Guanabenz ameliorates disease in vanishing white matter mice in contrast to sephin1

Witkamp, Diede; Oudejans, Ellen; Hu‐A‐Ng, Gino V.; Hoogterp, Leoni; Krzywańska, Aleksandra M; Žnidaršič, Milo; Marinus, Kevin; Mestdagh, Christina F de Veij; Bartelink, Imke H.; Bugiani, Marianna; Knaap, Marjo S. van der; Abbink, Truus E.M.

doi:10.1002/acn3.51611

Cited by 14 publications

(19 citation statements)

References 62 publications

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“…The cerebella were prepared for the qPCR and Western blot tests, as these parts of the brain showed amelioration of ISR components in previous studies and have relatively high ratios of white to gray matter ( Abbink et al, 2019 ; Wong et al, 2019 ; Witkamp et al, 2022 ). Samples were prepared in the presence of two researchers to minimize human error.…”

Section: Methodsmentioning

confidence: 99%

“…Treatment of these zebrafish resulted in improved motor behavior. Subsequent tests were performed in the 2b4 he 2b5 ho mouse model, an established preclinical model for human disease ( Abbink et al, 2019 ; Witkamp et al, 2022 ). This mouse model replicates clinical and neuropathological signs of human VWM, including the deregulated ISR in the central nervous system ( Dooves et al, 2016 ; Abbink et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

“…This mouse model replicates clinical and neuropathological signs of human VWM, including the deregulated ISR in the central nervous system ( Dooves et al, 2016 ; Abbink et al, 2019 ). The levels of ISR-regulated mRNAs in their brain correlate well with disease state and respond quickly to therapeutic targeting of the ISR [e.g., Figure 1 in Witkamp et al (2022) ]. Human eIF2Bε is more conserved in mice than in zebrafish.…”

Section: Introductionmentioning

confidence: 99%

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Lithium: effects in animal models of vanishing white matter are not promising

Witkamp,

Oudejans,

Hoogterp

et al. 2024

Front. Neurosci.

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Vanishing white matter (VWM) is a devastating autosomal recessive leukodystrophy, resulting in neurological deterioration and premature death, and without curative treatment. Pathogenic hypomorphic variants in subunits of the eukaryotic initiation factor 2B (eIF2B) cause VWM. eIF2B is required for regulating the integrated stress response (ISR), a physiological response to cellular stress. In patients’ central nervous system, reduced eIF2B activity causes deregulation of the ISR. In VWM mouse models, the extent of ISR deregulation correlates with disease severity. One approach to restoring eIF2B activity is by inhibition of GSK3β, a kinase that phosphorylates eIF2B and reduces its activity. Lithium, an inhibitor of GSK3β, is thus expected to stimulate eIF2B activity and ameliorate VWM symptoms. The effects of lithium were tested in zebrafish and mouse VWM models. Lithium improved motor behavior in homozygous eif2b5 mutant zebrafish. In lithium-treated 2b4he2b5ho mutant mice, a paradoxical increase in some ISR transcripts was found. Furthermore, at the dosage tested, lithium induced significant polydipsia in both healthy controls and 2b4he2b5ho mutant mice and did not increase the expression of other markers of lithium efficacy. In conclusion, lithium is not a drug of choice for further development in VWM based on the limited or lack of efficacy and significant side-effect profile.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Lithium: effects in animal models of vanishing white matter are not promising

Witkamp,

Oudejans,

Hoogterp

et al. 2024

Front. Neurosci.

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“…The year 2021 marked the rst therapeutic trial in VWM, an open label phase 2 drug repurposing trial to investigate Guanabenz (8,11,12). Several novel drugs targeting the ISR are under clinical development for neurological indications.…”

Section: Vanishing White Mattermentioning

confidence: 99%

Core protocol development for phase 2/3 clinical trials in the leukodystrophy Vanishing White Matter

Schoenmakers

Leferink

Vanderver

et al. 2023

Preprint

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Background: The leukodystrophy “Vanishing White Matter” (VWM) is an orphan disease with neurological decline and high mortality. Currently, VWM has no approved treatments, but advances in understanding pathophysiology have led to identification of promising therapies. Several investigational medicinal products are either in or about to enter clinical trial phase. Clinical trials in VWM pose serious challenges, as VWM has an episodic disease course; disease phenotype is highly heterogeneous and predictable only for early onset; and study power is limited by the small patient numbers. To address these challenges and accelerate therapy delivery, the VWM Consortium, a group of academic clinicians with expertise in VWM, decided to develop a core protocol to function as a template for trials, to improve trial design and facilitate sharing of control data, while permitting flexibility regarding other trial details. Overall aims of the core protocol are to collect safety, tolerability, and efficacy data for treatment assessment and marketing authorization. Methods: To develop the core protocol, the VWM Consortium designated a committee, including clinician members of the VWM consortium, family and patient group advocates, and experts in statistics, clinical trial design and alliancing with industries. We drafted three age-specific protocols, to stratify into more homogeneous patient groups, of ages ≥18 years, ≥6 to <18 years and <6 years. We chose double‐blind, randomized, placebo-controlled design for patients aged ≥6 years; and open-label non-randomized natural-history-controlled design for patients <6 years. The protocol describes study populations, age-specific endpoints, inclusion and exclusion criteria, study schedules, sample size determinations, and statistical considerations. Discussion: The core protocol provides a shared uniformity across trials, enables a pool of shared controls, and reduces the total number of patients necessary per trial, limiting the number of patients on placebo. All VWM clinical trials are suggested to adhere to the core protocol. Other trial components such as choice of primary outcome, pharmacokinetics, pharmacodynamics, and biomarkers are flexible and unconstrained by the core protocol. Each sponsor is responsible for their trial execution, while the control data are handled by a shared research organization. This core protocol benefits the efficiency of parallel and consecutive trials in VWM, and we hope accelerates time to availability of treatments for VWM. Trial registration: NA

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“…ISR activation also leads to the increased expression of stress response proteins, including activating transcription factor 4 (ATF4) and its downstream targets such as CHAC1 (Figure ). While the ISR is key to regulating cellular homeostasis, dysregulation of this pathway in neurons can lead to degeneration and is associated with multiple neurodegenerative disorders. , Depending on the context, both inhibition and activation of the ISR have been demonstrated to protect neurons from degeneration in disease models, highlighting the central role for this pathway in cellular health …”

Section: Introductionmentioning

confidence: 99%

Discovery of DNL343: A Potent, Selective, and Brain-Penetrant eIF2B Activator Designed for the Treatment of Neurodegenerative Diseases

Craig,

De Vicente,

Estrada

et al. 2024

J. Med. Chem.

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Eukaryotic translation initiation factor 2B (eIF2B) is a key component of the integrated stress response (ISR), which regulates protein synthesis and stress granule formation in response to cellular insult. Modulation of the ISR has been proposed as a therapeutic strategy for treatment of neurodegenerative diseases such as vanishing white matter (VWM) disease and amyotrophic lateral sclerosis (ALS) based on its ability to improve cellular homeostasis and prevent neuronal degeneration. Herein, we report the small-molecule discovery campaign that identified potent, selective, and CNS-penetrant eIF2B activators using both structure- and ligand-based drug design. These discovery efforts culminated in the identification of DNL343, which demonstrated a desirable preclinical drug profile, including a long half-life and high oral bioavailability across preclinical species. DNL343 was progressed into clinical studies and is currently undergoing evaluation in late-stage clinical trials for ALS.

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Guanabenz ameliorates disease in vanishing white matter mice in contrast to sephin1

Cited by 14 publications

References 62 publications

Lithium: effects in animal models of vanishing white matter are not promising

Lithium: effects in animal models of vanishing white matter are not promising

Core protocol development for phase 2/3 clinical trials in the leukodystrophy Vanishing White Matter

Discovery of DNL343: A Potent, Selective, and Brain-Penetrant eIF2B Activator Designed for the Treatment of Neurodegenerative Diseases

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