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).