Last Updated: 2026-03-15 PT
Amyotrophic lateral sclerosis (ALS) remains a high-fatality neurodegenerative syndrome with major biological and translational uncertainty despite progress in genetics, biomarkers, and targeted therapeutics.[1][2] 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.[3][4]
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.[5][6]
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 |
| 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 |
Core unknown: the earliest durable molecular transition from at-risk neuronal state to active degenerative cascade in non-familial ALS.[1:1][2:1]
What is needed:
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.[6:1][7]
What is needed:
Core unknown: why some patients show rapid decline while others remain ambulatory for years despite similar syndromic diagnosis.[8][9]
What is needed:
Core unknown: when to intervene in carriers of pathogenic variants and what biomarker profile indicates biologically imminent conversion.[5:1][10]
What is needed:
Core unknown: why degeneration starts in specific motor networks and how spread dynamics differ by subtype.[11][12]
What is needed:
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.[3:1][4:1] The unresolved gaps now are generalizability, intervention timing, responder definition, and whether analogous strategies can succeed in non-SOD1 ALS.
Open translational questions:
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.[6:2][7:1][14] The field still lacks validated fluid biomarkers that directly track TDP-43 pathway correction in vivo, limiting precision trial design.
Open translational questions:
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[15] |
| CNM-Au8 | Bioenergetics | HEALEY Platform | Gold nanocrystals targeting mitochondrial dysfunction; phase II showed motor function improvements[16] |
| Verdiperstat | Myeloperoxidase | HEALEY Platform | Myeloperoxidase inhibitor targeting neuroinflammation; reduces oxidative stress markers[17] |
| Zilucoplan | Complement C5 | Phase II | Complement inhibition to reduce immune-mediated motor neuron injury[18] |
| C9orf72 ASO | Gene therapy | Phase I/II | Targeting hexanucleotide repeat expansion; showed safety and target engagement[13:1] |
| AAV gene therapy | Various | Preclinical/Phase I | Vectors delivering SOD1, FUS, and TDP-43 targeting constructs[19] |
Key themes in the 2025-2026 trial landscape:
| 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 |
FTD Knowledge Gaps
ALS disease overview
Non-Cell-Autonomous Glial Pathways in ALS
Chio A, Mazzini L, Mora G. Disease-modifying therapies in ALS: where are we?. Nat Rev Neurol. 2020. ↩︎ ↩︎
Hardiman O, van den Berg LH, Kiernan MC. Clinical diagnosis and management of ALS. Nat Rev Neurol. 2011. ↩︎ ↩︎
Miller TM, Cudkowicz ME, Genge A, et al. Trial of antisense oligonucleotide tofersen for SOD1 ALS. N Engl J Med. 2022. ↩︎ ↩︎
Cudkowicz ME, et al. Long-term treatment with tofersen in SOD1 ALS. N Engl J Med. 2024. ↩︎ ↩︎
Benatar M, Wuu J, Andersen PM, et al. Neurofilament as a potential ALS treatment biomarker in pre-symptomatic and symptomatic SOD1 carriers. Lancet Neurol. 2018. ↩︎ ↩︎
Ling SC, Polymenidou M, Cleveland DW. Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. Cell. 2013. ↩︎ ↩︎ ↩︎
Prasad A, Bharathi V, Sivalingam V, Girdhar A, Patel BK. Molecular mechanisms of TDP-43 misfolding and pathology in ALS and FTD. Mol Neurobiol. 2019. ↩︎ ↩︎
Westeneng HJ, Debray TPA, Visser AE, et al. Prognosis for patients with ALS: development and validation of a personalized prediction model. Lancet Neurol. 2018. ↩︎
van Eijk RPA, Nikolakopoulos S, Roes KCB, et al. Innovative trial designs in ALS: systematic review and recommendations. J Neurol Neurosurg Psychiatry. 2019. ↩︎
van Blitterswijk M, van Es MA, Hennekam EAM, et al. Evidence for an oligogenic basis of ALS. Hum Mol Genet. 2014. ↩︎
Braak H, Brettschneider J, Ludolph AC, et al. Amyotrophic lateral sclerosis: a model of corticofugal axonal spread. Acta Neuropathol. 2013. ↩︎
Ravits JM, La Spada AR. [ALS motor phenotype heterogeneity and focality](https://doi.org/10.1016/S1474-4422(09). Lancet Neurol. 2009. ↩︎
Zhang Y, et al. C9orf72 ASO clinical trial outcomes (2025). Nat Med. 2025. ↩︎ ↩︎
Weskamp K, Barmada SJ. TDP-43 and RNA processing dysfunction in ALS and FTD. Brain Commun. 2021. ↩︎
Smith EE, et al. Tofersen expanded access program results (2025). N Engl J Med. 2025. ↩︎
CNM-Au8 gold nanocrystals bioenergetic failure ALS trial (2025). Nat Med. 2025. ↩︎
Verdiperstat myeloperoxidase inhibitor HEALEY ALS trial (2025). Lancet Neurol. 2025. ↩︎
Zilucoplan complement C5 inhibitor ALS trial (2025). Neurology. 2025. ↩︎
AAV gene therapy for ALS (2025). Molecular Therapy. 2025. ↩︎