Prime editing links the split integrated stress response to pathogenic eIF2B mutations and white matter degeneration.

ABSTRACT: Vanishing White Matter Disease (VWMD) is a devastating, currently incurable neurodevelopmental disorder primarily affecting white matter. The prevailing view attributes VWMD to the activation of the canonical integrated stress response (c-ISR). However, recent studies have identified a novel, distinct pathway called the split ISR (s-ISR), though its activation has so far only been documented in mouse stem cells harboring a single eIF2B mutation, leaving uncertainty about whether it occurs in human cells, whether other mutations can trigger it, and what role it plays in the disease. Here, we used prime editing (PE) to engineer multiple eIF2B pathogenic mutations into HEK293T and induced pluripotent stem cells (iPSCs), generating human models. We demonstrated PE's effectiveness and safety, m

SUBMITTER: Scagliola A 

PROVIDER: S-EPMC12848117 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature