Hereditary haemorrhagic telangiectasia (Osler-Weber-Rendu) OMIM 187300

In Hereditary haemorrhagic telangiectasia (ENG, OMIM 187300), the master switch sits on the ↑ UP branch ([F] forced below); the healthy state is the ON well. The forced corrective direction is to raise s toward ON 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 0.5632, γ 1.5009, spinodal 0.7077). 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 Hereditary haemorrhagic telangiectasia is an R19 double-well emerged from the real proximal-promoter DNA of ENG. Its geometry is fixed by measured stiffness γ (never fitted); the numbers below are read directly off that cusp.

emergent axis: ↑ UP [F]
healthy branch: ON
lesion: LOF_null
γ (stiffness): 1.5009
barrier: 0.5632
spinodal: 0.7077
s_on / s_off: 1.2251 / -1.2251
fragility: 0.16
corrective polarity: clear
forced direction: raise s toward ON branch

Chemistry feasibility (DIRECTION only [O]). small-molecule recrossing of the fold is geometrically harder (barrier 0.5632 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).

h-restore (drive modulator)sign: decreasegeometric rank 0.16

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 VEGFA does NOT relieve the disease branch in a ENG model, the h-restore(clear) lever is refuted for this axis.

gamma-restore (stabiliser / chaperone)sign: Nonegeometric rank 0.00

Mechanism. N/A

Applies to. none (honest exclusion)

EXCLUDED: null allele -- no product to stiffen

Falsifier. If a folding-stabiliser/chaperone does NOT re-deepen the healthy well for a residual ENG 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
anti-VEGF antibody (bevacizumab; used OFF-LABEL for HHT, not approved for HHT) Dupuis-Girod 2012 JAMA 307:948 (systemic bevacizumab reduces HHT epistaxis / cardiac output); Al-Samkari 2021 (international bevacizumab survey in HHT) -- off-label, no HHT approval	decrease	clinical	3	◇ in trials
immunomodulatory anti-angiogenic (pomalidomide; approved for multiple myeloma / Kaposi sarcoma, used OFF-LABEL for HHT) Al-Samkari 2024 N Engl J Med (PATH-HHT randomised trial: pomalidomide reduced epistaxis severity in HHT); Al-Samkari 2026 Blood Adv 10:1799 (PATH-HHT ATLAS long-term) -- off-label, no HHT approval	decrease	clinical	3	◇ in trials
ALK1/endoglin-pathway restoration (ALK1 agonist / BMP9-BMP10 supplementation / ENG or ACVRL1 restoration; investigational) David 2007 Blood 109:1953 (BMP9-ALK1-endoglin maintains endothelial quiescence -- the restoration target); investigational, no approved HHT brake-restoration therapy	decrease	investigational	2	◇ 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.

bevacizumab○ novel leaddir: decrease · approved_elsewhere

Class. anti-VEGF monoclonal antibody

Mechanism. Sequesters VEGF-A, lowering the pro-angiogenic drive that contributes to the abnormal vessels of HHT when endoglin (ENG) signalling is disrupted. Direction: decrease / oppose the angiogenic over-drive downstream of the ENG lesion. Engaged node: VEGF-A (the agent neutralises the ligand, not ENG itself). Allele scope: agnostic -- acts downstream of the lesion. Mapped to hereditary haemorrhagic telangiectasia. NOVEL: bevacizumab is approved in oncology and studied off-label in HHT but is not an established standard here; this is a direction-only [O] lead, not an efficacy claim.

Prior-art. Bevacizumab (approved in oncology) has been used off-label for HHT vascular malformations but is not an established standard; surfaced here as a direction-only [O] lead, not an efficacy claim.

Safety (qualitative; no magnitude). anti-angiogenic antibody; bleeding, hypertension, thrombosis and wound-healing signals noted on label (qualitative; no magnitude)

Falsifier. If bevacizumab (a pathway decrease agent) clearing/opposing the accumulating load does NOT relieve the UP [F] disease branch in a ENG model, the h-restore(clear) direction is refuted for bevacizumab here.

Source: Dupuis-Girod 2012 JAMA 307:948 (bevacizumab in HHT)

⚠ 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 `ENG`; 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).