RNA-Targeting Therapies in ALS — PatSnap Eureka
RNA-Targeting Therapies in ALS: ASOs, Small Molecules & Combination Approaches
ALS 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 patent and clinical landscape across SOD1, C9ORF72, TDP-43, and downstream targets.
A Small Set of Genes Drive the ALS RNA-Targeting Patent Landscape
Amyotrophic lateral sclerosis is a fatal, progressive motor neuron disease driven by genetic mutations in genes including SOD1, C9ORF72, TDP-43/TARDBP, and FUS, as well as poorly understood sporadic mechanisms affecting roughly 90% of patients. According to NIH's National Institute of Neurological Disorders and Stroke, ALS affects approximately 30,000 Americans at any given time, making therapeutic innovation critical.
SOD1 is the most extensively targeted gene in the PatSnap Eureka dataset, 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, and retrieved results confirm its targeting via ASOs, siRNA, shRNA, miRNA, and AAV-encoded RNAi constructs.
C9ORF72 hexanucleotide repeat expansions [r(G₄C₂)exp] are addressed by both ASO-based and small molecule strategies, with multiple filings noting that the repeat-expanded pre-mRNA sequesters nuclear RNA-binding proteins, disrupting normal splicing. TDP-43 (encoded by TARDBP) and FUS are highlighted as RNA-binding proteins whose mislocalization and aggregation underlie both familial and sporadic ALS. The ALS Association recognizes TDP-43 pathology as present in over 97% of all ALS cases — a key rationale for targeting its downstream consequences.
UNC13A and STMN2 emerge as RNA splicing targets — retrieved patent filings disclose splice-switching ASOs that reduce cryptic exon inclusion in UNC13A and STMN2 transcripts downstream of TDP-43 loss of function. These targets are relevant to both familial and sporadic ALS, making them strategically important for the broader patient population. PatSnap's life sciences platform enables researchers to map this evolving IP landscape across all these targets simultaneously.
ADAR2-dependent RNA editing at specific adenosine-to-inosine sites in motor neurons is also flagged as a diagnostic and potentially therapeutic target, with defective A-to-I editing correlating with ALS pathology in motor neurons as identified by University of Tokyo researchers.
Five RNA-Targeting Modality Clusters in the ALS Patent Landscape
From clinically advanced ASOs to preclinical small molecule RNA degraders, the ALS RNA-therapy patent landscape spans five distinct mechanistic clusters with different assignee profiles and translational maturity levels.
Antisense Oligonucleotides (ASOs)
The largest cluster of retrieved results. Gapmer ASOs induce RNase H-mediated cleavage of target mRNA; splice-switching ASOs redirect splicing by steric blocking. Key programs include Biogen MA's SOD1-targeting intrathecal ASO (Tofersen context), Clarice Corporation's UNC13A/STMN2 splice-switching platform with phosphorothioate and phosphorodiamidate morpholino backbone chemistries, and Amylyx's novel calpain-2 (CAPN2) ASOs disclosed in a 2026 WO filing. The PatSnap analytics platform maps sequence-level and backbone-chemistry claim overlaps across these filings.
Tofersen Phase 3: biomarker positive, functional endpoint not metAAV-Delivered RNAi & Gene Silencing
Recombinant AAV vectors delivering miRNA, siRNA, or shRNA aim for CNS-wide gene silencing following a single intrathecal or intravenous administration. Voyager Therapeutics disclosed AAV vectors encoding SOD1-targeting siRNA (antisense strands 17–22 nucleotides). Biogen MA filed patents on AAV-miR-SOD1 constructs encoding multiple miRNAs simultaneously against both wild-type and mutant SOD1. University of Massachusetts covers a dual-target rAAV co-delivering C9ORF72 and SOD1 inhibitory nucleic acids in a single vector. Columbia University discloses AAV-encoded transcription factors Islet1 and Lhx3 driven by motor-neuron-specific enhancers.
Dual-target rAAV: C9ORF72 + SOD1 in one vector (UMass)Small Molecule RNA Degraders (RIBOTACs)
University of Florida Research Foundation discloses pyridocarbazole-based bifunctional RIBOTAC molecules — an RNase-recruiting moiety linked via polyethylene glycol to an r(G₄C₂)exp RNA-binding moiety. In iPSC-derived neurons from c9ALS/FTD patients, these molecules reduced intron 1:exon 2 ratios at 50 nM with minimal transcriptome-wide off-target effects, outperforming benchmark ASOs in selectivity for the repeat RNA tertiary hairpin structure over primary sequence. This approach recognizes tertiary RNA structure rather than primary sequence, conferring structural selectivity advantages. The WIPO patent database confirms active US and JP filing status for this platform.
50 nM activity in iPSC-derived c9ALS neurons · preclinicalmiRNA-Based Therapeutics
Several retrieved results specifically address microRNA biology as a therapeutic target distinct from siRNA/miRNA embedded within gene therapy vectors. miR-155 is upregulated in both sporadic and familial ALS spinal cord; Miragen Therapeutics discloses an inhibitor with anti-neuroinflammatory effects in CNS cells. miR-485 inhibition (Bioorchestra) targets downstream restoration of SIRT1, STMN2, PGC-1α, and NRG1 signaling. The mir-17~92 cluster is identified by Academia Sinica as decreased before motor neuron loss onset in SOD1G93A mice. Yeda Research and Development Company discloses Dicer-activating quinolones (enoxacin) to enhance pre-miRNA processing.
miR-155 inhibition · miR-485 inhibition · mir-17~92 restorationKinase Inhibitors & iPSC-Screen Hits
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, reducing development timelines and regulatory risk. PatSnap customers use this type of landscape analysis to prioritize repurposing candidates.
Multiple approved kinase inhibitor classes · Kyoto University EP activeCNS-Targeting Conjugate Platforms
Dyne Therapeutics discloses CNS-targeting conjugates covalently linking oligonucleotides, polypeptides, or small molecules to CNS-targeting agents for delivery to CNS cells — a delivery-focused platform relevant to ALS ASO and RNAi candidates. Assignees controlling both the therapeutic RNA payload IP and the CNS delivery IP will hold disproportionate strategic advantage. Competing delivery paradigms include intrathecal ASO delivery (Biogen/Ionis), systemically administered AAV (Penn State, University of Massachusetts, Voyager), and conjugate platforms (Dyne Therapeutics). PatSnap's open API enables systematic tracking of delivery platform IP across these assignees.
Delivery IP as strategic differentiator · intrathecal vs. systemic AAVALS RNA-Targeting Patent Landscape: Data Visualised
Key quantitative signals from the PatSnap Eureka patent dataset, covering modality distribution and assignee activity across the ALS RNA-therapy space.
ALS RNA Therapeutic Modality Distribution
ASOs (gapmer + splice-switching) represent the largest share of retrieved patent filings, followed by AAV-delivered RNAi and miRNA-based approaches.
Key Assignee Filing Activity by Period
Filing activity across key assignees shows a clear shift toward splice-switching ASOs (Clarice, Quris) and novel platforms (Amylyx CAPN2, Columbia TF re-expression) in 2023–2026.
Key Assignees in the ALS RNA-Targeting Patent Dataset
Commercial and academic filers shaping the IP landscape across ASOs, AAV-RNAi, and small molecule RNA-targeting platforms in ALS.
| Assignee | Primary Modality | Key Target(s) | Jurisdiction Status | Filing Period |
|---|---|---|---|---|
| Biogen MA Inc. | ASO (gapmer), AAV-miRNA | SOD1 | Active (CO, TW) | 2021–2022 |
| Voyager Therapeutics | AAV-siRNA | SOD1 | Pending (JP) | 2017–2021 |
| Clarice Corporation | Splice-switching ASO | UNC13A, STMN2, SMN2, KCNQ2 | Active (JP, CN) | 2023–2025 |
| Quris Corporation | Splice-switching ASO | UNC13A | Active (JP, CN) | 2023–2025 |
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Six Convergent Combination Approaches Emerging in ALS
Retrieved results signal multiple convergent combination strategies — from small molecule + RNA combinations to multi-target AAV vectors and unified splice-switching backbone platforms.
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.
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.
RIBOTAC vs. ASO at C9ORF72
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 greater structural selectivity and fewer transcriptome-wide off-targets at 50 nM — signaling a design rationale for preferring RIBOTAC for structured RNA repeat targets.
Multi-Target Splice Switching (Single Backbone)
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 Tofersen's Phase 3 to Emerging Preclinical Programs
Among retrieved results, the most explicit clinical reference is to Tofersen (BIIB067/IONIS-SOD1Rx), described in retrieved filings 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 FDA subsequently granted accelerated approval to Tofersen in April 2023 based on biomarker data.
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. AMX0035 (sodium phenylbutyrate/taurursodiol) is noted as FDA-approved but failing in a late-stage confirmatory trial to differentiate from placebo — a clinical context relevant to Amylyx Pharmaceuticals' pivot toward ASO development (CAPN2 ASO filing).
PIKfyve kinase inhibitors are mentioned in the Yale University WO filing as having entered early clinical trials based on autophagy-mediated protein clearance rationale. NurOwn (MSC-NTF cells, BrainStorm Cell Therapeutics) and Reldesemtiv (Cytokinetics) are referenced in the Methodist Hospital biomarker patent as ALS therapy candidates in clinical evaluation.
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. Monitoring translational milestones for these programs is a key strategic priority. PatSnap's analytics tools enable systematic tracking of clinical-stage transitions across these programs. The ClinicalTrials.gov registry provides complementary trial status data.
RNA-Targeting Therapies in ALS — Key Questions Answered
The main RNA-targeting modalities in ALS include antisense oligonucleotides (ASOs), AAV-delivered RNA interference (RNAi), splice-switching oligonucleotides, and small molecules that directly engage pathogenic RNA structures such as the C9ORF72 r(G₄C₂)exp repeat expansion.
SOD1 is the dominant target across retrieved results by volume, appearing in at least ten patent filings spanning multiple assignees and jurisdictions. Other key targets include C9ORF72, TDP-43/TARDBP, FUS, UNC13A, and STMN2.
Tofersen (BIIB067/IONIS-SOD1Rx) is described in retrieved filings 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. It is the most advanced RNA-targeting program represented in the dataset.
RIBOTACs (ribonuclease-targeting chimeras) are bifunctional small molecules that recruit endogenous RNase L to degrade the C9ORF72 r(G₄C₂)exp repeat RNA selectively. University of Florida's data show the small molecule achieves greater structural selectivity and fewer transcriptome-wide off-targets compared to ASOs, because it recognizes the tertiary RNA hairpin structure rather than primary sequence. The approach was validated in iPSC-derived neurons from c9ALS/FTD patients at 50 nM.
UNC13A and STMN2 emerge as the principal downstream RNA splicing targets of TDP-43 dysfunction. TDP-43 loss of nuclear function drives cryptic exon inclusion in both UNC13A and STMN2 transcripts. Multiple retrieved filings by Clarice Corporation and Quris Corporation describe splice-switching ASOs that redirect splicing toward full-length productive transcripts in both ALS and FTD contexts, making these targets relevant to both familial and sporadic ALS.
Key combination strategies include: (1) Dicer-activating quinolone (enoxacin) combined with riluzole, claimed by Yeda Research and Development Company; (2) dual-target rAAV vectors co-targeting C9ORF72 and SOD1 simultaneously (University of Massachusetts); (3) multi-target splice-switching platforms covering UNC13A, STMN2, KCNQ2, and SMN2 with a single backbone chemistry (Clarice Corporation); and (4) neuronal reprogramming AAV vectors combining NeuroD1 with mir124 and mir218 for astrocyte-to-neuron conversion (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 — Quris Corporation, 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 — University of Florida Research Foundation, 2024, China [Patent]
- Compositions and methods of treating amyotrophic lateral sclerosis (ALS) — Voyager Therapeutics, Inc., 2021, Japan [Patent]
- Compositions and methods of treatment for ALS using re-expression of embryonic motor neuron transcription factors — Columbia University, 2024, WO [Patent]
- A mir-155 inhibitor for the treatment of amyotrophic lateral sclerosis (ALS) — Miragen Therapeutics, Inc., 2018, Japan [Patent]
- Mir-17~92 as therapeutic or diagnostic target of motor neuron degeneration diseases — Academia Sinica, 2019, Taiwan [Patent]
- Methods of Diagnosing and Treating Motor Neuron Disease — Yeda Research and Development Company, Ltd., 2018, Japan [Patent]
- Use of MIRNA-485 inhibitors to treat amyotrophic lateral sclerosis (ALS) — Bioorchestra Company, Ltd., 2023, Japan [Patent]
- National Institute of Neurological Disorders and Stroke (NINDS) — ALS Information
- ALS Association — Disease Biology and Research
- U.S. Food and Drug Administration (FDA) — ALS Drug Approvals
- ClinicalTrials.gov — ALS Clinical Trial Registry
- World Intellectual Property Organization (WIPO) — Patent Database
All data and statistics on this page are sourced from the references above and from PatSnap's proprietary innovation intelligence platform. This report is derived from a limited set of patent and literature records retrieved across targeted searches and represents a snapshot of innovation signals within this dataset only. It should not be interpreted as a comprehensive view of the full field, clinical pipeline, or regulatory landscape.
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