Vanishing White Matter (eIF2B) Mouse Models
Test novel vanishing white matter disease therapeutics with relevant models possessing mutations in genes encoding the eukaryotic translation initiation factor 2B (eIF2B)
Leukodystrophies refer to a over 50 conditions characterised by extensive brain white matter degeneration. Vanishing white matter (VWM) disease is a rare and fatal leukodystrophy characterised by chronic and progressive motor dysfunction as well as mild cognitive decline. VWM is caused by recessive mutations in the five genes encoding the protein complex eukaryotic translation initiation factor 2B (eIF2B). VWM can be studied using eIF2B mouse models of VWM that have a genetic mutation in the same gene (eIF2B) that causes VWM in humans.
In line, eIF2B mouse models with homozygous point mutations in Eif2b5 and Eif2b4 that recapitulate the human VWM pathology form part of InnoSer’s rare genetic disease portfolio and expertise through a collaboration with the Amsterdam Leukodystrophy Center at Amsterdam UMC. VWM mutant mice show motor impairments, VWM-related alterations in mRNA expression, astrocyte and oligodendrocyte immaturity and dysfunction, and an immature myelin structure. The eIF2B mouse models have been extensively characterized (Dooves et al. 2016), with poof of concept intervention studies showing deregulated integrated stress response as a clear therapeutic target (Abbink et al. 2019).
Take advantage of InnoSer’s expertise, flexibility and collaborative approach for your research. We support our clients in identifying new drugs or applications, characterizing their pharmacological properties, and conducting safety and efficacy testing with state-of-the-art readout capabilities and histopathological analysis.
InnoSer’s neurology expert team possesses relevant experience in working with multiple therapy types ranging from small molecules, peptides, enzymes, oligonucleotides, and gene therapy (viral vectors – e.g.. AAVs).
eIF2B mouse key model characteristics:
- VWM mice have homozygous point mutations in Eif2b4 or Eif2b5.
- VWM mice recapitulate motor symptoms that mimic those seen in humans with the disease, such as coordination problems. and tremors.
- VWM mice recapitulate cellular dysfunction seen in patients (e.g., deregulated ISR, astrocyte dysfunction).
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Key readouts in the eIF2B mouse models:
Test the efficacy of your treatments in the following battery of behavioural tests:
- Histology (e.g., nestin/GFAP, S100B)
- RT-qPCR (ISR markers)
- Western blot (MBP)
Example data featuring the eIF2B mouse models:
eIF2B mutant mice show impairments in the Balance Beam test
The Balance Beam sensorimotor coordination test scores the ability of mice to traverse a stationary horizontal rod. Coordination of the mouse is measured by the latency to cross the beam and the number of foot slips made.
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References
- Dooves S, Bugiani M, Postma NL, Polder E, Land N, Horan ST, van Deijk AL, van de Kreeke A, Jacobs G, Vuong C, Klooster J. Astrocytes are central in the pathomechanisms of vanishing white matter. The Journal of clinical investigation. 2016 Apr 1;126(4):1512-24.
- Abbink TE, Wisse LE, Jaku E, Thiecke MJ, Voltolini‐González D, Fritsen H, Bobeldijk S, Ter Braak TJ, Polder E, Postma NL, Bugiani M. Vanishing white matter: deregulated integrated stress response as therapy target. Annals of clinical and translational neurology. 2019 Aug;6(8):1407-22.
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