2025 Latest Amyotrophic Lateral Sclerosis (ALS) Research Review: TDP-43, C9ORF72, SOD1, FUS Core Targets and Clinical Progress
Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig’s disease, is a fatal progressive neurodegenerative disorder primarily affecting upper and lower motor neurons, leading to muscle weakness, atrophy, paralysis, and eventually respiratory failure. Global incidence is approximately 1/30,000, with 2–3 new cases per 100,000 annually and a median survival of only 3–5 years. About 90% of cases are sporadic and 10% familial. The pathological hallmark in nearly all ALS cases (~97%) is cytoplasmic mislocalization and aggregation of TDP-43 protein with concomitant nuclear clearance.
Fig 1. Average age of onset of amyotrophic lateral sclerosis (ALS) in different countries
Key Targets in ALS Research
Over the past decade, genetic and pathological studies have identified multiple core pathogenic genes and proteins. TDP-43 proteinopathy is recognized as the common pathological feature in nearly all ALS cases, while C9ORF72, SOD1, and FUS are the most frequent genetic drivers. The table below summarizes the four major recognized targets (TDP-43, C9ORF72, SOD1, FUS) regarding their normal functions, pathological roles in ALS, and primary research applications.
| Target |
Normal Biological Function |
Pathological Role in ALS |
Main Research Applications |
| TDP-43 (TARDBP) |
RNA-binding protein involved in splicing, transport, and stability regulation |
Nuclear loss + cytoplasmic aggregation (97% of cases), causing cryptic exon mis-splicing and RNA homeostasis disruption |
Inclusion body IHC, cryptic exon detection, STMN2 rescue assays |
| C9ORF72 |
Regulates autophagy, endocytosis, and immune responses |
G4C2 hexanucleotide repeat expansion → RNA foci toxicity, dipeptide repeat protein (DPR) toxicity, haploinsufficiency |
DPR ELISA, RNA foci FISH, ASO efficacy evaluation |
| SOD1 |
Cu/Zn superoxide dismutase, scavenges free radicals |
Mutation → misfolding and aggregation, oxidative stress, mitochondrial damage |
Misfolded SOD1 ELISA, oxidative stress models, ASO knockdown |
| FUS |
RNA/DNA-binding protein involved in splicing and transport |
Mutation → nucleocytoplasmic transport defects, cytoplasmic aggregation, stress granule abnormalities |
FUS localization ICC, RNA-binding assays, ASO screening |
In-Depth Interpretation of TDP-43 Proteinopathy (2025 Latest Consensus)
TDP-43 (TAR DNA-binding protein 43) is a predominantly nuclear RNA/DNA-binding protein that normally participates in nearly all aspects of RNA metabolism, including pre-mRNA splicing, mRNA transport and stability, stress granule formation, and miRNA biogenesis.
In ≈97% of ALS cases (including nearly all sporadic cases) and ≈50% of frontotemporal dementia (FTD) cases, the hallmark pathology is significant nuclear clearance of functional TDP-43 coupled with cytoplasmic aggregation of hyperphosphorylated, ubiquitinated, and truncated (primarily C-terminal 25/35 kDa fragments) TDP-43 into inclusions.
Core Pathogenic Mechanisms (Loss-of-Function + Gain-of-Toxicity Double Hit):
- Nuclear Loss-of-Function (LOF): TDP-43 clearance from the nucleus abolishes repression of cryptic exons, leading to mis-splicing of hundreds of genes. The most representative are STMN2 (causing microtubule dynamics dysregulation and impaired axonal regeneration) and UNC13A (causing defective synaptic vesicle release). Studies in 2024–2025 further confirm that STMN2 is more sensitive to TDP-43 depletion and is a preferred early biomarker.
- Toxic Gain-of-Function (GOF): Cytoplasmic aggregates of phosphorylated/truncated TDP-43 sequester normal TDP-43 and other RNA-binding proteins, forming pathological stress granules, disrupting proteostasis and autophagy-lysosomal pathways, and promoting prion-like propagation.
- 2025 Research Highlights: Long-read RNA-seq has uncovered additional TDP-43-dependent cryptic exons (e.g., MNAT1, KCNQ2); inhibiting nonsense-mediated decay (NMD) exposes more cryptic events; restorative ASOs targeting STMN2/UNC13A significantly improve axonal growth and synaptic function in iPSC-derived motor neurons and humanized mouse models.
In summary, TDP-43 proteinopathy represents the most central “common final pathway” in ALS. Strategies targeting nuclear function restoration, cryptic exon blockade, or aggregate clearance are among the most promising disease-modifying approaches.
Therapeutic Implications: Targeting TDP-43 proteinopathy, C9ORF72 repeat expansion, SOD1 knockdown, autophagy activation, and mitochondrial protection remain the most promising disease-modifying strategies.
Fig 2. Integrated ALS pathogenic pathways (doi.org/10.3390/ijms26115240)
ALS Latest Research & Clinical Progress
| Topic |
Key Findings/Trial Results |
Publication/Update |
Potential Impact |
Citation |
| Tofersen (SOD1-ASO, QALSODY) |
Long-term follow-up and real-world data show that early treatment significantly reduces SOD1 and NfL levels and slows functional decline. |
NEJM 2022; subsequent EClinicalMedicine 2024, Neurology 2025 follow-up and real-world studies |
One of the only approved gene-specific disease-modifying therapies, applicable only to SOD1-mutant ALS (≈2% of patients). |
[1] |
| C9orf72-targeted therapy |
BIIB078 reduced some pathological markers in Phase I but provided no clinical benefit and was terminated; dual-targeted CRISPR-CasRx in 2025 significantly reduced pathogenic repeat transcripts and DPRs in iPSC neurons and mouse models, improving cellular and behavioral phenotypes (preclinical). |
BIIB078: company announcement 2021; CasRx: Nat Commun 2025 |
Traditional ASO route setback, but CasRx and other RNA-targeted gene editing offer new hope for C9orf72-ALS (preclinical). |
[2] |
| Engensis (VM202, HGF plasmid) |
Phase 2a small-sample trial with safety as primary endpoint showed HGF plasmid gene therapy was safe and well-tolerated in ALS patients; efficacy endpoints exploratory only. |
Topline results announced 2022; still regarded as early clinical-stage in 2024–2025 reviews |
Provides feasibility safety signal for HGF-based gene therapy; larger efficacy-focused trials remain to be seen. |
[3] |
| AMX0035 (Relyvrio / PB-TURSO) |
PHOENIX Phase III trial in 2024 failed primary and key secondary endpoints; company voluntarily withdrew marketing authorization in the US and Canada and offered free drug to existing patients. |
Amylyx official announcement Apr 2024 and subsequent updates |
Highlights major challenges for small-molecule cytoprotective combination strategies in ALS and the need for precise stratification and more sensitive endpoints. |
[4] |
Current R&D Challenges: High ALS heterogeneity limits single-target coverage; blood-brain barrier penetration remains difficult; neuroinflammation and prion-like propagation mechanisms are not fully elucidated; reliable early biomarkers for diagnosis and efficacy assessment are lacking; endpoint sensitivity in clinical trials is insufficient, leading to multiple Phase III failures. Single-mechanism drugs rarely deliver significant, reproducible clinical benefit, underscoring the need for multi-pathway, multi-target ALS network research.
Fig 3. 2024–2025 ALS major candidate drug development pipeline overview
abinScience ALS Research Recombinant Proteins & Antibodies
| Type |
Catalog No. |
Product Name |
| Recombinant Proteins |
HP195012 |
Recombinant Human CHCHD10 Protein, N-GST & C-His |
| HW826012 |
Recombinant Human FUS Protein, N-His |
| HW826022 |
Recombinant Human FUS Protein, N-His-SUMO |
| HV287012 |
Recombinant Human HDAC6 Protein, N-His |
| HW326012 |
Recombinant Human MATR3 Protein, N-His-SUMO |
| HP702012 |
Recombinant Human NEK1 Protein, N-GST & C-His |
| HP451012 |
Recombinant Human OPTN Protein, N-GST & C-His |
| HY555012 |
Recombinant Human PFN1 Protein, N-His |
| HC317012 |
Recombinant Human RIPK1 Protein, N-His |
| HF876012 |
Recombinant Human SOD1 Protein, N-His |
| HC648012 |
Recombinant Human SQSTM1 Protein, N-His |
| HB883022 |
Recombinant Human TIA1 Protein, N-GST & C-His |
| HX018012 |
Recombinant Human TUBA4A Protein, N-His |
| HX922012 |
Recombinant Human VCP Protein, N-His |
| Antibodies |
HA376013 |
Anti-Human C9orf72 Antibody (SAA1886) |
| HW826014 |
Anti-FUS Polyclonal Antibody |
| HV287014 |
Anti-HDAC6 Polyclonal Antibody |
| HW326014 |
Anti-Human MATR3 Polyclonal Antibody |
| HP451014 |
Anti-Human OPTN Polyclonal Antibody |
| HF876013 |
Anti-Human SOD1 Nanobody (SAA1203) |
| HF876014 |
Anti-SOD1 Polyclonal Antibody |
| HC648014 |
Anti-SQSTM1/p62 Polyclonal Antibody |
| HX018014 |
Anti-Human TUBA4A Polyclonal Antibody |
| HX922014 |
Anti-VCP Polyclonal Antibody |
| HF876010 |
InVivoMAb Anti-Human SOD1 Antibody (AP-101) |
abinScience —Empowering Bioscience Discovery
abinScience continuously empowers ALS mechanism research, drug screening, and biomarker development, helping researchers get closer to the truth of ALS, while building key target protein and antibody matrices for Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, multiple sclerosis, and other neurodegenerative diseases.
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