — edit the hub’s frontmatter (tier, mech, deliv, misha_fit, next_step), not this file. All 18 numbered hypotheses (h01–h16, h26, h27) are covered. Ref rows (supporting notes, clinical plans) are listed separately below.
TABLE WITHOUT ID
hypothesis_num AS "#",
link(hypothesis_title) AS "Hypothesis",
mech AS "Mech",
deliv AS "Deliv",
misha_fit AS "Misha",
tier AS "Tier",
next_step AS "Next step",
file.link AS "Hub"
FROM "hypotheses"
WHERE type = "hypothesis-hub"
SORT hypothesis_num ASC| # | Hypothesis | Mech | Deliv | Misha | Tier | Next step | Hub |
|---|---|---|---|---|---|---|---|
| 1 | STRC Pharmacochaperone Virtual Screen E1659A | 3 | 4 | 4 | A | Phase 5e mutant re-dock running (v3b YELLOW pocket-stability gate); then Phase 3c v4 fragment-grow on 3-amino-benzofuran-2-COOH scaffold | index |
| 2 | STRC Piezoelectric TM Bioelectronic Amplifier | 2 | 1 | 5 | B | Find OHC ligand + FEM strain-share | index |
| 3 | STRC Mini-STRC Single-Vector Hypothesis | 5 | 5 | 4 | S | Order gBlock, clone pAAV, coIP | index |
| 4 | STRC mRNA-LNP Strategy B Full-Length | 3 | 2 | 2 | B | Academic/interim if AAV fails | index |
| 5 | STRC Calcium Oscillation Acoustic Therapy | 3 | 4 | 2 | A | SPR/BLI E1659A affinity penalty | index |
| 6 | STRC mRNA Therapy Hypothesis | 2 | 2 | 2 | B | Retrieve OHC RBM24 titration lit | index |
| 7 | Prime Editing for STRC | 3 | 2 | 1 | C | Wet-lab ribosome-profiling STRCP1 | index |
| 8 | STRC ASO Exon Skipping | 2 | 3 | 2 | C | Phase 3a morpholino + 3b gapmer | index |
| 9 | STRC Synthetic Peptide Hydrogel HTC | 4 | 3 | 3 | A | Phase 2c WH2 bundling + 4b AF3 | index |
| 10 | STRC In Situ SpyCatcher Assembly | 2 | 2 | 2 | C | Wet-lab only if #3 fails | index |
| 11 | STRC Engineered TECTA Chimera | 2 | 2 | 2 | C | Alt scaffold deferred | index |
| 12 | Sonogenetic STRC Computational Proof | 2 | 2 | 2 | C | Speculative; no near-term path | index |
| 13 | STRC Programmable Recombinases | 2 | 1 | 3 | C | Technology-watch only | index |
| 14 | STRC Protein Replacement Therapy | 2 | 1 | 3 | C | No delivery route | index |
| 15 | STRC OTOA Paralog Cross-Rescue | 2 | 2 | 2 | D | Chimera dead; upregulation weak | index |
| 16 | STRC ZP Domain Prion-Like Seeding | 3 | 2 | 1 | D | Wrong patient (paternal 98kb Δ) | index |
| 26 | STRC Engineered Homodimer Avidity | 2 | 5 | 4 | B | Phase 1d AF3 A1078C/S1080C/S1579C | index |
| 27 | STRC STRCP1 Activation Rescue | 2 | 2 | 4 | C | Email Holt lab ribosome-profiling | index |
Supporting notes (ref — no hub, not in active register)
These hypotheses/models feed into the active register above but don’t get their own hypothesis-hub folder. They’re either engineering sub-layers, survey notes, or clinical strategy docs.
| Hypothesis / model | Role |
|---|---|
| STRC RBM24 Regulatory Hypothesis | Rolled into Strategy A |
| STRC Stereocilia Bundle Mechanics Model | Supporting biophysics model |
| STRC AAV Vector Design | Mini-STRC implementation detail |
| STRC B8 Enhancer Selection | AAV pipeline |
| STRC Dual-Vector vs Single-Vector Transduction | Engineering layer |
| STRC Anti-AAV Immune Response Model | Re-dosing constraint |
| STRC Electrostatic Analysis E1659A | Pharmacochaperone input |
| Adult Treatment Window STRC | Constraint on all mechanisms |
| Alternative STRC Delivery Hypotheses | Delivery-layer survey |
| Misha Compound-Het Therapy Stack Model | Clinical plan: parallel h01+h03 stack |
All 18 numbered hypotheses (h01–h16, h26, h27) now live in hypotheses/h{N}/hub.md and render via the Dataview block above. Manual table removed 2026-04-23 — edit hub frontmatter to change tier/score/next-step.
Hypothesis → synthesis file slug
When Part 2 (hypothesis synthesis) needs to write a Recent Papers entry, use these slugs. null = no synthesis file yet; routine should skip synthesis for that hypothesis.
| Hypothesis | Synthesis file |
|---|---|
| STRC Pharmacochaperone Virtual Screen E1659A | null |
| STRC Piezoelectric TM Bioelectronic Amplifier | null |
| STRC Mini-STRC Single-Vector Hypothesis | hypotheses/mini-strc.md |
| STRC mRNA-LNP Strategy B Full-Length | null |
| STRC Calcium Oscillation Acoustic Therapy | null |
| STRC mRNA Therapy Hypothesis | null |
| Prime Editing for STRC | hypotheses/prime-editing.md |
| STRC ASO Exon Skipping | hypotheses/exon-skipping.md |
| STRC Synthetic Peptide Hydrogel HTC | null |
| STRC In Situ SpyCatcher Assembly | null |
| STRC Engineered TECTA Chimera | null |
| Sonogenetic STRC Computational Proof | hypotheses/sonogenetics.md |
| STRC Programmable Recombinases | hypotheses/recombinases.md |
| STRC Protein Replacement Therapy | null |
| STRC OTOA Paralog Cross-Rescue | null |
| STRC ZP Domain Prion-Like Seeding | null |
| STRC RBM24 Regulatory Hypothesis | null |
| STRC Stereocilia Bundle Mechanics Model | hypotheses/bundle-mechanics.md |
| STRC AAV Vector Design | null |
| STRC B8 Enhancer Selection | hypotheses/enhancer.md |
| STRC Dual-Vector vs Single-Vector Transduction | hypotheses/dual-vector.md |
| STRC Anti-AAV Immune Response Model | hypotheses/immune.md |
| STRC Electrostatic Analysis E1659A | hypotheses/electrostatics.md |
| Adult Treatment Window STRC | null |
| Alternative STRC Delivery Hypotheses | hypotheses/delivery.md |
Kill list (D-tier — do not pursue)
TABLE WITHOUT ID
link(hypothesis_title) AS "Hypothesis",
next_step AS "Reason killed",
file.link AS "Hub"
FROM "hypotheses"
WHERE type = "hypothesis-hub" AND tier = "D"
SORT hypothesis_num ASC| Hypothesis | Reason killed | Hub |
|---|---|---|
| STRC OTOA Paralog Cross-Rescue | Chimera dead; upregulation weak | index |
| STRC ZP Domain Prion-Like Seeding | Wrong patient (paternal 98kb Δ) | index |
How to use this file (agent directive)
- Before scanning: read this entire file. Understand S-tier (top compute), A-tier (backburner), killed. Skew relevance scoring toward S/A — papers advancing S-tier hypotheses are HIGH value. Papers on D-tier should only be indexed if they credibly flip the kill.
- For paper dedup: see routine Step 1 (builds DOI/PMID/bioRxiv lookup sets).
- For hypothesis synthesis (Part 2): match papers to hypotheses by tag + relevance + mechanism overlap. Append “Recent Papers” entries only to files listed in the slug table. If
null: logSKIP-NO-SYNTH-FILE: <hypothesis>and move on. - If this file feels stale (S-tier hypothesis with completed next-step, or paper mentions hypothesis not in the table): operate from this file anyway, flag drift in commit message.
Connections
[part-of]index[about]STRC Hearing Loss[about]Misha[see-also]STRC Hypothesis Ranking