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Correcting tau isoform ratios with a long-acting antisense oligonucleotide alleviates 4R-tauopathy phenotypes
Iwata-Endo K, Sahashi K, Kawai K, Fujioka Y, Okada Y, Watanabe E, Iwade N, Ishibashi M et al.. Molecular therapy. Nucleic acids, 2025-03-05
Topic: Brain proteins, microglia and lab models
Tau, a microtubule-binding protein linked to tauopathies like Alzheimer's disease and frontotemporal lobar degeneration (FTLD), has 3-repeat (3R) and 4-repeat (4R) isoforms. Accumulation of the 4R-tau is associated with FTLD, progressive supranuclear palsy (PSP), and cortico-basal degeneration (CBD). We previously showed that a loss of fused in sarcoma (FUS) or splicing factor, proline- and glutamine-rich (SFPQ) promoted 4R-tau accumulation, which induced FTLD-like behaviors and neurodegeneration in mice. Here, we developed antisense oligonucleotides (ASOs) modified with 2'- O , 4'- C -ethylene-bridged nucleic acids (ENAs), reducing the 4R-tau/3R-tau ratio while maintaining total tau expression from the MAPT gene. In vitro screening identified EN-06 as the most effective ENA. Intracerebroventricular (ICV) administration of EN-06 corrected the 4R/3R-tau ratio in FUS-silenced humanized tau mice and human iPSC-derived neurons. This treatment ameliorated disease phenotypes, including aberrant behaviors, spine dysmorphology, and neurodegeneration. The half-life of EN-06 after a single ICV administration was approximately 6 months in the brain, with splicing correction effects that persisted for 2 years. The efficacy of EN-06 was higher than that of 2'- O -methoxyethyl (MOE)-modified ASO (MO-06). These findings highlight the potential of ENA-modified ASOs to reduce 4R-tau while preserving total MAPT expression, thus offering a safe and long-acting treatment for 4R-tau-associated tauopathies.
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APA 7th
Iwata-Endo, K., Sahashi, K., Kawai, K., Fujioka, Y., Okada, Y., Watanabe, E., et al. (2025). Correcting tau isoform ratios with a long-acting antisense oligonucleotide alleviates 4R-tauopathy phenotypes. Molecular therapy. Nucleic acids. https://doi.org/10.1016/j.omtn.2025.102503
Vancouver
Iwata-Endo K, Sahashi K, Kawai K, Fujioka Y, Okada Y, Watanabe E, et al. Correcting tau isoform ratios with a long-acting antisense oligonucleotide alleviates 4R-tauopathy phenotypes. Molecular therapy. Nucleic acids. 2025. doi:10.1016/j.omtn.2025.102503. PMID: 40206658.
BibTeX
@article{iwataendo2025-40206658,
author = {Iwata-Endo, K. and Sahashi, K. and Kawai, K. and Fujioka, Y. and Okada, Y. and Watanabe, E. and Iwade, N. and Ishibashi, M. and others},
title = {{Correcting tau isoform ratios with a long-acting antisense oligonucleotide alleviates 4R-tauopathy phenotypes}},
journal = {Molecular therapy. Nucleic acids},
year = {2025},
doi = {10.1016/j.omtn.2025.102503},
pmid = {40206658},
url = {https://doi.org/10.1016/j.omtn.2025.102503}
}
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Key findings
- Accumulation of the 4R-tau is associated with FTLD, progressive supranuclear palsy (PSP), and cortico-basal degeneration (CBD).
- We previously showed that a loss of fused in sarcoma (FUS) or splicing factor, proline- and glutamine-rich (SFPQ) promoted 4R-tau accumulation, which induced FTLD-like behaviors and neurodegeneration in mice.
- These findings highlight the potential of ENA-modified ASOs to reduce 4R-tau while preserving total MAPT expression, thus offering a safe and long-acting treatment for 4R-tau-associated tauopathies.
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Study details
- Evidence strengthLow
How this study scored 45/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 26 of the 58 points we could judge it on, which is 45 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Molecular therapy. Nucleic acids) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40206658) |
| Free to read | 2 / 2 | Free to read |
| Points | 26 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 26 of the 58 points we could judge it on is 45 out of 100. |
| Total | 45 / 100 | — |
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