In Choroideremia (CHM, OMIM 303100), the master switch sits on the ↓ DOWN branch ([F] forced below); the healthy state is the ON well. The forced corrective direction is to raise s toward ON branch (polarity: supply). Classification: ○ Novel direction-only lead. Direction only — no dose, no efficacy magnitude.
The disease maps to an R19 double-well whose corrective lever is read straight off the cusp (barrier 0.4279, γ 1.3083, spinodal 0.5760). The corrective direction is forced [F]; the agent names below are direction-concordant labels at grade [O] (no dose, no efficacy or safety magnitude). This is a research hypothesis offered to experts, not medical advice.
The emergence switch
The switch for Choroideremia is an R19 double-well emerged from the real proximal-promoter DNA of CHM. Its geometry is fixed by measured stiffness γ (never fitted); the numbers below are read directly off that cusp.
emergent axis
↓ DOWN [F]
healthy branch
ON
lesion
LOF_null
γ (stiffness)
1.3083
barrier
0.4279
spinodal
0.5760
s_on / s_off
1.1438 / -1.1438
fragility
0.81
corrective polarity
supply
forced direction
raise s toward ON branch
Chemistry feasibility (DIRECTION only [O]). small-molecule recrossing of the fold is geometrically plausible (barrier 0.4279 at neutral drive; lower barrier = smaller drive to supply). [O] -- no affinity/potency/dose/efficacy asserted.
The derived corrective lever
The cusp forces a corrective direction: raise s toward ON branch. This is the load-bearing output of the framework — it is [F] forced, and it is falsifiable. 2 lever families are derived; the lead is h-restore (drive modulator).
Mechanism. supply / restore the positive drive (replace-or-agonise the missing competence)
Applies to. allele-agnostic (downstream/environmental tilt)
favoured when the switch is fragile -- a small drive shift recrosses the fold
Falsifier. If supplying/agonising CHM (raising the switch drive) does NOT move the DOWN [F] switch toward the healthy branch in a CHM-deficient model, the h-restore(supply) lever is refuted for this axis.
Falsifier. If a folding-stabiliser/chaperone does NOT re-deepen the healthy well for a residual CHM allele (no rescue that a null allele lacks), the gamma-restore lever is refuted; null alleles are excluded by construction.
Agents mapped onto the lever
Existing agents whose known action is direction-concordant with the derived lever (status as pinned in the corpus; no dose, no efficacy magnitude).
agent (class)
dir.
status
phase
map
subretinal AAV2-REP1 gene transfer (timrepigene emparvovec / BIIB111)
Biogen STAR phase 3 (NCT03496012) topline 2021 -- did not meet primary or key secondary endpoints; MacLaren 2014 Lancet 383:1129 (first choroideremia gene-therapy trial); Xue 2018 Nat Med 24:1507 (REP1 gene therapy phase 1/2 functional signals). No approved choroideremia therapy as of 2026
increase
clinical
3
◇ in trials
⚠ Mechanism-direction only — do not self-administer; no dose (unvalidated; set by a physician / national authority); not an approved use.
Direction-only candidate leads (corpus join)
Each lead is surfaced only because its known mechanism points the same way as the derived lever, and each comes with a source and a falsifier. None is a treatment.
Mechanism. Membrane-permeant thiol antioxidant and glutathione precursor. In inherited rod-cone degeneration, rod loss raises outer-retinal oxygen tension and drives progressive OXIDATIVE damage to the surviving cones; NAC scavenges reactive oxygen species and supports cone survival in a GENE-INDEPENDENT way, addressing a shared downstream stress rather than the primary gene defect. Direction: increase the corrective antioxidant / photoreceptor-survival drive. Allele scope: agnostic -- acts below the disease-gene lesion across rod-cone degenerations (strongest direct evidence in RP / Usher). Pathway-specific to the oxidative-stress / neuroprotection axis, NOT a gene correction.
Prior-art. NAC has no approved indication for choroideremia; trialed in retinitis pigmentosa broadly. Direction-only, untested here.
Safety (qualitative; no magnitude). post-marketing safety profile on record (long-approved as a mucolytic and for acetaminophen overdose; under phase-3 evaluation in retinitis pigmentosa; qualitative; no magnitude)
Falsifier. If N-acetylcysteine (NAC) (a pathway supply/increase agent) does NOT move the DOWN [F] switch toward the healthy branch in a CHM-deficient model, the h-restore(supply) direction is refuted for N-acetylcysteine (NAC) here.
Source: Clinical-trial activity: NAC in retinitis pigmentosa (not choroideremia specifically)
⚠ Mechanism-direction only — do not self-administer; no dose (unvalidated; set by a physician / national authority); not an approved use.
Evidence & provenance
What is reproduced vs. cited for this page.
element
grade
basis
R19 switch & cusp geometry (this page)
[V] verified
emerged from measured promoter γ of CHM; deterministic, 2×sha256 identical
corrective direction
[F] forced
forced by the cusp sign; falsifiable (see lever falsifiers)
mapped agents / leads
[O] open
direction-concordance only; corpus-pinned (2026-06-21); no dose, no efficacy/safety magnitude
Reading the agent column. VALIDATION SIGNAL -- the agent is already approved / established standard for this disease, so the direction logic recovered known clinical practice. Not a new claim by this kit. GENUINE HYPOTHESIS -- no approved indication for this disease; the direction match is a direction-only, untested [O] lead. Basis field grades the evidence (investigational here / in a related condition / off-label / speculative).