NIH Reporter #1R61NS140718-01A1

Evaluation of Gene Replacement Therapy in In Vivo and Patient-Derived In Vitro Models of Vanishing White Matter Disease

This award funds research to develop a gene replacement therapy for Vanishing White Matter Disease, a severe neurodegenerative disorder affecting children. The project focuses on using adeno-associated virus to deliver EIF2B5 gene therapy, testing different promoters, and validating efficacy in patient-derived organoids and mouse models.

Description

Leukodystrophy with vanishing white matter (VWM) is a severe, progressive neurodegenerative disease that most commonly afflicts infants and children. There are no disease modifying treatments. VWM is caused by autosomal recessive mutations in the five subunit genes of the Eukaryotic Initiation Factor 2B (eIF2B) complex, with most mutations occurring in EIF2B5. eIF2B is required for the first steps of protein translation, but also regulates the integrated stress response (ISR). The ISR can be triggered by minor stressors such as viral infection or trauma that decrease eIF2B activity; but in the context of VWM, results in acute and devastating neurological deterioration. Recent work, including ours, has shown abnormal, persistent activation of the ISR in VWM. This is caused by increased expression of stress response genes, such as ATF4, selectively in astrocytes. Concurrent work has shown that VWM astrocytes inhibit oligodendrocyte precursor cells (OPCs) from maturing, leading to decreased production of myelin, the core “vanishing white matter” pathology. Our preliminary data suggests that these two principal features of VWM pathogenesis, deregulated ISR and astrocyte-mediated oligodendrocyte impairment, are associated. However, studies of a therapeutic compound ISR inhibitor (ISRIB) in an EIF2B5-mutant mouse model failed to normalize disease pathologies and showed only partial efficacy. Our goal is to develop a targeted and highly translatable therapy for VWM using adeno-associated virus (AAV) EIF2B5 gene replacement therapy. We will compare cell-specific and ubiquitous promoters, including a novel astrocyte-specific promoter, to determine a lead AAV construct. We will validate expression and attenuation of disease markers in VWM human patient-derived organoids. We will determine a safe and efficacious dose in two VWM mouse models using outcome measures such as MRI and EEG. This approach aims to develop and optimize a lead candidate targeting astrocytic VWM pathogenesis, validated in three models to enhance translation.

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