RNA-Targeting Therapies in ALS — PatSnap Eureka
RNA-Targeting Therapies in ALS: ASOs, Small Molecules & Combination Strategies
Amyotrophic lateral sclerosis remains without a curative treatment. A new wave of RNA-directed modalities — antisense oligonucleotides, AAV-RNAi, splice-switching ASOs, and small molecule RIBOTACs — is reshaping the ALS patent landscape across SOD1, C9ORF72, TDP-43, and downstream targets UNC13A and STMN2.
Patent Filing Share by Therapeutic Modality
ASOs dominate the ALS RNA-targeting patent landscape, accounting for the largest share of retrieved filings across all modalities.
The Genetic Architecture Driving ALS RNA-Targeting Innovation
SOD1 is the dominant target across retrieved results by volume, appearing in at least ten patent filings spanning multiple assignees and jurisdictions. Gain-of-toxic-function mutations in SOD1 account for approximately 20–30% of familial ALS cases. Retrieved filings span gapmer ASOs, siRNA/shRNA, AAV-miRNA, base editing, and small molecule disruption of the MDH1-SOD1 interaction complex. According to the National Institutes of Health, SOD1 was one of the first identified genetic causes of familial ALS.
C9ORF72 hexanucleotide repeat expansions [r(G₄C₂)exp] are addressed by both ASO-based and small molecule strategies. Retrieved results note that the repeat-expanded pre-mRNA sequesters nuclear RNA-binding proteins, disrupting normal splicing. This target is uniquely contested between ASO and RIBOTAC modalities in the dataset.
TDP-43 (encoded by TARDBP) and FUS are RNA-binding proteins whose mislocalization and aggregation underlie both familial and sporadic ALS. Retrieved results describe ASO-mediated knockdown of RACK1 to reduce TDP-43 and FUS aggregation. The ALS Association identifies TDP-43 pathology as present in over 97% of all ALS cases, making it a critical convergent target.
UNC13A and STMN2 emerge as the most active recent filing cluster (2023–2025), driven by TDP-43 biology relevant to both familial and sporadic ALS. TDP-43 loss of nuclear function drives cryptic exon inclusion in both transcripts, rescued by splice-switching ASOs. ADAR2-dependent RNA editing at adenosine-to-inosine sites in motor neurons is also flagged as a diagnostic and potentially therapeutic target. Learn more about patent landscape analytics for neurodegenerative disease targets on PatSnap.
Five RNA-Targeting Mechanistic Clusters in the ALS Patent Landscape
Retrieved patent and literature records span five distinct mechanistic approaches, each addressing ALS pathology through RNA-directed mechanisms across different biological levels.
Antisense Oligonucleotides (ASOs)
The largest cluster of retrieved results. ASOs act by Watson-Crick base-pairing with target pre-mRNA or mRNA, inducing RNase H-mediated cleavage (gapmer ASOs) or sterically blocking splicing (splice-switching ASOs). Key programs include Biogen's SOD1-targeting ASO (Tofersen context), Clarice Corporation's UNC13A/STMN2 splice-switching platform, and Amylyx's novel CAPN2 ASOs. Backbone chemistries include phosphorothioate, phosphorodiamidate morpholino linkages, and 2'-O-methoxyethyl modifications. Explore the full life sciences patent intelligence platform on PatSnap.
Tofersen · UNC13A · STMN2 · CAPN2 · miR-155 · miR-485AAV-Delivered RNAi & Gene Silencing
Multiple retrieved patents cover recombinant adeno-associated virus (rAAV) vectors delivering miRNA, siRNA, or shRNA targeting ALS-relevant genes. This modality aims for durable, CNS-wide gene silencing following a single intrathecal or intravenous administration. Voyager Therapeutics disclosed AAV vector genomes encoding siRNA targeting SOD1 (antisense strands 17–22 nucleotides). Biogen MA filed patents on rAAV vectors containing miRNA constructs (AAV-miR-SOD1). University of Massachusetts disclosed dual-target rAAV covering both C9ORF72 and SOD1 simultaneously.
Voyager · Biogen · UMass · Penn State · Columbia UniversitySmall Molecule RIBOTACs for C9ORF72
University of Florida Research Foundation discloses pyridocarbazole-based RIBOTAC (ribonuclease-targeting chimera) molecules containing an RNase-recruiting moiety linked via polyethylene glycol to a r(G₄C₂)exp RNA-binding moiety. These bifunctional compounds were shown in iPSC-derived neurons from c9ALS/FTD patients to reduce intron 1:exon 2 ratios at 50 nM with minimal transcriptome-wide off-target effects, outperforming benchmark ASOs in selectivity for the repeat RNA structure over primary sequence. All retrieved RIBOTAC work appears preclinical.
UF Research Foundation · 50 nM efficacy · iPSC-derived neuronsSmall Molecule Kinase Inhibitors (iPSC Screen)
Kyoto University's filings represent an iPSC-based drug screening platform identifying kinase inhibitors with anti-ALS activity in SOD1-mutant motor neurons. Identified classes include EGFR inhibitors, FGFR inhibitors, Aurora kinase inhibitors, PKA/PKC inhibitors, MEK inhibitors, Met inhibitors, JNK inhibitors, Syk inhibitors, and JAK inhibitors, as well as prostaglandin analogues and estrogen receptor antagonists. This approach leverages already-approved compounds to accelerate ALS drug development.
Kyoto University · EGFR · FGFR · Aurora · MEK · JAK inhibitorsmiRNA-Based Therapeutics: Modulation of Non-Coding RNA
Several retrieved results specifically address microRNA biology as a therapeutic target distinct from siRNA/miRNA embedded within gene therapy vectors. The mir-17~92 cluster is identified by Academia Sinica as decreased before motor neuron loss onset in SOD1G93A mice. miR-155 inhibition (Miragen Therapeutics) targets neuroinflammation via CNS monocyte/microglial pathways. miR-485 inhibition (Bioorchestra) targets downstream restoration of multiple neuroprotective proteins including SIRT1, STMN2, PGC-1α, and NRG1 signaling. Pre-miRNA processing enhancement via Dicer activators (quinolones such as enoxacin) is disclosed by Yeda Research, noting combination with riluzole as an anti-ALS agent. According to Nature, miRNA dysregulation is increasingly recognized as a systemic feature of ALS pathology.
miR-17~92 · miR-155 · miR-485 · Dicer activators · enoxacin · riluzole combinationALS RNA-Targeting: Filing Activity & Target Distribution
Patent filing signals derived from retrieved records across targeted searches. Data represents innovation signals within this dataset only and should not be interpreted as a comprehensive view of the full field.
Patent Filings by Primary Gene Target
SOD1 leads with 10+ filings; UNC13A and STMN2 represent the fastest-growing recent cluster (2023–2025).
Key Assignee Filing Activity by Period
Clarice Corporation and Quris Corporation are the most active recent filers (2023–2025) in the splice-switching space; Biogen and Voyager represent earlier clinical-stage programs.
Key Patent Holders in ALS RNA-Targeting Therapeutics
Commercial activity is dominated by US-based biotechnology companies, with significant academic institution filing activity from Japan and the United States.
| Assignee | Primary Target(s) | Modality | Status | Key Jurisdictions |
|---|---|---|---|---|
| Biogen MA Inc. | SOD1 | ASO (Tofersen), AAV-miR-SOD1 | Clinical-stage | US, CO, TW |
| Clarice Corporation | UNC13A, STMN2, KCNQ2, SMN2 | Splice-switching ASOs (modified backbone) | Preclinical | JP, CN |
| Quris Corporation | UNC13A | Splice-switching ASOs | Preclinical | JP, CN |
| Voyager Therapeutics | SOD1 | AAV-siRNA (17–22 nt antisense strands) | Preclinical/Pending | PCT, JP |
Assess Freedom-to-Operate in ALS Splice-Switching IP
Clarice and Quris hold extensive sequence-level and backbone-chemistry claims in UNC13A and STMN2. PatSnap Eureka maps overlapping claim landscapes.
Six Convergent Combination Strategies in the ALS Patent Landscape
Retrieved results signal convergent combination strategies that address genetic heterogeneity and shared downstream pathology across familial and sporadic ALS.
Dicer Activator + Riluzole
Yeda Research and Development Company's filings explicitly claim combination of a Dicer-activating quinolone (e.g., enoxacin) with riluzole as a therapeutic regimen, arguing that restoring miRNA biogenesis synergizes with glutamate suppression. This is the most explicitly articulated small molecule + RNA-targeting combination in the dataset.
RIBOTAC vs. ASO at C9ORF72: Selectivity Signal
University of Florida's RIBOTAC filing directly compares its pyridocarbazole-PEG-RNase-recruiting compound against a benchmark LNA/2'-O-methyl ASO targeting r(G₄C₂)exp, demonstrating that the small molecule achieves greater structural selectivity and fewer transcriptome-wide off-targets — recognizing the tertiary RNA hairpin structure rather than primary sequence.
Dual-Target rAAV: C9ORF72 + SOD1
University of Massachusetts filings cover a single rAAV vector delivering inhibitory nucleic acids targeting both C9ORF72 (pre-mRNA and mRNA) and SOD1 mRNA simultaneously, addressing genetic heterogeneity in the ALS patient population within one delivery vehicle.
Multi-Target Splice Switching Platform
Clarice Corporation's 2024 filing covers oligonucleotides with a unified modified backbone (phosphorothioate, phosphorodiamidate variants, 3-methoxypropyl phosphonate) applicable across STMN2, UNC13A, KCNQ2, and SMN2 — a platform strategy for RNA splicing correction across multiple TDP-43 downstream targets with shared chemistry.
From Preclinical Promise to Clinical Reality in ALS RNA Therapy
The most explicit clinical reference in retrieved results is to Tofersen (BIIB067/IONIS-SOD1Rx), described as an intrathecal ASO that in Phase 3 trials showed acceptable tolerability and favorable biomarker trends (neurofilament light chain reduction), but did not achieve its primary functional efficacy endpoint. This is the most advanced RNA-targeting program represented in the dataset.
The retrieved dataset also explicitly references four FDA-approved ALS drugs: riluzole, edaravone, Nuedexta (dextromethorphan/quinidine), and Tiglutik (thickened riluzole), noted primarily as background comparators or combination partners in patent claim strategies. The FDA has approved these agents across different mechanisms, underscoring the unmet need for RNA-directed approaches.
AMX0035 (sodium phenylbutyrate/taurursodiol) is noted as FDA-approved but failing in a late-stage confirmatory trial — a clinical context relevant to Amylyx Pharmaceuticals' pivot toward ASO development (CAPN2 ASO filing). PIKfyve kinase inhibitors are mentioned as having entered early clinical trials based on autophagy-mediated protein clearance rationale.
The small molecule RIBOTAC approach (University of Florida) and all splice-switching UNC13A/STMN2 ASO programs appear preclinical in the retrieved dataset, with no clinical trial references attached to those specific filings. PatSnap's life sciences intelligence platform can help teams track translational milestones as these programs advance. For broader ALS clinical trial context, the ClinicalTrials.gov registry provides up-to-date trial status across all modalities.
What the ALS RNA-Targeting Patent Landscape Signals for R&D Strategy
Four strategic signals emerge from the retrieved patent and literature dataset for teams developing or licensing RNA-targeting ALS therapies.
Tofersen's Endpoint Gap Resets the Bar for Next-Gen ASOs
Tofersen's Phase 3 outcome — biomarker positive, functional endpoint negative — suggests next-generation RNA-targeting strategies in ALS will need to establish functional endpoints, patient stratification by disease stage, and biomarker correlation frameworks early in development. Amylyx's pivot to CAPN2 ASOs from its failed small molecule combination further illustrates how clinical setbacks are redirecting IP toward ASO modalities. PatSnap's customer case studies show how IP intelligence informs clinical strategy decisions.
Biomarker strategy · Patient stratification · Endpoint designUNC13A/STMN2 IP Concentrated in Two Assignees
UNC13A and STMN2 splice-switching ASOs represent the most active recent filing cluster (2023–2025) in this dataset, driven by TDP-43 biology relevant to both familial and sporadic ALS. IP in this space is concentrated in Clarice Corporation and Quris Corporation with extensive sequence-level and backbone-chemistry claims; entrants seeking freedom to operate will face a complex landscape of overlapping oligonucleotide sequence and chemistry patents. Use PatSnap Analytics to map claim overlap.
Freedom-to-operate · Clarice Corp · Quris Corp · Backbone chemistry claimsC9ORF72: ASO vs. RIBOTAC — Structural Selectivity Advantage
C9ORF72 r(G₄C₂)exp is uniquely contested between ASO and small molecule RIBOTAC modalities. University of Florida's data suggests the small molecule approach has structural selectivity advantages over ASOs — recognizing the tertiary RNA hairpin rather than primary sequence. However, all retrieved RIBOTAC work appears preclinical; biotech licensing or academic spinout activity around this platform warrants monitoring for translational milestones.
RIBOTAC · Structural RNA selectivity · UF Research Foundation · Licensing signalsCNS Delivery IP Is a Critical Strategic Differentiator
Genetic heterogeneity in ALS (SOD1, C9ORF72, TDP-43, FUS, and more than 12 other loci) combined with approximately 90% sporadic cases argues for modality strategies addressing shared downstream pathology. Delivery remains a critical IP and technical bottleneck: intrathecal ASO delivery (Biogen/Ionis), systemically administered AAV (Penn State, UMass, Voyager), and CNS-targeting conjugate platforms (Dyne Therapeutics) represent competing paradigms. Assignees controlling both therapeutic RNA payload IP and CNS delivery IP hold disproportionate strategic advantage. Explore PatSnap's open API for delivery platform IP screening.
Intrathecal delivery · AAV systemic · CNS conjugates · Dyne TherapeuticsRNA-Targeting Therapies in ALS — Key Questions Answered
Retrieved results consistently identify SOD1, C9ORF72, TDP-43 (TARDBP), and FUS as the central ALS disease drivers. SOD1 is the most extensively targeted gene in this dataset, appearing in at least ten patent filings spanning multiple assignees and jurisdictions. C9ORF72 hexanucleotide repeat expansions are addressed by both ASO-based and small molecule strategies. TDP-43 and FUS are highlighted as RNA-binding proteins whose mislocalization and aggregation underlie both familial and sporadic ALS.
Tofersen (BIIB067/IONIS-SOD1Rx) is an intrathecal ASO described in retrieved filings as showing acceptable tolerability and favorable biomarker trends (neurofilament light chain reduction) in Phase 3 trials, but it did not achieve its primary functional efficacy endpoint. It is the most advanced RNA-targeting program represented in the dataset.
TDP-43 loss of nuclear function drives UNC13A and STMN2 cryptic exon inclusion. Splice-switching ASOs disclosed by Clarice Corporation and Quris Corporation use modified backbone chemistries (phosphorothioate, phosphorodiamidate morpholino linkages) to redirect splicing toward full-length productive transcripts in both ALS and FTD contexts, rescuing the downstream consequences of TDP-43 dysfunction.
The University of Florida Research Foundation discloses pyridocarbazole-based RIBOTAC (ribonuclease-targeting chimera) molecules containing an RNase-recruiting moiety linked via polyethylene glycol to a r(G4C2)exp RNA-binding moiety. These bifunctional compounds were shown in iPSC-derived neurons from c9ALS/FTD patients to reduce intron 1:exon 2 ratios at 50 nM with minimal transcriptome-wide off-target effects, outperforming benchmark ASOs in selectivity for the repeat RNA structure over primary sequence.
Commercial patent activity is dominated by US-based biotechnology companies. Biogen MA Inc. holds multiple active filings covering SOD1-targeting ASO dosing and AAV-miR-SOD1 compositions, representing the most clinically advanced RNA-targeting program for ALS in this dataset. Clarice Corporation and Quris Corporation are the most active recent filers (2023–2025) in the splice-switching space, covering UNC13A, STMN2, KCNQ2, and SMN2 targets.
Retrieved results signal several convergent combination strategies including: (1) Dicer-activating quinolone (enoxacin) combined with riluzole by Yeda Research; (2) dual-target rAAV vectors covering both C9ORF72 and SOD1 from University of Massachusetts; (3) multi-target splice-switching platforms covering UNC13A, STMN2, KCNQ2, and SMN2 with unified backbone chemistry from Clarice Corporation; and (4) neuronal reprogramming AAV vectors combining NeuroD1, Ngn2, Isl1, and miRNAs from Penn State Research Foundation.
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References
- Compositions and methods for treating and preventing amyotrophic lateral sclerosis — Biogen MA Inc., 2021, Colombia [Patent]
- Compositions and methods for treating amyotrophic lateral sclerosis (ALS) with AAV-mir-sod1 — Biogen MA Inc., 2022, Taiwan [Patent]
- rAAV-based compositions and methods for treating amyotrophic lateral sclerosis — University of Massachusetts, 2017, Japan [Patent]
- Treatment of neurological disorders using modulators of UNC13A gene transcripts — Clarice Corporation, 2024, Japan [Patent]
- Splice switcher antisense oligonucleotides with modified backbone chemistry — Clarice Corporation, 2024, Japan [Patent]
- Treatment of neurological disorders using modulators of UNC13A gene transcripts (CN) — Quris Corporation (Quris Co., Ltd.), 2025, China [Patent]
- Treatment of neurological disorders using modulators of gene transcripts — Clarice Corporation, 2023, Japan [Patent]
- Antisense oligonucleotides targeting calpain-2 — Amylyx Pharmaceuticals, Inc., 2026, WO [Patent]
- Compositions and methods for inhibiting TDP-43 and FUS aggregation — University of British Columbia, 2023, Japan [Patent]
- Small molecule degrading methods for treating ALS/FTD — University of Florida Research Foundation, 2024, Japan [Patent]
- Method for treating ALS/FTD through degradation of RNA repeat expansion — University of Florida Research Foundation, 2023, United States [Patent]
- Small molecule degrading methods for treating ALS/FTD (CN) — University of Florida Research Foundation, 2024, China [Patent]
- A mir-155 inhibitor for the treatment of amyotrophic lateral sclerosis (ALS) — Miragen Therapeutics, Inc., 2018, Japan [Patent]
- National Institutes of Health — ALS Genetic Research Resources — NIH, United States
- ALS Association — TDP-43 Pathology in ALS — ALSA, United States
- Nature — miRNA Dysregulation in ALS Pathology — Nature Publishing Group
- FDA — Approved Treatments for ALS — U.S. Food & Drug Administration
- ClinicalTrials.gov — ALS Clinical Trial Registry — U.S. National Library of Medicine
All data and statistics on this page are sourced from the references above and from PatSnap's proprietary innovation intelligence platform. Patent data represents a snapshot of innovation signals within the retrieved dataset only and should not be interpreted as a comprehensive view of the full field, clinical pipeline, or regulatory landscape.
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