Vanishing White Matter (VWM)
Vanishing white matter is caused by mutations in genes encoding the eukaryotic translation initiation factor 2B (eIF2B)
Sylics is a proud partner of the VWM consortium, which aims to find treatments for this fatal brain white matter disorder (leukodystrophy). VWM is clinically characterized by progressive motor dysfunction and mild cognitive decline. The disease is caused by recessive mutations in the five genes encoding the protein complex eukaryotic translation initiation factor 2B (eIF2B).
Eif2b4 / Eif2b5 mouse model
Sylics offers unique services with an Eif2b4 / Eif2b5 mouse model of vanishing white matter (VWM) disease through a collaboration with the Amsterdam Leukodystrophy Center at Amsterdam UMC. The VWM model mice have homozygous point mutations in Eif2b4 or Eif2b5 and a phenotype that recapitulates human VWM. Sylics has contributed to the characterization of this mouse model, developed by our academic collaborators (Dooves et al, 2016). Proof of concept intervention studies in this model have identified a deregulated integrated stress response as a clear therapeutic target (Abbink et al, 2019).
Clinically relevant motor function deficit in VWM mice
The behavioural phenotype of VWM mice recapitulates human VWM: progressive abnormal motor skills. Well characterized behavioral readouts in VWM mice include changes in Catwalk Gait Analysis, latency to cross the Beam Test and Spontaneous Behaviours in PhenoTyper automated home cage (Dooves et al, 2016).
Biological readouts in VWM mice
Several molecular and cellular makers are deregulated in VWM mouse brain tissue. These biomarkers are relevant readouts of therapeutic efficacy. For instance, we also offer RT-qPCR services to detect mRNA transcripts known to be dysregulated in this VWM model (e.g. ATF4). Histological or western blot readouts that Sylics offers for the VWM model include markers for myelin deficiency and abnormal glial phenotypes (Abbink et al, 2019).
Abbink et al 2019 Ann Clin Transl Neurol
Vanishing white matter: deregulated integrated stress response as therapy target. Abbink TEM, Wisse LE, Jaku E, Thiecke MJ, Voltolini-González D, Fritsen H, Bobeldijk S, Ter Braak TJ, Polder E, Postma NL, Bugiani M, Struijs EA, Verheijen M, Straat N, van der Sluis S, Thomas AAM, Molenaar D, van der Knaap MS. Ann Clin Transl Neurol. 2019 Aug;6(8):1407-1422. doi: 10.1002/acn3.50826. Epub 2019 Jul 18. PMID: 31402619; PMCID: PMC6689685. https://pubmed.ncbi.nlm.nih.gov/31402619/
Keywords: VWM, Vanishing White Matter
Dooves et al 2016
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, Kamermans M, Wortel J, Loos M, Wisse LE, Scheper GC, Abbink TE, Heine VM, van der Knaap MS. Astrocytes are central in the pathomechanisms of vanishing white matter. J Clin Invest. 2016 Apr 1;126(4):1512-24. https://pubmed.ncbi.nlm.nih.gov/26974157/
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