In Huntington disease OMIM 143100 (HTT, OMIM 143100), the master switch sits on the ↓ DOWN branch ([F] forced below); the healthy state is the OFF well. The forced corrective direction is to lower s toward OFF branch (polarity: clear). 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 0.6514, γ 1.6142, spinodal 0.7894). 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 Huntington disease OMIM 143100 is an R19 double-well emerged from the real proximal-promoter DNA of HTT. 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
OFF
lesion
GOF
γ (stiffness)
1.6142
barrier
0.6514
spinodal
0.7894
s_on / s_off
1.2705 / -1.2705
fragility
0.00
corrective polarity
clear
forced direction
lower s toward OFF branch
Chemistry feasibility (DIRECTION only [O]). small-molecule recrossing of the fold is geometrically harder (barrier 0.6514 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: lower s toward OFF 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. remove / oppose the drive (clear the accumulating load that pins the disease branch)
Applies to. allele-agnostic (downstream/environmental tilt)
favoured when the switch is fragile -- a small drive shift recrosses the fold
Falsifier. If clearing/opposing the accumulating HTT does NOT relieve the disease branch in a HTT model, the h-restore(clear) lever is refuted for this axis.
EXCLUDED: gain-of-function -- the lesion is not a destabilised healthy product to stiffen; the corrective move is to clear/oppose the toxic drive (h-restore)
Falsifier. If a folding-stabiliser/chaperone does NOT re-deepen the healthy well for a residual HTT 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).
⚠ 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. An investigational AAV5 vector expressing an engineered microRNA that lowers huntingtin transcript, reducing the gain-of-function HTT product. Direction on the disease axis: decrease -- clear the toxic gain-of-function product. Engaged node: HTT (unique among the 113). Allele scope: agnostic (total-huntingtin lowering). Distinct from approved symptomatic agents (VMAT2 inhibitors reduce chorea but do not lower HTT and are not direction-matched). HTT-lowering as a class has had mixed clinical outcomes; this entry catalogues only the DIRECTION match. INVESTIGATIONAL direction-only hypothesis (no efficacy/approval/availability claim); status per training knowledge to Jan 2026 -- confirm current development.
Prior-art. Direction-only hypothesis: the geometry derives a decrease (clear the gain-of-function product) for HTT; the investigational AAV5-miHTT AMT-130 lowers huntingtin, a matched decrease. HTT-lowering as a class has had mixed trial outcomes; this catalogues only the direction match, not efficacy. Distinct from VMAT2-inhibitor symptomatic agents (not HTT-lowering). Investigational; confirm current status. No efficacy/availability claim.
Safety (qualitative; no magnitude). investigational intraparenchymal AAV gene therapy; neurosurgical-delivery and durability considerations (qualitative; no magnitude); HTT-lowering programmes have had mixed trial outcomes; confirm current status
Falsifier. If AMT-130 (a gene-specific decrease agent) clearing/opposing the accumulating load does NOT relieve the DOWN [F] disease branch in a HTT model, the h-restore(clear) direction is refuted for AMT-130 here.
Source: AMT-130 (AAV5-miHTT) investigational huntingtin-lowering gene-therapy programme in Huntington disease
⚠ 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 HTT; 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).