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

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

Abstract 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 b...

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Main Authors: Brittany N. Flores, Seungyoon B. Yu, Isaac V. Cohen, Melania H. Fanok, Wei Luan, Romeo D. Maciuca, Linus D. Sun, Richard M. Tsai, Maurits Vissers, Lars Smits, Tommy M. Bunte, Anna Bakardjiev, Srijana Balasundar, Meredith E. K. Calvert, Marcus Y. Chin, Sarah K. Dobbins, William E. Dowdle, Meng Fang, Jules A. A. C. Heuberger, Connie L. Ha, Fen Huang, Takashi Miyamoto, Maksim Osipov, Lidia Madrid San Martin, Katie Saund, David Tatarakis, Anthony Q. Vu, Chenling Xiong, Gene W. Yeo, Geert Jan Groeneveld, Leonard H. van den Berg, Shyeilla Dhuria, Anthony A. Estrada, Danna Jennings, Thomas Sandmann, Carole Ho, Kimberly Scearce-Levie, Ernie Yulyaningsih, Adam K. Walker, Gilbert Di Paolo, Lesley A. Kane, Matthew D. Troyer, Joseph W. Lewcock
Format: Article
Language:English
Published: Nature Portfolio 2025-08-01
Series:Nature Communications
Online Access:https://doi.org/10.1038/s41467-025-63031-y
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https://doi.org/10.1038/s41467-025-63031-y

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