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

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.

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Publication Details

Journal
Nature Communications
Published
2025-08-18
DOI
https://doi.org/10.1038/s41467-025-63031-y
Citations
4
Primary Topic
Amyotrophic Lateral Sclerosis Research
Type
article
Field-Weighted Citation Impact
5.56

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article

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

Romeo Maciuca, Carole Ho, Anthony Q. Vu, Thomas Sandmann et al.
4 citations
Nature Communications
Amyotrophic Lateral Sclerosis Research
5.56
article

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

Romeo Maciuca, Carole Ho, Anthony Q. Vu, Thomas Sandmann, Takashi Miyamoto, Geert Jan Groeneveld, Melania H. Fanok, Wei Luan, Lidia Madrid San Martin, Kimberly Scearce‐Levie, Srijana Balasundar, William E. Dowdle, David Tatarakis, Seungyoon B. Yu, Adam K. Walker, Katie Saund, Anna I. Bakardjiev, Shyeilla V. Dhuria, Maksim Osipov, Matthew D. Troyer, Brittany N. Flores, Danna Jennings, Marcus Y. Chin, Sarah Dobbins, Anthony A. Estrada, Tommy M. Bunte, Isaac V. Cohen, Lesley A. Kane, Leonard H. van den Berg, Maurits F. J. M. Vissers, Joseph W. Lewcock, Gilbert Di Paolo, Jules A. A. C. Heuberger, Ernie Yulyaningsih, Chenling Xiong, G Yeo, Meng Fang, Meredith Calvert, Lisa Smits, Fen Huang, Linus D. Sun, Connie Ha, Richard M. Tsai
article en
4 citations

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.

Nature CommunicationsVol. 16(1)
Leiden University (NL), The University of Sydney (AU), Southeastern University (US), The University of Queensland (AU), Regeneron (United States) (US), Utrecht University (NL), University of Applied Sciences Leiden (NL), Heidelberg University (DE), Leiden University Medical Center (NL), University Hospital Heidelberg (DE), University Medical Center Utrecht (NL), University of California San Diego (US), Rapt Therapeutics (United States) (US), Denali Therapeutics (United States) (US), Emergency University (US), La Jolla Alcohol Research (US), Centre for Human Drug Research (NL), Stem Cell Institute (PA), Takeda (United States) (US), Gilead Sciences (United States) (US), Cellular Research (United States) (US), Center for Genomic Science (IT), Innovative Research (United States) (US), International Neuromodulation Society (US), Takeda (Japan) (JP), Sunesis (United States) (US)
Target ALS, Cedars-Sinai Medical Center, Tow Foundation, Denali Therapeutics, National Institutes of Health, University of California, San Diego
Openalex Percentile: Top 4%
Amyotrophic Lateral Sclerosis Research
5.56
DOIOpen Access PDFOpenAlex
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