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A single dose of a vectorized mAb targeting TDP-43 potently inhibits the neuropathology in a model of ALS/FTD
Greg del Val, Florence Gauye, Mickaël Audrain, Sébastien Menant, Monisha Ratnam, Elodie Chevalier, Romain Ollier, Daisy Bhatia et al.. Molecular Therapy, 2025-06-14
Topic: Brain proteins, microglia and lab models
Transactive response DNA binding protein-43 (TDP-43)-mediated pathology is a hallmark of devastating neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Thus, monoclonal antibodies (mAbs) are being developed to target the pathological forms of this protein. To improve mAb exposure within the central nervous system, a potent anti-TDP-43 mAb, ACI-5891, was generated as a vectorized full-length antibody (vmAb) and evaluated for brain delivery using adeno-associated virus 9 (AAV9). Among the expression cassettes explored, the selected construct utilized an internal ribosome entry site (IRES), which produced high expression yields in vitro (>200 mg/L) with comparable quality, binding, and functional properties to the conventionally produced mAb. A single intracisternal administration of vmAb ACI-5891 demonstrated a broad brain distribution and sustained expression (i.e., months) in the serum, cerebrospinal fluid, and brain of mice. In a mouse model of ALS/FTD, treatment with a vmAb reduced the amount of pathological phospho-TDP-43 in neurons by 58% and 68% when expressed using either a ubiquitous promoter or a brain-selective promoter, respectively. This innovative approach sufficiently delivers effective immunotherapy with a single dose and illustrates the enormous potential of using vectorized antibodies to target neuropathology, including TDP-43 in patients suffering from ALS, FTD, and other TDP-43 proteinopathies.
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APA 7th
del Val, G., Gauye, F., Audrain, M., Menant, S., Ratnam, M., Chevalier, E., et al. (2025). A single dose of a vectorized mAb targeting TDP-43 potently inhibits the neuropathology in a model of ALS/FTD. Molecular Therapy. https://doi.org/10.1016/j.ymthe.2025.06.026
Vancouver
del Val G, Gauye F, Audrain M, Menant S, Ratnam M, Chevalier E, et al. A single dose of a vectorized mAb targeting TDP-43 potently inhibits the neuropathology in a model of ALS/FTD. Molecular Therapy. 2025. doi:10.1016/j.ymthe.2025.06.026. PMID: 40518671.
BibTeX
@article{delval2025-40518671,
author = {del Val, Greg and Gauye, Florence and Audrain, Mickaël and Menant, Sébastien and Ratnam, Monisha and Chevalier, Elodie and Ollier, Romain and Bhatia, Daisy and others},
title = {{A single dose of a vectorized mAb targeting TDP-43 potently inhibits the neuropathology in a model of ALS/FTD}},
journal = {Molecular Therapy},
year = {2025},
doi = {10.1016/j.ymthe.2025.06.026},
pmid = {40518671},
url = {https://doi.org/10.1016/j.ymthe.2025.06.026}
}
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
Key findings
- A single intracisternal administration of vmAb ACI-5891 demonstrated a broad brain distribution and sustained expression (i.e., months) in the serum, cerebrospinal fluid, and brain of mice.
Why it matters
In mice, a single dose of a vectorized antibody targeting TDP-43 spread widely in the brain and was expressed for months, reducing pathological phospho-TDP-43 in neurons by 58% to 68% in a model of ALS/FTD. This is an early animal study showing a possible way to deliver antibody treatment to the brain with one dose.
Study details
- Evidence strengthLow
How this study scored 36/100
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.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Molecular Therapy) |
| Journal's citation record | 3 / 4 | Molecular Therapy: journal h-index 258 (OpenAlex, 2026-10-29) |
| 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 | 2 / 7 | Cited 5 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 1.7 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 2 / 6 | Cited 2.8× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 1 / 4 | Cited 5 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 1 / 4 | Last-listed author Damien Névoltris: h-index 11 (OpenAlex, whole career) |
| Institution's track record | 0 / 3 | AC Immune (Switzerland): institution h-index 83 (OpenAlex) |
| Multi-centre collaboration | 0 / 3 | OpenAlex lists 1 institution(s) in 1 country — scores zero (affiliation lists can be incomplete) |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40518671) |
| Free to read | 2 / 2 | Free to read |
| Total | 36 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1016/j.ymthe.2025.06.026
- PubMed: 40518671
- Original source →
- Free full text: Molecular Therapy →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
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