In vivo base editing in a murine model of vanishing white matter improves the phenotype through multiple mechanisms

Vanishing white matter (VWM) is a fatal leukodystrophy caused by recessive point mutations in subunits of the eukaryotic translation initiation factor 2B. Currently, there are no effective therapies for VWM. Here, we assessed the potential of adenine base editing to correct human pathogenic VWM variants in mouse models. Using adeno-associated viral vectors, we delivered intein-split adenine base editors into the cerebral ventricles of newborn VWM mice. Treatment slightly increased mature astrocyte populations and partly recovered the integrated stress response (ISR) in VWM animals, leading to notable improvements in bodyweight and grip strength. However, locomotor disabilities were not rescued. Further molecular analyses suggest that higher editing in deep brain regions as well as oligodendrocytes would be required for a broader phenotypic rescue. Our study emphasizes the potential, but also identifies limitations, of current in vivo base editing approaches for the treatment of VWM or other leukodystrophies.