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

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. Berg, Shyeilla Dhuria, Anthony A. Estrada, Danna Jennings, Thomas Sandmann, Carole Ho, Kimberly Scearce-Levie, Ernie Yulyaningsih, Adam K. Walker, Gilbert Paolo (), Lesley A. Kane (), Matthew D. Troyer () and Joseph W. Lewcock ()
Additional contact information
Brittany N. Flores: Denali Therapeutics Inc.; 161 Oyster Point Blvd.
Seungyoon B. Yu: Denali Therapeutics Inc.; 161 Oyster Point Blvd.
Isaac V. Cohen: Denali Therapeutics Inc.; 161 Oyster Point Blvd.
Melania H. Fanok: Denali Therapeutics Inc.; 161 Oyster Point Blvd.
Wei Luan: The University of Queensland
Romeo D. Maciuca: Denali Therapeutics Inc.; 161 Oyster Point Blvd.
Linus D. Sun: Denali Therapeutics Inc.; 161 Oyster Point Blvd.
Richard M. Tsai: Denali Therapeutics Inc.; 161 Oyster Point Blvd.
Maurits Vissers: Centre for Human Drug Research; Zernikedreef 8
Lars Smits: Centre for Human Drug Research; Zernikedreef 8
Tommy M. Bunte: The University Medical Center Utrecht; Heidelberglaan 100
Anna Bakardjiev: Denali Therapeutics Inc.; 161 Oyster Point Blvd.
Srijana Balasundar: Denali Therapeutics Inc.; 161 Oyster Point Blvd.
Meredith E. K. Calvert: Denali Therapeutics Inc.; 161 Oyster Point Blvd.
Marcus Y. Chin: Denali Therapeutics Inc.; 161 Oyster Point Blvd.
Sarah K. Dobbins: Denali Therapeutics Inc.; 161 Oyster Point Blvd.
William E. Dowdle: Denali Therapeutics Inc.; 161 Oyster Point Blvd.
Meng Fang: Denali Therapeutics Inc.; 161 Oyster Point Blvd.
Jules A. A. C. Heuberger: Centre for Human Drug Research; Zernikedreef 8
Connie L. Ha: Denali Therapeutics Inc.; 161 Oyster Point Blvd.
Fen Huang: Denali Therapeutics Inc.; 161 Oyster Point Blvd.
Takashi Miyamoto: Denali Therapeutics Inc.; 161 Oyster Point Blvd.
Maksim Osipov: Denali Therapeutics Inc.; 161 Oyster Point Blvd.
Lidia Madrid San Martin: The University of Queensland
Katie Saund: Denali Therapeutics Inc.; 161 Oyster Point Blvd.
David Tatarakis: Denali Therapeutics Inc.; 161 Oyster Point Blvd.
Anthony Q. Vu: University of California; San Diego
Chenling Xiong: Denali Therapeutics Inc.; 161 Oyster Point Blvd.
Gene W. Yeo: University of California; San Diego
Geert Jan Groeneveld: Centre for Human Drug Research; Zernikedreef 8
Leonard H. Berg: The University Medical Center Utrecht; Heidelberglaan 100
Shyeilla Dhuria: Denali Therapeutics Inc.; 161 Oyster Point Blvd.
Anthony A. Estrada: Denali Therapeutics Inc.; 161 Oyster Point Blvd.
Danna Jennings: Denali Therapeutics Inc.; 161 Oyster Point Blvd.
Thomas Sandmann: Denali Therapeutics Inc.; 161 Oyster Point Blvd.
Carole Ho: Denali Therapeutics Inc.; 161 Oyster Point Blvd.
Kimberly Scearce-Levie: Denali Therapeutics Inc.; 161 Oyster Point Blvd.
Ernie Yulyaningsih: Denali Therapeutics Inc.; 161 Oyster Point Blvd.
Adam K. Walker: The University of Queensland
Gilbert Paolo: Denali Therapeutics Inc.; 161 Oyster Point Blvd.
Lesley A. Kane: Denali Therapeutics Inc.; 161 Oyster Point Blvd.
Matthew D. Troyer: Denali Therapeutics Inc.; 161 Oyster Point Blvd.
Joseph W. Lewcock: Denali Therapeutics Inc.; 161 Oyster Point Blvd.

Nature Communications, 2025, vol. 16, issue 1, 1-23

Abstract: 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 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.

Date: 2025
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DOI: 10.1038/s41467-025-63031-y

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