DNL343 is an investigational CNS penetrant eukaryotic initiation factor 2B activator that prevents and reverses the effects of neurodegeneration caused by the integrated stress response DOI Creative Commons
Ernie Yulyaningsih, Jung H. Suh,

Melania H. Fanok

и другие.

eLife, Год журнала: 2023, Номер 12

Опубликована: Ноя. 14, 2023

The integrated stress response (ISR) is a conserved pathway in eukaryotic cells that activated to multiple sources of cellular stress. Although acute activation this restores homeostasis, intense or prolonged ISR perturbs cell function and may contribute neurodegeneration. DNL343 an investigational CNS-penetrant small-molecule inhibitor designed activate the initiation factor 2B (eIF2B) suppress aberrant activation. reduced CNS activity neurodegeneration dose-dependent manner two established vivo models – optic nerve crush injury eIF2B loss (LOF) mutant demonstrating neuroprotection both preventing motor dysfunction LOF mouse. Treatment with at late stage disease model reversed elevation plasma biomarkers neuroinflammation prevented premature mortality. Several proteins metabolites are dysregulated mouse brains were normalized by treatment, detectable human biofluids. these show differential levels CSF from patients vanishing white matter (VWMD), neurodegenerative driven chronic activation, supporting their potential translational relevance. This study demonstrates brain-penetrant capable attenuating identifies several biomarker candidates be used assess treatment responses clinic.

Язык: Английский

Applications of Bridgehead Heterocycles in Drug Design and Medicinal Chemistry DOI
Simona Di Martino, Pietro Amico, Maria De Rosa

и другие.

Topics in Current Chemistry, Год журнала: 2025, Номер 383(2)

Опубликована: Март 21, 2025

Язык: Английский

Процитировано

0
Decoding Stress Granules Dynamics: Implications for Neurodegenerative Disease DOI
Zixuan Wang, Chenyi Yang, Xinyi Wang

и другие.

Progress in Neurobiology, Год журнала: 2025, Номер unknown, С. 102758 - 102758

Опубликована: Март 1, 2025

Язык: Английский

Процитировано

0
The integrated stress response: From basic mechanisms to a unified approach to treating cognitive disorders of different etiologies DOI
Yuwei Liu, Morgane Boone, Peter Walter

и другие.

Elsevier eBooks, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Язык: Английский

Процитировано

0
Targeting Protein Aggregation in ALS DOI Creative Commons
Michele Perni, Benedetta Mannini

Biomolecules, Год журнала: 2024, Номер 14(10), С. 1324 - 1324

Опубликована: Окт. 18, 2024

Proteinopathies involve the abnormal accumulation of specific proteins. Maintaining balance proteome is a finely regulated process managed by complex network cellular machinery responsible for protein synthesis, folding, and degradation. However, stress ageing can disrupt this balance, leading to widespread aggregation. Currently, several therapies targeting aggregation are in clinical trials ALS. These approaches mainly focus on two strategies: addressing proteins that prone due mutations mechanisms maintain homeostasis prevent This review will cover these emerging drugs. Advances ALS research not only offer hope better outcomes patients but also provide valuable insights methodologies benefit broader field neurodegenerative disease drug discovery.

Язык: Английский

Процитировано

1
DNL343 is an investigational CNS penetrant eukaryotic initiation factor 2B activator that prevents and reverses the effects of neurodegeneration caused by the integrated stress response DOI Creative Commons
Ernie Yulyaningsih, Jung H. Suh,

Melania H. Fanok

и другие.

eLife, Год журнала: 2024, Номер 12

Опубликована: Сен. 17, 2024

The integrated stress response (ISR) is a conserved pathway in eukaryotic cells that activated to multiple sources of cellular stress. Although acute activation this restores homeostasis, intense or prolonged ISR perturbs cell function and may contribute neurodegeneration. DNL343 an investigational CNS-penetrant small-molecule inhibitor designed activate the initiation factor 2B (eIF2B) suppress aberrant activation. reduced CNS activity neurodegeneration dose-dependent manner two established vivo models – optic nerve crush injury eIF2B loss (LOF) mutant demonstrating neuroprotection both preventing motor dysfunction LOF mouse. Treatment with at late stage disease model reversed elevation plasma biomarkers neuroinflammation prevented premature mortality. Several proteins metabolites are dysregulated mouse brains were normalized by treatment, detectable human biofluids. these show differential levels CSF from patients vanishing white matter (VWMD), neurodegenerative driven chronic activation, supporting their potential translational relevance. This study demonstrates brain-penetrant capable attenuating identifies several biomarker candidates be used assess treatment responses clinic.

Язык: Английский

Процитировано

0
DNL343 is an investigational CNS penetrant eIF2B activator that prevents and reverses the effects of neurodegeneration caused by the Integrated Stress Response DOI Creative Commons
Ernie Yulyaningsih, Jung H. Suh,

Melania H. Fanok

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Авг. 22, 2023

ABSTRACT The integrated stress response (ISR) is a conserved pathway in eukaryotic cells that activated to multiple sources of cellular stress. Although acute activation this restores homeostasis, intense or prolonged ISR perturbs cell function and may contribute neurodegeneration. DNL343 an investigational CNS-penetrant small molecule inhibitor designed activate the initiation factor 2B (eIF2B) suppress aberrant activation. reduced CNS activity neurodegeneration dose-dependent manner two established vivo models – optic nerve crush injury eIF2B loss (LOF) mutant demonstrating neuroprotection both preventing motor dysfunction LOF mouse. Treatment with at late stage disease model reversed elevation plasma biomarkers neuroinflammation prevented premature mortality. Several proteins metabolites are dysregulated mouse brains were normalized by treatment, detectable human biofluids. these show differential levels CSF from patients vanishing white matter (VWMD), neurodegenerative driven chronic activation, supporting their potential translational relevance. This study demonstrates brain penetrant capable attenuating identifies several biomarker candidates be used assess treatment responses clinic.

Язык: Английский

Процитировано

1
DNL343 is an investigational CNS penetrant eukaryotic initiation factor 2B activator that prevents and reverses the effects of neurodegeneration caused by the integrated stress response DOI Creative Commons
Ernie Yulyaningsih, Jung H. Suh,

Melania H. Fanok

и другие.

eLife, Год журнала: 2023, Номер 12

Опубликована: Ноя. 14, 2023

The integrated stress response (ISR) is a conserved pathway in eukaryotic cells that activated to multiple sources of cellular stress. Although acute activation this restores homeostasis, intense or prolonged ISR perturbs cell function and may contribute neurodegeneration. DNL343 an investigational CNS-penetrant small-molecule inhibitor designed activate the initiation factor 2B (eIF2B) suppress aberrant activation. reduced CNS activity neurodegeneration dose-dependent manner two established vivo models – optic nerve crush injury eIF2B loss (LOF) mutant demonstrating neuroprotection both preventing motor dysfunction LOF mouse. Treatment with at late stage disease model reversed elevation plasma biomarkers neuroinflammation prevented premature mortality. Several proteins metabolites are dysregulated mouse brains were normalized by treatment, detectable human biofluids. these show differential levels CSF from patients vanishing white matter (VWMD), neurodegenerative driven chronic activation, supporting their potential translational relevance. This study demonstrates brain-penetrant capable attenuating identifies several biomarker candidates be used assess treatment responses clinic.

Язык: Английский

Процитировано

1