| Title: |
Investigational eIF2B activator DNL343 modulates the integrated stress response in preclinical models of TDP-43 pathology and individuals with ALS in a randomized clinical trial |
| Authors: |
Flores,Brittany N; Yu,Seungyoon B; Cohen,Isaac V; Fanok,Melania H; Luan,Wei; Maciuca,Romeo D; Sun,Linus D; Tsai,Richard M; Vissers,Maurits; Smits,Lars; Bunte, Tommy M; Bakardjiev,Anna; Balasundar,Srijana; Calvert,Meredith E K; Chin,Marcus Y; Dobbins,Sarah K; Dowdle,William E; Fang,Meng; Heuberger, Jules A A C; Ha,Connie L; Huang,Fen; Miyamoto,Takashi; Osipov,Maksim; Madrid San Martin,Lidia; Saund,Katie; Tatarakis,David; Vu,Anthony Q; Xiong,Chenling; Yeo,Gene W; Groeneveld,Geert Jan; van den Berg, Leonard H; Dhuria,Shyeilla; Estrada,Anthony A; Jennings,Danna; Sandmann,Thomas; Ho,Carole; Scearce-Levie,Kimberly; Yulyaningsih,Ernie; Walker,Adam K; Di Paolo,Gilbert; Kane,Lesley A; Troyer,Matthew D; Lewcock,Joseph W; ALS Trial team; Brain; Neurologen; Projectafdeling ALS |
| Publication Year: |
2025 |
| Subject Terms: |
Journal Article |
| Description: |
Neuronal TDP-43 aggregates are a hallmark ALS pathology. The integrated stress response (ISR) occurs downstream of TDP-43 pathology and may promote neurodegeneration. Here we demonstrate that a CNS penetrant small molecule eIF2B activator inhibits the ISR in cellular models of ALS and the brain of an inducible mouse model of TDP-43 pathology, where it transiently slowed progression of locomotor deficits and neurodegeneration. ISR activation was observed in ALS patient spinal cord and CSF. The investigational drug DNL343 was advanced into Phase 1 and Phase 1b randomized, double-blind, placebo-controlled trials in healthy and ALS participants, respectively (NCT04268784/NCT05006352); the primary objective in both studies was to investigate the safety and tolerability DNL343. DNL343 demonstrated a half-life supporting once-daily dosing and showed extensive CSF distribution. DNL343 was generally well tolerated and reduced ISR biomarkers in peripheral blood mononuclear cells and CSF of ALS participants. Therefore, DNL343 is a useful investigational drug to explore the effects of ISR inhibition in ALS models and individuals with neurological diseases. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| ISSN: |
2041-1723 |
| Relation: |
https://dspace.library.uu.nl/handle/1874/467332 |
| Availability: |
https://dspace.library.uu.nl/handle/1874/467332 |
| Rights: |
info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.ECBB2DCD |
| Database: |
BASE |