Therapeutics

DNL343

Overview

Name: DNL343
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Amyotrophic Lateral Sclerosis
U.S. FDA Status: Amyotrophic Lateral Sclerosis (Phase 1)
Company: Denali Therapeutics Inc.

Background

DNL343 is a brain-penetrant activator of the eukaryotic initiation factor EIF2b. It inhibits the cell's unfolded protein response in an attempt to restore protein synthesis. Normally, EIF2b, with its EIF2a subunit, functions to initiate mRNA translation. Under conditions of cellular stress, phosphorylation of the EIF2a subunit by the PERK kinase leads to inhibition of EIF2b, and pauses protein synthesis as part of the cell’s integrated stress response (ISR). Loss-of-function mutations in EIF2b that impair protein translation cause a progressive neurodegenerative syndrome affecting the brain and spinal cord, called vanishing white matter disease (see OMIM).

In some neurodegenerative diseases, maladaptive PERK activation and EIF2b inhibition occur as part of the cellular response to an accumulation of misfolded proteins in the endoplasmic reticulum (for example, Stutzbach et al., 2013). The resulting deficit in protein synthesis contributes to synaptic dysfunction and memory impairment. EIF2b inhibition is also linked to stress granule formation and pathogenic protein aggregation.

Restoring EIF2b activity using PERK inhibitors or genetic approaches has been shown to protect against neurodegeneration in preclinical models of prion disease, frontotemporal dementia, and ALS (reviewed in Smith and Mallucci, 2016).

There are no published data on DNL343 in preclinical models. However, there is a growing literature on a different activator of EIF2b, ISRIB, that forms the basis for research at Denali and at least one other company, Calico Life Sciences (see Wong et al., 2019). ISRIB counteracts the effects of EIF2a phosphorylation, increasing protein synthesis and preventing stress granule formation; it also improves learning and memory in mice (Sidrauski et al., 2013; Sidrauski et al., 2015; Sidrauski et al., 2015). The ISRIB binding site on EIF2b has been resolved by X-ray crystallography (Zyryanova et al., 2018; Tsai et al., 2018; and review by Marintchev and Ito, 2020).

In preclinical work, ISRIB was neuroprotective in models of head trauma, Down's syndrome, and vanishing white-matter disease (Chou et al., 2017; Zhu et al., 2019; Abbink et al., 2019). It also protected neurons from TDP-43 toxicity in a cellular model of ALS (Bugallo et al., 2020). In prion-infected mice, ISIRB appeared safer than the PERK inhibitor GSK2606414, which showed pancreatic toxicity (Halliday et al., 2015).

In Alzheimer’s models, ISRIB prevented Aβ-induced cell death (Hosoi et al., 2016) but did not improve cognition in either the APPswe or hAPP-J20 models of AD, and daily dosing led to significant mortality in the former (Briggs et al., 2017; Johnson and Kang, 2016).

Findings

In February 2020, Denali began a Phase 1 trial testing single and multiple ascending oral doses of DNL343 in 88 healthy adults. The primary outcomes are safety and plasma pharmacokinetics measured up to 20 days. Secondary outcomes include DNL343 uptake into the CSF, renal clearance, and pharmacodynamic measures of integrated stress response protein and mRNA levels in blood by ELISA and quantitative PCR. The study was expected to end in October 2020, but may be delayed after enrollment was paused in April due to COVID-19 (press release).

In December 2020, a second Phase 1 trial began to investigate effects of formulation and food on DNL343's safety and pharmacokinetics, in 24 healthy men and women.

For details on DNL343 trials, see clinicaltrials.gov.

Last Updated: 22 Dec 2020

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References

Paper Citations

  1. . The unfolded protein response is activated in disease-affected brain regions in progressive supranuclear palsy and Alzheimer's disease. Acta Neuropathol Commun. 2013 Jul 6;1(1):31. PubMed.
  2. . The unfolded protein response: mechanisms and therapy of neurodegeneration. Brain. 2016 Aug;139(Pt 8):2113-21. Epub 2016 May 11 PubMed.
  3. . eIF2B activator prevents neurological defects caused by a chronic integrated stress response. Elife. 2019 Jan 9;8 PubMed.
  4. . Pharmacological brake-release of mRNA translation enhances cognitive memory. Elife. 2013;2:e00498. PubMed.
  5. . The small molecule ISRIB reverses the effects of eIF2α phosphorylation on translation and stress granule assembly. Elife. 2015 Feb 26;4 PubMed.
  6. . Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B. Science. 2018 Mar 30;359(6383):1533-1536. PubMed.
  7. . Structure of the nucleotide exchange factor eIF2B reveals mechanism of memory-enhancing molecule. Science. 2018 Mar 30;359(6383) PubMed.
  8. . eIF2B and the Integrated Stress Response: A Structural and Mechanistic View. Biochemistry. 2020 Apr 7;59(13):1299-1308. Epub 2020 Mar 26 PubMed.
  9. . Inhibition of the integrated stress response reverses cognitive deficits after traumatic brain injury. Proc Natl Acad Sci U S A. 2017 Aug 1;114(31):E6420-E6426. Epub 2017 Jul 10 PubMed.
  10. . Activation of the ISR mediates the behavioral and neurophysiological abnormalities in Down syndrome. Science. 2019 Nov 15;366(6467):843-849. PubMed.
  11. . Vanishing white matter: deregulated integrated stress response as therapy target. Ann Clin Transl Neurol. 2019 Aug;6(8):1407-1422. Epub 2019 Jul 18 PubMed.
  12. . Fine tuning of the unfolded protein response by ISRIB improves neuronal survival in a model of amyotrophic lateral sclerosis. Cell Death Dis. 2020 May 26;11(5):397. PubMed.
  13. . Partial restoration of protein synthesis rates by the small molecule ISRIB prevents neurodegeneration without pancreatic toxicity. Cell Death Dis. 2015 Mar 5;6:e1672. PubMed.
  14. . Unique pharmacological property of ISRIB in inhibition of Aβ-induced neuronal cell death. J Pharmacol Sci. 2016 Aug;131(4):292-5. Epub 2016 Aug 12 PubMed.
  15. . Role of Endoplasmic Reticulum Stress in Learning and Memory Impairment and Alzheimer's Disease-Like Neuropathology in the PS19 and APPSwe Mouse Models of Tauopathy and Amyloidosis. eNeuro. 2017 Jul-Aug;4(4) Epub 2017 Jul 14 PubMed.
  16. . A small molecule targeting protein translation does not rescue spatial learning and memory deficits in the hAPP-J20 mouse model of Alzheimer's disease. PeerJ. 2016;4:e2565. Epub 2016 Oct 19 PubMed.

External Citations

  1. press release
  2. clinicaltrials.gov
  3. OMIM

Further Reading

Papers

  1. . eIF2B and the Integrated Stress Response: A Structural and Mechanistic View. Biochemistry. 2020 Apr 7;59(13):1299-1308. Epub 2020 Mar 26 PubMed.
  2. . Astrocyte Unfolded Protein Response Induces a Specific Reactivity State that Causes Non-Cell-Autonomous Neuronal Degeneration. Neuron. 2020 Mar 4;105(5):855-866.e5. Epub 2020 Jan 7 PubMed.
  3. . Stress responses. Mutations in a translation initiation factor identify the target of a memory-enhancing compound. Science. 2015 May 29;348(6238):1027-30. Epub 2015 Apr 9 PubMed.
  4. . Small molecule ISRIB suppresses the integrated stress response within a defined window of activation. Proc Natl Acad Sci U S A. 2019 Feb 5;116(6):2097-2102. Epub 2019 Jan 23 PubMed.
  5. . eIF2B-catalyzed nucleotide exchange and phosphoregulation by the integrated stress response. Science. 2019 May 3;364(6439):491-495. PubMed.
  6. . Small molecule ISRIB suppresses the integrated stress response within a defined window of activation. Proc Natl Acad Sci U S A. 2019 Feb 5;116(6):2097-2102. Epub 2019 Jan 23 PubMed.
  7. . The small molecule ISRIB rescues the stability and activity of Vanishing White Matter Disease eIF2B mutant complexes. Elife. 2018 Feb 28;7 PubMed.
  8. . Integrated Stress Response Inhibitor Reverses Sex-Dependent Behavioral and Cell-Specific Deficits after Mild Repetitive Head Trauma. J Neurotrauma. 2020 Jun 1;37(11):1370-1380. Epub 2020 Feb 11 PubMed.
  9. . Stress responses. Mutations in a translation initiation factor identify the target of a memory-enhancing compound. Science. 2015 May 29;348(6238):1027-30. Epub 2015 Apr 9 PubMed.