STRC Hypothesis Ranking

Live tier table across all 18 numbered hypotheses (h01–h16, h26, h27). Every row links to its hypothesis hub with phase history and artifacts. Scores update as proofs land.

Rubric

Axes 1-5: Mech (biology plausible), Deliv (cochlear delivery 3-5 yr), Misha-fit (compound het, age, OHC window).

Tier heuristic: min(Mech, Deliv, Misha-fit). S = top 5 active. A = backburner. B = watch. C = paused, needs external catalyst. D = killed.

Active register

All 18 numbered hypotheses. Ref rows (supporting notes, clinical plans) appear 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

S-tier (live)

TABLE WITHOUT ID
  link(hypothesis_title) AS "Hypothesis",
  next_step AS "Next step",
  file.link AS "Hub"
FROM "hypotheses"
WHERE type = "hypothesis-hub" AND tier = "S"
SORT hypothesis_num ASC

Hypothesis	Next step	Hub
STRC Mini-STRC Single-Vector Hypothesis	Order gBlock, clone pAAV, coIP	index

Clinical plan for Misha per Misha Compound-Het Therapy Stack Model: pursue #1 (PC for maternal E1659A) + #3 (AAV for paternal null) in parallel. h01 is the only monotherapy route to NORMAL (≤ 25 dB ABR); stack provides redundancy and lower drug/AAV burden. Phase 5 MD on #1 is the critical-path compute that produces the f_PC parameter.

Kill list (D-tier, live)

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

Decision gates

• → D: mechanism falsified OR Misha-fit=1 OR delivery impossible 10 yr.
• → C: no near-term computational step; log external catalyst.
• → B: evidence neutral, shallow engagement.
• → A: real progress possible, not highest-leverage today.
• → S: top 5 max, advances Misha directly, actionable next step.

Literature-audit status

Per-hypothesis audit of parameter provenance against primary literature. Status (fixed / partial / deferred) is carried on each hub.

TABLE WITHOUT ID
  hypothesis_num AS "#",
  link(hypothesis_title) AS "Hypothesis",
  tier AS "Tier",
  lit_audit AS "Audit",
  lit_audit_date AS "Date",
  file.link AS "Hub"
FROM "hypotheses"
WHERE type = "hypothesis-hub"
SORT hypothesis_num ASC

#	Hypothesis	Tier	Audit	Date	Hub
1	STRC Pharmacochaperone Virtual Screen E1659A	A	fixed	2026-04-23	index
2	STRC Piezoelectric TM Bioelectronic Amplifier	B	fixed	2026-04-23	index
3	STRC Mini-STRC Single-Vector Hypothesis	S	deferred	2026-04-23	index
4	STRC mRNA-LNP Strategy B Full-Length	B	fixed	2026-04-23	index
5	STRC Calcium Oscillation Acoustic Therapy	A	fixed	2026-04-23	index
6	STRC mRNA Therapy Hypothesis	B	partial	2026-04-23	index
7	Prime Editing for STRC	C	fixed	2026-04-23	index
8	STRC ASO Exon Skipping	C	fixed	2026-04-23	index
9	STRC Synthetic Peptide Hydrogel HTC	A	partial	2026-04-23	index
10	STRC In Situ SpyCatcher Assembly	C	fixed	2026-04-23	index
11	STRC Engineered TECTA Chimera	C	fixed	2026-04-23	index
12	Sonogenetic STRC Computational Proof	C	deferred	2026-04-23	index
13	STRC Programmable Recombinases	C	deferred	2026-04-23	index
14	STRC Protein Replacement Therapy	C	deferred	2026-04-23	index
15	STRC OTOA Paralog Cross-Rescue	D	deferred	2026-04-23	index
16	STRC ZP Domain Prion-Like Seeding	D	deferred	2026-04-23	index
26	STRC Engineered Homodimer Avidity	B	fixed	2026-04-23	index
27	STRC STRCP1 Activation Rescue	C	fixed	2026-04-23	index

• 2026-04-23-digest — latest literature-watch auto-digest (1 new paper, 45 filtered)

Legacy synthesis pages (pre-hub structure)

Older flat synthesis notes from 2026-04-21/22, superseded by the h{N}/hub.md structure but kept for historical context:

• delivery — sonoporation + LNP through round window (now in h04-mrna-lnp)
• dual-vector — dual vs single vector math (now referenced by h03-mini-strc)
• electrostatics — E1659A electrostatic analysis (reference tier)
• immune — anti-AAV antibodies + re-dosing (supporting)
• mini-strc — mini-STRC synthesis (now h03-mini-strc)
• prime-editing — prime editing feasibility (now h07-prime-editing)
• sonogenetics — sound-activated gene expression (now h12-sonogenetic)

Connections

• [part-of] STRC Research Portal
• [see-also] STRC Hypothesis Ranking Log
• [see-also] STRC Mini-STRC Single-Vector Hypothesis
• [see-also] STRC Pharmacochaperone Virtual Screen E1659A
• [see-also] STRC Piezoelectric TM Bioelectronic Amplifier
• [see-also] STRC Calcium Oscillation Acoustic Therapy
• [see-also] STRC Synthetic Peptide Hydrogel HTC
• [about] Misha