SHORT DESCRIPTION
Antisense oligonucleotides (ASOs) that correct TDP‑43–dependent mis‑splicing of KCNQ2 thereby reducing neuronal hyperexcitability in ALS/FTD and related TDP‑43 proteinopathies.
* Principal Investigator
NU Tech ID: NU 2023-020
IP STATUS
US Patent pending
DEVELOPMENT STAGE
TRL-3 Experimental Proof-of-Concept: Active R&D is underway with preliminary validation in cellular models.
BACKGROUND
Amyotrophic lateral sclerosis (ALS) is a rapidly fatal motor neuron disease with an incidence of roughly 2–3 per 100,000 person-years and a prevalence of about 7–9 per 100,000 in European and North American populations. Median survival from symptom onset is typically 2–4 years, and only a small minority of patients live beyond 10 years, making ALS one of the most devastating adult‑onset neurologic disorders. Frontotemporal dementia (FTD) is one of the most common causes of young-onset dementia, with pooled incidence estimates of roughly 2–4 per 100,000 and prevalence estimates of about 9–22 per 100,000. It causes profound behavioral, language, and executive dysfunction during working-age years. Currently available disease-modifying therapies for ALS do not directly tackle the root causes of neuronal hyperexcitability and provide only modest benefit, while the newer ASO therapy Tofersen is approved only for the small SOD1-mutant subset, leaving the >90% of ALS cases without a targeted therapy. Moreover, there are currently no approved disease‑modifying therapies for FTD and management is symptomatic, largely off‑label, and supported by relatively weak trial evidence. ALS and FTD are now understood as two ends of a shared TDP-43 proteinopathy spectrum, with TDP-43 pathology present in approximately 90% of ALS and about 50% of FTD cases. TDP-43 pathology leads to nuclear depletion and cytoplasmic aggregation, which in turn causes mis-splicing of key mRNAs. This dysregulation compromises ion channel function and contributes to disease progression and worsening patient development. There is therefore a clear unmet need for therapies that directly correct TDP‑43–driven splice defects in key ion channel genes to normalize excitability and potentially slow or prevent disease.
ABSTRACT
Northwestern researchers developed family of antisense oligonucleotides (ASOs), 10–30 nucleotides in length, designed to prevent TDP-43-dependent mis-splicing of KCNQ2, a key gene implicated in loss of functional ion channels, neuronal hyperexcitability, and earlier onset in ALS/FTD. This approach restores proper splicing in human iPSC-derived motor and cortical neurons subjected to TDP-43 depletion and patient tissue samples. The corrected splicing re-establishes functional Kv7.2 channels and reduces intrinsic hyperexcitability. The oligonucleotides use clinically validated chemistries, including phosphorothioate linkages and 2'-O-methoxyethyl modifications, and are positioned as a CNS-directed, splice-correcting therapeutic platform for ALS and FTD that complements the precedent established by approved ASO medicines in neurology. This strategy offers a promising therapeutic avenue for ALS/FTD by directly addressing a key molecular defect.
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