eIF2B Modulators in Vanishing White Matter

Vanishing White Matter (VWM) disease is a rare and fatal leukodystrophy, caused by recessive mutations in the five genes encoding the protein complex eukaryotic translation initiation factor 2B (eIF2B).

eIF2B plays a crucial role in initiating and regulating the translation of proteins that orchestrate the cells’ central homeostasis system; the integrated stress response (ISR). Although beneficial to maintaining cellular health, dysregulation and chronic activation of the ISR resulting from mutations in eIF2B cause degeneration of the brain’s white matter.

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. VWM mutant mice show motor impairments, VWM-related alterations in mRNA expression, astrocyte and oligodendrocyte immaturity and dysfunction, and an immature myelin structure. Together with our academic collaborators, InnoSer’s neurology research team has contributed to the characterisation of the Eif2b5 and Eif2b4 mutant mouse models (Dooves et al. 2016; Abbink et al. 2019), demonstrating that VWM mutant mice show:

• Latency to cross the Balance Beam (as shown in figure below) and increased number of slips (Figure 5C; Abbink et al. 2019)
• Changes in CatWalk^TM Gait Analysis (Figure 5D; Abbink et al. 2019)
• Changes in Spontaneous Behaviour in PhenoTyper^TM automated home cage
• Loss in Grip Strength  
• Relevant markers as measured by gene expression (for e.g., mRNAs regulated by the transcription factor ATF4) and protein quantification (e.g. myelin basic protein) and histopathology (e.g. myelin deficiency and abnormal glial phenotypes)

The Balance Beam sensorimotor coordination test confirms the progressive (from 16 to 20 wk) motor impairments in the Eif2b5 mutant mouse model of VWM.  

Proof of concept intervention studies in this model have confirmed that the deregulated ISR is a putative therapeutic target for VWM (Abbink et al. 2019). Although currently there are no approved treatments for VWM, evidence suggests that small molecule eIF2B modulators rescue neurological deficits caused by persistent and increasing ISR dysregulation in the CNS. Moreover, eIF2B modulators are being investigated for other indications, such as:  

• Amyotrophic Lateral Sclerosis  
• Promotion of increased lifespan and amelioration of ageing