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<p>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.</p>

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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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月18日

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  • 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

摘要

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.