ALS Knowledge Gaps

Amyotrophic Lateral Sclerosis Knowledge Gaps

Last Updated: 2026-03-15 PT

Introduction

Amyotrophic lateral sclerosis (ALS) remains a high-fatality neurodegenerative syndrome with major biological and translational uncertainty despite progress in genetics, biomarkers, and targeted therapeutics.[@chio2020][@hardiman2011] The approval of tofersen for SOD1-associated ALS and rapid expansion of TDP-43 biology have shifted priorities, but they also exposed unresolved gaps in trial design, patient stratification, and causal mechanism mapping.[@miller2022][@cudkowicz2024]

This page ranks 20 ALS knowledge gaps using a four-dimension rubric and emphasizes two 2024-2026 priority themes required for near-term progress: (1) interpreting and extending the tofersen model beyond SOD1 and (2) translating TDP-43 advances into measurable therapeutic hypotheses.[@benatar2018][@ling2013]

Scoring Methodology

Each gap is scored from 0 to 10 in four dimensions (maximum total 40):

| Dimension | What It Measures | High Score Means |
|---|---|---|
| Impact if solved | Potential to change clinical outcomes | Could materially alter ALS prevention or treatment |
| Tractability | Feasibility with current tools | Can be tested using current cohorts, models, and assays |
| Under-exploration | Relative neglect versus importance | Important area with insufficient direct effort |
| Data availability | Availability of high-quality datasets/models | Strong human, fluid-biomarker, and model-system support |

Ranked ALS Knowledge Gaps

Amyotrophic Lateral Sclerosis Knowledge Gaps

Last Updated: 2026-03-15 PT

Introduction

Amyotrophic lateral sclerosis (ALS) remains a high-fatality neurodegenerative syndrome with major biological and translational uncertainty despite progress in genetics, biomarkers, and targeted therapeutics.[@chio2020][@hardiman2011] The approval of tofersen for SOD1-associated ALS and rapid expansion of TDP-43 biology have shifted priorities, but they also exposed unresolved gaps in trial design, patient stratification, and causal mechanism mapping.[@miller2022][@cudkowicz2024]

This page ranks 20 ALS knowledge gaps using a four-dimension rubric and emphasizes two 2024-2026 priority themes required for near-term progress: (1) interpreting and extending the tofersen model beyond SOD1 and (2) translating TDP-43 advances into measurable therapeutic hypotheses.[@benatar2018][@ling2013]

Scoring Methodology

Each gap is scored from 0 to 10 in four dimensions (maximum total 40):

| Dimension | What It Measures | High Score Means |
|---|---|---|
| Impact if solved | Potential to change clinical outcomes | Could materially alter ALS prevention or treatment |
| Tractability | Feasibility with current tools | Can be tested using current cohorts, models, and assays |
| Under-exploration | Relative neglect versus importance | Important area with insufficient direct effort |
| Data availability | Availability of high-quality datasets/models | Strong human, fluid-biomarker, and model-system support |

Ranked ALS Knowledge Gaps

| Rank | Gap | Impact | Tractability | Under-exploration | Data | Total |
|---:|---|---:|---:|---:|---:|---:|
| 1 | What initiates sporadic ALS in cases without a high-penetrance causal mutation? | 10 | 6 | 8 | 7 | 31 |
| 2 | Which mechanisms convert TDP-43 dysfunction into irreversible motor neuron loss? | 10 | 7 | 7 | 8 | 32 |
| 3 | What determines rapid versus slow progression trajectories across ALS phenotypes? | 10 | 7 | 8 | 7 | 32 |
| 4 | How can we identify pre-symptomatic conversion windows in genetic-risk carriers? | 10 | 7 | 8 | 7 | 32 |
| 5 | Which cellular programs drive regional onset (bulbar, limb, respiratory) and spread patterns? | 9 | 7 | 8 | 7 | 31 |
| 6 | Why does C9orf72 expansion produce ALS in some individuals and FTD in others? | 9 | 7 | 7 | 8 | 31 |
| 7 | Which non-cell-autonomous glial pathways are causal rather than reactive? | 9 | 7 | 7 | 7 | 30 |
| 8 | What defines selective vulnerability of upper versus lower motor neurons? | 9 | 7 | 7 | 7 | 30 |
| 9 | Why have many neuroprotective phase II/III ALS trials failed despite strong preclinical rationale? | 10 | 6 | 6 | 8 | 30 |
| 10 | Is ALS a single disease spectrum or a set of molecularly distinct syndromes needing subtype-specific therapy? | 9 | 6 | 8 | 7 | 30 |
| 11 | How should peripheral and CNS immune signatures be incorporated into ALS trial stratification? | 8 | 7 | 7 | 7 | 29 |
| 12 | Which biomarker composites best predict progression and treatment response? | 9 | 8 | 6 | 8 | 31 |
| 13 | What is the hierarchy between RNA-processing stress, proteostasis collapse, and axonal degeneration? | 9 | 7 | 7 | 7 | 30 |
| 14 | How does systemic metabolic dysfunction accelerate ALS progression? | 8 | 7 | 7 | 7 | 29 |
| 15 | What role do viral and post-infectious mechanisms play in a subset of sporadic ALS? | 8 | 6 | 7 | 6 | 27 |
| 16 | Which combination-therapy logic is most likely to outperform single-pathway approaches? | 9 | 7 | 6 | 6 | 28 |
| 17 | Can microbiome and gut-barrier signatures be linked to reproducible ALS progression biology? | 7 | 6 | 7 | 6 | 26 |
| 18 | How do sleep and respiratory-control networks interact with neurodegenerative progression rather than late-stage disability alone? | 7 | 6 | 7 | 6 | 26 |
| 19 | Which long-term environmental exposures are truly causal versus correlational in ALS risk? | 8 | 6 | 6 | 6 | 26 |
| 20 | How can precision RNA and gene-editing platforms be extended beyond SOD1 into broader ALS populations? | 9 | 7 | 7 | 7 | 30 |

Priority Visualization

Top 5 Gaps: What It Will Take To Resolve

1. Sporadic ALS initiation biology

Core unknown: the earliest durable molecular transition from at-risk neuronal state to active degenerative cascade in non-familial ALS.[@chio2020][@hardiman2011]

What is needed:

• Deep phenotyping of pre-diagnostic cohorts and at-risk relatives.
• Exposure-linked molecular atlases integrating longitudinal plasma, CSF, and imaging.
• Cross-validation of candidate initiation signatures across independent biobanks.
• Human model systems for exposure-by-genotype interaction testing.

2. TDP-43 causal sequence and reversibility

Core unknown: whether TDP-43 mislocalization, aggregation, and loss of normal RNA-binding function are separable therapeutic nodes or inseparable stages of one irreversible process.[@ling2013][@prasad2019]

What is needed:

• Time-resolved human and model-system studies linking soluble dysfunction to aggregate states.
• Clinical biomarkers reflecting TDP-43 pathway activity, not just downstream injury.
• Therapeutic programs that test early correction windows before fixed neuronal loss.
• Standardized pathology frameworks for subtype and stage comparisons.

3. Progression-rate heterogeneity

Core unknown: why some patients show rapid decline while others remain ambulatory for years despite similar syndromic diagnosis.[@westeneng2018][@van2019]

What is needed:

• Unified modeling using ALSFRS-R slope, respiratory metrics, and digital progression traces.
• Multi-layer effect-modifier analysis combining genetics, neuroinflammation, and metabolism.
• Prospective validation in trial-like cohorts to support enrichment strategy adoption.

4. Pre-symptomatic conversion in genetic carriers

Core unknown: when to intervene in carriers of pathogenic variants and what biomarker profile indicates biologically imminent conversion.[@benatar2018][@van2014]

What is needed:

• Harmonized longitudinal protocols for SOD1, C9orf72, FUS, and TARDBP families.
• Practical conversion-risk models linking neurofilament trajectories to clinical endpoints.
• Prevention-trial templates with explicit stop and escalation criteria.

5. Regional onset and spread logic

Core unknown: why degeneration starts in specific motor networks and how spread dynamics differ by subtype.[@braak2013][@ravits2009]

What is needed:

• Network-level staging models combining connectomics with pathology.
• Spatial transcriptomics comparing onset regions at matched disease stages.
• Mechanistic testing of axonal transport and local glial support failure hypotheses.

Required 2024-2026 Evidence Updates

Tofersen: what it solved and what remains open

Tofersen has validated target-lowering feasibility in SOD1-ALS and demonstrated that molecular target engagement plus neurofilament shifts can guide inference even when short-window functional endpoints are difficult to separate from noise.[@miller2022][@cudkowicz2024] The unresolved gaps now are generalizability, intervention timing, responder definition, and whether analogous strategies can succeed in non-SOD1 ALS.

Open translational questions:

• Which endpoint combinations are most reliable for slow but meaningful disease modification?
• Can response predictors be derived from baseline inflammatory and neuroaxonal markers?
• How should early treatment decisions balance uncertain long-term benefit and procedural burden?
• Can ASO approaches for C9orf72, FUS, and TARDBP follow the tofersen model?[@c9orf722025]

TDP-43 advances: toward trial-ready mechanism models

Recent work strengthened TDP-43 as a core convergence axis across ALS phenotypes, including links among nuclear loss-of-function, cryptic exon dysregulation, proteostasis stress, and spread-associated pathology signatures.[@ling2013][@prasad2019][@weskamp2021] The field still lacks validated fluid biomarkers that directly track TDP-43 pathway correction in vivo, limiting precision trial design.

Open translational questions:

• Which molecular readouts can serve as TDP-43-target engagement biomarkers?
• Is early-stage correction biologically reversible after clinical onset?
• How should TDP-43-directed therapies be combined with anti-inflammatory or metabolic interventions?

2025-2026 ALS Clinical Trial Pipeline

The 2025-2026 period has seen significant expansion in ALS therapeutic approaches across multiple mechanisms:

| Agent | Mechanism | Trial Status | Key Findings |
|---|---|---|---|
| Tofersen (Qalsody) | SOD1 ASO | Approved | First disease-modifying therapy for SOD1-ALS; neurofilament reduction correlates with clinical benefit[@tofersen2025] |
| CNM-Au8 | Bioenergetics | HEALEY Platform | Gold nanocrystals targeting mitochondrial dysfunction; phase II showed motor function improvements[@cnmau82025] |
| Verdiperstat | Myeloperoxidase | HEALEY Platform | Myeloperoxidase inhibitor targeting neuroinflammation; reduces oxidative stress markers[@verdiperstat2025] |
| Zilucoplan | Complement C5 | Phase II | Complement inhibition to reduce immune-mediated motor neuron injury[@zilucoplan2025] |
| C9orf72 ASO | Gene therapy | Phase I/II | Targeting hexanucleotide repeat expansion; showed safety and target engagement[@c9orf722025] |
| AAV gene therapy | Various | Preclinical/Phase I | Vectors delivering SOD1, FUS, and TDP-43 targeting constructs[@aav2025] |

Key themes in the 2025-2026 trial landscape:

• Platform trials (HEALEY) enabling multiple drug testing in parallel
• Biomarker-driven enrichment strategies using neurofilament light chain (NfL)
• Combination therapy approaches targeting multiple disease mechanisms
• Gene therapy advances for both SOD1 and C9orf72 populations

Cross-Disease Shared Gaps

| ALS Gap Theme | Shared Disease Context | Related Page |
|---|---|---|
| Proteostasis and aggregate toxicity | FTD, AD | TDP-43 pathology in neurodegeneration |
| Selective neuronal vulnerability | PD, PSP | Selective neuronal vulnerability |
| Immune and glial drivers | AD, PD | Microglia and neuroinflammation |
| Biomarker-guided trial enrichment | All major neurodegenerative diseases | ALS biomarkers |
| Network spread biology | FTD, synucleinopathies | ALS pathway |

Recommendations For Researchers and Funders

See Also

• [ALS Trial Failures Knowledge Gap](/gaps/als-trial-failures)
• [Knowledge Gaps Index](/gaps)
• [Parkinson's Disease Knowledge Gaps](/gaps/parkinsons-disease)
• FTD Knowledge Gaps
• ALS disease overview
• [Tofersen](/therapeutics/tofersen)
• Non-Cell-Autonomous Glial Pathways in ALS

Pathway Diagram

The following diagram shows the key molecular relationships involving ALS Knowledge Gaps discovered through SciDEX knowledge graph analysis: