Drug Hypotheses

Target: HTT1a transcript isoform / selective mHTT lowering

Selectively targeting the HTT1a isoform provides superior molecular rescue vs. lowering canonical HTT. HTT1a is enriched in disease-vulnerable neurons. Isoform-selective lowering preserves full-length HTT function while eliminating the toxic truncated species, avoiding the safety concerns that limited IONIS-HTTRx at high doses.

Target: mHTT oligomers / lipid raft disruption

Oligomer inhibitor that ameliorates pathological phenotypes in HD mouse and cellular models. Exp 7 (lipid-proteostasis cascade) suggests anle138b may also stabilize membrane microdomains, making it potentially active at Stage 1 of the cascade, not just aggregate clearance.

Target: CYP46A1 / cholesterol catabolism / lipid raft stabilization

Exp 7 identified CYP46A1 activation as the top early-stage intervention: restoring cholesterol catabolism stabilizes lipid raft microdomains disrupted by mHTT, potentially preventing the entire downstream proteostasis cascade. Efavirenz (HIV drug) is a known CYP46A1 activator with existing CNS penetrance data.

Target: Msh3 / somatic CAG expansion / DNA mismatch repair

June 2026 paper: somatic CRISPR knockout of Msh3 mitigates HD pathology in mice. Msh3 drives somatic CAG repeat expansion in neurons, without it, the repeat stays stable. One-time intervention targeting the root cause of progressive neurodegeneration, not symptoms.

Target: IL-6 / neuroinflammation

IL-6 receptor blockade may reduce neuroinflammation driven by mHTT aggregation. NLRP3 inflammasome activation (Exp 5 signal) produces IL-6 as a downstream effector. Tocilizumab is approved for RA/cytokine storm and has CNS penetrance data in other conditions.

Target: UCHL3 / deubiquitinase / proteostasis

UCHL3 loss-of-function precedes major neuronal decline in HD. Modulating UCHL3 may redirect ubiquitin flux toward mHTT clearance. Exp 7: best used as mid-stage rescue alongside early lipid interventions, doesn't address root cause alone.

Target: Kinesin-1 / dynein / BDNF vesicle transport

June 2026: polyQ expansions misdirect BDNF vesicle transport toward distal neuronal tips, depleting BDNF from cell bodies under neuroinflammatory stress. Restoring motor/adaptor stoichiometry on BDNF endosomes could rescue striatal neuron survival.

Target: mTOR / AMPK / autophagy

Promotes autophagy which may help clear mutant HTT aggregates. AMPK activation also intersects with mitochondrial biogenesis, relevant to the Stage 2 copper/energy failure identified in Exp 7. Well-tolerated, cheap, widely available.

Target: Extracellular matrix / extracellular mHTT propagation

New 2026 perspective: mHTT is biologically active in the ECM outside cells and may propagate prion-like between neurons. ECM-targeting agents (matrix metalloproteases, hyaluronidase) could prevent mHTT seeding, a mechanism parallel to lecanemab's approach in Alzheimer's.

Target: mTOR / autophagy induction

mTOR inhibitor demonstrated clearance of mutant HTT in preclinical models. Autophagy induction helps clear aggregates. Same Stage 3 cascade position as Metformin, but less tolerable for chronic use.

Target: TDP-43 / GSK-3β

May reduce TDP-43 phosphorylation and aggregation via GSK-3β inhibition. TDP-43 pathology has been observed in some HD cases. Lithium has a long clinical history but narrow therapeutic window.

Target: Glutamate excitotoxicity

Glutamate release inhibitor, may reduce excitotoxicity in HD. Score downgraded: 2026 systematic review confirms glutamatergic drugs show limited evidence for cognitive/functional outcomes in HD, primarily motor symptom management only.