Vanishing white matter: deregulated integrated stress response as therapy target

Abstract

Objective Vanishing white matter (VWM) is a fatal, stress‐sensitive leukodystrophy that mainly affects children and is currently without treatment. VWM is caused by recessive mutations in eukaryotic initiation factor 2B (eIF2B) that is crucial for initiation of mRNA translation and its regulation during the integrated stress response (ISR). Mutations reduce eIF2B activity. VWM pathomechanisms remain unclear. In contrast with the housekeeping function of eIF2B, astrocytes are selectively affected in VWM. One study objective was to test our hypothesis that in the brain translation of specific mRNAs is altered by eIF2B mutations, impacting primarily astrocytes. The second objective was to investigate whether modulation of eIF2B activity could ameliorate this altered translation and improve the disease. Methods Mice with biallelic missense mutations in eIF2B that recapitulate human VWM were used to screen for mRNAs with altered translation in brain using polysomal profiling. Findings were verified in brain tissue from VWM patients using qPCR and immunohistochemistry. The compound ISRIB (for “ISR inhibitor”) was administered to VWM mice to increase eIF2B activity. Its effect on translation, neuropathology, and clinical signs was assessed. Results In brains of VWM compared to wild‐type mice we observed the most prominent changes in translation concerning ISR mRNAs; their expression levels correlated with disease severity. We substantiated these findings in VWM patients’ brains. ISRIB normalized expression of mRNA markers, ameliorated brain white matter pathology and improved motor skills in VWM mice. Interpretation The present findings show that ISR deregulation is central in VWM pathomechanisms and a viable target for therapy.

DNL343 is an investigational CNS penetrant eIF2B activator that prevents and reverses the effects of neurodegeneration caused by the Integrated Stress Response

“…ISR activation appears to be most prominent in the CNS since tissues such as peripheral blood mononuclear cells (PBMC) or spleen have no marked upregulation of the ISR markers in homozygous mice relative to wild-type controls ( Supplemental Figure 1C and D ). This is consistent with the reported CNS and peripheral phenotypes of independently generated models (Dooves, Bugiani et al 2016, Abbink, Wisse et al 2019, Wong, LeBon et al 2019). .…”

“…Consistent with the characterization of previously published eIF2B mutant models (Abbink, Wisse et al 2019, Wong, LeBon et al 2019), eIF2B HOM animals gain less weight over time compared to their wild-type counterparts. The two highest doses of DNL343 (3 and 10 mg/kg) significantly improved body weight increase ( Figure 4E ), despite a modest reduction in food intake in these groups ( Supplemental Figure 2B ).…”

DNL343 is an investigational CNS penetrant eukaryotic initiation factor 2B activator that prevents and reverses the effects of neurodegeneration caused by the integrated stress response

“…ISR activation appears to be most prominent in the CNS since tissues such as peripheral blood mononuclear cells or spleen have no marked upregulation of the ISR markers in HOM mice relative to wild-type controls ( Figure 2—figure supplement 1C and D and Supplementary file 4 and 5 ). This is consistent with the reported CNS and peripheral phenotypes of independently generated models ( Dooves et al, 2016 ; Abbink et al, 2019 ; Wong et al, 2019 ).…”

“…Consistent with the characterization of previously published eIF2B mutant models ( Abbink et al, 2019 ; Wong et al, 2019 ), eIF2B HOM animals gain less weight over time compared to their wild-type counterparts. The two highest doses of DNL343 (3 and 10 mg/kg) significantly improved body weight increase ( Figure 4E and Figure 4—figure supplement 2A ), despite a modest reduction in food intake in these groups ( Figure 4—figure supplement 1B ).…”

Guanabenz ameliorates disease in vanishing white matter mice in contrast to sephin1

“…Only GBZ improved expression of ATF4‐regulated markers in VWM mouse brain, whereas S1 did not, suggesting that it is the attenuation of ATF4‐regulated mRNAs that contributes to improvement of VWM. This conclusion is in line with previous studies, which showed that reduction of effectors downstream of ATF4 is associated with amelioration of VWM 13,14 …”