Hypotheses — Live Ranking

Eighteen therapeutic hypotheses for Misha’s DFNB16 compound-het (maternal E1659A + paternal 98kb Δ). Tiers update as proofs land. Every row links to the hypothesis hub, which carries phase history, active compute, and scripts.

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. Auto-rendered from h{N}/index.md frontmatter. To change a row — edit the hub’s frontmatter (tier, mech, deliv, misha_fit, next_step), not this file.

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 tier ASC, hypothesis_num ASC

Supporting notes (ref — no hub, not in active register)

Engineering sub-layers, survey notes, and clinical strategy docs that feed the active register.

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

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

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. See AGENTS §0c.

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

Legacy synthesis pages (pre-hub structure)

Older flat synthesis notes from 2026-04-21/22, superseded by the h{N}/index.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
• [see-also] AGENTS
• [see-also] Misha Compound-Het Therapy Stack Model
• [about] Misha