Summary

A research group led by Shinsuke Ishigaki and colleagues has discovered a novel antisense oligonucleotide (ASO) that safely and sustainably regulates the isoforms of tau protein.

The study found that ENA-ASO effectively adjusts the 4R-tau/3R-tau ratio without altering the total tau protein levels, leading to the alleviation of behavioral abnormalities, phosphorylated tau accumulation, and hippocampal atrophy in FTLD model mice.

The results were published in the Molecular Therapy Nucleic Acids journal on March 6, 2025.

Key Findings

• No effective treatment exists for four-repeat tauopathies like PSP and CBD.
• ASO treatment in FTLD model mice improved behavioral and neurological symptoms.
• ENA-ASO demonstrated long-lasting effects and confirmed safety.
• This approach may lead to a new treatment for FTLD, PSP, and four-repeat tauopathies.

Research Background

Tau protein is a pathological factor in Alzheimer’s disease (AD), frontotemporal lobar degeneration (FTLD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). Current treatments targeting tau expression, phosphorylation, and aggregation have not yet reached clinical trials.

The research team previously identified that imbalances in tau isoforms in four-repeat tauopathies were caused by dysfunction of RNA-binding protein complexes.

In response, they developed an ENA-ASO that specifically targets MAPT exon 10 to regulate tau isoform balance, reduce toxicity, and enhance stability.

Research Methods and Results

Design of ENA-ASO for MAPT Exon 10 Splicing

Several ENA-ASOs targeting exon 10 were screened, with the most effective ones selected for in vivo analysis.

Therapeutic Effect in FTLD Model Mice

Following intracerebroventricular injection of EN-06 in FTLD model mice:

• Exon 10 skipping was significantly induced.
• The 4R-tau/3R-tau ratio was reduced by up to 92%.
• Improvements in behavioral abnormalities, synaptic function, and neurodegeneration were observed.
• The optimal dosage was determined to be 50 µg.

Pharmacokinetics and Safety

• ENA-ASO was widely distributed in brain tissues and localized in neurons.
• No acute toxicity or liver/kidney toxicity was observed.
• Compared to MOE-ASO, ENA-ASO had:
  • Twice the half-life (~6 months) in brain tissues.
  • Longer-lasting effects (~2 years) after a single dose.

Future Outlook

The study confirms that EN-06 alleviates symptoms of four-repeat tauopathies with long-lasting efficacy and safety, making it a potential fundamental treatment requiring fewer administrations.

Next steps include non-clinical trials at higher doses to further assess safety and feasibility, paving the way for the first human clinical trials.