This roadmap outlines the path from current standard of care to disease modification and ultimately cure for Huntington's disease (HD). HD is a monogenic autosomal-dominant neurodegenerative disorder caused by CAG repeat expansion in the HTT gene, leading to mutant huntingtin (mHTT) protein with toxic gain-of-function properties. Unlike AD and PD, HD has a clearly defined genetic cause, enabling direct targeting of the underlying genetic driver. The challenge lies in effectively lowering mHTT throughout the CNS and addressing downstream pathology.
This roadmap outlines the path from current standard of care to disease modification and ultimately cure for Huntington's disease (HD). HD is a monogenic autosomal-dominant neurodegenerative disorder caused by CAG repeat expansion in the HTT gene, leading to mutant huntingtin (mHTT) protein with toxic gain-of-function properties. Unlike AD and PD, HD has a clearly defined genetic cause, enabling direct targeting of the underlying genetic driver. The challenge lies in effectively lowering mHTT throughout the CNS and addressing downstream pathology.
Related: [Huntington's Disease](/diseases/huntingtons) | [Huntington's Knowledge Gaps](/gaps/huntingtons) | [AD Cure Roadmap](/mechanisms/ad-cure-roadmap) | [PD Cure Roadmap](/mechanisms/pd-cure-roadmap) | [Experiment Priority Index](/experiments/experiment-priority-index)
Goal: Accurate genetic diagnosis, symptom optimization, biomarker baseline
| Action | Status | Timeline |
|--------|--------|----------|
| Confirmatory genetic testing (CAG repeat) | Available | Week 1 |
| Baseline neurological exam + UHDRS | Standard of care | Week 1-2 |
| Blood biomarker panel (NfL, p-tau217, GFAP) | Available | Week 1 |
| Brain MRI (volumetrics, caudate/putamen) | Available | Week 1-2 |
| Cognitive testing (CAP-INTERNIST, SDMT) | Standard of care | Week 2 |
| Psychiatric evaluation | Standard of care | Week 2 |
| Tetrabenazine/Deutetrabenazine for chorea | FDA approved | Ongoing |
| Antipsychotics for behavioral symptoms | Off-label | Ongoing |
| Exercise program (150+ min/week) | Strong evidence | Ongoing |
| Multidisciplinary care (neurology, psychiatry, PT, OT, speech) | Standard of care | Ongoing |
Understanding gaps at this phase:
Goal: Lower mHTT protein throughout the CNS to slow or halt disease progression
| Agent | Company | Mechanism | Trial Status | Expected Data |
|-------|---------|-----------|--------------|---------------|
| Tominersen (RG6042) | Roche/Ionis | ASO - all HTT mRNA | Phase 3 GENERATION-HD1 (completed) | Mixed - target engagement achieved but no clinical benefit in manifest patients[@kieburtz2023] |
| Tominersen (lower dose) | Roche/Ionis | ASO - all HTT | Phase 2 (exploring lower dose) | 2026 |
| Other HTT-ASOs | Various | allele-selective | Preclinical/Phase 1 | 2027+ |
Key learnings from tominersen:
| Approach | Vector | Mechanism | Status | Timeline |
|----------|--------|-----------|--------|----------|
| AAV-HTT-ASO | AAV9 | CNS-delivered ASO | IND-enabling | 2026-2027 |
| AAV-miRNA | AAV9/AAV10 | Non-coding RNA silencing | Preclinical | 2027+ |
| CRISPR-based | Various | Gene editing | Preclinical | 2028+ |
| Antisense Villages | AAV-PHP.B | Wild-type sparing | Preclinical | 2028+ |
Critical experiments needed:
| Approach | Target | Status | Timeline |
|----------|--------|--------|----------|
| HTT aggregation inhibitors | mHTT aggregation | High-throughput screening | 2027+ |
| Autophagy enhancers | mHTT clearance | Phase 1/2 | 2026-2027 |
| Epigenetic modulators | Transcriptional dysregulation | Preclinical | 2027+[@sanchez2024] |
| BDNF mimetics | Synaptic function | Preclinical | 2028+ |
Understanding gaps:
Goal: Multi-target intervention tailored to individual patient biology
Given HD's complex pathophysiology, combining mHTT lowering with downstream targets may provide synergistic benefit:
| Combination | Rationale | Status |
|-------------|-----------|--------|
| mHTT-ASO + autophagy enhancer | Lower production + increase clearance | Preclinical |
| mHTT-ASO + epigenetic modulator | Lower mHTT + restore transcriptional patterns | Preclinical |
| mHTT-ASO + neurotrophic support | Protect remaining neurons | Conceptual |
| mHTT-ASO + neuroinflammation target | Address microglial activation | Preclinical |
Biomarker-guided patient selection:
Goal: Replace lost neurons and restore function
| Approach | Status | Mechanism | Timeline |
|----------|--------|-----------|----------|
| iPSC-based cell therapy | Preclinical | Striatal neuron replacement | 2030+ |
| In vivo neuronal reprogramming | Preclinical | Convert glia to neurons | 2030+ |
| Mitochondrial transplantation | Phase 1 (stroke) | Restore cellular energy | HD trials 2028+ |
| Gene therapy for BDNF delivery | Preclinical | Neurotrophic support | 2028+ |
| Exosome-based delivery | Preclinical | BBB-penetrant delivery | 2028+ |
Critical experiments needed:
Goal: Identify and treat individuals before symptom onset
| Approach | Status | Timeline |
|----------|--------|----------|
| Genetic testing for at-risk individuals | Available | Now |
| Premanifest natural history studies | Ongoing | 2025-2030 |
| Early biomarker detection | In development | 2027+ |
| Pre-symptomatic mHTT lowering | Pending trial design | 2030+ |
| Population-wide genetic screening | Ethical framework needed | 2035+ |
Understanding gaps:
| Biomarker | Type | Clinical Utility | Status |
|-----------|------|------------------|--------|
| mHTT protein (CSF) | Direct | Target engagement, dose selection | Validated[@tabrizi2023] |
| NfL | Axonal injury | Progression, treatment response | Validated[@troncoso2023] |
| p-tau217 | Tau pathology | Disease staging | In development |
| GFAP | Astrocyte activation | Progression | In development |
| Neurofilament heavy (NfH) | Axonal injury | Progression marker | In development |
| Modality | Target | Clinical Utility | Status |
|----------|--------|------------------|--------|
| MRI (volumetry) | Caudate, putamen volume | Progression, treatment response | Standard |
| Diffusion tensor imaging | White matter integrity | Disease staging | Research |
| PET (mHTT tracer) | mHTT aggregates | Target engagement | In development |
| PET (TSPO) | Microglial activation | Neuroinflammation | Research |
| Type | Target | Status |
|------|--------|--------|
| Wearable accelerometers | Chorea, gait, activity | Validation |
| Smartphone-based | Cognitive, speech | Validation |
| Digital timed up-and-go | Motor function | Validation |
| Trial | Phase | Intervention | Population | Status |
|-------|-------|--------------|------------|--------|
| PRECODE | Natural history | N/A | Premanifest HD | Recruiting |
| HDClarity | Biomarker | N/A | Manifest HD | Recruiting |
| Various | Phase 1/2 | Autophagy enhancers | Manifest HD | Various |
| Trial | Intervention | Key Finding |
|-------|--------------|-------------|
| GENERATION-HD1 | Tominersen 120mg | Robust target engagement, no clinical benefit in manifest |
| SIGNAL | RG6042 | Safety confirmed in premanifest |
| Gap | Addressed in Phase | Solution |
|-----|-------------------|----------|
| mHTT clearance mechanisms | Phase 2-3 | ASO + small molecule combinations |
| Biomarker development | Phase 1-2 | NfL, mHTT, imaging endpoints |
| Timing of intervention | Phase 2-3 | Premanifest trials |
| Gene therapy delivery | Phase 2-3 | AAV vectors, novel routes |
| Striatal vulnerability | Phase 3-4 | Cell therapy, targeted delivery |
| Epigenetic dysregulation | Phase 3 | Epigenetic modulators |
| Microglial contributions | Phase 3 | Anti-inflammatory combinations |