Why TDP-43 and SOD1 dominate ALS target biology

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease in which upper and lower motor neurons progressively degenerate, leading to paralysis and respiratory failure within one to five years of diagnosis. More than 90% of cases are sporadic; the remaining 5–10% are familial, with SOD1 mutations accounting for 15–20% of those familial cases. TARDBP (encoding TDP-43), FUS, and C9ORF72 are the other most frequently cited causative genes in European populations, according to data from the University Medical Center Rostock, with convergent dysfunction across DNA repair, axonal transport, and protein homeostasis.

TDP-43 (TAR DNA-binding protein 43 kDa) is the most broadly targeted protein across the patent dataset analysed here. In the majority of sporadic ALS cases, TDP-43 abnormally accumulates in the cytoplasm of neurons and glial cells across the primary motor cortex, brainstem motor nuclei, and spinal cord. Key phosphorylation sites at residues S379, S403, S404, S409, and S410 are the preferred epitopes for antibody-based approaches. Critically, TDP-43 nuclear loss of function disrupts splicing of two downstream targets — STMN2 (Stathmin-2) and UNC13A — both of which are now the subject of dedicated splice-switch antisense oligonucleotide (ASO) programs.

Additional risk-associated loci named in retrieved patent filings include ATXN2, UBQLN2, TBK1, OPTN, KIF5A, NEK1, HNRNPA1, and VCP, reflecting the genetic heterogeneity that makes ALS one of the most challenging targets in neurology. This heterogeneity is also driving a move toward molecularly defined patient subpopulations, with a 2024 patent from Arizona State University disclosing genomic and transcriptomic biomarker panels — including COL3A1 and MIRLET7BHG — for diagnosis of distinct ALS subtypes such as ALS-TD.

Antisense oligonucleotides: the leading ALS drug modality

Antisense oligonucleotides are the most heavily patented therapeutic modality in the ALS dataset, appearing across filings from multiple assignees and spanning two distinct mechanistic subtypes: gene-silencing gapmers that reduce mutant transcript expression, and splice-switching ASOs that correct aberrant splicing caused by TDP-43 dysfunction. The clinical translation signals in the dataset are also most advanced for the ASO class, with a Phase 3 randomized, placebo-controlled trial for asymptomatic SOD1 mutation carriers and Phase 1 trials for C9ORF72 and FUS-targeting ASOs referenced in retrieved filings.

SOD1 gene-silencing: from RNAi to biomarker-guided selection

Alnylam Pharmaceuticals discloses dsRNAi agents targeting the SOD1 gene to suppress SOD1 expression in SOD1-associated neurodegenerative diseases including ALS, with claims encompassing efficacy monitoring via cognitive and functional parameters. Biogen MA Inc. takes this further by explicitly linking neurofilament measurement to therapeutic decision-making: its patent discloses a method using neurofilament light chain (NfL) levels in patient plasma or CSF to select SOD1-mutation carriers for treatment with a SOD1-targeting ASO. Biogen’s patent data documents plasma NfH declining longitudinally at approximately 1.8% per month in treated patients and documents neuromuscular junction preservation in SOD1G93A mice treated with SOD1-active ASO versus inactive ASO control.

STMN2 splice-switch ASOs: restoring a TDP-43 downstream target

University of Massachusetts patent filings document significantly reduced STMN2 immunoreactivity in lumbar spinal motor neurons of ALS patients compared to controls (bilateral t-test, P<0.05), confirmed across three independent published datasets. Quralis Corporation and the University of Massachusetts are both active in this space, with ASOs designed to suppress cryptic exon inclusion in STMN2 transcripts arising from TDP-43 loss of function, thereby restoring full-length STMN2 transcript. Development stage appears preclinical based on retrieved data.

UNC13A splice-switch ASOs: the largest patent cluster in the dataset

The largest single cluster of filings in the dataset pertains to UNC13A-targeting oligonucleotides from Quralis Corporation, filed across US, WO, IL, AU, CA, BR, CL, CN, and JP jurisdictions (the last via its Japanese entity Claris Corporation). TDP-43 loss causes UNC13A mis-splicing; ASOs with modified spacer backbones — including phosphorothioate, phosphorodithioate, and phosphoramidate chemistries — are claimed to reduce mis-spliced UNC13A transcripts and increase full-length UNC13A transcripts. Claims specify at least 50–90% reduction in mis-spliced transcript and up to 100% rescue of full-length UNC13A protein in some embodiments.

“UNC13A splice-switch ASOs claim at least 50–90% reduction in mis-spliced transcript and up to 100% rescue of full-length UNC13A protein — the most precisely quantified efficacy benchmarks in the ALS ASO patent landscape.”

PPM1A/TBK1 pathway ASOs

Quralis Corporation holds a family of filings covering PPM1A (protein phosphatase Mg²⁺/Mn²⁺ dependent 1A) ASOs for ALS and FTD associated with reduced TBK1 activity or expression, with claims across WO, US, AU, IL, IN, CA, NZ, and CN jurisdictions. PPM1A is a phosphatase that negatively regulates TBK1; in ALS and FTD associated with TBK1 loss-of-function mutations, PPM1A inhibition is postulated to restore TBK1-dependent autophagy and inflammation signalling. These filings also couple the therapeutic strategy with phosphorylated neurofilament heavy chain (pNFH) in CSF as a patient selection and treatment monitoring biomarker — a design feature that anticipates enriched clinical trial populations.

Anti-TDP-43 antibodies, gene therapy, and emerging modalities

Beyond ASOs, the ALS patent landscape encompasses antibody-based immunotherapy, AAV-mediated gene therapy, small-molecule screens, microRNA targets, and neuronal reprogramming strategies — each at varying stages of preclinical and early clinical development.

AC Immune S.A.: antibodies and PET imaging for TDP-43 aggregates

AC Immune S.A. holds the most extensive TDP-43 antibody IP portfolio in the dataset, with multiple active, pending, and continuing CN and JP filings covering anti-TDP-43 antibodies, humanized anti-TDP-43 antibodies, and antigen-binding fragments. Multiple filings specify phosphorylated TDP-43 as the preferred epitope — directly targeting the S379, S403, S404, S409, and S410 phosphorylation sites identified in ALS neuropathology. Critically, AC Immune S.A. also discloses small-molecule PET imaging compounds for TDP-43 aggregates, enabling non-invasive diagnostic and patient-stratification applications. This dual therapeutic-plus-diagnostics strategy mirrors the amyloid PET approach that defined Alzheimer’s disease clinical development, as noted in the patent intelligence analysis from PatSnap’s innovation intelligence platform.

Gene therapy: AAV vectors and neuronal reprogramming

Voyager Therapeutics discloses gene therapy compositions for ALS using adeno-associated viral (AAV) vectors, with patent classifications encompassing constructs targeting relevant ALS genes. This filing was published as PCT WO 2018/204786 and appears at preclinical stage based on available retrieved data. A Yale University filing (Chinese national phase, 2025) discloses in vivo neuronal modification via Kcnn1 protein expression or activity modulation to alter neuronal firing and enhance clearance of ALS-causative proteins; the same filing references ongoing Phase 3 randomized trials for asymptomatic SOD1 mutation carriers and Phase 1 trials for C9ORF72 and FUS-targeting ASOs, situating the broader gene therapy platform within a field where ASO programs are already in clinical testing.

Penn State Research Foundation takes a distinct regenerative approach: its filings disclose methods for administering NeuroD1-encoding exogenous nucleic acid — alone or combined with Isl1 — to ALS patients, with the mechanism being in vivo conversion of glial cells into functional motor neurons. This neuronal reprogramming strategy aims to replace lost motor neurons rather than slow degeneration, representing a conceptually separate innovation direction from gene-silencing ASOs.

Small molecules and microRNA approaches

Kyoto University discloses iPSC-based drug screening platforms and identified anacardic acid derivatives as ALS prophylactic and therapeutic agents, validated in TDP-43-overexpressing iPSC-derived motor neurons. A broader kinase inhibitor panel was also disclosed, encompassing EGFR inhibitors, FGFR inhibitors, Aurora kinase inhibitors, PKA/PKC inhibitors, and MEK inhibitors, screened using ALS patient-derived iPSCs. Biohaven Therapeutics discloses myeloperoxidase (MPO) inhibitors for ALS treatment, positioning neuroinflammation reduction as a mechanistic target. The mir-17~92 cluster is disclosed by Academia Sinica as a candidate therapeutic target, with evidence that mir-17~92 expression in spinal motor neurons specifically declines before motor neuron loss onset in SOD1G93A transgenic mice. Standards for RNA-based therapeutic development are increasingly informed by guidance from WHO and FDA, whose frameworks for oligonucleotide and gene therapy products are shaping how ALS developers structure their IND submissions.

Neurofilament biomarkers as codeveloped companion diagnostics

Neurofilament proteins — specifically neurofilament light chain (NfL) and phosphorylated neurofilament heavy chain (pNFH) — are emerging as codevelopment targets alongside oligonucleotide therapeutics, with patent filings from Biogen MA Inc. and Quralis Corporation explicitly integrating neurofilament measurement into patient selection algorithms. This represents a structural shift in how ALS trials are being designed: rather than enrolling all patients with a given mutation, developers are stratifying by baseline neurofilament levels to enrich for populations most likely to show measurable treatment response.

Biogen MA Inc.’s neurofilament guidance patent explicitly shows plasma NfH declining longitudinally at approximately 1.8% per month in treated ALS patients, with NfH tertile stratification predicting differential treatment response. The same patent family also documents neuromuscular junction preservation in SOD1G93A mice treated with SOD1-active ASO versus inactive ASO control, providing the preclinical mechanistic rationale for the biomarker-guided clinical design. The Brigham and Women’s Hospital holds multi-jurisdictional patents on ALS diagnosis and therapy selection via monocyte or CSF microRNA panels — including hsa-miR-19b, hsa-miR-106b, and hsa-miR-155 — providing a complementary liquid biopsy-based stratification approach.

The convergence of neurofilament biomarker IP with therapeutic ASO programs is consistent with broader trends in precision neurology documented by NIH and the EMA, both of which have published guidance on biomarker qualification for neurodegenerative disease trials. As ALS trials move toward enriched designs, IP around biomarker-guided treatment selection may become competitively significant in its own right.

Assignee landscape and freedom-to-operate signals

Quralis Corporation dominates the dataset by filing volume, with patent families covering PPM1A ASOs, STMN2 ASOs, UNC13A ASOs, and splice-switch ASOs with modified backbone chemistry filed across WO, US, IL, AU, CA, IN, NZ, BR, CL, CN, and JP jurisdictions. This breadth indicates a coordinated, platform-level IP strategy targeting the TDP-43 downstream RNA splicing axis. Quralis Corporation is identified as both direct assignee and as the entity behind the Japanese entity Claris Corporation (Kuraris Kabushiki Kaisha), which covers the same oligonucleotide platforms in Japan and China — a jurisdictional extension strategy that maximises geographic coverage of the core platform.

Any entity seeking to develop TDP-43 downstream splice-correction therapies will likely face substantial freedom-to-operate considerations against the Quralis portfolio. AC Immune S.A.’s TDP-43 antibody and imaging compound strategy is the most concentrated biologics position in the dataset. Biogen MA Inc. contributes biomarker-guided therapeutic patents linking neurofilament proteins to SOD1-targeting ASO treatment selection, integrating biomarker science with clinical drug development in a way that creates IP at the intersection of diagnostics and therapeutics. The University of Massachusetts contributes foundational STMN2 biology patents that underpin the Quralis splice-switch ASO programs. Academic assignees — including Kyoto University, Penn State Research Foundation, Academia Sinica, and Arizona State University — contribute platform and screening IP that may be available for licensing or partnership with downstream pharma developers.

Combination strategies and the ALS–FTD molecular continuum

Retrieved patent filings signal several combination and emerging strategic directions that are reshaping how ALS therapeutics are being positioned commercially and clinically. Quralis Corporation gapmer ASO filings explicitly claim combination with riluzole (Rilutek), edaravone (Radicava), and AMX0035 (sodium phenylbutyrate/ursodoxicol), among other agents — signalling that next-generation ASO programs are being positioned as combination partners with currently approved ALS therapeutics rather than as standalone replacements.

The multi-target scope of Quralis and Claris filings — covering STMN2, UNC13A, KCNQ2, and SMN2 on a shared modified-backbone oligonucleotide platform — suggests a modular approach to ALS, FTD, and SMA therapy using a single chemistry platform tunable to multiple gene targets. This is a potential portfolio licensing strategy that extends the commercial reach of the core ASO chemistry beyond ALS alone. According to global patent data accessible through PatSnap’s innovation intelligence resources, this kind of platform chemistry IP is increasingly central to partnership and licensing negotiations in neurodegeneration.

“Therapeutic claims across nearly all retrieved ALS filings uniformly extend to FTD, ALS-FTD, and TDP-43 proteinopathies more broadly — signalling that ALS-derived platforms are being repositioned for larger, potentially more tractable patient populations.”

The ALS–FTD molecular continuum is reflected across nearly all retrieved filings. The extension of ALS therapeutic claims to FTD and TDP-43 proteinopathies more broadly is not incidental: it reflects the shared neuropathological substrate of TDP-43 aggregation across these conditions, and it signals that developers are seeking to maximise addressable patient populations from a single therapeutic platform. For competitive intelligence purposes, this means that monitoring the ALS patent space requires simultaneous tracking of the FTD and TDP-43 proteinopathy landscapes — a point reinforced by Alzforum‘s ongoing coverage of TDP-43 as a cross-disease target.

Clinical translation signals in the dataset reference Phase 1 and Phase 3 activity for SOD1, C9ORF72, FUS, and ATXN2 ASOs, confirming the ASO modality as most advanced. Retrieved data does not contain clinical evidence of efficacy for anti-TDP-43 antibodies, STMN2 ASOs, or UNC13A ASOs, indicating these remain in earlier development stages based on this dataset. The C9ORF72 ASO Phase 1 data referenced in the Yale University filing achieved CSF polyGP reduction but noted a trend toward greater clinical decline in treated patients — an important translational caveat that underscores the difficulty of converting target engagement into clinical benefit in ALS, a challenge well documented by NIH and clinical trial registries.